Dementia is an acquired clinical condition characterized by persistent and often progressive impairment in multiple intellectual domains, such as memory and the ability to think, reason, and use language. Dementia is most common in the elderly. The prevalence of dementia increases with age, from about 1 percent of individuals aged 65 years to approximately 30-50 percent of individuals 85 years suffering from some form of dementia. Because in the United States the number of people over the age of 65 years is expected to double by the year 2030 to approximately 70 million, the diagnosis and treatment of dementia represents a public health concern of vital and increasing importance. There are multiple causes (etiologies) of dementia, but Alzheimer’s disease (AD), vascular disease (VaD), and diffuse Lewy body dementia (DLBD) are responsible for the majority of dementia cases.
Alzheimer’s Disease
In 1906, a German neuropathologist named Alois Alzheimer described a case of a 51-year-old woman with cognitive impairment, delusions, and confusion. After her death, he conducted an autopsy and reported dense material outside the nerve cells and twisted bands of fibers inside the cells. This condition was named “Alzheimer’s disease” and is the most common type of dementia, accounting for about 50 percent of all cases. Although estimates vary across studies, AD afflicts about 3 percent of persons between the ages of 65 and 74 years, 20 percent of persons between 75 and 84 years, and up to 47 percent of individuals over the age of 85 years. The incidence of AD increases sharply with age, from approximately 1.2 percent at age 65 years to about 6.4 percent at age 90 years. Approximately 4.6 million individuals suffer from AD, but projections indicate that by the year 2050 this number could more than triple to 16 million. The estimated annual cost in the United States of AD is between $80 and 100 billion in lost productivity and medical care. The average cost of caring for a patient with AD from the time of their diagnosis to the time of their death (an average of 8 years) is approximately $174,000, making AD one of the most costly illnesses.
The neuropathology of AD begins in the entorhinal cortex in the hippocampus, which is a structure in the brain important for normal memory function. Tiny, insoluble lumps of protein called amyloid begin to accumulate around nerve cells in the brain (neurons), forming insoluble plaques. Although these amyloid plaques are a hallmark of AD, it is not known whether they are a cause or consequence of the disease. A second type of neuropathology in AD is neurofibrillary tangles, which are abnormal twisted fibers that develop inside nerve cell bodies in brains with AD. These tangles are the remains of microtubules, which are a major support structure in healthy neurons. The breakdown of microtubules into neurofibrillary tangles may impair the ability of neurons to communicate with each other and result in cell death. Plaques and tangles develop first in the hippocampus, which coincides with memory impairment, but spread to other areas of the brain as more widespread cognitive impairment (e.g., agnosia, aphasia, impaired judgment and reasoning) occurs.
The hallmark symptom of AD is amnesia, which first manifests as the loss of memory for recent events and newly learned information, but eventually progresses to the loss of remote events and well-learned information. Other cognitive symptoms include agnosia (the inability to recognize familiar words and people), aphasia (difficulties in naming familiar objects), and impaired judgment and reasoning. Ultimately these symptoms progress to a stage that causes problems in common activities of daily living, such as forgetting the route to familiar locations and becoming unable to perform tasks that were once easy (e.g., balancing a checkbook, preparing meals). At later stages of the disease, changes in personality may occur, with afflicted individuals exhibiting high levels of restlessness, becoming prone to wandering and displaying unpredictable anger.
Several genes have been implicated in the development of AD. Familial AD occurs in young individuals, often before the age of 60 years, and is associated with genetic mutations on chromosomes 1, 14, and 21. This type of AD is quite rare, accounting for fewer than 5 percent of all diagnosed cases of AD. Another gene located on chromosome 19, that for apolipoprotein E (APOE), has been linked to the occurrence of AD. In particular, having the E4 allele of this gene is associated with increased risk for AD; however, only 40 percent of AD cases have the E4 allele, indicating that other factors play a role in development of this disease.
Vascular Dementia
Vascular dementia (VaD) refers to cognitive impairment that results from problems in the circulation of blood to the brain (cerebrovascular disease). Alone, VaD accounts for approximately 10-15 percent of all dementia cases, and for about another 20 percent in combination with AD. Since criteria for its diagnosis were established in 1993, there has been disagreement regarding how best to diagnose VaD. Lack of a consensus for diagnosing VaD has made estimating its prevalence problematic, but reasonable estimates place the prevalence rate at 0.3 percent at age 65 years, with an increase to 5.2 percent by age 90 years in Western countries. The prevalence of VaD is much higher in some Asian countries.
Vascular dementia can result from a number of causes. Most commonly, it results from the blockage of small blood vessels, or arteries, within the brain, causing death in the cortex, the area of the brain involved in higher order cognitive abilities, such as learning, memory, and language use. This is called a stroke. Sometimes these strokes affect a very small area of the cortex and may go unnoticed for years. After a number of such “ministrokes” have occurred, damage to the brain accumulates and afflicted persons begin to display the behavioral symptoms of dementia. Another common cause of VaD is Binswanger’s disease, which affects white matter deep within the brain. Individuals with Binswanger’s disease display slowness, impairments in gait, and fluctuations in emotion.
The presentation of symptoms in VaD differs from that of AD. Whereas AD is characterized as a slow, progressive disease with insidious onset, VaD commonly manifests as stepwise deterioration spanning a period of several years. Comparisons of patients with AD and VaD show that the latter group typically exhibits less severe long-term memory impairment. Individual diagnosed with VaD do show more severe impairment on cognitive tests that measure executive function. Tests of executive function measure the ability to develop strategies (e.g., completing a visual maze puzzle) and to coordinate complex behaviors. Individuals with VaD also present with focal neurological symptoms, such gait abnormalities, weakness of an extremity, and impaired reflexes.
Diffuse Lewy Body Dementia
Diffuse Lewy body dementia (DLBD) is perhaps the second most common form of degenerative dementia, accounting for approximately 15 percent of all dementia cases in people over the age of 65 years. Lewy bodies are tiny spherical structures that develop in nerve cells and may contribute to premature neuronal death. Because the neuropathology and symptomology of DLBD are associated with AD and Parkinsons disease, scientists do not yet know whether DLBD is a variant of these two illnesses or is a distinct illness. A hallmark symptom of DLBD is fluctuating cognition, such that on some days individuals exhibit significant impairments in thinking and memory and appear unimpaired on other days. Other core features of DLBD include highly detailed and recurrent visual hallucinations and symptoms consistent with Parkinson’s disease, such as falls, slowness, and tremors.
Secondary Problems in Dementia
There are a number of noncognitive behavioral disturbances in dementia. The most common of these disturbances (and their approximate prevalence in patients with dementia) include agitation (80 percent), incontinence (50 percent), wandering (25 percent), aggression (20 percent), and sexual disinhibition (10 percent). Estimates of the frequency of these noncognitive behavioral disturbances are highly variable because they are very difficult to measure and quantify. Moreover, the frequency and severity of behavioral disturbances increase as the severity of dementia progresses. These disturbances are particularly important because they place increased burden and stress on caregivers and represent symptoms that can be effectively targeted for behavioral and pharmacologic therapeutic interventions.
Dementia Treatment
There is no cure for AD or the other dementias described here, but there are a number of therapies that can slow disease progression and reduced symptom severity. The neuropathology of AD leads to a loss of the neurotransmitter acetylcholine from the brain. Most of the pharmacologic therapies for AD involve a class of drugs known as cholinesterase inhibitors, which inhibit the breakdown of acetylcholine in the brain. Approved cholinesterase inhibitors include tacrine, donepezil, and rivastigmine. Clinical trials have shown that these drugs slow the progression of symptoms and can even improve activities of daily living and common behavioral disturbances. However, as the disease progresses and the number of viable neurons in the brain decreases, these therapies become ineffective. There are no approved pharmacologic treatments for VaD or DLBD.
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