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.

Figure 59-1 Human life span is increasing. Changes in human longevity illustrate the rapid extension in life span that has occurred in the United States over the past 100 years. (Modified, with permission, from Strehler 1975; Arias 2004.)

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.

The Structure and Function of the Brain Change with Age

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.

Figure 59-2 Variation in age-related cognitive decline.

A. Cognitive scores of three people who were given a battery of cognitive tests annually for decades. Person A declined rapidly. Persons B and C showed similar cognitive performances into their 80s but then diverged. (Adapted, with permission, from Rubin et al. 1998.)

B. Average scores on several cognitive tests administered to a large number of people. Long-term declarative memory and working memory decline throughout life, and more so in advanced age. In contrast, knowledge of vocabulary is maintained. (Reproduced, with permission, from Park et al. 1996.)

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.

Figure 59-3 Magnetic resonance imaging reveals changes in brain structure during aging and at the onset of Alzheimer disease.

A. Images of normal 22- and 89-year-old brains reveal changes in the structure of the living brain. (Reproduced, with permission, from R. Buckner.)

B. Images of the same individual over a 4-year period illustrate the progressive shrinking of cortical structures and the beginnings of ventricular enlargement (red). Note that these structural changes are evident prior to the onset of behavioral symptoms. (Reproduced, with permission, from N. Fox.)

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. Moreover, 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).

Figure 59-4 Age-related changes in dendritic and synaptic structure. Reconstructions of cortical pyramidal neurons in aging rodents show the loss of dendritic spines with age. Neuromuscular synapses in rodents also exhibit age-related changes in structure. (Spine images reproduced, with permission, from J. Luebke; synapse images reproduced, with permission, from G. Valdez.)

Figure 59-5 Age-related changes in synaptic density. Cognitive capacity during early development is accompanied by a marked increase in synapse density in different regions of the cerebral cortex. Developmental landmarks through age 10 months are indicated. The density of cortical synapses declines with age. (Adapted, with permission, from P. Huttenlocher.)

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).

Figure 59-6 Life span can be increased through genetic mutation. Genetic mutations in specific receptors and signaling proteins markedly enhance life span in mutant strains of the worm, fly, and mouse, indicating that genetic regulatory mechanisms affect aging and life span. (Top reproduced, with permission, from Hekimi 2003; middle reproduced, with permission, from Yi 1998; bottom reproduced with permission, from Brown-Borg 1996.)

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.

Cognitive Decline Is Dramatic in a Small Percentage of the Elderly

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.

Figure 59-7 Cognitive performance can vary widely with age. Normal age-related memory loss does not impair cognitive abilities. Mild cognitive impairment is accompanied by a gradual and modest loss of cognitive abilities. Dementia is accompanied by a severe and accelerating loss of cognitive performance. The distinction between mild cognitive impairment and dementia becomes apparent only after the initial decline in cognitive performance. (From the National Institute on Aging: http://www.nia.nih.gov/alzheimers/publication/part-2-what-happens-brain-ad/changing-brain-ad)

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.

Alzheimer Disease Is the Most Common Senile Dementia

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.