based studies, the percentage of mixed dementia cases is considerably higher.21 The likelihood of having mixed dementia increases with age and is highest in people age 85 or older.26-27 Symptoms Symptoms vary depending on the combination of brain changes present. *This table describes the most common causes of dementia. Emerging causes such as limbic-predominant age-related TDP-43 encephalopathy (LATE) are under active investigation. 8 Alzheimer’s Association. 2022 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2022;18. 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 taken up by another neuron. The brain contains about 100 trillion synapses. They allow signals to travel rapidly through the brain. These signals create 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. These changes are followed by the damage and destruction of neurons, called neurodegeneration, which along with tau and beta-amyloid accumulation are key features of Alzheimer’s disease. Plaques and smaller accumulations of beta-amyloid called oligomers may damage neurons 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.19-20 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. Great progress has been made in measuring these brain changes. For example, we can now identify abnormal levels of beta-amyloid and tau in cerebrospinal fluid (the fluid surrounding the brain), and a scanning technique known as positron emission tomography (PET) can produce images showing where beta-amyloid and tau have accumulated. Beta-amyloid and tau accumulation are 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. Biomarkers are commonly used in health care. 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. Biomarkers are not equivalent to a diagnosis but might be used to help determine underlying brain changes that are causing dementia. Some individuals have a rare genetic mutation that causes Alzheimer’s disease. This is called dominantly inherited Alzheimer’s disease (DIAD). A study7 of people with DIAD found that levels of beta-amyloid in the brain were significantly increased starting 22 years before symptoms were expected to develop (individuals with 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. More research is ongoing to understand how these biomarkers operate in individuals without the genetic mutations of DIAD. Mixed Dementia Many people with dementia have brain changes associated with more than one cause of dementia.21,28-33 This is called mixed dementia. Some studies21-22 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 disease 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.21