59: The Aging Brain

• The Structure and Function of the Brain Change with Age

• Cognitive Decline Is Dramatic in a Small Percentage of the Elderly

• Alzheimer Disease Is the Most Common Senile Dementia

• The Brain in Alzheimer Disease Is Altered by Atrophy, Amyloid Plaques, and Neurofibrillary Tangles

  • Amyloid Plaques Contain Toxic Peptides That Contribute to Alzheimer Pathology

  • Neurofibrillary Tangles Contain Microtubule-Associated Proteins

  • Risk Factors for Alzheimer Disease Have Been Identified

• Alzheimer Disease Can Be Diagnosed Well but Available Treatments Are Poor

• Overall View

The average life span in the United States in 1900 was about 50 years. Today it is approximately 76 years for men and 81 for women (Figure 59–1), and is higher still in 30 other countries. These increases result largely from a reduction in infant mortality, the development of vaccines and antibiotics, better nutrition, improved public health measures, and advances in the treatment and prevention of heart disease and stroke. Because of increased life expectancy, along with the large cohort of "baby boomers" born after World War II, the elderly are the most rapidly growing segment of the U.S. population.

Increased longevity is a double-edged sword: Age-related cognitive alterations are increasingly prevalent. Their extent varies widely among individuals. For many, the alterations are mild and have relatively little impact on the quality of life—the momentary lapses we jokingly call "senior moments." Other cognitive impairments, although not debilitating, are troubling enough to hinder the ability of the elderly to manage their lives independently. At the far extreme are the severe dementias, which rob the elderly of memory and reasoning. Of these, Alzheimer disease is the most prevalent.

As the population ages, research on age-related changes in the brain has become a more prominent area of focus for neuroscientists, neurologists, and psychologists. The main aim of research on aging has been to find treatments for Alzheimer disease and other dementias, but it is also important to understand the normal process of cognitive decline with age. After all, age is the greatest susceptibility factor for a wide variety of neurodegenerative disorders. Understanding what happens to our brains as we age may not only improve the quality of life for the general population but may also provide clues that will eventually help us vanquish seemingly unrelated pathological changes.

With this in mind, we begin this chapter with a consideration of how the normal brain ages. We then proceed to consider the broad range of pathological changes in cognition, and finally focus on Alzheimer disease, the most common cause of severe memory loss and intellectual deterioration in the elderly.

As we grow old our bodies change—our hair thins, our skin wrinkles, and our joints creak. It is no surprise then that our brain also changes. Indeed, many of the behavioral alterations that occur with age affect almost everyone, providing evidence of underlying alterations in the nervous system.

For example, motor skills decline in the elderly. The posture of an old person is less erect than that of a young adult. Gait is slower and stride length is shorter. Postural reflexes are often sluggish, making individuals more susceptible to loss of balance. Although muscles weaken and bones become more brittle, these motor abnormalities result in large part from subtle processes that involve the peripheral and central nervous systems. Sleep patterns also change with age: Older people sleep less and wake more frequently. Mental functions ascribed to the forebrain, such as memory and problem-solving abilities, also decline.

Age-related declines in mental abilities are highly variable. First, there are considerable differences in the rate and severity of cognitive decline among individuals (Figure 59–2A). Although most people experience a gradual decline in mental agility, for some the decline is rapid, whereas others retain their cognitive powers throughout life. Giuseppe Verdi, Eleanor Roosevelt, and Pablo Picasso are well-known members of this latter, unusual category. Titian continued to paint masterpieces in his late 80s, and Sophocles is said to have written Oedipus at Colonus in his 92nd year. The rarity of completely preserved function suggests that its retention may reflect special properties in the life experiences or genes of these people. Accordingly, there has been great interest in studying rare individuals who retain nearly intact cognition into their tenth or even eleventh decade. These so-called "centenarians" may provide insight into environmental or genetic factors that protect against normal age-related cognitive decline or that protect against the more devastating pathological descent into dementia. For the moment, however, no such factors have been found.

Second, when data from many individuals are averaged, it is clear that some cognitive capacities decline significantly with age while others are largely spared (Figure 59–2B). For example, working and long-term memories, visuospatial abilities (measured by arranging blocks into a design or drawing a three-dimensional figure), and verbal fluency (as measured by rapid naming of objects or naming as many words as possible that start with a specific letter of the alphabet) usually decline with old age. On the other hand, measures of vocabulary, information, and comprehension often show minimal decline in normal individuals well into the 80s.

Age-related alterations in memory, motor activity, mood, sleep pattern, appetite, and neuroendocrine function result from alterations in the structure and function of the brain. Even the healthiest 80-year-old brain does not look like its 20-year-old self. Elderly people exhibit mild shrinkage in the volume of the brain and a loss in brain weight, as well as enlargement of the ventricles (Figure 59–3A). The decreases in brain weight average 0.2% per year from college age onward, and about 0.5% per year in the 70s. One might imagine that these changes result from death of neurons, and indeed some neurons are lost with age. For example, 25% or more of the motor neurons that innervate skeletal muscles die in generally healthy elderly individuals. This loss contributes to sarcopenia, the muscle weakness and atrophy that can be a serious clinical problem in the elderly.

In general, however, there is minimal neuronal loss in most parts of the brain, so brain shrinkage must arise from other factors. Indeed, analysis of the brain of humans and experimental animals reveals structural alterations in both neurons and glia. Myelin is fragmented and lost, leading to a decline in the integrity of white matter. At the same time, the density of the dendritic arbors of cortical and other neurons decreases, resulting in shrinkage of neuropil. In addition, levels of enzymes that synthesize some neurotransmitters, such as dopamine, norepinephrine, and acetylcholine, decrease with age, presumably resulting in functional defects in synapses that use these transmitters. More-over, synapse structure is clearly aberrant, at least at the neuromuscular junction (Figure 59–4), raising the possibility that structural changes may also lead to functional deficits at central synapses. Finally, the number of synapses in the neocortex and many other regions of the brain declines (Figure 59–5).

These cellular changes lead to alterations in the integrity of the neural circuits that mediate our mental activities. Loss of synapses along with impairment in function of remaining synapses are thought to be important contributors to age-related cognitive decline. Changes in white matter are widespread but are especially notable in the prefrontal and temporal cortex. They may underlie alterations in executive functions and the ability to focus attention and to encode and store memory, functions that are localized in frontal-striatal systems and the temporal lobes. The loss of white matter may also help explain the recent finding that the elderly brain is less able to support synchronization of activity in widely separated areas that normally work together to carry out complex mental activities. Disruption of these large-scale networks could be an important cause of cognitive decline.

It was long thought that aging resulted from progressive deterioration of cells and tissues due to accumulated genetic damage or toxic waste products. In support of this idea, mitotic cells removed from animals and placed in a tissue culture dish divide only for a limited number of times before they age and die. This view of "preordained" aging has changed radically over the past decade, primarily as a result of studies in model organisms in which mutations that significantly extend life span have been found (Figure 59–6).

These dramatic discoveries establish that the aging process is under active genetic control. One such regulatory pathway that has been characterized includes insulin and insulin-like growth factors, their receptors, and the signaling programs they activate. Disruption of these genes leads to increased resistance of cells to lethal oxidative damage. Presumably, the normal forms of these genes benefit the organism during the reproductive period and have therefore been selected by evolution. Their deleterious effects on longevity, once the animals are past reproductive age, may be an unfortunate side effect about which evolution cares little.

These findings have two major implications for understanding how aging affects the nervous system. First, the biochemical mechanisms that lead to, or protect from, the ravages of age are likely to underlie the changes in neurons that lead to cognitive decline. Research to explore this link between cellular change and cognitive functioning is now underway in model organisms. Second, and perhaps more excitingly, research on model organisms is leading to strategies for extending life span or health span (the period during which one remains generally healthy) by pharmacological intervention in the pathways uncovered by genetic studies.

For example, the best-validated environmental intervention for extending life span in organisms ranging from yeast to worms to primates is caloric restriction, a strategy unlikely to be broadly acceptable to people. However, it appears that caloric restriction acts through genes in the insulin pathway mentioned above, and may involve a set of enzymes called sirtuins. The sirtuins are activated by a compound called resveratrol, originally isolated from red wine, a longevity-promoting beverage. Resveratrol, in turn, retards some aspects of aging, including cognitive measures, when administered to mice. While it is unlikely that resveratrol will serve as a fountain of youth in humans, it nevertheless exemplifies the new chemistries that are currently under consideration. These chemical strategies use model organisms to explore not only the positive factors that lead to aging but also the inhibitory constraints that prevent model organisms and presumably humans from achieving their full life span in a reasonably healthy state.

In most people age-related cognitive changes do not seriously compromise the quality of life. In a subset of elderly people, however, cognitive decline reaches a level that can be viewed as pathological. At the lesser end of the pathological range is a constellation of changes known as mild cognitive impairment, or MCI. This syndrome is characterized by memory impairments that may be alarming to the individual but are not serious enough to affect daily life; general cognition remains intact.

Owing to its subtlety, MCI is difficult to diagnose, but longitudinal studies have convinced neurologists that it is a real condition. Approximately 15% of individuals diagnosed with MCI progress to Alzheimer disease within a few years of diagnosis, and an additional 50% of them will eventually succumb to Alzheimer disease. Conversely, some elderly people with MCI remain at a stable plateau for decades (Figure 59–7). There is currently intense interest in learning how to distinguish individuals who will progress to more severe difficulties from those who will age relatively normally.

More troubling are the age-related or senile dementias. Senile dementia is a clinical syndrome in the elderly that involves progressive impairment of memory as well as cognitive faculties such as language, problem solving, judgment, calculation, or attention. Dementia syndromes are associated with a variety of diseases. The most common, Alzheimer disease, is discussed in detail below. The second most common cause of dementia in the elderly is cerebrovascular disease, particularly strokes that lead to focal ischemia and consequent infarction in the brain.

Large lesions in the cortex are often associated with language disturbances (aphasia), hemipareses, or neglect syndromes, depending on which portions of the brain are compromised. Small infarctions in white matter or deeper structures of the brain, termed lacunes, also occur as a consequence of hypertension. In small numbers they may be asymptomatic, or they may contribute to the normal cognitive decline of aging or underlie certain cases of mild cognitive impairment that do not progress to Alzheimer disease. As vascular lesions increase in number and size, however, their impact becomes heightened; eventually they can lead to dementia.

Numerous other conditions that can lead to dementia include Parkinson disease, alcoholism, drug intoxications, infections such as AIDS and syphilis, brain tumors, vitamin deficiencies (notably lack of vitamin B₁₂), thyroid disease, and a variety of other metabolic disorders. In some patients schizophrenia or depression may mimic a dementia syndrome. Emil Kraepelin chose the term "dementia praecox" to highlight the cognitive deficit in a disease that affects young people, a disease we now call schizophrenia. Although the clinical features of these dementias may resemble those of Alzheimer disease or cerebrovascular disease in some respects, the symptoms and tempo of dementia may vary, depending on the nature and site of the neurological abnormality. Because some dementias can be treated, it is important for the physician to probe the differential diagnoses of dementia with clinical history, examinations, and laboratory studies.

In 1901 Alois Alzheimer examined a middle-aged woman who had developed memory deficits and progressive loss of cognitive abilities. One of the first noticeable symptoms of this woman's illness was unprovoked suspicion of her husband's behavior. Her memory became increasingly impaired. She could no longer orient herself, even in her own home, and she hid objects in her apartment. At times she believed that people intended to murder her.

She was institutionalized in a psychiatric hospital and died less than five years after the onset of illness. Alzheimer performed an autopsy that disclosed specific alterations in the cerebral cortex, described below. The constellation of behavioral symptoms and physical alterations was subsequently given the name Alzheimer disease (AD).

The first case of the disease caught Alzheimer's attention because it occurred in middle age, but in general the disease afflicts the elderly. Most patients with AD exhibit the first clinical signs during their seventh decade. Early onset cases are often familial, and mutations have been discovered in many of these patients, as we shall discuss below. Late-onset cases are sporadic, and their cause remains unknown.

In both the sporadic and familial forms of AD there is a remarkably selective defect in declarative memory. At first, language, strength, reflexes, and sensory abilities and motor skills are nearly normal. Gradually, however, memory is lost along with cognitive abilities such as problem solving, language, calculation, and visuospatial perception. Unsurprisingly, these cognitive losses lead to other behavioral alterations, and some patients develop psychotic symptoms, such as hallucinations and delusions. In all patients mental functions and activities of daily living progressively become impaired; in the late stages these individuals are mute, incontinent, and bedridden.

Alzheimer disease affects approximately one-eighth of people older than 65 years. Five million people in the United States now suffer from dementia. Because the number of elderly is increasing rapidly, the population at risk for AD is the fastest growing segment of our society (Figure 59–8). During the next 25 years the number of people with AD in the United States will triple, as will the cost of caring for patients no longer able to care for themselves. Thus, AD is one of society's major public health problems.

Alzheimer disease is characterized by three dramatic abnormalities of the brain, all of which Alzheimer described. First, the brain is atrophied, with narrowed gyri, widened sulci, reduced brain weight, and enlarged ventricles (Figure 59–9). These changes, seen in mild form in cognitively intact elderly people who die from other causes, are severe in advanced AD. Moreover, neuron death is widespread in AD, whereas in normal aged brains it is minimal. Thus AD is a neurodegenerative disease.

Second, sections of brains of AD patients obtained at autopsy reveal extracellular plaques of dense material called amyloid, large aggregates of fibrillar peptides arranged as sheets (Figure 59–10). Amyloid can be detected when stained with dyes such as Congo red, and is refractive when viewed in polarized light or when stained with thioflavin and viewed with fluorescence optics. The extracellular deposits of amyloid are surrounded by swollen axons and dendrites. These neuronal processes in turn are associated with processes of astrocytes and microglia (inflammatory cells). Amyloid plaques also occur in the walls of cerebral blood vessels in the Alzheimer brain.

Third, neurons that are affected but still alive have cytoskeletal abnormalities, the most dramatic of which is the accumulation of neurofibrillary tangles (Figure 59–10). These tangles are filamentous inclusions in the cell bodies and proximal dendrites that contain paired helical filaments and 15 nm straight filaments. Other cytoskeletal abnormalities occur in axons and terminals (dystrophic neurites) and dendrites (neuropil threads). Both types of lesions include intracellular paired helical filaments, suggesting that these fibrillar inclusions result from common mechanisms.

In AD these alterations do not occur uniformly throughout the brain, but rather affect specific regions. The entorhinal area, the hippocampus, the neocortex, and the nucleus basalis are especially vulnerable (Figure 59–11). Alterations in the entorhinal cortex and hippocampus are likely the structural underpinnings of problems with declarative memory that are the first symptoms of AD. These alterations contrast with those in frontostriatal circuits that correlate with age-related cognitive decline in normal subjects. Abnormalities in the basal forebrain cholinergic systems may contribute to cognitive difficulties and attention deficits that appear later in the progression of the disease. These anatomical differences, along with widespread neuronal death, argue against the idea, once prevalent, that AD is an extreme form of the normal aging processes.

Amyloid Plaques Contain Toxic Peptides That Contribute to Alzheimer Pathology

To characterize amyloid plaques, George Glenner, Konrad Beyreuther, and their colleagues isolated the plaques by centrifugation, based on their low solubility, and determined some of their components. The principal constituent turned out to be a group of small peptides that together were named Aβ.

Two main forms of the peptide were found. The predominant peptide is 40 amino acids in length and the minor one 42 amino acids (the original 40 residues plus two additional amino acids at the carboxy terminal end). Biochemical studies showed that the Aβ42 peptide nucleates more rapidly than Aβ40 into amyloid fibrils. In individuals with AD, amyloid deposition begins with Aβ42, while Aβ40 accumulates later. Moreover, when applied to neurons in culture, the Aβ42 peptide is more toxic than Aβ40. These results implicate Aβ42 as a key component of amyloid plaques.

In general, short peptides are formed by cleavage from a precursor protein, so researchers set out to isolate the protein from which Aβ was derived. The precursor was soon found and molecularly cloned, and named amyloid precursor protein or APP (Figure 59–12). APP is a large transmembrane glycoprotein that is present in the dendrites, cell bodies, and axons of many types of neurons as well as a variety of nonneuronal cells. Despite intensive study, the normal functions of APP in the brain remain poorly understood.

Once APP was isolated it became possible to ask how it is processed to form Aβ peptides. The answer has turned out to be complex. Three proteolytic activities—α-, β-, and γ-secretases—cut APP into pieces. The β- and γ-secretases cleave APP to generate a soluble extracellular fragment that is released into the interstitial fluid, the Aβ peptides that include part of the transmembrane segment, and a cytosolic or intracellular fragment (Figure 59–12). The cleavage by γ-secretase is unusual in that it occurs in a membrane-spanning portion of APP, a region long thought to be immune from hydrolysis because it is surrounded by lipids rather than water. In nonneuronal cells α-secretase cleaves APP in the middle of the Aβ sequence. This cleavage prevents the formation of Aβ peptides and helps explain why Aβ peptides are largely confined to the nervous system even though APP is present in neuronal and nonneuronal cells alike.

The enzymes that account for α-, β-, and γ-secretases have been isolated and characterized. α-Secretase is a member of a large family of extracellular proteases called ADAM (A Disintegrin and Metalloproteinase) that are responsible for degrading many components of the extracellular matrix. β-secretase, called β-site APP cleaving enzyme 1 or BACE1, is a transmembrane protein in central neurons and concentrated in synaptic areas. Brain cells derived from mutant mice lacking BACE1 do not produce Aβ peptides, proving that BACE1 is indeed the neuronal β-secretase. γ-Secretase, the most complicated of the three, and the most recently isolated, is actually a multiprotein complex that cleaves several different transmembrane proteins. As expected, given its peculiar ability to act within the membrane, γ-secretase itself includes membrane proteins. Two are called presenilin-1 and presenilin-2, reflecting their association with AD. Other components of the complex are nicastrin, Aph-1, and Pen-2, also transmembrane proteins.

Although the biochemical properties of Aβ and APP appeared interesting, the critical question remained: Are they causally related to the debilitating symptoms of AD? One might imagine that the disease is caused by Aβ accumulation, but Aβ might also form as a result of another pathological process or even be an innocuous correlate. Genetic evidence in humans and experimental animals has been critical in demonstrating that APP plays a central role in AD.

The first clue came from the observation that the APP gene lies on chromosome 21. Chromosome 21 is present in three copies (rather than the normal two) in people with Down syndrome. For this reason Down syndrome is also referred to as trisomy 21. Interestingly, it had long been known that most people with Down syndrome who live to the age of 40 develop AD. This association is consistent with the idea that excessive APP predisposes to AD.

More direct genetic evidence came from the analysis of patients with familial AD. Only a small number of cases of AD are familial, usually those in which onset occurs early, younger than age 60 years, and most of these are inherited as simple dominant mutations. As new methods of molecular cloning became available in the late 1980s, several groups began using them to identify the genes mutated in familial AD. Remarkably, the first three genes identified were those encoding APP, presenilin-1, and presenilin-2 (Figure 59–13). By now many different mutations have been found in all three genes, and the majority of them influence cleavage of APP, increasing the production of Aβ peptides or the proportion of the more toxic Aβ42 species.

Some APP mutations are amino acid substitutions flanking or within the Aβ region. Cells that express these mutant sequences secrete several-fold more Aβ peptide than cells expressing wild-type APP. Another APP mutation influences γ-secretase to selectively generate Aβ42 rather than Aβ40. Likewise, in most presenilin mutants the mutant γ-secretase has higher than normal activity or generates peptides with an increased ratio of Aβ42 to Aβ40. Thus mutants in the APP or presenilin genes do not lead to loss of the proteins but rather to increased production of Aβ42.

These human studies offer compelling evidence that cleavage of APP plays a key causative role in at least some cases of familial, early-onset AD, and point to a role for Aβ42. Because Aβ42-rich amyloid plaques are a cardinal feature of the far larger group of patients with sporadic, late-onset AD, it is likely that APP cleavage is also involved in generating symptoms in this larger group.

Finally, genetic studies of mice have strengthened the case that APP cleavage contributes to AD. Transgenic mice that express relatively high levels of wild-type or mutant APP exhibit structural, physiological, and behavioral abnormalities associated with AD. Transgenic expression of mutant APP forms identical to those found in familial AD leads to appearance of amyloid plaques in the hippocampus and cortex, swollen neurites in proximity to Aβ deposits, decreased density of synaptic terminals in the forebrain, decrements in synaptic transmission, and degeneration of neurons. Moreover, these transgenic mice are deficient in tasks assessing spatial and episodic-like memory. Alterations are more severe in transgenic mice that express altered forms of both APP and presenilin-1. These lines of mice are invaluable tools for addressing mechanistic issues about the pathogenesis of AD and for testing potential therapies. Moreover, AD-like alterations in transgenic mice appear in a year or less rather than over decades, as in humans.

Given the strong evidence that APP cleavage is involved in the pathogenesis of AD, the next question is how the accumulation of cleavage products contributes to the symptoms. There are three sets of cleavage products: the secreted extracellular region (ectodomain), the Aβ peptide, and the cytoplasmic fragment. Greatest attention has been paid to the Aβ peptides, which were the first to be discovered. One view holds that Aβ in plaques, especially Aβ42, poisons neurons in the vicinity, leading to synaptic dysfunction, degeneration of axon terminals, and eventually death of neurons.

An alternative explanation is that aggregation of soluble forms of Aβ into plaques is the body's incompletely successful attempt to sequester toxic protein fragments. The Aβ peptides can bind to synaptic proteins and affect trafficking of postsynaptic neurotransmitter receptors, including glutamate receptors. Regulated trafficking of these receptors may be essential for forms of synaptic plasticity such as long-term depression and potentiation. As a result, memory defects in AD could involve interference by Aβ in plasticity. In turn, interference in synaptic function could lead to withdrawal and loss of synapses.

Involvement of Aβ peptides in AD does not mean that the other two cleavage products of APP, the cytoplasmic and extracellular fragments (Figure 59–12), have no role in AD. The cytoplasmic fragment can form a complex with other proteins, including Fe65, translocate to the nucleus, and influence transcription in ways that could be deleterious. Although there is little evidence that this mechanism contributes to AD, it is well established that Notch, a critical regulator of neurogenesis (see Chapter 53), is activated by γ-secretase cleavage and that its cleaved cytoplasmic fragment is transported to the nucleus, where it acts as a transcription factor. Likewise, the secreted extracellular fragment of APP appears to have toxic effects on nearby neurons. Thus it is possible that APP is a potent instigator of AD because the fragments generated from it by proteolytic cleavage damage neurons in different ways.

Neurofibrillary Tangles Contain Microtubule-Associated Proteins

Most research on the molecular and cellular basis of AD has focused on amyloid plaques but the neurofibrillary tangles have also been implicated in disease progression (Figure 59–10). Molecular analysis revealed that these abnormal inclusions in cell bodies and proximal dendrites contain aggregates of hyperphosphorylated isoforms of tau, a microtubule-binding protein that is normally soluble (Figure 59–14). Tau plays a key role in intracellular transport, particularly in axons, by binding to and stabilizing microtubules. Impairments in axonal transport compromise synaptic stability, trophic support, and other interactions. Eventually, affected nerve cells die and the neurofibrillary tangles remain in the extracellular space as tombstones of the cells destroyed by disease.

Although tangles are a defining feature of AD, it remains unclear what role they, and the hyperphosphorylated tau of which they are made, play in the pathogenesis of the disease. Whereas mutations of APP and presenilin genes can lead to AD, no mutations of the tau gene have been found in familial AD. This difference leads some to view tangles as a consequence or correlate, but not a cause, of AD symptoms.

Other observations suggest a more causal relationship. First, filamentous deposits of hyperphosphorylated tau are seen in a variety of neurodegenerative disorders. Second, mutations in the tau gene have been found to underlie another form of inherited dementia, frontotemporal dementia with Parkinson disease type 17 (FTPD17), which shares some features with AD but lacks plaques. Third, symptoms of AD correlate better with the number and distribution of tangles than that of plaques seen in autopsy material. For example, tangles are usually first evident in neurons of the entorhinal cortex, the likely site of early memory disturbance, before plaques appear in this area.

For many years controversy has raged between those who believe that Aβ is the main causal agent of AD and those who believe that tau-rich tangles play a major role. These advocates have been called "Baptists" and "Taoists," respectively. It now seems most likely that both Aβ and tau are involved, and that pathology results from their combined effects. For example, transgenic mice that express both mutant APP and mutant tau develop more severe AD-like behavioral deficits than mice overexpressing either alone. Moreover, there appears to be interplay between plaques and tangles. Thus injection of Aβ42 into specific brain regions of transgenic mice that express a mutant tau protein increases the number of tangles in nearby neurons, and a manipulation that reduces the number and size of plaques leads to a decrease in levels of hyperphosphorylated tau. Thus, even if tangles are not sufficient to "cause" AD, they are likely to play a role in symptoms and disease progression.

Risk Factors for Alzheimer Disease Have Been Identified

A few individuals develop AD because they bear mutant alleles of the APP or presenilin genes, but in most cases no genetic or environmental causes are obvious. Can we, then, predict who will get AD?

The major risk factor is age. The disease is present in a vanishingly small fraction of people younger than age 60 (these being mostly familial cases), 1–3% of those between ages 60 and 70, 3–12% of those between ages 70 and 80, and 25–35% of those older than age 85. Thus one safe prediction is that elderly people are prime candidates for AD. However, this statistical association is of little therapeutic use because modern medicine can do nothing to slow the passage of time. There has therefore been intense interest in other factors that affect the incidence of AD.

The most significant genetic risk factor discovered to date in sporadic late-onset AD is an allele of the gene ApoE. The ApoE protein is the major carrier of cholesterol and other lipids in the blood. The gene is expressed as three alleles, ApoE2, ApoE3, and ApoE4, which differ from each other at only a few amino acids (Figure 59–15). People with the ApoE4 allele are at risk for AD. This allele is present in only a few percent of the general population but in 40–50% of those with AD. Put another way, carrying one ApoE4 allele increases by about fourfold one's chance of developing AD, compared to people who carry only ApoE2 or ApoE3 alleles. The mechanism by which ApoE4 predisposes one to AD is not known. Moreover, ApoE4 is a risk factor for several neurological diseases, including Parkinson disease and multiple sclerosis, so it may act in ways that do not involve APP or Aβ directly.

Diagnosing AD at its early stages is challenging as its initial symptoms are similar to the changes that are part of normal age-related cognitive decline. Until recently, even diagnosis of more advanced AD was difficult. In the 1970s diagnostic error rates were approximately 30%, as judged by the best objective measure: the detection of plaques and tangles at autopsy. Indeed, until biological and genetic research provided a deeper understanding of the pathology, it remained somewhat controversial whether AD was best viewed as a discrete disease or as one end of a continuum that passed from normal aging through mild cognitive impairment to dementia.

During the past few decades the situation has improved, largely because of three factors. First, protocols for physical, neurological, and neuropsychological examination have become more sophisticated and standardized. Second, increased knowledge of the structural changes revealed by magnetic resonance imaging (MRI) have helped in diagnosing AD at early stages. For example, it is now possible to predict, with approximately 80% accuracy, which patients with mild cognitive impairment will proceed to AD based on the cortical thinning and ventricular enlargement visible by MRI. These imaging and diagnostic methods also assist in distinguishing dementia syndromes from each other and relating structural to functional defects. For example, early in a disease called semantic dementia, patients have difficulty naming objects, and MRI reveals atrophy of the temporal poles. In contrast, in AD initial difficulties center on memory, and MRI reveals initial alterations in the medial temporal cortex and hippocampus.

Third, and perhaps most promising, amyloid plaques can now be visualized by positron emission tomography (PET) using new compounds that avidly bind amyloid. The first of these, called Pittsburgh compound B (PIB), binds with high affinity to Aβ, and its radioactive form, labeled with short-lived isotopes of carbon or fluorine, is readily detected by PET (Figure 59–16). The availability of safe molecular markers of AD permits early stages of the disease to be studied, before clinical symptoms are present. Of equal importance, the ability to distinguish older adults with and without amyloid plaques permits, for the first time, detailed analyses of normal aging uncomplicated by confounding early-stage AD.

Improved diagnosis of AD is, of course, most useful if treatments are available that can halt or slow its progression at an early stage. Here the news is not so good. At present there is no cure for Alzheimer disease. Present-day therapies focus on treating associated symptoms, such as depression, agitation, sleep disorders, hallucinations, and delusions. One of the principal targets is the cholinergic system in the basal forebrain, a region of the brain that is severely damaged in Alzheimer disease. Several strategies have been developed to influence this cholinergic system. Acetyl- cholinesterase inhibitors increase levels of acetyl-choline by inhibiting its breakdown, and represent one of the few drugs approved by the FDA for treatment of AD. Unfortunately, these drugs exert, at best, a modest effect on cognitive functions and the activities of daily living. Likewise, addition of precursors of acetylcholine (choline, lecithin, etc) or cholinergic agonists have not proven effective.

On the other hand, recent increases in our understanding of the biological basis of AD have highlighted several promising new therapeutic targets, all of which are being explored intensively. One approach is to develop drugs that reduce the activity of the β- and γ-secretases that cleave APP to generate Aβ peptides and the associated soluble extracellular and intracellular fragments. In fact, decreasing either β- or γ-secretase levels in transgenic mice that overexpress mutant APP decreases both Aβ deposition and age-associated memory abnormalities in these models. Accordingly, pharmaceutical companies are trying to develop drugs that will decrease levels of β- and γ-secretases in humans. An obstacle to this approach is that the secretases have other substrates in addition to APP, so decreasing their levels can have deleterious side effects. For example, one promising inhibitor of γ-secretase also decreased production of T and B cells of the immune system. As an alternative, it may be possible to find cleavage-inhibiting drugs that bind to critical sites on APP rather than to the secretases.

Other researchers are targeting the different proteins that have been implicated in AD: α-secretase, ApoE4, and tau. Because α-secretase cleaves in the middle of Aβ, it prevents Aβ accumulation. Researchers are exploring ways to increase α-secretase levels or activity. Conversely, ApoE4 predisposes to AD, whereas ApoE3 is innocuous or protective. Researchers are therefore seeking ways to convert the properties of ApoE4 into those of ApoE3, or to target the receptors through which it acts. Likewise, interventions that prevent hyperphosphorylation of tau could slow generation of neurofibrillary tangles, which appear to worsen neuronal health in a variety of neurodegenerative diseases.

Another approach is to decrease levels of Aβ through immunological means. Immunization with Aβ, which leads to generation of antibodies of Aβ, and passive transfer of antibodies to Aβ have been tested in transgenic mice models of Alzheimer disease. Both treatments reduce levels of Aβ and plaques. The mechanisms of enhanced Aβ clearance are not certain. Serum antibodies likely serve as a "sink" to extract low molecular weight Aβ peptides from the brain into the circulation, thus changing the equilibrium of Aβ in different compartments and promoting removal of Aβ from the brain. Alternatively, a small amount of Aβ antibody could reach the brain, bind Aβ, and recruit microglia to enter the affected regions and remove Aβ. Whatever the mechanism, Aβ immunotherapy in mice appears to reduce Aβ levels (Figure 59–17) and thus attenuate the otherwise severe impact of amyloid plaque on learning and cognition. These findings suggest that immunotherapeutic strategies may be successful in AD patients.

Aging affects the brain in many ways. Some changes are subtle, and the neurobiological basis of accompanying behavioral disturbances is unclear. Other problems are moderate, as in mild cognitive impairment (MCI). Some deficits are progressive and disabling as occurs in the various dementia syndromes. The most common dementia in the elderly is Alzheimer disease (AD), one of the most complex diseases in clinical medicine.

Alheimer disease is a common cause of morbidity and mortality in the elderly. In recent years there have been major advances in understanding this disease. Investigators have more accurately documented the relationship of MCI to early AD, identified genetic causes and risk factors, developed a variety of new diagnostic approaches that allow detection of amyloid plaques in living people, and clarified the ways in which the character, distributions, and stages of pathology are related to clinical signs. The mechanisms that lead to formation of plaques and tangles have begun to be delineated and studies of in vitro and in vivo models systems have led investigators to identification of potential new targets for treatment.

We are now on the threshold of implementing novel therapies based on an understanding of the neurobiology, neuropathology, biochemistry, and genetics of this illness. Moreover, a variety of tools, including biomarkers, brain imaging, and measures of Aβ flux between brain and plasma compartments, are now being developed to assess efficacies of treatments. Over the next few years it seems possible that these discoveries will lead to the rational design of new therapies that can be tested in animal models. With perseverance and luck, some of these approaches may be introduced into the clinic to benefit AD patients, for whom medicine has so far had very little to offer.