ALZHEIMER'S MEMORY SUPPORT

Alzheimer’s disease is a type of brain disease, just as coronary artery disease is a type of heart disease. It is also a progressive disease, meaning that it becomes worse with time. Alzheimer’s disease is thought to begin 20 years or more before symptoms arise.1-8 It starts with changes in the brain that are unnoticeable to the person affected. Only after years of brain changes do individuals experience noticeable symptoms such as memory loss and language problems. Symptoms occur because nerve cells (neurons) in parts of the brain involved in thinking, learning and memory (cognitive function) have been damaged or destroyed. As the disease progresses, neurons in other parts of the brain are damaged or destroyed as well. Eventually, neurons in parts of the brain that enable a person to carry out basic bodily functions, such as walking and swallowing, are affected. Individuals become bed-bound and require around-the-clock care. Alzheimer’s disease is ultimately fatal. Brain Changes of Alzheimer’s Disease A healthy adult brain has about 100 billion neurons, each with long, branching extensions. These extensions enable individual neurons to form connections with other neurons. At such connections, called synapses, information flows in tiny bursts of chemicals that are released by one neuron and detected by another neuron. The brain contains about 100 trillion synapses. They allow signals to travel rapidly through the brain, and the information they carry creates the cellular basis of memories, thoughts, sensations, emotions, movements and skills. The accumulation of the protein fragment beta-amyloid into clumps (called beta-amyloid plaques) outside neurons and the accumulation of an abnormal form of the protein tau (called tau tangles) inside neurons are two of several brain changes associated with Alzheimer’s. Plaques and smaller accumulations of beta-amyloid called oligomers may contribute to the damage and death of neurons (neurodegeneration) by interfering with neuron-to-neuron communication at synapses. Inside neurons, tau tangles block the transport of nutrients and other molecules essential for normal function and neurons’ survival. Although the complete sequence of events is unclear, beta-amyloid may begin accumulating before abnormal tau, and increasing beta-amyloid accumulation is associated with subsequent increases in tau.9-10 Other brain changes associated with Alzheimer’s include inflammation and atrophy (decreased brain volume). The presence of toxic beta-amyloid and tau proteins are believed to activate immune system cells in the brain called microglia. Microglia try to clear the toxic proteins as well as widespread debris from dead and dying cells. Chronic inflammation may set in when the microglia can't keep up with all that needs to be cleared. Atrophy occurs because of cell loss. Normal brain function is further compromised in Alzheimer’s disease by decreases in the brain's ability to metabolize glucose, its main fuel. These brain changes are considered biomarkers of Alzheimer's. Biomarkers are biological changes that can be measured to indicate the presence or absence of a disease or the risk of developing a disease. For example, the level of glucose in blood is a biomarker of diabetes, and cholesterol level is a biomarker of one's risk of cardiovascular disease. A study7 of people with rare genetic mutations that cause Alzheimer’s, called dominantly inherited Alzheimer’s disease (DIAD), found that levels of beta-amyloid in the brain were significantly increased starting 22 years before symptoms were expected to develop (individuals with Overview Alzheimer’s Disease or Dementia? Many people wonder what the difference is between Alzheimer’s disease and dementia. Dementia is an overall term for a particular group of symptoms. The characteristic symptoms of dementia are difficulties with memory, language, problem-solving and other thinking skills that affect a person's ability to perform everyday activities. Dementia has many causes (see Table 1, page 6). Alzheimer’s disease is the most common cause of dementia. In this report, Alzheimer’s dementia refers to dementia that is caused by, or believed to be caused by, the brain changes of Alzheimer’s disease. 6 Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Common Causes of Dementia and Associated Characteristics Alzheimer’s disease Alzheimer's disease is the most common cause of dementia, accounting for an estimated 60% to 80% of cases. Recent large autopsy studies show that more than half of individuals with Alzheimer's dementia have Alzheimer's disease brain changes (pathology) as well as the brain changes of one or more other causes of dementia, such as cerebrovascular disease or Lewy body disease.11-12 This is called mixed pathologies, and if recognized during life is called mixed dementia. Difficulty remembering recent conversations, names or events is often an early clinical symptom; apathy and depression are also often early symptoms. Later symptoms include impaired communication, disorientation, confusion, poor judgment, behavioral changes and, ultimately, difficulty speaking, swallowing and walking. The hallmark pathologies of Alzheimer’s disease are the accumulation of the protein fragment beta-amyloid (plaques) outside neurons in the brain and twisted strands of the protein tau (tangles) inside neurons. These changes are accompanied by the death of neurons and damage to brain tissue. Alzheimer's is a slowly progressive brain disease that begins many years before symptoms emerge. Cerebrovascular disease Cerebrovascular disease refers to the process by which blood vessels in the brain are damaged and/or brain tissue is injured from not receiving enough blood, oxygen or nutrients. People with dementia whose brains show evidence of cerebrovascular disease are said to have vascular dementia. About 5% to 10% of individuals with dementia show evidence of vascular dementia alone.11-12 However, it is more common as a mixed pathology, with most people living with dementia showing the brain changes of cerebrovascular disease and Alzheimer's disease.11-12 Impaired judgment or impaired ability to make decisions, plan or organize may be the initial symptom, but memory may also be affected, especially when the brain changes of other causes of dementia are present. In addition to changes in cognitive function, people with vascular dementia commonly have difficulty with motor function, especially slow gait and poor balance. Vascular dementia occurs most commonly from blood vessel blockage, such as that which occurs with stroke, or damage leading to areas of dead tissue or bleeding in the brain. The location, number and size of the brain injuries determine whether dementia will result and how the individual’s thinking and physical functioning will be affected. Lewy body disease Lewy bodies are abnormal aggregations (or clumps) of the protein alpha-synuclein in neurons. When they develop in a part of the brain called the cortex, dementia can result. This is called dementia with Lewy bodies or DLB. People with DLB have some of the symptoms common in Alzheimer’s, but are more likely to have initial or early symptoms of sleep disturbances, well-formed visual hallucinations and visuospatial impairment. These symptoms may occur in the absence of significant memory impairment but memory loss often occurs, especially when the brain changes of other causes of dementia are present. About 5% of individuals with dementia show evidence of DLB alone, but most people with DLB also have Alzheimer's disease pathology. Frontotemporal lobar degeneration (FTLD) FTLD includes dementias such as behavioral-variant FTLD, primary progressive aphasia, Pick’s disease, corticobasal degeneration and progressive supranuclear palsy. Typical early symptoms include marked changes in personality and behavior and/or difficulty with producing or comprehending language. Unlike Alzheimer’s, memory is typically spared in the early stages of disease. Nerve cells in the front (frontal lobe) and side regions (temporal lobes) of the brain are especially affected, and these regions become markedly atrophied (shrunken). In addition, the upper layers of the cortex typically become soft and spongy and have abnormal protein inclusions (usually tau protein or the transactive response DNA-binding protein, TDP-43). The symptoms of FTLD may occur in those age 65 years and older, similar to Alzheimer’s, but most people with FTLD develop symptoms at a younger age. About 60% of people with FTLD are ages 45 to 60.13 Scientists think that FTLD is the most common cause of dementia in people younger than 60.13 In a systematic review, FTLD accounted for about 3% of dementia cases in studies that included people 65 and older and about 10% of dementia cases in studies restricted to those younger than 65.14 Cause Characteristics TABLE 1 7 Common Causes of Dementia and Associated Characteristics Parkinson’s disease (PD) Problems with movement (slowness, rigidity, tremor and changes in gait) are common symptoms of PD. Cognitive symptoms develop either just before movement symptoms or later in the disease. In PD, clumps of the protein alpha-synuclein appear in an area deep in the brain called the substantia nigra. These clumps are thought to cause degeneration of the nerve cells that produce dopamine.15 As PD progresses, alpha-synuclein can also accumulate in the cortex of the brain (similar to dementia with Lewy bodies). Dementia may result. Hippocampal sclerosis (HS) HS is the hardening of tissue in the hippocampus of the brain. The hippocampus plays a key role in forming memories. The most pronounced symptom of HS is memory loss, and individuals may be misdiagnosed as having Alzheimer's disease. HS brain changes are often accompanied by accumulations of a misfolded form of a protein called TDP-43. HS is a common cause of dementia in the "oldest-old," individuals age 85 or older. Mixed pathologies When an individual shows the brain changes of more than one cause of dementia, mixed pathologies are considered the cause. When these pathologies result in dementia symptoms during life, the person is said to have mixed dementia. Studies suggest that mixed dementia is more common than previously recognized, with more than 50% of people with dementia who were studied at Alzheimer's Disease Research Centers having pathologic evidence of more than one cause of dementia.12 In community-based studies, the percentage of mixed dementia cases is considerably higher.11 The likelihood of having mixed dementia increases with age and is highest in people age 85 or older.16-17 Overview these genetic mutations usually develop symptoms at the same or nearly the same age as their parent with Alzheimer’s). Glucose metabolism began to decrease 18 years before expected symptom onset, and brain atrophy began 13 years before expected symptom onset. Another study1 of people with DIAD found abnormal levels of the neurofilament light chain protein, a biomarker of neurodegeneration, 22 years before symptoms were expected to develop. A third study2 found that levels of two types of tau protein begin to increase when beta-amyloid starts clumping together as amyloid plaques. Levels of these types of tau increase as early as two decades before the characteristic tau tangles of Alzheimer’s begin to appear. Mixed Dementia Many people with dementia have brain changes associated with more than one cause of dementia.11,18-23 This is called mixed dementia. Some studies11-12 report that the majority of people with the brain changes of Alzheimer’s also have the brain changes of a second cause of dementia on autopsy. One autopsy study showed that of 447 older people who were believed to have Alzheimer’s dementia when they died, only 3% had the brain changes of Alzheimer’s disease alone, 15% had the brain changes of a different cause of dementia, and 82% had the brain changes of Alzheimer’s plus at least one other cause of dementia.11 Studies suggest that mixed dementia is the norm, and the number of distinct combinations of mixed dementia is extensive.24-25 Mixed dementia is especially common at advanced ages.18,26 For example, the oldest-old, those age 85 or older, are more likely to have evidence of two or more causes of dementia than those younger than 85.16-17 Having Alzheimer’s brain changes plus another type of brain change makes it more likely that a person will show dementia symptoms in their lifetime11,18 compared with someone with Alzheimer’s brain changes alone. It may also account for the wide variety of memory and thinking problems experienced by people living with dementia. Cause Characteristics TABLE 1 (cont.) 8 While we know the continuum starts with preclinical Alzheimer’s and ends with severe Alzheimer’s dementia, how long individuals spend in each part of the continuum varies. The length of each phase of the continuum is influenced by age, genetics, biological sex and other factors.31 Preclinical Alzheimer’s Disease In this phase, individuals have measurable brain changes that indicate the earliest signs of Alzheimer’s disease (biomarkers), but they have not yet developed symptoms such as memory loss. Examples of Alzheimer's biomarkers include abnormal levels of beta-amyloid as shown on positron emission tomography (PET) scans32 and in analysis of cerebrospinal fluid (CSF), and decreased metabolism of glucose as shown on PET scans. When the early changes of Alzheimer’s occur, the brain compensates for them, enabling individuals to continue to function normally. While research settings have the tools and expertise to identify some of the early brain changes of Alzheimer’s, additional research is needed to fine-tune the tools’ accuracy before they become available for widespread use in hospitals, doctors’ offices and other clinical settings. It is important to note that not all individuals with evidence of Alzheimer’s-related brain changes go on to develop symptoms of MCI or dementia due to Alzheimer’s.33-34 For example, some individuals have beta-amyloid plaques at death but did not have memory or thinking problems in life. MCI due to Alzheimer’s Disease People with MCI due to Alzheimer’s disease have biomarker evidence of Alzheimer’s brain changes plus subtle problems with memory and thinking. These cognitive problems may be noticeable to the individual, Symptoms interfere with most everyday activities Symptoms interfere with many everyday activities Symptoms interfere with some everyday activities Very mild symptoms that do not interfere with everyday activities No symptoms Preclinical AD Mild Cognitive Impairment due to AD Mild Moderate Severe Dementia due to AD Dementia due to AD Dementia due to AD *Although these arrows are of equal size, the components of the AD continuum are not equal in duration. Alzheimer's Disease (AD) Continuum* FIGURE 1 Alzheimer’s Disease Continuum The progression of Alzheimer’s disease from brain changes that are unnoticeable to the person affected to brain changes that cause problems with memory and eventually physical disability is called the Alzheimer’s disease continuum. On this continuum, there are three broad phases: preclinical Alzheimer’s disease, mild cognitive impairment (MCI) due to Alzheimer’s disease and dementia due to Alzheimer’s disease (see Figure 1).27-30 The Alzheimer’s dementia phase is further broken down into the stages of mild, moderate and severe, which reflect the degree to which symptoms interfere with one’s ability to carry out everyday activities. Alzheimer's Begins Before Dementia In the past, Alzheimer’s disease was often used to describe the dementia phase of the disease. Today we know that dementia is only one part of the disease. It is preceded by mild cognitive impairment (MCI), a period when individuals have subtle cognitive changes that do not interfere with everyday activities. When biomarker tests show that individuals with MCI have the brain changes of Alzheimer’s disease, they are said to have MCI due to Alzheimer’s disease, another part of the Alzheimer’s disease continuum. MCI is a key area of interest to researchers involved in drug development. Because individuals with MCI are still able to function independently, a treatment that prevents MCI from progressing to dementia would have a significant impact on quality of life, caregiver burden, and use and cost of care. Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Overview 9 family members and friends, but not to others, and they do not interfere with individuals’ ability to carry out everyday activities. The mild changes in thinking abilities occur when the brain can no longer compensate for the damage and death of nerve cells caused by Alzheimer’s disease. Among those with MCI, about 15% develop dementia after two years.35 About one-third (32%) of individuals with MCI develop Alzheimer’s dementia within five years’ follow-up.36 It’s important to note that some individuals are diagnosed as having MCI several years after cognitive decline began, and these individuals are likely to develop dementia sooner than those whose cognitive decline is more recent. It’s also important to note that some individuals with MCI revert to normal cognition or do not have additional cognitive decline. In other cases, such as when a medication inadvertently causes cognitive changes, MCI is mistakenly diagnosed and cognitive changes can be reversed. Identifying which individuals with MCI are more likely to develop dementia is a major goal of current research. Dementia due to Alzheimer’s Disease Dementia due to Alzheimer’s disease, or Alzheimer's dementia, is characterized by noticeable memory, thinking or behavioral symptoms that impair a person’s ability to function in daily life, combined with biomarker evidence of Alzheimer’s-related brain changes. As Alzheimer's progresses, individuals commonly experience multiple types of symptoms that change with time. These symptoms reflect the degree of damage to nerve cells in different parts of the brain. The pace at which symptoms of dementia advance from mild to moderate to severe differs from person to person. Mild Alzheimer’s Dementia In the mild stage of Alzheimer’s dementia, most people are able to function independently in many areas but are likely to require assistance with some activities to maximize independence and remain safe. They may still be able to drive, work and participate in favorite activities. Moderate Alzheimer’s Dementia In the moderate stage of Alzheimer’s dementia, which is often the longest stage, individuals may have difficulties communicating and performing routine tasks, including activities of daily living (such as bathing and dressing); become incontinent at times; and start having personality and behavioral changes, including suspiciousness and agitation. Severe Alzheimer’s Dementia In the severe stage of Alzheimer’s dementia, individuals need help with activities of daily living and are likely to require around-the-clock care. The effects of Alzheimer's disease on individuals’ physical health become especially apparent in this stage. Because of damage to areas of the brain involved in movement, individuals become bed-bound. Being bed-bound makes them vulnerable to conditions including blood clots, skin infections and sepsis, which triggers body-wide inflammation that can result in organ failure. Damage to areas of the brain that control swallowing makes it difficult to eat and drink. This can result in individuals swallowing food into the trachea (windpipe) instead of the esophagus (food pipe). Because of this, food particles may be deposited in the lungs and cause lung infection. This type of infection is called aspiration pneumonia, and it is a contributing cause of death among many individuals with Alzheimer’s (see Mortality and Morbidity section, page 28). When Dementia-Like Symptoms Are Not Dementia It is important to note that some individuals have dementia-like symptoms without the progressive brain changes of Alzheimer’s or other degenerative brain diseases. Causes of dementia-like symptoms include depression, untreated sleep apnea, delirium, side effects of medications, Lyme disease, thyroid problems, certain vitamin deficiencies and excessive alcohol consumption. Unlike Alzheimer’s and other dementias, these conditions often may be reversed with treatment. Consulting a medical professional to determine the cause of symptoms is critical to one’s physical and emotional well-being. Normal Age-Related Cognitive Changes or Symptoms of Dementia? The differences between normal age-related cognitive changes and the cognitive changes of Alzheimer’s dementia can be subtle (see Table 2, page 10). People experiencing cognitive changes should seek medical help to determine if the changes are normal for one’s age, reversible or a symptom of Alzheimer’s or another dementia. The Medicare Annual Wellness Visit, available to all Medicare enrollees each year at no cost, includes a cognitive evaluation and is an opportune time for individuals age 65 or older to discuss cognitive changes with their physician. Signs of Alzheimer’s Dementia Typical Age-Related Changes Memory loss that disrupts daily life: One of the most common signs of Alzheimer’s dementia is memory loss, especially forgetting recently learned information. Others include forgetting important dates or events, asking for the same information over and over, and increasingly needing to rely on memory aids (for example, reminder notes or electronic devices) or family members for things that used to be handled on one’s own. Sometimes forgetting names or appointments, but remembering them later. Challenges in planning or solving problems: Some people experience changes in their ability to develop and follow a plan or work with numbers. They may have trouble following a familiar recipe, keeping track of monthly bills or counting change. They may have difficulty concentrating and take much longer to do things than they did before. Making occasional errors when balancing a checkbook. Difficulty completing familiar tasks at home, at work or at leisure: People with Alzheimer’s often find it hard to complete daily tasks. Sometimes, people have trouble driving to a familiar location, managing a budget at work or remembering the rules of a favorite game. Occasionally needing help to use the settings on a microwave or record a television show. Confusion with time or place: People with Alzheimer’s can lose track of dates, seasons and the passage of time. They may have trouble understanding something if it is not happening immediately. Sometimes they forget where they are or how they got there. Getting confused about the day of the week but figuring it out later. Trouble understanding visual images and spatial relationships: For some people, having vision problems is a sign of Alzheimer’s. They may have difficulty reading, judging distance and determining color or contrast, which may cause problems with driving. Vision changes related to cataracts, glaucoma or agerelated macular degeneration. New problems with words in speaking or writing: People with Alzheimer’s may have trouble following or joining a conversation. They may stop in the middle of a conversation and have no idea how to continue or they may repeat themselves. They may struggle with vocabulary, have problems finding the right word or call things by the wrong name (e.g., calling a watch a “hand clock”). Sometimes having trouble finding the right word. Misplacing things and losing the ability to retrace steps: People with Alzheimer’s may put things in unusual places and lose things and be unable to go back over their steps to find them again. Sometimes, they accuse others of stealing. This may occur more frequently over time. Misplacing things from time to time and retracing steps to find them. Decreased or poor judgment: People with Alzheimer’s may experience changes in judgment or decision-making. For example, they may use poor judgment when dealing with money, giving large amounts to telemarketers. They may pay less attention to grooming or keeping themselves clean. Making a bad decision once in a while. Withdrawal from work or social activities: People with Alzheimer’s may start to remove themselves from hobbies, social activities, work projects or sports. They may have trouble keeping up with a favorite sports team or remembering how to complete a favorite hobby. They may also avoid being social because of the changes they have experienced. Sometimes feeling weary of work, family and social obligations. Changes in mood and personality: The mood and personalities of people with Alzheimer’s can change. They can become confused, suspicious, depressed, fearful or anxious. They may be easily upset at home, at work, with friends or in places where they are out of their comfort zones. Developing very specific ways of doing things and becoming irritable when a routine is disrupted. *For more information about the symptoms of Alzheimer’s, visit alz.org/alzheimers-dementia/10_signs. Signs of Alzheimer’s Dementia Compared with Typical Age-Related Changes* TABLE 2 10 Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Overview 11 Diagnosis of Dementia due to Alzheimer’s Disease There is no single test for dementia due to Alzheimer’s disease. Instead, physicians (often with the help of specialists such as neurologists, neuropsychologists, geriatricians and geriatric psychiatrists) use a variety of approaches and tools to help make a diagnosis. They include the following: • Obtaining a medical and family history from the individual, including psychiatric history and history of cognitive and behavioral changes. • Asking a family member to provide input about changes in thinking skills and behavior. • Conducting problem-solving, memory and other cognitive tests, as well as physical and neurologic examinations. • Having the individual undergo blood tests and brain imaging to rule out other potential causes of dementia symptoms, such as a tumor or certain vitamin deficiencies. • In some circumstances, using PET imaging of the brain to find out if the individual has high levels of beta-amyloid, a hallmark of Alzheimer’s; normal levels would suggest Alzheimer’s is not the cause of dementia.37 • In some circumstances, using lumbar puncture to determine the levels of beta-amyloid and certain types of tau in CSF; normal levels would suggest Alzheimer’s is not the cause of dementia.38 Although physicians can almost always determine if a person has dementia, it may be difficult to identify the exact cause. Alzheimer’s disease is the most common cause of dementia, but most people with the brain changes of Alzheimer’s also have the brain changes of another cause of dementia.25,39-40 Many individuals who would meet the diagnostic criteria for Alzheimer’s and other dementias are not diagnosed by a physician,41-44 and fewer than half of Medicare beneficiaries who have a diagnosis of Alzheimer’s or another dementia in their Medicare billing records report (or their caregiver reports, if the beneficiary’s cognitive impairment prevented him or her from responding) being told of the diagnosis.45-48 It is important that individuals who are living with dementia receive a diagnosis and are aware of the diagnosis. It is also important that individuals receive an accurate diagnosis to ensure they receive treatment or follow-up care appropriate for their specific cause of dementia. Treatment of Alzheimer’s Dementia Pharmacologic Treatment None of the pharmacologic treatments (drugs) available today for Alzheimer’s dementia slow or stop the damage and destruction of neurons that cause Alzheimer’s symptoms and make the disease fatal. The U.S. Food and Drug Administration (FDA) has approved five drugs for the treatment of Alzheimer’s — rivastigmine, galantamine, donepezil, memantine, and memantine combined with donepezil. A sixth drug, aducanumab, is under FDA review for potential approval at this writing. Of these drugs, aducanumab is the only one that may potentially slow the progression of Alzheimer’s, and it has been tested only for individuals with MCI or early Alzheimer’s dementia. With the exception of memantine, the remaining drugs temporarily improve cognitive symptoms by increasing the amount of chemicals called neurotransmitters in the brain. Memantine blocks certain receptors in the brain from excess stimulation that can damage nerve cells. The effectiveness of these drugs varies from person to person. No drugs are specifically approved by the FDA to treat behavioral and psychiatric symptoms that may develop in the moderate and severe stages of Alzheimer’s dementia. If nonpharmacologic therapy is not successful and these symptoms have the potential to cause harm to the individual or others, physicians may prescribe drugs approved for similar symptoms in people with other conditions. A type of drug called antipsychotics may be prescribed to treat hallucinations, aggression and agitation. However, research has shown that some antipsychotics are associated with an increased risk of stroke and death in individuals with dementia.49-50 The decision to use antipsychotics must be considered with extreme caution. The FDA has ordered manufacturers to label such drugs with a “black box warning” about their risks and a reminder that they are not approved to treat dementia symptoms. Many factors contribute to the difficulty of developing effective treatments for Alzheimer’s. These include the slow pace of recruiting sufficient numbers of participants and sufficiently diverse participants to clinical studies, gaps in knowledge about the precise molecular changes and biological processes in the brain that cause Alzheimer’s disease, and the relatively long time needed to observe whether an investigational treatment affects disease progression. In addition, because mixed dementia is so common, even more brain changes than previously thought may be contributing to symptoms, further complicating decisions about which brain changes to target. 12 Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Researchers believe that future treatments to slow or stop the progression of Alzheimer’s disease and preserve brain function may be most effective when administered early in the disease continuum, either at the MCI due to Alzheimer’s or preclinical Alzheimer’s phase. Biomarker tests, such as PET brain imaging and analysis of proteins in blood and CSF, will be essential to identify which individuals are in these phases of the continuum and should receive treatments when they are available. Biomarkers also will be critical for monitoring the effects of treatment. Biomarker tests are already playing an important role in drug development because they enable researchers to recruit into clinical trials only those individuals with the Alzheimer’s brain changes that a drug has been designed to affect.51 The most effective biomarker test or combination of tests may differ depending on where the individual is on the disease continuum and other factors.52 Nonpharmacologic Therapy Nonpharmacologic therapies are those that do not involve drugs. They are often used for people with Alzheimer’s dementia with the goal of maintaining or improving cognitive function, overall quality of life or the ability to perform activities of daily living. They also may be used with the goal of reducing behavioral symptoms such as depression, apathy, wandering, sleep disturbances, agitation and aggression. A recent review and analysis of nonpharmacologic treatments for agitation and aggression in people with dementia concluded that nonpharmacologic interventions seemed to be more effective than pharmacologic interventions for reducing aggression and agitation.53 Examples of nonpharmacologic therapies include computerized memory training, listening to favorite music as a way to stir recall, and using special lighting to lessen sleep disorders. As with current pharmacologic therapies, nonpharmacologic therapies do not slow or stop the damage and destruction of neurons that cause Alzheimer’s symptoms and make the disease fatal. Determining the effectiveness of nonpharmacologic therapies can be difficult because of the large number of unique therapies tested; the diversity of therapeutic aims (from improved overall quality of life to improvements in specific symptoms); the range of dementia stages represented (from mild to moderate to severe); the multiple types of dementia that may be present among participants in a particular study given the pervasiveness of mixed dementia; and the lack of a standard method for carrying out any individual therapy. With these multiple factors to consider, it is challenging to group together and compare nonpharmacologic therapies. Nevertheless, researchers have pooled data from multiple studies of nonpharmacologic therapies to provide insight into their potential effectiveness. • A meta-analysis54 found that aerobic exercise and a combination of aerobic and non-aerobic exercise had positive effects on cognitive function in people living with Alzheimer’s dementia. A systematic review55 found that exercise has a positive effect on overall cognitive function and may slow the rate of cognitive decline in people with Alzheimer’s dementia. • A systematic review56 found that cognitive stimulation had beneficial effects on cognitive function and some aspects of well-being in people with Alzheimer’s dementia. Another systematic review57 reported that cognitive stimulation was associated with improved scores on tests of depression in people with mild-tomoderate Alzheimer’s dementia. A summary of systematic reviews58 reported that cognitive stimulation, music-based therapies and psychological treatment (for example, cognitive behavioral therapy) improved depression, anxiety and quality of life in people with dementia. • A summary of systematic reviews59 of cognitive training for people with mild-to-moderate dementia found cognitive training may show some benefits in overall cognition that may last for at least a few months. The Lancet Commission 2020 report60 on dementia prevention, intervention and care recommends postdiagnostic care for people with dementia that includes physical and mental health, social care, and support; management of neuropsychiatric symptoms, noting that multicomponent interventions are the treatments of choice to decrease neuropsychiatric symptoms; and care for family caregivers, pointing out that specific interventions for family caregivers have long-lasting effects on depression and anxiety symptoms, increase quality of life, are cost-effective and might save money (see Caregiving section, page 35). Active Management of Alzheimer’s Dementia Studies have consistently shown that active management of Alzheimer’s and other dementias can improve the quality of life of affected individuals and their caregivers.61-63 Active management includes: • Appropriate use of available treatment options. • Effective management of coexisting conditions. • Providing family caregivers with effective training in managing the day-to-day life of the care recipient. • Coordination of care among physicians, other health care professionals and lay caregivers. Overview 13 • Participation in activities that are meaningful to the individual with dementia and bring purpose to his or her life. • Having opportunities to connect with others living with dementia; support groups and supportive services are examples of such opportunities. • Becoming educated about the disease. • Planning for the future. To learn more about Alzheimer’s disease, as well as practical information for living with Alzheimer’s and being a caregiver, visit alz.org. Risk Factors for Alzheimer’s Dementia The vast majority of people who develop Alzheimer’s dementia are age 65 or older. This is called late-onset Alzheimer’s. Experts believe that Alzheimer’s, like other common chronic diseases, develops as a result of multiple factors rather than a single cause. Exceptions are cases of Alzheimer’s related to uncommon genetic changes that greatly increase risk. Age, Genetics and Family History The greatest risk factors for late-onset Alzheimer’s are older age,64-65 genetics66-67 — especially the apolipoprotein e4 gene (APOE-e4) — and having a family history of Alzheimer’s.68-71 Age Age is the greatest of these three risk factors. The percentage of people with Alzheimer’s dementia increases dramatically with age: 5.3% of people age 65 to 74, 13.8% of people age 75 to 84 and 34.6% of people age 85 or older have Alzheimer’s dementia (see Prevalence section, page 18). The aging of the babyboom generation will significantly increase the number of people in the United States with Alzheimer's.72 However, it is important to note that Alzheimer’s dementia is not a normal part of aging,73 and older age alone is not sufficient to cause Alzheimer’s dementia. Genetics Researchers have found several genes that increase the risk of Alzheimer’s. The APOE-e4 gene is the gene with the strongest impact on risk of late-onset Alzheimer’s. APOE-e4 provides the blueprint for a protein that transports cholesterol in the bloodstream. Everyone inherits one of three forms (alleles) of the APOE gene — e2, e3 or e4 — from each parent, resulting in six possible APOE pairs: e2/e2, e2/e3, e2/e4, e3/e3, e3/e4 and e4/e4. Researchers have found differences in the frequency of these pairs in different racial and ethnic groups. For example, data show that a higher percentage of African Americans than European Americans have at least one copy of the e4 allele (see Table 3).74-76 Having the e4 form of APOE increases one’s risk of developing Alzheimer’s compared with having the e3 form, but does not guarantee that an individual will develop Alzheimer’s. Having the e2 form may decrease one’s risk compared with having the e3 form. Those who inherit one copy of the e4 form have about three times the risk of developing Alzheimer’s compared with those with two copies of the e3 form, while those who inherit two copies of the e4 form have an eight- to 12-fold risk.77-79 In addition, those with the e4 form are more likely to have beta-amyloid accumulation80 and Alzheimer’s dementia at a younger age than those with the e2 or e3 forms of the APOE gene.81 A meta-analysis including 20 published articles describing the frequency of the e4 form among people in the United States who had been diagnosed with Alzheimer’s found that 56% had one copy of the APOE-e4 gene, and 11% had two copies of the APOE-e4 gene.82 Another study found that among 1,770 diagnosed individuals from 26 Alzheimer’s Disease Research Centers across the United States, 65% had at least one copy of the APOE-e4 gene.83 However, a recent study84 found that individuals with the APOE-e4 risk gene had a decreased risk of developing dementia if they had more years of early life education, had mentally challenging work in midlife, participated in leisure activities in late life, and/or had strong social networks in late life. APOE Pair African Americans* European Americans* e3/e3 45.2 63.4 e3/e4 28.6 21.4 e3/e2 15.1 10.2 e2/e4 5.7 2.4 e4/e4 4.5 2.4 e2/e2 0.7 0.2 Created from data from Rajan et al.74 *Percentages do not total 100 due to rounding. Percentage of African Americans and European Americans with Specified APOE Pairs TABLE 3 14 Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Studies of Alzheimer’s risk based on APOE status among Blacks have had inconsistent results. For example, some have found that having the e4 allele did not increase risk among Blacks,75-76,85 while other studies have found that it significantly increased risk.86-87 More research is needed to better understand the genetic mechanisms involved in Alzheimer’s risk among different racial and ethnic groups. Family History A family history of Alzheimer’s is not necessary for an individual to develop the disease. However, individuals who have a parent or sibling (first-degree relative) with Alzheimer’s are more likely to develop the disease than those who do not have a first-degree relative with Alzheimer’s.68,77 Those who have more than one firstdegree relative with Alzheimer’s are at even higher risk.71 A large, population-based study found that having a parent with dementia increases risk independent of known genetic risk factors such as APOE-e4.88 When diseases run in families, heredity (genetics) and shared non-genetic factors (for example, access to healthy foods and habits related to physical activity) may play a role. Modifiable Risk Factors Although age, genetics and family history cannot be changed, other risk factors can be changed or modified to reduce the risk of cognitive decline and dementia. Examples of modifiable risk factors are physical activity, smoking, education, staying socially and mentally active, blood pressure, and diet. In fact, the 2020 recommendations of The Lancet Commission on dementia prevention, intervention and care60 suggest that addressing modifiable risk factors might prevent or delay up to 40% of dementia cases. Modifiable risk factors have been the subject of much research. In addition to The Lancet Commission report,60 the 2019 World Health Organization (WHO) recommendations89 to reduce risk of cognitive decline and dementia, an Alzheimer’s Association article90 evaluating the effects of modifiable risk factors on cognitive decline and dementia, and a report from the National Academy of Medicine91 all point to the promising role of addressing these risk factors to reduce risk of dementia and cognitive decline. This section focuses on risk factors common to these reports. It is important to note that “reducing risk” of cognitive decline and dementia is not synonymous with preventing cognitive decline and dementia altogether. Individuals who take measures to reduce risk may still develop dementia, but they may be less likely to develop it or they may develop it later in life than they would have if they had not taken steps to reduce their risk. It is also important to note that factors that increase or decrease the risk of cognitive decline and dementia may not necessarily do so by directly affecting the brain changes associated with Alzheimer’s disease.85 For example, it is possible that smoking may contribute to cerebrovascular disease, which in turn increases the risk of dementia, but it may not directly contribute to the development of the amyloid plaques and tau tangles that characterize Alzheimer's disease. Cardiovascular Disease Risk Factors, Physical Activity and Diet Brain health is affected by the health of the heart and blood vessels. Although it makes up just 2% of body weight, the brain consumes 20% of the body’s oxygen and energy supplies.92 A healthy heart ensures that enough blood is pumped to the brain, while healthy blood vessels enable the oxygen- and nutrient-rich blood to reach the brain so it can function normally. Many factors that increase the risk of cardiovascular disease are also associated with a higher risk of dementia.93 These factors include smoking94-98 and diabetes.99-102 Some studies propose that impaired glucose processing (a precursor to diabetes) may also increase risk for dementia.103-105 The age at which some risk factors develop appears to affect dementia risk. For example, midlife obesity,103,106-109 hypertension,103,110-114 prehypertension (systolic blood pressure from 120 to 139 mm Hg or diastolic pressure from 80 to 89 mm Hg)114 and high cholesterol115-116 are associated with an increased risk of dementia. Regarding hypertension, evidence from a large-scale clinical trial suggests that intensive medical treatment to reduce blood pressure may safely decrease the occurrence of MCI and dementia.117 In contrast to mid-life, late-life obesity118 and hypertension onset after age 80119 are associated with decreased risk of dementia. It is possible that the disease causing dementia affects body mass and blood pressure rather than the reverse. More research is needed to understand why the effects of some modifiable risk factors may change with age. Building on the connection between heart health and brain health, researchers have found that factors that protect the heart may also protect the brain and reduce the risk of developing Alzheimer’s or other dementias. Physical activity120-130 appears to be one of these factors. Although researchers have studied a wide variety of exercises, they do not yet know which specific types of exercises, what frequency of exercise or what duration of activity may be most effective in reducing risk. In addition to physical activity, emerging evidence suggests that consuming a heart-healthy diet may be associated with reduced dementia risk.131-135 A heart-healthy diet 15 emphasizes fruits, vegetables, whole grains, fish, chicken, nuts and legumes while limiting saturated fats, red meat and sugar. A systematic review136 of the use of supplements, including vitamins C, D and E, omega-3 fatty acids and ginkgo biloba, found little to no benefit in preventing cognitive decline, MCI or Alzheimer’s dementia. Researchers have begun studying combinations of health factors and health behaviors (for example, blood pressure as a health factor and physical activity as a health behavior) to learn whether combinations of risk factors better identify Alzheimer’s and dementia risk than individual risk factors. They are also studying whether intervening on multiple risk factors simultaneously is more effective at reducing risk than addressing a single risk factor. Indeed, one such study,137 the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), found that a multidomain intervention was associated with beneficial effects on cognitive function in older adults at high risk for cognitive decline and dementia. The success of FINGER has led to the launch of multidomain intervention studies in other countries, including the Alzheimer's Association’s U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER).138 Education People with more years of formal education are at lower risk for Alzheimer’s and other dementias than those with fewer years of formal education.75,139-143 Some researchers believe that having more years of education builds “cognitive reserve.” Cognitive reserve refers to the brain’s ability to make flexible and efficient use of cognitive networks (networks of neuron-to-neuron connections) to enable a person to continue to carry out cognitive tasks despite brain changes.144-145 The number of years of formal education is not the only determinant of cognitive reserve. Having a mentally stimulating job and engaging in other mentally stimulating activities may also help build cognitive reserve.146-149 It is important to note that the underlying reason for the relationship between formal education and reduced Alzheimer’s risk is unclear. It is possible that the generally higher socioeconomic status of individuals with more years of formal education is a protective factor. Having fewer years of formal education is associated with lower socioeconomic status.150 This in turn may increase one’s likelihood of experiencing poor nutrition; decrease one’s ability to afford health care or medical treatments, such as treatments for cardiovascular disease risk factors that are so closely linked to brain health; and limit one’s access to physically safe housing and employment. The latter could increase one’s risk of being exposed to substances that are toxic to the nervous system such as air pollution,151 lead152 and pesticides.153 In addition, people with fewer years of education tend to have more cardiovascular risk factors for Alzheimer’s, including being less physically active,154 having a higher risk of diabetes,155-157 and being more likely to have hypertension158 and to smoke.159 Social and Cognitive Engagement Additional studies suggest that remaining socially and mentally active throughout life may support brain health and possibly reduce the risk of Alzheimer’s and other dementias.121,160-172 Socially and cognitively stimulating activity might help build cognitive reserve. However, it is also possible that undetected cognitive impairment decreases one’s interest in and ability to participate in activities involving social and cognitive skills. In this case, the association may reflect the effect of cognitive impairment on social and cognitive engagement rather than the effect of engagement on dementia risk. More research is needed to better understand the biological processes that link social and cognitive engagement to dementia risk. Traumatic Brain Injury (TBI) TBI is the disruption of normal brain function caused by a blow or jolt to the head or penetration of the skull by a foreign object. TBI increases the risk of dementia.173 According to the Centers for Disease Control and Prevention (CDC), nearly 3 million TBI-related emergency department visits, hospitalizations and deaths occurred in 2014, the latest year for which information is available.174 The leading causes of TBI that resulted in emergency department visits were falls, being struck by an object and motor vehicle crashes.174 Two ways to classify the severity of TBI are by the duration of loss of consciousness or post-traumatic amnesia175 and by the individual’s initial score on the 15-point Glasgow Coma Scale.176 • Mild TBI (also known as a concussion) is characterized by loss of consciousness or post-traumatic amnesia lasting 30 minutes or less, or an initial Glasgow score of 13 to 15; about 75% of TBIs are mild.177 • Moderate TBI is characterized by loss of consciousness or post-traumatic amnesia lasting more than 30 minutes but less than 24 hours, or an initial Glasgow score of 9 to 12. • Severe TBI is characterized by loss of consciousness or post-traumatic amnesia lasting 24 hours or more, or an initial Glasgow score of 8 or less. Overview 16 The risk of dementia increases with the number of TBIs sustained.173 Even those who experience mild TBI are at increased risk of dementia compared with those who have not had a TBI. A recent study found that mild TBI is associated with a two-fold increase in the risk of dementia diagnosis.178 Studies have also found that people with a history of TBI who develop Alzheimer’s do so at a younger age than those without a history of TBI.179-180 Whether TBI causes Alzheimer’s disease, other conditions that lead to dementia, or both, is still being investigated. Chronic traumatic encephalopathy (CTE) is a neuropathologic diagnosis (meaning it is characterized by brain changes that can only be identified at autopsy) associated with repeated blows to the head, such as those that may occur while playing contact sports. Among former amateur and professional football players, the risk of developing CTE, which is associated with dementia, increased 30% per year played.181 Currently, there is no test to determine if someone has CTE-related brain changes during life. A review article indicates that the greatest risk factor for developing CTE-related brain changes is repetitive brain trauma — repeated, forceful blows to the head that do not, individually, result in symptoms.182 Like Alzheimer’s disease, CTE is characterized by tangles of an abnormal form of the protein tau in the brain. Unlike Alzheimer’s, beta-amyloid plaques are uncommon in CTE.183-184 How the brain changes associated with CTE are linked to cognitive or behavioral changes is unclear. Other Modifiable Risk Factors Researchers are studying a variety of other potential modifiable risk factors. Among the many risk factors being studied are inadequate sleep or poor sleep quality,185 excessive alcohol use,186 depression187 and hearing impairment.188 In addition, a growing body of evidence indicates that critical illness and medical encounters such as hospitalization in older people increase their risk of long-term cognitive impairment.189-195 The emergence of novel coronavirus disease in 2019 (COVID-19) has resulted in tens of thousands of hospitalizations. This has the potential to increase the number of cases of cognitive impairment following critical illness. Furthermore, many of these individuals will receive or have received mechanical ventilation, which increases one’s risk of delirium,196 an acute state of short-term confusion that is a risk factor for dementia.197-199 There is also rapidly emerging evidence on how exposure to air pollution may be related to dementia risk. A number of different air pollutants have been studied in relation to cognition, cognitive decline, brain imaging and dementia itself. The most consistent and rigorous results concern fine particulate matter air pollution, which consists of tiny solid particles and liquid droplets generated by fuel combustion, fires and processes that produce dust. Higher levels of long-term exposure to fine particulate matter air pollution is associated with worse cognitive function and cognitive decline.200-207 Uncommon Genetic Changes That Greatly Increase Risk Certain genetic mutations and the extra copy of chromosome 21 that characterizes Down syndrome are uncommon genetic factors that greatly influence Alzheimer’s risk. Genetic Mutations A small percentage of Alzheimer’s cases (an estimated 1% or less)208 develop as a result of mutations to any of three specific genes. A genetic mutation is an abnormal change in the sequence of chemical pairs that make up genes. These mutations involve the gene for the amyloid precursor protein (APP) and the genes for the presenilin 1 and presenilin 2 proteins. Those inheriting an Alzheimer’s mutation to these genes are virtually guaranteed to develop the disease if they live a normal life span.209 Symptoms tend to develop before age 65, sometimes as young as age 30, while the vast majority of individuals with Alzheimer’s have late-onset Alzheimer’s. Trisomy in Down Syndrome In Down syndrome, an individual is born with three copies of chromosome 21 (called trisomy 21) instead of two. People with Down syndrome have an increased risk of developing Alzheimer’s, and this is believed to be related to trisomy 21. Chromosome 21 includes the gene that encodes for the production of APP, which in people with Alzheimer’s is cut into beta-amyloid fragments that accumulate into plaques. Having an extra copy of chromosome 21 may increase the production of beta-amyloid fragments in the brain. Overall, people with Down syndrome develop Alzheimer’s at an earlier age than people without Down syndrome. By age 40, most people with Down syndrome have significant levels of beta-amyloid plaques and tau tangles in their brains.210 As with all adults, advancing age increases the likelihood that a person with Down syndrome will exhibit symptoms of Alzheimer’s. According to the National Down Syndrome Society, about 30% of people with Down syndrome who are in their 50s have Alzheimer’s disease.211 About 50% of people with Down syndrome who are in their 60s have Alzheimer’s disease.211 Looking to the Future With the discovery that Alzheimer’s may begin 20 years or more before the onset of symptoms, a substantial window of time has been opened to intervene in the progression of the disease. During this window of time, advances in the identification of biomarkers for Alzheimer’s will enable earlier detection of the disease, giving those affected the opportunity to address modifiable risk factors that may delay cognitive decline and participate in clinical studies of potential new treatments. Biomarker advances will also accelerate the development of these new treatments by enabling clinical trials to specifically recruit individuals with the brain changes experimental therapies target. In addition, biomarker, basic science and other research advances offer the potential to expand the field’s understanding of which therapies may be most effective at which points in the Alzheimer's disease continuum. However, a fuller understanding of Alzheimer's — from its causes to how to prevent it, how to manage it and how to treat it — depends on other crucial factors. Among these is the inclusion of participants from diverse racial and ethnic groups in all realms of Alzheimer's research. Most of the research to date has not included sufficient numbers of Blacks, Hispanics, Asian Americans/ Pacific Islanders and Native Americans to be representative of the U.S. population. Moreover, because Blacks and Hispanics are at increased risk for Alzheimer’s (see Prevalence section, page 18), their underrepresentation hampers the conduct of rigorous research to understand factors that may contribute to their increased risk. Improving inclusion also increases the diversity of lived experiences of participants (and investigators), which opens the door to discovering environmental and societal factors that may influence health behaviors and other factors that increase risk. It is important that researchers identify risk factors that can be addressed to alter the disparate burden of Alzheimer's. Only by improving representation in clinical trials, observational studies and other investigations will everyone have the potential to benefit from advances in Alzheimer’s science. Overview 17 By 2050, the number of people age 65 and older with Alzheimer’s dementia is projected to reach 12.7 million. Prevalence 19 Prevalence of Alzheimer’s and Other Dementias in the United States Based on updated calculations, an estimated 6.2 million Americans age 65 and older are living with Alzheimer’s dementia in 2021.A1,216 Seventy-two percent are age 75 or older (Figure 2).216 Of the total U.S. population: • More than 1 in 9 people (11.3%) age 65 and older has Alzheimer’s dementia.216 • The percentage of people with Alzheimer’s dementia increases with age: 5.3% of people age 65 to 74, 13.8% of people age 75 to 84, and 34.6% of people age 85 and older have Alzheimer’s dementia.216 People younger than 65 can also develop Alzheimer's dementia, but it is much less common and prevalence is uncertain. The estimated number of people age 65 and older with Alzheimer’s dementia comes from an updated study using the latest data from the 2020 projections from the U.S. Census Bureau and the Chicago Health and Aging Project (CHAP), a population-based study of chronic health conditions of older people.216 National estimates of the prevalence of all dementias are not available from CHAP, but they are available from other population-based studies including the Aging, Demographics, and Memory Study (ADAMS), a nationally representative sample of older adults.A2,217-218 Based on estimates from ADAMS, 11% of people age 65 and older in the United States have dementia.219 Millions of Americans are living with Alzheimer’s or other dementias. As the size of the U.S. population age 65 and older continues to increase, the number of Americans with Alzheimer’s or other dementias will grow. Both the number and proportion will escalate rapidly in coming years, as the population of Americans age 65 and older is projected to grow from 58 million in 2021 to 88 million by 2050.212-213 The baby-boom generation (Americans born between 1946 and 1964) has already begun to reach age 65 and beyond,214 the age range of greatest risk of Alzheimer’s dementia215; in fact, the oldest members of the baby-boom generation turn age 75 in 2021. This section reports on the number and proportion of people with Alzheimer’s dementia to describe the magnitude of the burden of Alzheimer’s on the community and health care systems. The prevalence of Alzheimer’s dementia refers to the number and proportion of people in a population who have Alzheimer’s dementia at a given point in time. Incidence refers to the number or rate of new cases per year. Estimates from selected studies on the number and proportion of people with Alzheimer’s or other dementias vary depending on how each study was conducted. Data from several studies are used in this section. FIGURE 2 Created from data from Rajan et al.A1,216 *Percentages do not total 100 due to rounding. 65-74 years: 1.72 million (27.6%) 75-84 years: 2.25 million (36.1%) 85+ years: 2.27 million (36.4%) Number and Ages of People 65 or Older with Alzheimer's Dementia, 2021* Total: 6.2 Million Prevalence 20 Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Prevalence Estimates The 6.2 million prevalence estimate included in this section refers to people age 65 and older who have Alzheimer’s dementia based on symptoms such as memory loss and difficulty thinking. It is based on data from a single longitudinal study in which all individuals who exhibited the clinical symptoms of Alzheimer's were classified as having Alzheimer’s dementia. Future prevalence estimates will be different. First, the number of Americans with Alzheimer’s dementia (the 6.2 million figure reported here) is likely to be lower. This is because future estimates of Alzheimer’s dementia are more likely to be based on whether individuals have the actual brain changes of Alzheimer’s in addition to whether they have clinical changes in memory, thinking and other cognitive skills. Evidence from biomarkerbased studies11,73,220-222 indicates that some individuals counted as having Alzheimer’s dementia based on symptoms do not have the biological brain changes of Alzheimer’s disease; that is, their dementia is caused by something other than Alzheimer’s disease. Both autopsy studies and clinical trials have found that 15% to 30% of individuals who met the criteria for Alzheimer’s dementia based on symptoms did not have Alzheimer’s-related brain changes.11,73,220-222 Thus, these studies indicate that biomarker-based prevalence estimates — rather than symptom-based prevalence estimates — will likely result in up to a 30% decrease in prevalence estimates of Alzheimer’s dementia. Another potential contributor to a decrease in prevalence estimates of Alzheimer’s dementia is the use of multiple symptom-based longitudinal studies when determining prevalence rather than one.A2,219 Second, the estimate of how many people have Alzheimer’s disease (not just dementia due to Alzheimer’s disease) will be higher. For decades it has been recognized that all individuals with dementia pass through a precursor stage frequently referred to as mild cognitive impairment (MCI). More recently, with the advent of biomarkers that detect elevated levels of the betaamyloid and tau proteins that characterize Alzheimer’s, it is now possible to determine which individuals diagnosed with MCI have MCI due to Alzheimer’s disease. As biomarker-based diagnoses become more common, individuals with MCI due to Alzheimer’s disease will be included in prevalence estimates of the number of Americans with Alzheimer’s disease. As reported in this section, the limited data available to date show that about half of individuals age 65 and older with MCI — roughly 5 million Americans — have MCI due to Alzheimer’s disease. Because MCI develops years before dementia, and potentially affects individuals before age 65, there are likely far more than 5 million Americans with MCI due to Alzheimer’s disease. Lastly, the National Institute on Aging – Alzheimer’s Association (NIA-AA) Framework223 hypothesizes that there is an incipient and silent stage of Alzheimer’s disease in which the individual appears not to have the cognitive symptoms of either MCI or dementia. An estimate of the prevalence of “preclinical” Alzheimer’s disease population has been previously published,224 but we clearly need more research to validate preclinical Alzheimer's and determine how to measure it with biomarkers that conclusively represent Alzheimer’s disease. What does all this mean for future prevalence estimates? Prevalence estimates of Alzheimer’s disease reported in future Facts and Figures reports will continue to report clinically diagnosed individuals in the dementia stage, currently estimated to be 6.2 million Americans, in addition to the best-available estimates of MCI due to Alzheimer’s disease. Facts and Figures will not include prevalence estimates for the preclinical Alzheimer’s disease stage until (1) there is conclusive evidence of a connection between biomarkers in this silent stage and the development of MCI due to Alzheimer’s disease and (2) prevalence studies have then attempted to calculate the number of individuals impacted. Ultimately, with these refinements, future prevalence estimates of Alzheimer’s disease will be higher, although estimates of Alzheimer’s dementia (the currently reported 6.2 million) will be lower. For example, in 2021, biomarker-based estimates of Alzheimer’s disease could result in up to 30% fewer individuals in the dementia stage of the disease, leaving roughly 4 million Americans age 65 and older with Alzheimer’s dementia, while also including an additional 50% of those over age 65 with MCI (those with MCI due to Alzheimer’s disease). A conservative estimate of the number of people with MCI due to Alzheimer’s disease is 5 million Americans. This would result in a very rough current estimate of 9 million Americans with Alzheimer’s disease. It should be noted that both symptom-based and biomarker-based prevalence estimates will rapidly increase in the future due to growth in the proportion of Americans age 65 and over, the population most at risk. When epidemiological studies include biomarker-based diagnoses and a conclusive connection is shown between biomarkers and the preclinical stage, an Alzheimer’s disease prevalence estimate ought to include individuals throughout the continuum of Alzheimer’s disease: those with biomarker-confirmed Alzheimer’s dementia, those with biomarker-confirmed MCI due to Alzheimer’s disease and those with preclinical Alzheimer’s disease — making the true prevalence of Alzheimer’s disease even higher. Prevalence 21 older patients for cognitive impairment are (1) the patient presents with no symptoms or complaints (68%) and (2) lack of time (58%). Prevalence of Subjective Cognitive Decline The experience of worsening or more frequent confusion or memory loss (often referred to as subjective cognitive decline) is one of the earliest warning signs of Alzheimer’s disease and may be a way to identify people who are at high risk of developing Alzheimer’s or other dementias as well as MCI.229-233 Subjective cognitive decline refers to self-perceived worsening of memory and other thinking abilities by an individual, separate from cognitive testing, clinical diagnosis or anyone else noticing. Not all those who experience subjective cognitive decline go on to develop MCI or dementia, but many do.234-236 One study showed those who over time consistently reported subjective cognitive decline that they found worrisome were at higher risk for developing Alzheimer’s dementia.237 The Behavioral Risk Factor Surveillance System survey, which includes questions on subjective cognitive decline, found that 11% of Americans age 45 and older reported subjective cognitive decline, but 54% of those who reported it had not consulted a health care professional.238 Individuals concerned about declines in memory and other cognitive abilities should consult a health care professional. Estimates of the Number of People with Alzheimer’s Dementia by State Table 4 lists the estimated number of people age 65 and older with Alzheimer’s dementia by state for 2020 (the most recent year for which these numbers are available), the projected number for 2025 and the projected percentage change in the number of people with Alzheimer’s between 2020 and 2025.A3,239 As shown in Figure 3, between 2020 and 2025 every state across the country is expected to experience an increase of at least 6.7% in the number of people with Alzheimer’s. These projected increases in the number of people with Alzheimer’s are based on projected increases in the population age 65 and older in these states. Because risk factors for dementia such as midlife obesity and diabetes can vary dramatically by region and state, the regional patterns of future burden may be different than reported here. Based on these projections, the West and Southeast are expected to experience the largest percentage increases in people with Alzheimer’s dementia between 2020 and 2025. These increases will have a marked impact on states’ health care systems, as well as the Medicaid program, which covers the costs of long-term care and support for many older residents with dementia, including more than a quarter of Medicare beneficiaries with Alzheimer’s or other dementias.240 Mild Cognitive Impairment due to Alzheimer’s Disease The number and proportion of older adults who have MCI due to Alzheimer’s disease is currently difficult to estimate because it requires population-based prevalence measures of MCI and Alzheimer’s biomarkers, and these studies are in their infancies. Furthermore, there is variation across studies in both the threshold of cognitive impairment required for an MCI diagnosis and the level of biomarker burden that defines the presence of Alzheimer’s disease. However, we can roughly estimate this prevalence indirectly using multiple data sources. A systematic review of more than 30 studies of MCI reported that 16.6% of people age 65 and older had MCI.35 Meanwhile, studies assessing biomarkers for Alzheimer’s disease with PET scans have reported that about half of people with MCI have Alzheimer’s-related brain changes.225-226 Therefore, roughly 8% of people age 65 and older — or approximately 5 million older Americans — may have MCI due to Alzheimer’s disease. This prevalence estimate needs to be confirmed with population-based studies involving biomarkers. Underdiagnosis of Alzheimer’s and Other Dementias in the Primary Care Setting Prevalence studies such as CHAP and ADAMS are designed so that everyone in the study undergoes evaluation for dementia. But outside of research settings, a substantial portion of those who would meet the diagnostic criteria for Alzheimer’s and other dementias are not diagnosed with dementia by a physician.41-44 Furthermore, only about half of Medicare beneficiaries who have a diagnosis of Alzheimer’s or another dementia in their Medicare billing records report being told of the diagnosis.45-48,227 Because Alzheimer’s dementia is often underdiagnosed — and if it is diagnosed by a clinician, people are often unaware of their diagnosis — a large portion of Americans with Alzheimer’s may not know they have it. For more detailed information about detection of Alzheimer’s and other dementias in the primary care and clinical setting, see the Special Report from 2019 Alzheimer's Disease Facts and Figures. 228 Since 2011, the Medicare Annual Wellness Visit has included a required cognitive evaluation. A survey by the Alzheimer’s Association found that only 1 in 3 older adults were aware that these visits should include a cognitive assessment.228 Furthermore, while 82% of older adults believe it is important to have their memory and thinking checked, only 16% report having their memory and thinking checked. Most (93%) older adults said they trust their doctor to recommend testing for memory and thinking problems; however, despite 94% of primary care physicians stating that it is important to assess all older patients for cognitive impairment, fewer than half (47%) say it is their standard protocol to do so. The primary reasons given by surveyed physicians for not assessing 22 Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Created from data provided to the Alzheimer’s Association by Weuve et al.A3,239 Projections of Total Numbers of Americans Age 65 and Older with Alzheimer's Dementia by State Projected Number with Alzheimer’s (in thousands) Percentage Increase State 2020 2025 2020-2025 Alabama 96 110 14.6 Alaska 8.5 11 29.4 Arizona 150 200 33.3 Arkansas 58 67 15.5 California 690 840 21.7 Colorado 76 92 21.1 Connecticut 80 91 13.8 Delaware 19 23 21.1 District of Columbia 8.9 9 1.1 Florida 580 720 24.1 Georgia 150 190 26.7 Hawaii 29 35 20.7 Idaho 27 33 22.2 Illinois 230 260 13.0 Indiana 110 130 18.2 Iowa 66 73 10.6 Kansas 55 62 12.7 Kentucky 75 86 14.7 Louisiana 92 110 19.6 Maine 29 35 20.7 Maryland 110 130 18.2 Massachusetts 130 150 15.4 Michigan 190 220 15.8 Minnesota 99 120 21.2 Mississippi 57 65 14.0 Missouri 120 130 8.3 Projected Number with Alzheimer’s (in thousands) Percentage Increase State 2020 2025 2020-2025 Montana 22 27 22.7 Nebraska 35 40 14.3 Nevada 49 64 30.6 New Hampshire 26 32 23.1 New Jersey 190 210 10.5 New Mexico 43 53 23.3 New York 410 460 12.2 North Carolina 180 210 16.7 North Dakota 15 16 6.7 Ohio 220 250 13.6 Oklahoma 67 76 13.4 Oregon 69 84 21.7 Pennsylvania 280 320 14.3 Rhode Island 24 27 12.5 South Carolina 95 120 26.3 South Dakota 18 20 11.1 Tennessee 120 140 16.7 Texas 400 490 22.5 Utah 34 42 23.5 Vermont 13 17 30.8 Virginia 150 190 26.7 Washington 120 140 16.7 West Virginia 39 44 12.8 Wisconsin 120 130 8.3 Wyoming 10 13 30.0 TABLE 4 23 Sound (now Kaiser Permanente Northwest), a health care delivery system in the Seattle, Washington, area, reported similar incidence rates to the CHAP study.242 The number of new cases of Alzheimer’s increases dramatically with age: according to estimates from CHAP, in 2011 the average annual incidence in people age 65 to 74 was 0.4% (meaning four of every 1,000 people age 65 to 74 developed Alzheimer’s dementia in 2011); in people age 75 to 84, the annual incidence was 3.2% (32 of every 1,000 people); and for age 85 and older (the “oldest-old”), the incidence was 7.6% (76 of every 1,000 people).241 Because of the increasing number of people age 65 and older in the United States, particularly the oldest-old, the annual number of new cases of Alzheimer’s and other dementias is projected to double by 2050.243 Incidence of Alzheimer’s Dementia While prevalence refers to existing cases of a disease in a population at a given time, incidence refers to new cases of a disease that develop in a given period of time in a defined population — in this case, the U.S. population age 65 or older. Incidence provides a measure of risk for developing a disease. According to estimates using data from the CHAP study and the U.S. Census, approximately 910,000 people age 65 or older developed Alzheimer’s dementia in the United States in 2011, a number that would be expected to be even higher in 2021 if CHAP estimates were available for that year.241 A study using data from the Adult Changes in Thought Study, a cohort of members of Group Health Cooperative of Puget Change from 2020 to 2025 for Washington, D.C.: 1.1% Created from data provided to the Alzheimer’s Association by Weuve et al.A3,239 AK AL AR AZ CA CO CT DC DE FL GA HI IA ID IL IN KS KY LA MA MD ME MI MN MO MS MT NC ND NE NH NJ NM NV NY OH OK OR PA RI SC SD TN TX UT VA VT WA WI WV WY 6.7%-12% 12.1%-17.3% 17.4%-22.6% 22.7%-27.9% 28.0%-33.3% Projected Increases Between 2020 and 2025 in Alzheimer’s Dementia Prevalence by State FIGURE 3 Prevalence 24 Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Lifetime Risk of Alzheimer’s Dementia Lifetime risk is the probability that someone of a given age who does not have a particular condition will develop the condition during his or her remaining life span. Data from the Framingham Heart Study were used to estimate lifetime risks of Alzheimer’s dementia by age and sex.A4,244 As shown in Figure 4, the study found that the estimated lifetime risk for Alzheimer’s dementia at age 45 was approximately 1 in 5 (20%) for women and 1 in 10 (10%) for men. The risks for both sexes were slightly higher at age 65.244 Differences Between Women and Men in the Prevalence and Risk of Alzheimer’s and Other Dementias More women than men have Alzheimer’s or other dementias. Almost two-thirds of Americans with Alzheimer’s are women.216 Of the 6.2 million people age 65 and older with Alzheimer’s in the United States, 3.8 million are women and 2.4 million are men.216 This represents 12% of women and 9% of men age 65 and older in the United States.213 The prevailing reason that there are more women living with Alzheimer’s or other dementias than men is most likely the fact that women live longer than men on average, and older age is the greatest risk factor for Alzheimer’s.244-246 However, when it comes to differences in the actual risk of developing Alzheimer’s or other dementias for men and women of the same age (i.e., incidence), findings have been mixed. Most studies of incidence in the United States have found no significant difference between men and women in the proportion who develop Alzheimer’s or other dementias at any given age.75,242,246-248 Some European studies have reported a higher incidence among women at older ages,249-250 and one study from the United Kingdom reported higher incidence for men.251 Differences in the risk of dementia between men and women may therefore depend on age and/or geographic region.252-253 Although there do not appear to be large or consistent differences in the rate at which men and women develop Alzheimer’s or other dementias, there may be differences in the reasons they develop dementia. These differences may be based in biology such as chromosomal or hormonal differences (i.e., sex differences) or differences in environmental, social and cultural influences on men and women (i.e., gender differences), or the combination of the two.252,254 There are many instances of gender difference in the distribution of or even the effect of known risk factors for dementia, such as education, occupation and health behaviors. For example, lower educational attainment in women than in men born in the first half of the 20th century could account for elevated risk in women, as limited formal education is a risk factor for dementia.255 This explanation requires more research, but there is evidence that increases in educational attainment over time in the United States — which have been more substantial for women than men — have led to decreased risk for dementia.256 Interestingly, European studies have found that the relationship of lower education with dementia outcomes may actually be stronger in women than men.257-258 Other societal gender differences may also be at play, such as differences in occupational attainment between men and women, with a recent study showing that women who participated in the paid workforce earlier in life had better cognitive outcomes after age 60.259-260 Other studies have provided evidence that any observed difference in risk for dementia between men and women may be an artifact of who is more or less likely to die of other health factors before developing dementia. A study using Framingham Heart Study data suggested that men in the study appear to have a lower risk for dementia due to “survival bias,” in which the men who survived beyond age 65 and were included in the study were the ones with a healthier cardiovascular risk profile (men have a higher rate of death from cardiovascular disease in middle age than women) and thus a lower risk for dementia.245 More research is needed to support this interpretation. Created from data from Chene et al.244 10.3% 19.5% 25 20 15 10 5 0 Age 45 65 11.6% 21.1% Percentage Men Women Estimated Lifetime Risk for Alzheimer’s Dementia, by Sex, at Ages 45 and 65 FIGURE 4 25 behaviors and socioeconomic risk factors across racial groups.277 Despite some evidence that the influence of genetic risk factors on Alzheimer’s and other dementias may differ by race,85,87,285 genetic factors do not account for the large differences in prevalence or incidence among racial groups.284,286 Instead, the difference in risk for Alzheimer’s and other dementias is explained by disparities in health conditions, socioeconomics, and life experiences for older Black and Hispanic populations compared with older White populations. Many studies suggest that racial and ethnic differences in dementia risk do not persist in rigorous analyses that account for health and socioeconomic factors.140,217,284 Chronic health conditions that are associated with higher dementia risk, such as cardiovascular disease and diabetes, disproportionately affect Black and Hispanic populations.287-288 Social and environmental disparities including lower levels and quality of education, higher rates of poverty, and greater exposure to adversity and discrimination increase risk for these chronic conditions and risk for dementia in Black and Hispanic populations.85,287-289 These health and socioeconomic disparities are rooted in the history of discrimination against Black and other people of color in the United States, not only during interpersonal interactions, but also as enshrined in the rules, practices and policies of U.S. banks, laws, medical systems and other institutions — that is, structural racism.290-291 Structural racism influences environmental factors such as where people can live, the quality of schools in their communities, and exposure to harmful toxicants and pollutants. It also influences sociocultural factors such as access to quality health care, employment prospects, occupational safety, the ability to pass wealth to subsequent generations, treatment by the legal system and exposure to violence. Structural racism impacts many aspects of life that may directly or indirectly alter the ability to adhere to healthy behaviors or access resources that influence dementia risk. For example, some studies indicate that early life experiences with residential and school segregation can have detrimental effects on the cognitive health of Black Americans in later life.292-293 This points to a need for health disparities research that employs lifecourse perspectives to account for the many environmental and sociocultural factors that may put disproportionately affected populations at increased risk for Alzheimer’s and other dementias.288-289 There is evidence that missed diagnoses of Alzheimer’s and other dementias are more common among older Blacks and Hispanics than among older Whites.294-296 Based on data for Medicare beneficiaries age 65 and Research into biological sex differences has examined whether genetic risk operates differently in women and men or whether there are sex differences in the development of or susceptibility to Alzheimer’s pathology.261 A number of studies have shown that the APOE-e4 genotype, the best known genetic risk factor for Alzheimer’s dementia, may have a stronger association with Alzheimer’s dementia262-263 and neurodegeneration264 in women than in men. However, a recent meta-analysis found no difference between men and women in the association between APOE genotype and Alzheimer’s dementia overall, though there was an elevated risk for women with the APOE-e4 genotype at certain age ranges.265 It is unknown why the APOE gene could convey different risk for women, but some evidence suggests that it may be due to an interaction between the APOE genotype and the sex hormone estrogen.266-267 Finally, there is some evidence that women show more rapid cognitive decline and neurodegeneration than men despite having similar levels of beta-amyloid and tau, meaning the hallmark proteins of Alzheimer’s disease may have more negative effects for women than men.268-270 Racial and Ethnic Differences in the Prevalence of Alzheimer’s and Other Dementias Although there are more Whites living with Alzheimer’s and other dementias than any other racial or ethnic group in the United States (because Whites are the largest racial/ethnic group in the country), older Black and Hispanic Americans are disproportionately more likely than older White Americans to have Alzheimer’s or other dementias.271-277 Data from the CHAP study indicates 18.6% of Blacks and 14% of Hispanics age 65 and older have Alzheimer’s dementia compared with 10% of White older adults.216 Most other prevalence studies also indicate that older Blacks are about twice as likely to have Alzheimer’s or other dementias as older Whites.241,278-279 Some studies indicate older Hispanics are about one and one-half times as likely to have Alzheimer’s or other dementias as older Whites.279-281 However, Hispanics comprise very diverse groups with different cultural histories, genetic ancestries and health profiles, and there is evidence that prevalence may differ from one specific Hispanic ethnic group to another (for example, Mexican Americans compared with Caribbean Americans).282-283 The higher prevalence of Alzheimer’s dementia in underrepresented racial and ethnic groups compared with Whites appears to be due to a higher risk of developing dementia in these groups compared with whites of the same age.284 This higher risk, or incidence, of Alzheimer’s and other dementias appears to stem from variations in medical conditions, health-related Prevalence 26 Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). older, it has been estimated that Alzheimer’s or another dementia has been diagnosed in 10.3% of Whites, 12.2% of Hispanics and 13.8% of Blacks.297 Although rates of diagnosis were higher among Blacks and Hispanics than among Whites, according to prevalence studies that detect all people who have dementia irrespective of their use of health care systems, the rates should be even higher for Blacks and Hispanics. Data from population-based cohort studies regarding the national prevalence of Alzheimer’s and other dementias in racial and ethnic groups other than Whites, Blacks and Hispanics are relatively sparse. However, a study examining electronic medical records of members of a large health plan in California indicated that dementia incidence — determined by the first presence of a dementia diagnosis in members’ medical records — was highest for African Americans, intermediate for Latinos (the term used in the study for those who self-reported as Latino or Hispanic) and Whites, and lowest for Asian Americans.298 A follow-up study with the same cohort showed heterogeneity within AsianAmerican subgroups, but all subgroups studied had lower dementia incidence than Whites.299 A recent systematic review of the literature found that Japanese Americans were the only Asian American subgroup with reliable prevalence data, and that they had the lowest prevalence of dementia compared with all other ethnic groups.283 More studies, especially those involving populationbased cohorts, are necessary to draw conclusions about the prevalence of Alzheimer’s and other dementias in different racial groups and subgroups. Trends in the Prevalence and Incidence of Alzheimer’s Dementia Over Time A growing number of studies indicate that the prevalence219,256,300-307 and incidence251,303,307-315 of Alzheimer’s and other dementias in the United States and other higher income Western countries may have declined in the past 25 years,251,256,302-314 though results are mixed.64,241,316-317 One recent systematic review found that incidence of dementia has decreased over the last four decades while incidence of Alzheimer’s dementia, specifically, has held steady, but more research on this distinction is needed, especially in non-Western countries.318 Declines in dementia risk have been attributed to increasing levels of education and improved control of cardiovascular risk factors.256,302,309,312,319-320 Such findings are promising and suggest that identifying and reducing risk factors for dementia may be effective. Although these findings indicate that a person’s risk of dementia at any given age may be decreasing slightly, Created from data from Rajan et al.A5,216 FIGURE 5 14 12 10 8 6 4 2 0 Year 2020 2030 2040 2050 2060 Millions of people Ages 65-74 Ages 75-84 Ages 85+ 6.1 8.5 11.2 12.7 13.8 Projected Number of People Age 65 and Older (Total and by Age) in the U.S. Population with Alzheimer’s Dementia, 2020 to 2060 27 the total number of people with Alzheimer’s or other dementias in the United States and other high-income Western countries is expected to continue to increase dramatically because of the increase in the number of people at the oldest ages. It is unclear whether these encouraging trends will continue into the future given worldwide trends showing increases in diabetes and obesity — potential risk factors for Alzheimer’s dementia — which may lead to a rebound in dementia risk in coming years,107,301,303,321-323 or if these positive trends pertain to all racial and ethnic groups.241,273,300,319-320,324 Thus, while recent findings are promising, the social and economic burden of Alzheimer’s and other dementias will continue to grow. Moreover, 68% of the projected increase in the global prevalence and burden of dementia by 2050 will take place in low- and middle-income countries, where there is currently no evidence that the risk of Alzheimer’s and other dementias has been declining.325 Looking to the Future: Aging of the Baby-Boom Generation A large segment of the American population — the babyboom generation — has started reaching age 65 and older, when the risk for Alzheimer’s and other dementias is elevated. By 2030, the segment of the U.S. population age 65 and older will have grown substantially, and the projected 74 million older Americans will make up over 20% of the total population (up from 17% in 2021).213,326 As the number of older Americans grows rapidly, so too will the numbers of new and existing cases of Alzheimer’s dementia, as shown in Figure 5.A5,72 • By 2025, the number of people age 65 and older with Alzheimer’s dementia is projected to reach 7.2 million — a 16% increase from the 6.2 million age 65 and older affected in 2021.216 • By 2060, the number of people age 65 and older with Alzheimer’s dementia is projected to reach 13.8 million, barring the development of medical breakthroughs to prevent, slow or cure Alzheimer’s disease.A5,216 Growth of the Oldest-Old Population The number of Americans surviving into their 80s, 90s and beyond is expected to grow dramatically due to the aging of the large baby-boom cohort, as well as longer life expectancies due to medical advances and changes to social and environmental conditions.326 This will lead to an increase in the number and percentage of Americans who will be 85 and older, the oldest-old. Between now and 2050, the oldest-old are expected to comprise an increasing proportion of the U.S. population age 65 and older — from 17% in 2021 to 22% in 2050.326 This will result in an additional 12 million oldest-old people — individuals at the highest risk for developing Alzheimer’s dementia.326 • In 2021, about 2.3 million people who have Alzheimer’s dementia are age 85 or older, accounting for 36% of all people with Alzheimer’s dementia.216 • By 2060, 6.7 million people age 85 and older are expected to have Alzheimer’s dementia, accounting for about half (48%) of all people 65 and older with Alzheimer’s dementia.216 Prevalence Mortality and Morbidity. Each year 500,000 surgical site infections occur in the US. Surgical site infections are the second most common healthcare-associated infections resulting in readmissions, prolonged hospital stays, higher medi-cal costs, and increased morbidity and mortality. Sur-gical site infections are preventable in most cases by following evidence-based guidelines for hand hygiene, administration of prophylactic antibiotics, and periop-erative patient temperature management. As attention to issues of healthcare quality heightens, the demand for positive surgical patient outcomes are intensify-ing. The Certified Registered Nurse Anesthetist can provide transparent high-quality care by implementing evidence-based guidelines for timely and appropriate antibiotic use, maintenance of normothermia, and hand washing. The Centers for Disease Control and Prevention (CDC) es-timates that 500,000 surgical site infections (SSIs) occur an-nually and account for 3% of surgical mortality, prolonged lengths of hospital stay, and increased medical costs. The literature suggests that 60% of the SSIs are preventable.1 Performance measures aimed at prevention of SSIs have been implemented nationally to enhance quality and mini-mize complications with respect to inpatient surgery.This course describes SSIs epidemiology, risk factors, and clinical consequences. It concludes by discussing the contribution of Certified Registered Nurse Anesthetists (CRNAs) to preventing SSIs by implementing guidelines for timely and appropriate use of antibiotics, mainte-nance of normothermia, and appropriate hand hygiene techniques.Surgical site infections are the second most common healthcare-associated infection. The CDC and the National Nosocomial Infection System have established criteria for defining SSIs that are widely used by SSI-surveillance and perioperative personnel.2 An SSI is an infection related to an operative procedure that occurs at or near the surgical incision within 30 days of the proce-dure.3,4 The CDC and the National Nosocomial Infection System define SSIs by the following clinical criteria:AANA Journal Course No. 34: AANA Journal course will consist of 6 successive articles, each with an objective for the reader and sources for additional reading. This educational activity is being presented with the understanding that any conflict of interest on behalf of the planners and presenters has been reported by the author(s). Also, there is no mention of off-label use for drugs or products. Please visit AANALearn.com for the corresponding exam questions for this article. Efforts to lower the incidence of SSIs date back to the 19th century when Lister pioneered antiseptic use to prevent infection in orthopedic patients.5 It is estimated that SSIs develop in 2% to 5% of the more than 30 million patients who undergo surgical procedures, representing 14% to 16% of all hospital-acquired infections annually in the US.6 These infections account for 3% of all surgical mortality and lead to increased readmissions, increased lengths of hospital stays, and higher costs.1 Patients who develop an SSI are 5 times more likely to be readmitted to the hospital, 60% more apt to require stay in an inten-sive care unit (ICU), and twice as likely to die compared with patients who are free of infection.2 Evidence further suggests that patients who contract multidrug-resistant infections face worse outcomes.5,7 The financial burden of SSIs is sizeable. An extensive epidemiologic review of surgical patient data revealed that lengths of hospital stay postoperatively extend 7 to 10 days, while hospital charges ranged from $3,000 to $29,000 per patient with a SSI diagnosis.3,5 Annually, hospital-acquired infections (HAIs) cost the healthcare system $9.8 billion.8 Compared with all HAIs nation-wide, SSIs occur most often and contribute the most to the overall cost, at 37.7% of the total cost.8 Death in the postoperative period was directly related to SSIs in 75% of patients in whom an SSI was diagnosed.3 The infection risk associated with primary hip and knee arthroplasty is approximately 1% and increases to 2% to 5% for arthroplasty revision.7 Compared with the infection rate for colon surgery, which is 20%, SSI rates in orthopedic surgery appear quite low. However, infec-tion in the bones and joints is very difficult to treat and is associated with a lifelong recurrence risk of 10% to 20%.9 When multiresistant pathogens such as methicillin-re-sistant Staphylococcus aureus (MRSA) infect a prosthetic joint, the treatment failure rate is 20% to 40%.7 Surgical infections that occur after total hip and knee arthroplasty are very costly and devastating for patients.7 Treatment of SSIs following joint replacement often requires removal and replacement of the prosthesis, prolonged systemic antibiotic therapy, and extensive rehabilitation because of impaired mobility. A consensus distinguishes timely antibiotic prophylaxis as essential in infection prevention, suggesting 30 minutes to 1 hour before incision as the ideal window for drug administra-tion.9,20 Merollini and colleagues20 determined through structured interviews with infectious disease physicians and orthopedic surgeons that antimicrobial prophylaxis is a relevant clinical practice for SSI prevention recom-mended by all participants. Uçkay et al9 conducted a comprehensive literature search using National Library of Medicine Medical Subject Headings (MeSH) terms infection, orthopedic, and prevention. They identified peer-reviewed literature, which revealed that antibi-otic prophylaxis for patients undergoing orthopedic joint surgery, when administered within 30 to 60 minutes before incision, helps to reduce SSI rates to 1% to 3% compared with 4% to 8% without preoperative antibiotic administration.9Based on published evidence, the SCIP established that an antibiotic received prophylactically within 1 hour before incision reduces the risk of infection.6,16,18,21,22 When a fluoroquinolone or vancomycin is the indicated antibiotic, administration should occur within 120 minutes before incision to avoid an adverse reaction associated with rapid infusion.6 Appropriate antibiotic selection is based on rec-ommended guidelines for procedures targeted for national surveillance.23 Although research demonstrates that many antibiotic regimens are effective preventive agents, the professional consensus supports using narrow-spectrum, first- and second generation cephalosporins, which are inexpensive, safe to use, and bactericidal, and have long half-lives. Contributing factors include low ambient temperatures in the surgi-cal suite, use of cold skin preparatory agents, exposed open wounds, cool fluid administration, and the anesthetic effects on a patient’s ability to control and conserve heat.24,25 The body’s core temperature is controlled by the hypothalamus, or the thermoregulation center of the brain. When a difference between core and skin tempera-ture is detected, the thermoregulation threshold triggers autonomic defense mechanisms to produce heat through vasoconstriction and shivering.26 Anesthetic inhalation agents, propofol, and opioids impair thermoregulatory control by decreasing heat production and increasing cu-taneous heat loss through vasodilation. Muscle relaxants also compromise thermoregulatory control by preventing shivering.25 The deleterious effects of hypothermia are well doc-umented. Adverse outcomes of hypothermia include increased blood loss and transfusion requirements, prolonged postoperative recovery times, heightened postoperative pain, and impaired immune function.25 Hypothermia compromises neutrophil function and pro-motes vasoconstriction, which leads to tissue hypoxia and increased incidence of SSIs.27 Numerous studies have demonstrated the impact of hypothermia on SSIs. Kurz et al12 studied patients undergoing colorectal surgery who were randomly assigned to a hypothermic and a normothermic group. Rates of infection were 3 times higher in the hypothermic group.12 Patients in the hypothermic group had hospital stays nearly 1 week longer than did normothermic patients.12 In a 1999 meta-analysis, Mahoney and Odom24 reported a 64% increased rate of SSIs in hypothermic patients. Conversely, when normothermia was maintained, a cost savings of up to $7,000 per patient was realized. Evidence-based practices to prevent perioperative hypothermia include identifying risk factors, measuring temperature, and initiating preventive and active warming measures.28 Risk factors are independent pre-dictors used to determine the potential for developing hypothermia. They include extremes of age, female gender, length and type of procedure, administration of general and spinal anesthesia, ambient temperature of the operating room (OR), and preexisting conditions (ex-tensive burns, endocrine disorders, pregnancy, and large open wounds).27 No single method of measuring temper-ature is deemed the gold standard. Core temperature may be measured in the distal esophagus, pulmonary artery, nasopharynx, or adjacent to the tympanic membrane.25 Use of an esophageal temperature probe in the intubated patient is the most reliable method. Skin temperature is approximately 2°C less than core temperature; thus, forehead skin temperature measurement only estimates core temperature. Clinical research suggests that rectal temperature lags behind temperature measured in the esophagus and the pulmonary artery. Moreover, rectal temperature measurement fails to appropriately rise during malignant hyperthermia and therefore must be used with caution.25The American Association of Nurse Anesthetists Standards for Nurse Anesthesia Practice29 requires tem-perature monitoring of all patients receiving anesthesia for whom large temperature changes are intended, an-ticipated, or suspected. Therefore, patient temperature should be monitored at no less than 15-minute intervals during all general and regional anesthetic procedures of more than 60-minute duration and during all pediatric procedures that are 30 minutes or longer. The greatest decline in patient temperature occurs during the first hour of surgery.27 The CRNA should intervene immediately on entering the surgical suite by applying warm blankets to limit the patient’s skin exposure to low ambient temperature. The Association of Operating Room Nurses recommends ambient tem-peratures between 20°C and 25°C. On induction of anesthesia, forced-air warming should be initiated using the manufacturer’s guidelines for use. The literature supports the use of forced air as the best warming approach because of its ease of use, efficacy, safety, and price.25,30 The use of warmed intravenous fluids in combination with forced-air warming has been shown to positively impact core temperature.27In 1825, a French pharmacist published an article recom-mending that physicians and healthcare workers would benefit from moistening their hands with liquid chloride solutions when caring for patients with contagious dis-eases.31 In 1846, an obstetrician and surgeon by the name of Semmelweis encouraged healthcare workers to incor-porate hand washing into their practice as a means to prevent HAIs. Semmelweis observed that women who delivered in the hospital setting were dying of febrile illness at much higher rates, compared with women who deliv-ered at home. He discovered that the hands of healthcare workers were transmitting the toxins that were causing the febrile illness from patient to patient.31 After his dis-covery, he demanded that his nurses and physicians wash their hands with a chlorine solution before caring for a patient. This intervention by Semmelweiss was the first evidence of preventing HAIs by adhering to strict hand hygiene practices. Semmelweis would be disappointed in our progress of reducing HAIs, because they continue to occur at a rate of 10% of hospitalized patients.32 Many of these infections have been attributed to the lack of hand washing by healthcare providers. Numerous studies have proved that healthcare workers’ hands transmit microorganisms to patients.33 Evidence proves that effective hand washing is the cor-nerstone for preventing healthcare-associated infections. It is also important in preventing specific site infections such as catheter-related bloodstream infections, catheter-related urinary tract infections, ventilator-associated pneumonia, and SSIs.33 Studies continue to demonstrate that hand hygiene practices among healthcare workers is at an abysmally low rate. An observational study of the hand hygiene practices of anesthesia providers was performed at a major metropolitan medical center. The study ob-served the hand hygiene practices of anesthesia provid-ers following the World Health Organization (WHO) Guidelines on Hand Hygiene in Health Care over a 4-week period. The results were daunting: “[T]he overall failure of hand hygiene ranged from 64% to 93% by pro-vider group with a mean aggregate failure rate of 82%”.32 The major categories where hand hygiene failures oc-curred were moving between patients in the preoperative phase, performing pain service interventions, using the keyboard when documenting in an electronic medical record, placing intravenous catheters and blood draws, preparing drugs and equipment for the following case, leaving soiled gloves on after airway manipulation, Foley catheter insertion or central or arterial line manipulation, and picking up something from the floor and using it.32An academic hospital in the Netherlands also reported results of poor hand hygiene, when an observer evaluated the hand hygiene practices in an OR. This study used an observational scoring tool that documented the hand hygiene practices of the staff members who touched pa-tients without the application of hand hygiene.34 The OR staff was categorized by profession, and staff members who were considered sterile were excluded. The observer evaluated 28 surgical procedures for more than 60 hours in a variety of surgical specialties. The results of this study revealed that the OR staff was observed participat-ing in hand hygiene in 7 of 363 opportunities (2%) and in 28 of 333 opportunities on leaving the OR (8.4%).34 This study also revealed that compliance with gloving guide-lines varied from 0% to 87%.34 Many providers donned gloves when performing invasive procedures such as intubation/extubation of the trachea, but the providers wore the gloves for long periods without appropriate hand hygiene.34A tertiary care hospital in Argentina revealed that with education and improved hand hygiene practices, there could possibly be a reduction in nosocomial infec-tions. This study was conducted in 2 ICUs in a 180-bed teaching hospital in Buenos Aires over a 2-year period. An intervention, which included educational classes on hand hygiene, the distribution of an infection control manual, and guidelines for appropriate hand hygiene practices, was provided to all healthcare providers.35 A trained nurse observed the hand hygiene practices of the healthcare practitioners. The observed hand hygiene practices were discussed at monthly meetings and posted in the ICUs. Nosocomial infections that occurred in the ICUs were recorded according to the CDC definitions of such infections. Baseline and postintervention data of hand hygiene practices were collected by trained in-fection control practitioners. The overall compliance of hand hygiene improved from baseline (23.1%) to the postintervention phase (64.5%).35 Hand hygiene is a simple measure that when imple-mented in the everyday care of patients can reduce SSIs and improve patient safety.36 Hand hygiene practices should always be a priority when participating in patient care. The 2009 WHO Guidelines on Hand Hygiene36 recommend that the healthcare provider engage in hand hygiene in the following situations: When the hands are visibly dirty or visibly soiled with blood or body fluids or after using the toilet If there is exposure to potential spore-forming pathogens, including outbreaks of Clostridium difficile Before and after touching a patient, before handling an invasive device for patient care, regardless of whether or not gloves are used; after contact with body fluids or excretions, mucous membranes, nonintact skin, or wound dressings; if moving from a contaminated body site to another body site during the care of the same patient; after contact with inanimate surfaces and objects (including medical equipment) in the immediate vicinity of the patient; and after removing sterile or nonsterile gloves Before handling medications or preparing food The Institute of Medicine has galvanized attention to issues of quality and medical error as they pertain to healthcare delivery in the US.37 Policymakers, health-care stakeholders, and professional organizations have launched initiatives targeted at improving hospital quality regarding inpatient surgery by minimizing complications, reducing medical expenses, and increasing favorable outcomes. As the need for transparency in healthcare heightens, the demand for positive surgical patient outcomes will intensify. The anesthesia provider can deliver transparent high-quality care by implement-ing timely and appropriate antibiotic use, maintenance of normothermia, and hand hygiene practices in accordance with evidence-based guidelines REFERENCES1. Meeks DW, Lally KP, Carrick MM, et al. Compliance with guidelines to prevent surgical site infections: as simple as 1-2-3? Am J Surg. 2011;201(1):76-83. 2. Prokuski L. Prophylactic antibiotics in orthopedic surgery. J Am Acad Orthop Surg. 2008;16(5):283-293. 3. Anderson DJ, Sexton DJ. Epidemiology and pathogenesis of and risk factors for surgical site infection. UpToDate. 2008. http://www. upto-date.com. 4. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection: 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol. 1999;20(4):250-278. 5. Anderson DJ. Surgical site infections. Infect Dis Clin North Am. 2011;25(1):135-153. 6. Bratzler DW, Hunt DR. The Surgical Infection Prevention and Surgical Care Improvement projects: national initiatives to improve outcomes for patients having surgery. Clin Infect Dis. 2006;43(3):322-330.