Alzheimer's Research

Alzheimer’s (AHLZ-high-merz) is a disease of the brain that causes problems with memory, thinking and behavior. It is not a normal part of aging. Alzheimer’s gets worse over time. Although symptoms can vary widely, the first problem many people notice is forgetfulness severe enough to affect their ability to function at home or at work, or to enjoy hobbies. The disease may cause a person to become confused, get lost in familiar places, misplace things or have trouble with language. It can be easy to explain away unusual behavior as part of normal aging, especially for someone who seems physically healthy. Any concerns about memory loss should be discussed with a doctor. More than 5 million Americans have Alzheimer’s disease, the most common form of dementia. Alzheimer’s accounts for 60 to 80 percent of all dementia cases. That includes 11 percent of those age 65 and older and one-third of those 85 and older. The disease also impacts more than 15 million family members, friends and caregivers. Dementia is a general term for the loss of memory and other cognitive abilities serious enough to interfere with daily life. Vascular dementia is a decline in thinking skills caused by conditions that block or reduce blood flow to the brain, depriving brain cells of vital oxygen and nutrients. These changes sometimes occur suddenly following strokes that block major brain blood vessels. It is widely considered the second most common cause of dementia after Alzheimer’s disease. Mixed dementia is a condition in which abnormalities characteristic of more than one type of dementia occur simultaneously. Symptoms may vary, depending on the types of brain changes involved and the brain regions affected, and may be similar to or even indistinguishable from those of Alzheimer’s or another dementia. Parkinson’s disease dementia is an impairment in thinking and reasoning that many people with Parkinson’s disease eventually develop. As brain changes gradually spread, they often begin to affect mental functions, including memory and the ability to pay attention, make sound judgments and plan the steps needed to complete a task. Dementia with Lewy bodies is a type of progressive dementia that leads to a decline in thinking, reasoning and independent function due to abnormal microscopic deposits that damage brain cells. Huntington’s disease dementia is a progressive brain disorder caused by a defective gene. It causes changes in the central area of the brain, which affect movement, mood and thinking skills. Creutzfeldt-Jakob disease is the most common human form of a group of rare, fatal brain disorders known as prion diseases. Misfolded prion protein destroys brain cells, resulting in damage that leads to rapid decline in thinking and reasoning as well as involuntary muscle movements, confusion, difficulty walking and mood changes. Frontotemporal dementia (FTD) is a group of disorders caused by progressive cell degeneration in the brain’s frontal lobes (the areas behind the forehead) or its temporal lobes (the regions behind the ears).Normal pressure hydrocephalus is a brain disorder in which excess cerebrospinal fluid accumulates in the brain’s ventricles, causing thinking and reasoning problems, difficulty walking and loss of bladder control. Down syndrome dementia develops in people born with extra genetic material from chromosome 21, one of the 23 human chromosomes. As individuals with Down syndrome age, they have a greatly increased risk of developing a type of dementia that’s either the same as or very similar to Alzheimer’s disease. Korsakoff syndrome is a chronic memory disorder caused by severe deficiency of thiamine (vitamin B-1). It is most commonly caused by alcohol misuse, but certain other conditions can also cause the syndrome.Posterior cortical atrophy (PCA) is the gradual and progressive degeneration of the outer layer of the brain (the cortex) located in the back of the head (posterior). It is not known whether PCA is a unique disease or a possible variant form of Alzheimer’s disease.The changes that take place in the brain begin at the microscopic level long before the first signs of memory loss.The brain has 100 billion nerve cells (neurons). Each nerve cell connects to many others to form communication networks. In addition to nerve cells, the brain includes cells specialized to support and nourish other cells. Groups of nerve cells have special jobs. Some are involved in thinking, learning and memory. Others help us see, hear, smell and tell our muscles when to move. Brain cells operate like tiny factories. They receive supplies, generate energy, construct equipment and get rid of waste. Cells also process and store information and communicate with other cells. Keeping everything running requires coordination as well as large amounts of fuel and oxygen. Scientists believe Alzheimer’s disease prevents parts of a cell’s factory from running well. They are not sure where the trouble starts. But just like a real factory, backups and breakdowns in one system cause problems in other areas. As damage spreads, cells lose their ability to do their jobs and, eventually, die. The brains of individuals with Alzheimer’s have an abundance of plaques and tangles. Plaques are deposits of a protein fragment called beta-amyloid that build up in the spaces between nerve cells. Tangles are twisted fibers of another protein called tau that build up inside cells. Though autopsy studies show that most people develop some plaques and tangles as they age, those with Alzheimer’s tend to develop far more and in a predictable pattern, beginning in the areas important for memory before spreading to other regions. Scientists do not know exactly what role plaques and tangles play in Alzheimer’s disease. Most experts believe that they disable or block communication among nerve cells and disrupt processes the cells need to survive. The destruction and death of nerve cells causes memory failure, personality changes, problems in carrying out daily activities and other symptoms of Alzheimer’s diseaWhile scientists know that Alzheimer’s disease involves the failure of nerve cells, it’s still unknown why this happens. However, they have identified certain risk factors that increase the likelihood of developing Alzheimer’s. The greatest known risk factor for Alzheimer’s is increasing age. Most individuals with the disease are 65 and older. One in nine people in this age group and nearly one-third of people age 85 and older have Alzheimer’s. Another risk factor is family history. Research has shown that those who have a parent, brother or sister with Alzheimer’s are more likely to develop the disease than individuals who do not. The risk increases if more than one family member has the illness. Two categories of genes influence whether a person develops a disease: risk genes and deterministic genes. Risk genes increase the likelihood of developing a disease but do not guarantee it will happen. Deterministic genes directly cause a disease, guaranteeing that anyone who inherits one will develop a disorder. Researchers have found several genes that increase the risk of Alzheimer’s. APOE-e4 is the first risk gene identified and remains the one with strongest impact. Other common forms of the APOE gene are APOE-e2 and APOE-e3. Everyone inherits a copy of some form of APOE from each parent. Those who inherit one copy of APOE-e4 have an increased risk of developing Alzheimer’s; those who inherit two copies have an even higher risk, but not a certainty. Rare deterministic genes cause Alzheimer’s in a few hundred extended families worldwide. These genes are estimated to account for less than 1 percent of cases. Individuals with these genes usually develop symptoms in their 40s or 50s. Research shows that older Latinos are about one-and-a-half times as likely as older whites to have Alzheimer’s and other dementias, while older African-Americans are about twice as likely to have the disease as older whites. The reason for these differences is not well understood, but researchers believe that higher rates of vascular disease in these groups may also put them at greater risk for developing Alzheimer’s. Age, family history and genetics are all risk factors we can’t change. However, research is beginning to reveal clues about other risk factors that we may be able to influence. There appears to be a strong link between serious head injury and future risk of Alzheimer’s. It’s important to protect your head by buckling your seat belt, wearing a helmet when participating in sports and proofing your home to avoid falls One promising line of research suggests that strategies for overall healthy aging may help keep the brain healthy and may even reduce the risk of developing Alzheimer’s. These measures include eating a healthy diet, staying socially active, avoiding tobacco and excess alcohol, and exercising both the body and mind. Some of the strongest evidence links brain health to heart health. The risk of developing Alzheimer’s or vascular dementia appears to be increased by many conditions that damage the heart and blood vessels. These include heart disease, diabetes, stroke, high blood pressure and high cholesterol. Work with your doctor to monitor your heart health and treat any problems that arise. Studies of donated brain tissue provide additional evidence for the heart-head connection. These studies suggest that plaques and tangles are more likely to cause Alzheimer’s symptoms if strokes or damage to the brain’s blood vessels are also present. Not everyone experiencing memory loss or other possible Alzheimer’s warning signs recognizes that they have a problem. Signs of dementia are sometimes more obvious to family members or friends. The first step in following up on symptoms is finding a doctor with whom a person feels comfortable. There is no single type of doctor that specializes in diagnosing and treating memory symptoms or Alzheimer’s disease. Many people contact their regular primary care physician about their concerns. Primary care doctors often oversee the diagnostic process themselves. In some cases, the doctor may refer the individual to a specialist, such as a: Neurologist, who specializes in diseases of the brain and nervous system Psychiatrist, who specializes in disorders that affect mood or the way the mind works. Psychologist with special training in testing memory and other mental functions. There is no single test that proves a person has Alzheimer’s. The workup is designed to evaluate overall health and identify any conditions that could affect how well the mind is working. When other conditions are ruled out, the doctor can then determine if it is Alzheimer’s or another dementia. Experts estimate that a skilled physician can diagnose Alzheimer’s with more than 90 percent accuracy. Physicians can almost always determine that a person has dementia, but it may sometimes be difficult to determine the exact cause. The doctor will interview the person being tested and others close to him or her to gather information about current and past mental and physical illnesses. It is helpful to bring a list of all the medications the person is taking. The doctor will also obtain a history of key medical conditions affecting other family members, especially whether they may have or had Alzheimer’s disease or other dementias. Evaluating mood and mental status Mental status testing evaluates memory, the ability to solve simple problems and other thinking skills. The doctor may ask the person his or her address, what year it is or who is serving as president. The individual may also be asked to spell a word backward, draw a clock or copy a design. The doctor will also assess mood and sense of well-being to detect depression or other illnesses that can cause memory loss and confusion. The physician will collect blood and urine samples and may order other laboratory tests. Information from these tests can help identify disorders such as anemia, infection, diabetes, kidney or liver disease, certain vitamin deficiencies, thyroid abnormalities, and problems with the heart, blood vessels or lungs. All of these conditions may cause confused thinking, trouble focusing attention, memory problems or other symptoms similar to dementia.The doctor is looking for signs of small or large strokes, Parkinson’s disease, brain tumors, fluid accumulation on the brain, and other illnesses that may impair memory or thinking. The neurological exam may also include a brain imaging study. The most common types are magnetic resonance imaging (MRI) or computed tomography (CT). MRIs and CTs can reveal tumors, evidence of small or large strokes, damage from severe head trauma or a buildup of fluid. Researchers are studying other imaging techniques so they can better diagnose and track the progress of Alzheimer’s. Once testing is complete, the doctor will make an appointment to review results and share his or her conclusions. A diagnosis of Alzheimer’s reflects a doctor’s best judgment about the cause of a person’s symptoms, based on the testing performed. Find out if the doctor will manage care going forward and, if not, who will be the primary doctor. The doctor can then schedule the next appointment or provide a referral. Alzheimer’s disease is life-changing for both the diagnosed individual and those close to him or her. While there is currently no cure, treatments are available that may help relieve some symptoms. Research has shown that taking full advantage of available treatment, care and support options can improve quality of lifIt is also important to begin making legal and financial plans. A timely diagnosis often allows the person with dementia to participate in this planning. The person can also decide who will make medical and financial decisions on his or her behalf in later stages of the disease. Alzheimer’s Navigator® helps guide individuals facing dementia when planning for the future. This interactive tool evaluates needs, outlines action steps and links the user to local services and Association programs. Visit alz.org/alzheimersnavigator to start planning. Alzheimer’s disease typically progresses slowly in three general stages: early, middle and late (sometimes referred to as mild, moderate and severe in a medical context). Since Alzheimer’s affects people in different ways, each person may experience symptoms — or progress through the stages — differently. The symptoms of Alzheimer’s worsen over time, but because the disease affects people in different ways, the rate of progression varies. On average, a person with Alzheimer’s lives four to eight years after diagnosis, but can live as long as 20 years, depending on other factors. Changes in the brain related to Alzheimer’s begin years before any signs of the disease. This period is referred to as preclinical Alzheimer’s disease. The following stages provide an overall idea of how abilities change once symptoms appear and should be used as a general guide. Stages may overlap, making it difficult to place a person with Alzheimer’s in a specific stage. In the early stage of Alzheimer’s, a person may function independently. He or she may still drive, work and be part of social activities. Despite this, the person may feel as if he or she is having memory lapses, such as forgetting familiar words or the location of everyday objects. Friends, family or others close to the individual begin to notice difficulties. During a detailed medical interview, doctors may be able to detect problems in memory or concentration. Common difficulties include: Middle-stage Alzheimer’s is typically the longest stage and can last for many years. As the disease progresses, the person with Alzheimer’s will require a greater level of care. You may notice the person with Alzheimer’s confusing words, getting frustrated or angry, or acting in unexpected ways, such as refusing to bathe. Damage to nerve cells in the brain can make it difficult to express thoughts and perform routine tasks. Personality and behavioral changes, including suspiciousness and delusions or compulsive, repetitive behavior like hand wringing or tissue shredding. Six out of 10 people with Alzheimer’s will wander and become lost. People can wander or become confused about their location at any stage of the disease. If not found within 24 hours, up to half of those who get lost risk serious injury or death. response service that provides assistance when a person with dementia becomes lost or has a medical emergency.In the final stage of the disease, individuals lose the ability to respond to their environment, carry on a conversation and, eventually, control movement. They may still say words or phrases, but communicating pain becomes difficult. As memory and cognitive skills worsen, significant personality changes may occur and extensive help with daily activities may be required. Currently, there is no cure for Alzheimer’s and no way to stop the underlying death of brain cells. But drugs and non-drug treatments may help with both cognitive and behavioral symptoms. Three types of drugs are currently approved by the FDA to treat cognitive symptoms of Alzheimer’s disease. The first, cholinesterase (KOH-luh-NES-ter-ays) inhibitors, prevents the breakdown of acetylcholine (a-SEA-til-KOH-lean), a chemical messenger important for memory and learning. By keeping levels of acetylcholine high, these drugs support communication among nerve cells. Three cholinesterase inhibitors are commonly prescribed: Donepezil (Aricept®), approved in 1996 to treat mild-to-moderate Alzheimer’s and in 2006 for the severe stage. Rivastigmine (Exelon®), approved in 2000 for mild-to-moderate Alzheimer’s. Galantamine (Razadyne®), approved in 2001 for mild-to-moderate stages. The second type of drug works by regulating the activity of glutamate, a different messenger chemical involved in information processing: Memantine (Namenda®), approved in 2003 for moderate-to-severe stages, is the only drug in this class currently available. The third type is a combination of cholinesterase inhibitor and a glutamate regulator: Donepezil and memantine (Namzaric®), approved in 2014 for moderate-to-severe stages. The effectiveness of these treatments varies from person to person. While they may temporarily help symptoms, they do not slow or stop the brain changes that cause Alzheimer’s to become more severe over time. Many find behavioral changes, like anxiety, agitation, aggression and sleep disturbances, to be the most challenging and distressing effect of Alzheimer’s disease. These changes can greatly impact the quality of life for individuals. As with cognitive symptoms of Alzheimer’s, the chief underlying cause of behavioral and psychiatric symptoms is the progressive damage to brain cells. Other possible causes of behavioral symptoms include: Side effects from prescription medications may be at work. Drug interactions may occur when taking multiple medications for several conditions. Symptoms of infection or illness, which may be treatable, can affect behavior. Pneumonia or urinary tract infections can bring discomfort. Untreated ear or sinus infections can cause dizziness and pain. Situations affecting behavior include moving to a new private residence or residential care facility; misperceived threats; or fear and fatigue from trying to make sense of a confusing world. There are two types of treatments for behavioral symptoms: non-drug treatments and prescription medications.Because people with Alzheimer’s gradually lose the ability to communicate, it is important to regularly monitor their comfort and anticipate their needs. Medications can be effective in managing some behavioral symptoms, but they must be used carefully and are most effective when combined with non-drug treatments. Medications should target specific symptoms so that response to treatment can be monitored. Prescribing any drug for a person with Alzheimer’s is medically challenging. Use of drugs for behavioral and psychiatric symptoms should be closely supervised. Some medications, called psychotropic medications (antipsychotics, antidepressants, anti-convulsants and others), are associated with an increased risk of serious side effects. These drugs should only be considered when non-pharmacological approaches are unsuccessful in reducing dementia-related behaviors that are causing physical harm to the person with dementia or his or her caregivers. Cognitive: Symptoms that affect memory, awareness, language, judgment, and an individual’s ability to plan, organize and carry out other thought processes. Behavioral: A group of additional symptoms that occur — at least to some degree — in many individuals with Alzheimer’s. Early on, people may experience personality changes such as irritability, anxiety or depression. In later stages, individuals may develop sleep disturbances; agitation (physical or verbal aggression, general emotional distress, restlessness, pacing, shredding paper or tissues, yelling); delusions (firmly held belief in things that are not real); or hallucinations (seeing, hearing or feeling things that are not there). Individuals with the disease may develop wandering impulses at any stage.FDA-approved: Medication approved by the U.S. Food and Drug Administration (FDA) that treats symptoms of Alzheimer’s disease.Non-drug: A treatment other than medication that helps relieve symptoms of Alzheimer’s disease. The Alzheimer’s Association is the world’s largest nonprofit funder of Alzheimer’s research. Since 1982, we have awarded over $350 million to more than 2,300 research investigations worldwide. When Dr. Alois Alzheimer first described the disease in 1906, a person in the United States lived an average of about 50 years. Few people reached the age of greatest risk. As a result, the disease was considered rare and attracted little scientific interest. That attitude changed as the average life span increased and scientists began to realize how often Alzheimer’s strikes people in their 70s and 80s. The Centers for Disease Control and Prevention recently estimated the average life expectancy to be 78.8 years. Today, Alzheimer’s is at the forefront of biomedical research, with 90 percent of what we know discovered in the last 20 years. Some of the most remarkable progress has shed light on how Alzheimer’s affects the brain. Better understanding of the disease’s impact may lead to better treatments. Scientists are constantly working to advance our understanding of Alzheimer’s. But without clinical research and the help of human volunteers, we cannot treat, prevent or cure Alzheimer’s. Clinical trials test new interventions or drugs to prevent, detect or treat disease for safety and effectiveness. Clinical studies are any type of clinical research involving people and those that look at other aspects of care, such as improving quality of life. Every clinical trial or study contributes valuable knowledge, regardless if favorable results are achieved Visit alz.org/TrialMatch to learn more about Alzheimer’s Association TrialMatch®, a clinical studies matching service that connects individuals living with Alzheimer’s, caregivers, healthy volunteers and physicians with current Alzheimer’s-related clinical studies. New directions in treatment and prevention One promising target is beta-amyloid. This protein fragment builds up into the plaques considered to be one hallmark of Alzheimer’s disease. Researchers have developed several ways to clear beta-amyloid from the brain or prevent it from clumping together into plaques. Experimental drugs that zero in on beta-amyloid are now being tested. Many other new approaches to treatment are also under investigation worldwide. We don’t yet know which of these strategies may work, but scientists say that with the necessary funding, the outlook is good for developing treatments that slow or stop Alzheimer’s. While there is no known way to prevent Alzheimer’s disease, emerging research suggests that the steps people take to maintain heart health may also reduce the risk of cognitive decline. This connection makes sense, because the brain is nourished by one of the body’s richest networks of blood vessels, and the heart is responsible for pumping blood through these blood vessels to the brain. It’s especially important for people to do everything they can to keep weight, blood pressure, cholesterol and blood sugar within recommended ranges to reduce the risk of heart disease, stroke and diabetes. Eating a diet low in saturated fats and rich in fruits and vegetables, exercising regularly, and staying mentally and socially active may all help protect the brain. The Alzheimer’s Association is the leading voluntary health organization in Alzheimer’s care, support and research. Our mission is to eliminate Alzheimer’s disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer’s disease®.This is an official publication of the Alzheimer’s Association but may be distributed by unaffiliated organizations and individuals. Such distribution does not constitute an endorsement of these parties or their activities by the Alzheimer’s Association. Loss of memory is among the first symptoms reported by patients suffering from Alzheimer's disease (AD) and by their caretakers. Working memory and long-term declarative memory are affected early during the course of the disease. The individual pattern of impaired memory functions correlates with parameters of structural or functional brain integrity. AD pathology interferes with the formation of memories from the molecular level to the framework of neural networks. The investigation of AD memory loss helps to identify the involved neural structures, such as the default mode network, the influence of epigenetic and genetic factors, such as ApoE4 status, and evolutionary aspects of human cognition. Clinically, the analysis of memory assists the definition of AD subtypes, disease grading, and prognostic predictions. Despite new AD criteria that allow the earlier diagnosis of the disease by inclusion of biomarkers derived from cerebrospinal fluid or hippocampal volume analysis, neuropsychological testing remains at the core of AD diagnosis.Asked to name a disease that affects “memory,” most physicians would probably choose Alzheimer's disease (AD). AD is the most common cause of dementia. Currently, 30 million people worldwide suffer from Alzheimer's dementia and the World Health organization projects that this number will triple over the next 20 years.¹ The cumulative incidence of Alzheimer dementia has been estimated to rise from about 5% by age 70 to 50% by age 90, making it a very common disease.² Increasing longevity and demographic shifts in many societies will stress the health systems unless a cure for AD is found—or at least any therapy that postpones the onset of the dementia by 5 to 10 years for the time being. AD is a polygenetic neurodegenerative brain disorder characterized by neocortical atrophy developing over decades, showing the increasing loss of synapses and neurons first described by Alois Alzheimer in 1907.³ Variations in the genes encoding the amyloid precursor proteins, presenilin-1 and presenilin-2, can directly cause Alzheimer's disease. The patients often display an early onset of dementia in their forties, and these deterministic genes affect whole families and patients with trisomy 21. They, however, account for only 1% of all cases of AD. The remaining 99% of sporadic AD occurs predominantly in patients older than 65 years;⁴ These patients also inherit 60% to 80% of their risk for late-onset AD, although it is not connected to the aforementioned genes, with the remainder being environmental.^4,5 In late-onset AD many different genes—some still unidentified—are involved, each only attributing a minor fraction of the individual's overall risk, making it a possible example of antagonistic pleiotropy.⁶ Recently, several genome-wide association studies have identified new candidates (for reviews and databases see http://www.alzgene.org). The best characterized genetic risk factor in late-onset AD is the apolipoprotein E4 (ApoE4) genotype with ApoE4 carriers having a 4- to 10-fold increased odds ratio of developing AD.⁷ The ApoE4 allele is an ancestral variant. The human ApoE2 and ApoE3 alleles are fairly recent mutations—less than 200 000 years old.⁸ ApoE3 is the most frequent allele, with frequencies of about 60% in human populations. In contrast, ApoE4 has a frequency of about 10%. This implies that ApoE3 and ApoE2 must possess an advantage in order to have gained prevalence in human populations so quickly; clinical and preclinical data point to higher synaptic plasticity and repair capacities in carriers of ApoE2 and ApoE3, which may explain the selection bias.⁹ The consumption and adaption of humans to a diet rich in meat and animal fats can also be a reason for the selection of ApoE3.¹⁰The neuropathological hallmarks of the atrophy process in AD are the presence of senile plaques (amyloid deposits) and neurofibrillary tangles in autopsied brains.¹¹ Neurofibrillary tangles are composed of hyperphosphorylated tau protein located within neurons, whereas senile plaques are made up largely of amyloid-P species aggregating in the extracellular space. These neuropathological changes start in the entorhinal cortex and hippocampal formations, later spreading into other temporal, parietal, and finally frontal association cortices.^12-14 The first lesions characteristic of AD appear in poorly myelinated limbic neurons in system areas related to memory and learning, such as the hippocampus and the association cortex. Highly myelinated neurons are only affected in the final phases of the disease.¹⁵ Low myelinization increases the overall energy expenditure of neurons. In addition, subcortical neuron loss occurs in the nucleus basalis of Meynert and the locus ceruleus, impairing the cholinergic and noradrenergic transmitter systems in the neocortex.^16,17 The parietal lobe, along with certain areas of the prefrontal lobe, is one of the last areas of the human brain to myelinate, and many of its neurons remain poorly myelinated for the entire lifespan, which may explain their vulnerability to factors capable of triggering AD.^18-20 The atrophy runs slowly, but while in healthy aging only 0.2% to 0.41% of the brain volume vanishes per year, the rates in AD may be ten times that, and in especially vulnerable regions like the hippocampal formation atrophy rates might be even more devastatingly high and surpass 10% per year (see also Figure 1).^21-23 In terms of neuropsychological tests, regional atrophy, and glucose metabolism correlate well with test results.^24,25 Left hippocampal gray matter volume, for example, significantly correlates with performance in memory tasks, and left temporal gray-matter volume is related to performance in language tasks. The rate of change in the left hippocampus correlates with decline of performance in the Boston Naming Test Mini-Mental Status Examination, and the trailmaking test B.²⁴ Such analyses help with the definition of special AD subtypes like posterior cortical atrophy, or the logopenic variant of AD.^24-31 On the molecular level we find a downregulation of synaptic genes across multiple brain regions and widespread proteomic signs of synaptic stress or decay in the cerebrospinal fluid (CSF) or blood.^32-34 Changes in the molecular fine structure of AD brains also arise independently of atrophy as resonance spectroscopic investigations in AD imply.³⁵Atrophy in a case of AD over 4 years. (A) Reduction of gray matter (lateral view; corrected for age; P<0.05), (B) coronal view of the left hippocampus at baseline and after 4 years (hippocampal gray matter volume at T0 5.3±0.4 mL, at T4 3.5±0.2 ml), (C) average hippocampal volume reduction of 0.2 mL per year (-12%/year), (D) average increase of lateral ventricle volume of 2.7 mL/per year (+ 6.7%/year). (Courtesy of L. Spies, Jung-diagnostics GmbH, Hamburg, Germany)This review aims to highlight some aspects concerning the development of memory deficits in AD that recently have or should have gained attention.Recently workgroups of the Alzheimer's Association and the National Institute on Aging have issued new criteria and guidelines to diagnose Alzheimer's disease supplanting the previous guidelines first published in 1984.^36-40 This marks a complete overhaul, and attemps to implement advances in our understanding of the disease in the way we diagnose the disease. Hie most notable differences are the use of biomarkers such as hippocampal atrophy, and the formalization of earlier disease stages before dementia is apparent, such as mild cognitive impairment due to AD and the newly defined preclinical AD stage.^38,39 While the recommendations of the preclinical AD workgroup are intended purely for research purposes and the aim of diagnosing the disease earlier appears sensible since it is likely that any intervention has to be started early to be successful, it is also clear that we would almost all be defined as having the disease using this definition, given the increasing prevalence of AD in the very old. From a scientific point of view, it might be more interesting to know why a few of us might not develop AD, even when we are not dying from other diseases. As clinicians AD patients may first approach us with mere subjective concerns about cognitive decline. This can develop into mild cognitive impairment with pathological neuropsychological test results and progress into dementia, at which time daily activities can no longer be performed properly. When brain atrophy progresses other psychiatric and neurological symptoms arise, and typically AD patients lose weight and frequently develop difficulties in swallowing. This may lead to aspiration and subsequently pneumonia, which is often the final cause of death in demented patients.Consensus exists that AD starts clinically with memory complaints, which may affect episodic memory, speech production, with naming or semantic problems, or visual orientation. Memory can be defined as a process of encoding, storing, and retrieving information about outer and inner stimuli, or presentation of information to the nervous system of an organism that can be used to react and position the organism towards new stimuli. Different categories of memory have been defined which also have different neuroanatomical and neurophysiological correlates: short-term memory vs long-term memory or implicit versus declarative memory. Short-term memory is limited to just a few “chunks” in capacity, and lasts only seconds to minutes.⁴¹ It depends on regions of the frontal lobe and the parietal lobe. In contrast, long-term memory seems almost limitless regarding its storage capacities, for a potentially unlimited duration. It depends on de novo protein synthesis and changes in the molecular components of the neuronal networks involved in the specific cortical areas that can be attributed to different memory types. Declarative memory, for example, can be further subdivided into semantic memory, where context-independent information is stored, and episodic memory, which stores information specific to a particular context, mainly time and place. Semantic memory is at first impaired in the language of AD patients, affecting verbal fluency and naming. Semantic loss in AD may occur several years prior to diagnosis.⁴² The hippocampus is essential to the consolidation of information from short-term to long-term memory. Destruction of the hippocampal formation makes the storage of new memories impossible. In the clinical context we use neuropsychological test batteries like the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) examination, the Mini-Mental State examination, and various other test constructs and scales, like the clinical dementia rating scale, that investigate different aspects of memory over a broad range of various cognitive domains.^43-45 Patients get profiled in relation to tests they show abnormalities on, compared with a healthy reference group adjusted for age and education. AD patients typically display a cognitive profile with impairments in multiple cognitive domains. This cognitive profile develops over time, and AD patients often start to show a progressive decay of working memory. The patients display increased sensitivity to distraction in memory tasks, the capacity of working memory measured, eg, digit span is, however, at first still intact. Interestingly, the medications used currently to treat AD like acetylcholinesterase inhibitors or memantine work partly by increasing attention and concentration and work mainly in mild-to-moderate AD.^46,47The deficits in attention and working memory associated with damage to frontal subcortical circuits also influence executive functions in AD, impairing planning, problem solving, and goal-directed behavior such as the ability to deploy response alternatives or modify behavior. AD patients show impaired results in tests that require planning, problem solving, or cognitive flexibility, eg, the Wisconsin Card Sorting Test, the Stroop test, or the Tower of London Test. The manifestation of impairment in such tests of executive functioning corresponds to the onset of difficulties in the performance of daily activities in these patients and marks the progression to the state of full dementia. The Boston Naming test assesses the ability to name pictures of objects through spontaneous responses, and the need for various types of cueing. Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with mild cognitive impairment. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.⁴⁸ Another surprisingly simple test is the Clock Drawing test. AD patients show early difficulties in visuospatial processing and conceptual errors like misrepresentation of numbers in the command, but not in the copy, condition, pointing to deficits in semantic memory. The Trail Making Test A+B is a neuropsychological test of visual attention measuring mental processing speed, and the ability to switch between different tasks. It consists of two parts in which the subject is asked to connect a set of 25 dots as fast as possible while maintaining accuracy. Visual search speed, scanning and processing abilities, mental flexibility, and executive functioning can be assessed with this test.Regarding animal models, there are plenty of paradigmata available to test memory functions, but there is an overall lack of validated animal data that can be aligned with similar tests in human settings. Snigdha et al started with the comprehensive toolbox for Neurologic Behavioral Function from the National Institutes of Health (NIH) which contains evaluated tests for cognitive, motor, sensory, and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age and analyzed strengths and limitations of available animal behavioral tests to find matches. They defined a preclinical battery that aims to parallel the NIH Toolbox, and may help to close the gap between data from different species.⁴⁹Subjective cognitive impairment without detectable objective memory deficit may no longer merely regarded as “normal aging” since it has been shown that it is a major risk factor for the development of dementia.⁵⁰ A clear definition of what subjective memory impairment or subjective cognitive impairment actually mean is currently lacking. An international task force is, however, working on standard operating procedures that would enable comparable study designs. A consensus regarding naming the concept “subjective cognitive impairment” in view of previously used terminology such as “subjective memory impairment” seems to be arising. Subjective cognitive impairment is defined as the individual coming up with the mere feeling that something is not in order, without any objective parameters supporting that notion in the first place. Such a stage labeled subjective cognitive impairment may precede mild cognitive impairment in the continuum of Alzheimer disease manifestation. Using such a definition and without objective neuropsychological test alterations, the atrophy pattern of patients with subjective cognitive impairment seem to be related to the atrophy pattern seen in AD.⁵¹ Individuals with subjective memory impairment showed greater similarity to an AD gray matter pattern, and episodic memory decline was associated with an AD gray matter pattern in probands with subjective memory impairment.⁵² Patients with subjective memory impairment also already showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe using (fludeoxyglucose positron emission tomography, FDG-PET). Their gray matter volume was reduced in the right hippocampus. At follow-up, these patients showed poorer performance on measures of episodic memory. The observed memory decline was associated with reduced glucose metabolism in the right precuneus at baseline. The authors conclude that their concept of subjective memory impairment may define the earliest clinical manifestation of AD.⁵³ In another study patients with subjective memory underwent an associative episodic memory task matching faces to professions, including encoding, recall, and recognition, and a working memory task during functional magnetic resonance imaging (f'MRI). They showed a reduction in right hippocampal activation during episodic memory recall, still in the absence of performance deficits. This was accompanied by increased activation of the right dorsolateral prefrontal cortex. No such differences in performance and brain activation were detected for working memory. This may indicate subtle early neuronal dysfunction on the hippocampal level and compensatory mechanisms that preserve memory performance.⁵⁴Regarding ApoE4, cognitively unimpaired young elderly with and without subjective memory impairment were tested on episodic memory and on tasks of speed and executive function. Medial temporal lobe volumetric measures were calculated from MRI images. In the subjective memory impairment group, ApoE4 carriers performed worse on the episodic memory and showed smaller left hippocampal volumes. In the individuals without memory complaints, the ApoE4 carriers performed better on episodic memory and had larger right hippocampal volumes (P=0.039). The interaction of group and ApoE genotype was significant for episodic memory and right and left hippocampal volumes. The negative effect of ApoE4 on episodic memory and hippocampal volume in the group suffering from subjective memory decline also supports the notion that this may be a prodromal condition of AD.⁵⁵ In conclusion, the mere subjective feeling of being cognitively altered compared with the individual's reference past can already be accompanied by subtle brain changes that if ongoing may herald increasing memory decline in the future.Impaired sense of smell or hyposmia is one of the earliest clinical features in neurodegenerative disorders like both AD or Parkinson's disease.⁵⁶ This has been known for decades and relates well to the finding that, for example, plaque formation in AD starts in the entorhinal cortex, the region also responsible for processing of information on smell. A recent meta-analysis of 81 studies indicated that AD and PD patients are more impaired on odor identification and recognition tasks than on odor detection threshold tasks. AD patients were found to be more impaired on higher-order olfactory tasks involving specific cognitive processes.⁵⁷ Odor identification and recognition tests can be easily implemented in cognitive test batteries to detect already subclinical cases of AD. The impairment of smell recognition is of clinical importance, as patients often report malodorous sensations and changes in, eg, the taste of foods leading to behavioral alterations. Consequences may range from increasing malnutriton to the development of delusions of poisoning that may trigger aggressive behavior. The deterioration of the neural network in the entorhinal cortex leads to an impairment in the ability to store and retrieve different representations of smell, with the decaying network yielding increasingly “default values” that have the tendency to be of rather unpleasant character. This feature of the neural network of smell memory reflects the evolutionary pressure towards the secure recognition of “bad” smells pointing to poisonous or rotten food that is pivotal for the survival of the organism.The incidence of unprovoked seizures is clearly higher in sporadic AD than in reference populations with implications for memory functions. Nonconvulsive epileptiform activity could underlie at least some of the cognitive impairments observed in AD. Up to 1 in 5 patients with sporadic AD has at least 1 unprovoked clinically apparent seizure during their illness, and clinical guidelines recommend obligatory treatment for this condition. The risk of epileptic activity is greater in early-onset AD. Many mutations in the presenilin-1 gene are associated with epilepsy. Trisomy-21 patients with early-onset AD also have frank seizures in 84% of cases. Many patients with AD show fluctuations in cognitive functions such as transient episodes of amnestic wandering or disorientation. While an intermittent inability to retrieve memories cannot be easily explained by relatively protracted processes such as neuronal loss, plaque deposition, or tangle formation, an abnormal epileptic activity of neuronal networks can. Extensive work in this field was published by the group of Lennart Mucke. They see the possibility that high levels of β-amyloid induce epileptiform activity, which triggers compensatory inhibitory responses to counteract overexcitation that lead to changes in synaptic circuitry and an increase in inhibitory activity in, eg, the temporal cortex. This leads to changes in the texture of the neural networks involved and might explain disruptions of the networks as seen in the default mode network (DMN) in AD.^58-60 Transynaptic progression of toxicity effects of β-amyloid inducing epileptic activity from the entorhinal cortex to other brain regions may explain cognitive dysfunctions in AD.⁶¹AD affects the default mode network (DMN). This network comprises brain regions that are active and interconnected in a wakeful state when the mind is not focused on something specific. Anatomically it includes part of the medial temporal lobe, the medial prefrontal cortex, the posterior cingulate cortex, ventral precuneus, and the medial, lateral, and inferior parietal cortex. This networks develops during childhood and adolescence and reaches full integration in adults, characterized by coherent infraslow EEG oscillations smaller than 0.1 Hz. The DMN is linked to other low-frequency resting state networks in the brain and is anti-correlated with the ventral and dorsal attention network. Measurements of glucose metabolism with positron emission tomography (PET), of structural atrophy with MRI, and intrinsic and task-evoked brain activity with fMRI in AD all suggest an increasing disruption in the DMN.⁶²When AD patients undergo a FDG-PET the pattern of hypometabolism often mirrors the same regions that belong to the posterior parts of the DMN, namely the posterior cingulate cortex, the retrosplenial cortex, inferior parietal lobule, and the lateral temporal cortex.⁶³ Such hypometabolism correlates with the mental status while AD progresses.⁶⁴ Probands with a genetic risk for AD of being homozygous for ApoE4 develop this hypometabolism already quite early in the course of the disease.^62,65 Disruption in the DMN at the preclinical stages of the disease by accelerated cortical atrophy affects the medial temporal lobe and the posterior cingulum and the retrosplenial cortex.^63,66 Also, analysis of task-induced deactivation and analysis of intrinsic activity correlations show an impaired DMN consistent with metabolic and structural changes.^67-69 The DMN is coupled with hippocampus during memory retrieval but not during memory encoding, pointing to the special positioning of the hippocampus between short-term and long-term memory.⁷⁰ Encoding structures of the DMN are among the first to show accumulation of β-amyloid even before symptoms emerge and images of β-amyloid plaques taken at the earliest stages of AD show a distribution that is remarkably similar to the anatomy of the default network.⁷¹ Buckner et al speculate that AD pathology forms preferentially throughout the DMN and may be linked to DMN activity.⁶³ Their basic idea is that the DMN's continuous activity augments an activity-dependent or metabolism-dependent cascade that starts the β-amyloid cascade in these brain regions. Hence, memory would be affected preferentially by the disease because the DMN is mainly relying on cortical structures that are also vital to memory functions and “burns” them during activity. Interestingly, ApoE4 carriers have also been found to have a higher rate of activity in the DMN at rest compared with ApoE2 or ApoE3 carriers, and decreased connectivity.^72-74 A successful connection of this hypothesis with the β-amyloid hypothesis of AD may require any kind of upregulation of β-amyloid during neural activity. Indeed, there are some studies that may support such a link. Cirrito et al showed that β-amyloid increased following stimulation of the brain in mice expressing human amyloid precursor protein. They demonstrated that β-amyloid in the brain interstitial fluid was dynamically and directly influenced by synaptic activity on a timescale of minutes to hours.⁷⁵ This observation suggests that synaptic activity can increase the presence of extracellular β-amyloid. A further supporting observations come from a new PET method of mapping glycolysis based on measuring the ratio of oxygen to glucose consumption. Vlassenko et al calculated the spatial distribution of the regional glucose use apart from that entering oxidative phosphorylation.⁷⁶ The so-called “aerobic glycolysis,” the process by which glucose is metabolized into cellular energy, might be more closely associated with neuronal or synaptic activity than the mere glucose utilization. In humans, aerobic glycolysis represents 35% of the glucose turnover in the brain of a newborn and 19% of the glucose used in the brain of an alert adult.⁷⁷ Certain association areas in the human brain retain elevated levels of aerobic glycolysis in adulthood related to cognitive functions such as the dorsolateral prefrontal cortex, which is associated with working memory, and the ventromedial prefrontal cortex, the dorsomedial prefrontal cortex, the posterior cingulate cortex, the inferior parietal lobe, the lateral temporal cortex, and the hippocampus.^62,76-79 In normal young adults aerobic glycolysis correlated positively and spatially with β-amyloid deposition observed in individuals with Alzheimer's dementia and cognitively normal participants with already elevated β-amyloid levels, suggesting a possible link between regional aerobic glycolysis in young adulthood and later development of AD pathology. The map of resting-state glycolysis correlated remarkably well with the distribution of amyloid plaques.⁷⁶ On the other side DMN activity and coherence is diminished during deep sleep. Here only partial network involvement was observed, with apparent decoupling of frontal areas from the DMN⁸⁰ An important study by Kang et al used in vivo micro-dialysis in mice and found that the amount of pamyloid in the interstitial brain fluid correlated positively with wakefulness. The amount of interstitial β-amyloid also significantly increased during acute sleep deprivation. Furthermore, chronic sleep restriction significantlyincreased, and a dual orexin receptor antagonist decreased β-amyloid plaque formation in human amyloid precursor protein transgenic mice.⁸¹ Interestingly, sleep deprivation, which is known to impair memory storage and retrieval, reduces default mode network connectivity and anti-correlation with the default attention networks during rest and task performance.⁸² Regarding AD subtypes, Lehmann et al report that the posterior DMN and precuneus network are commonly affected in all AD variants, whereas syndrome-specific neurodegenerative patterns are driven by the involvement of specific networks outside the DMN and characterize differentially early-onset AD (anterior salience network), logopenic variant of AD (language network), and posterior cortical atrophy (visual network).⁸³Sleep and the functional connectome are overlapping research areas. Neuroimaging studies of sleep based on EEG-PET and EEG-fMRI are revealing the brain networks that support sleep. Such infraslow oscillations may organize sleep-dependent neuroplastic processes including consolidation of episodic memory, for example. Picchioni et al found positive correlations between the power in the infraslow EEG band and MRI blood oxygen level-dependent (BOLD) response in subcortical regions and negative correlations in the cortex. Robust negative correlations were detected principally in paramedian heteromodal cortices whereas positive correlations were seen in cerebellum, thalamus, basal ganglia, lateral neocortices, and hippocampus.⁸⁴ Sleep has adaptive and recreating functions that uphold waking activity in humans and mammals in general. Our understanding of DMN activity and its regulation during sleep may be also important for our general understanding of phenomena like memory, arousal, and consciousness.^80,84-86 Clinically sleep-wake disturbances such as increased inadvertent daytime napping and insomnia at night affect 25% to 40% of patients with mild-to-moderate AD.⁸⁷ Even in mild cognitive impairment there are already abnormalities in sleep architecture and electroencephalography measures. Sleep changes in patients with amnestic mild cognitive impairment may contribute to memory deficits by interfering with sleep-dependent memory consolidation.⁸⁸In a small study, Ju investigated sleep in 145 cognitively healthy probands older than 45 years. Amyloid deposition, as assessed by β-amyloid levels, was present in 32 participants. This group had worse sleep quality, as measured by sleep efficiency compared with those without amyloid deposition, after correction for age, sex, and ApoE4 allele carrier status, while the quantity of sleep did not differ between groups. Frequent napping, 3 or more days per week, was associated with amyloid deposition. The authors concluded that indices for amyloid deposition in the preclinical stage of AD appears to be associated with worse sleep quality.⁸⁹Taken together the brain activity patterns may directly modulate the molecular cascades that are relevant to diseases. In the case of AD, increased resting-state activity may accelerate the formation of amyloid pathology. This opens up perspectives for new interventions that may take the form of a therapy that attempts to modify glycolysis or other aspects of brain metabolism or to boost prophylaxis by the promotion of healthy sleep behavior or working behavior.For the clinician the easily applicable neuropsychological test batteries augmented by a test for olfactory recognition continue to be at the heart of the diagnostic process for dementias, although new methods like CSF analyses or MRI volumetry are increasingly available and validated for clinical use. The use of amyloid-tracer PET or fMRI to investigate, for example, the DMN are still more preclinical than clinical in character. Despite enormous progress in our knowledge of some pathophysiologic mechanisms in the last decade, we are still far from understanding AD and also probably from finding a cure. The available medications or medications may, however, help us to manage some symptoms for our patients, and gain some time for them. To date the recent scientific advancements primarily offer earlier diagnosis. With new diagnostic criteria properly applied, we will likely be able to diagnose Alzheimer's disease many years before any relevant impairment is experienced by the patient. In light of the fact that most of us would suffer from AD, were we only to get old enough, one question arises: when the gods put the diagnosis before the therapy, how much “before” did they actually mean? As a clinician, I would appreciate any measure of “momentum” that would help me to translate biomarker findings, eg, a positive amyloid scan in PET, to the patient. Perhaps CSF tau concentrations could be helpful, but at the moment only time will tell us the individual course of the disease. 1. Wimo A., Jonsson L., Winblad B. An estimate of the worldwide prevalence and direct costs of dementia in 2003. Dement Geriatr Cogn Dis. 2006;21:175–181. [PubMed] [Google Scholar]2. Hebert LE., Scherr PA., Beckett LA., et al Age-specific incidence of Alzheimer's disease in a community population. JAMA. 1995;273:1354–1359. [PubMed] [Google Scholar]3. Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie. 1907;64:146–148. [Google Scholar]4. Blennow K., de Leon MJ., Zetterberg H. Alzheimer's disease. Lancet. 2006;368:387–403. [PubMed] [Google Scholar]5. Gerrish A., Russo G., Richards A., et al The role of variation at A beta PP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease. J Alzheimers Dis. 2012;28:377–387. [PMC free article] [PubMed] [Google Scholar]6. Williams GC. Pleiotropy, natural selection, and the evolution of senescence. Evolution. 1957;11:398–411. [Google Scholar]