As an unprecedented number of Americans approach old age, there is growing public concern about the loss of mental acuity that often is attributed to aging. Progress in health care has dramatically increased the likelihood of surviving into the period of life that, since ancient times, has been associated both with wisdom and mental decline. It has become relatively common to enter into the eighth and ninth decades of life in generally good physical health, increasing the probability that the body will outlive the mind.

More than four million Americans have dementia due to Alzheimer's disease or related disorders, and this number is projected to grow to 14 million in the next 50 years. Currently, there is no cure for Alzheimer's disease. All people are at risk for dementia, with the greatest risk factor being increased age. Even if one is fortunate enough to escape the ravages of Alzheimer's disease, brain function in old age can be affected by numerous other factors, from stroke to medication toxicity.

Given the major implications of cognitive competency for personal independence and quality of life, together with growing evidence that how one lives in earlier stages of life affects cognitive aging, greater attention to memory and the aging brain is likely to have significant public health benefits. It is now clear that significant cognitive decline is not an inevitable consequence of advanced age. Furthermore, Alzheimer's disease and related disorders, which in the past have been approached with a sense of therapeutic nihilism, are increasingly being seen as targets for active intervention.

Memory is a complex function, encompassing the encoding, storage, and retrieval of diverse types of information. There are multiple memory systems in the brain. For example, there are dissociable systems underlying such memory functions as new learning of verbal information, acquisition of a procedural skill, and retrieval of semantic knowledge from long-term storage. It has been known since the 1950s that epileptic patients who underwent bilateral temporal lobectomies developed severe memory impairments (amnesia).

The mesial temporal lobe memory system, including the hippocampus, parahippocampal gyrus, entorhinal cortex, and perirhinal cortex (Fig. 1), is essential for the acquisition of new information (anterograde memory). When this system is damaged, it becomes difficult or impossible to remember what happened yesterday or even a few hours or minutes ago. Remote memory for information acquired in the distant past remains relatively preserved, as does procedural memory (e.g., memory for skills, such as golfing or driving a car). The mesial temporal lobe region is vulnerable to damage from various age-related causes, including anoxia /hypoxia that may result from cardiac arrest, and head trauma from falls or motor vehicle accidents. This region also appears to be selectively affected in the early stages of Alzheimer's disease.

Figure 1.
Gross anatomy of the mesial temporal lobe memory system that is essential for anterograde memory. Left =in Alzheimer 's disease; right =in a healthy senior individuals

New Facts

The relationship between normal aging and cognitive decline depends on many factors, and there is considerable variability in the extent of cognitive change experienced by different individuals as they age. A key factor in understanding the relationship between brain function and aging is how normal aging is defined.

First, there is a correlation between good physical health in old age and preservation of cognitive abilities. Studies that look at only the healthiest elderly tend to find minimal cognitive decline even into the ninth decade. The greater the extent CME to which studies include patients with diabetes, hypertension, major surgeries, depression, and other common disorders of the elderly, the greater the measured change in cognition with increased age.

Second, age does not affect all domains of cognition equally. For some functions, such as speed of visual-motor processing, slight decline often can be detected as people enter their 40s and 50s. However, for most cognitive abilities, no measurable decline is evident until age 65 or older. For example, the average expected number of words recalled from a 15-word list after a 30-minute delay is approximately 10 for people aged 55-65, nine for those aged 66- 70, and eight for those up to age 85. These changes, while noticeable, are not disabling. Furthermore, some aspects of cognition, such as one's general fund of information, can actually continue to improve throughout one's lifetime.

Finally, in addition to maintaining good physical health, other factors known to facilitate preservation of cognitive abilities in aging include maintaining a cognitively challenging lifestyle, regular physical exercise, and generally positive emotions and relationships, as well as limiting exposure to chronic stress. As far as their influence on cognitive abilities in old age is concerned, these factors appear to be operative throughout the lifespan. Genetic factors also affect the chances of normal aging, leading to a lower or higher risk of developing Alzheimer's disease and other less common demential syndromes.

Cognitive decline (dementia) is defined as an acquired impairment of memory and other cognitive abilities, which is sufficient to interfere with normal daily activities. Dementia may be progressive (e.g., inexorably worsening), such as the dementia caused by Alzheimer's disease; relatively stable, such as that resulting from a vascular event or anoxia; or partially or completely reversible, such as that caused by medication toxicity or depression. Alzheimer's disease accounts for over 50 percent of dementias. Cerebrovascular disease and Lewy body disease, either alone or together with Alzheimer's disease, are other common causes.

Alzheimer's disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in characteristic patterns, involving primarily the mesial temporal lobe and higher-order association cortices. This distribution of the pathology results in a profile of cognitive deficits in the context of preserved basic neurological function. Alzheimer's disease typically presents as an insidious impairment of recent memory. Over time, language, personality, and most other aspects of cognition become progressively impaired. The course is variable, typically running over eight to 12 years.

Although memory impairment is most often the first sign of dementia, memory may be relatively preserved in the early stages of other demential syndromes, with primary involvement of language, vision, or personality. These more unusual syndromes typically involve relatively focal degeneration in frontal, temporal, or occipitoparietal regions and can be caused by variants of Alzheimer's disease or other frontotemporal lobar degenerative conditions.

Before Alzheimer's disease causes dementia, it passes through a pre-symptomatic stage. The next stage is one of mild cognitive impairment (MCI) in which recent memory is impaired but competence in daily living is not. Many, but not all, patients with MCI go on to develop Alzheimer's dementia at a rate of about 15 percent per year. Detection of disease at the stage of MCI is becoming a high priority, because at this early stage, interventions that slow or reverse Alzheimer's disease are most likely to be effective and preserve the most function. At the current time, expert neurologic and neuropsychologic assessment is the most appropriate way to identify MCI.

Practice

When impairment of memory is suspected, it is important to pursue a careful evaluation to determine if dementia or MCI is present and if any potentially treatable factors are contributing. A comprehensive dementia evaluation includes a neurological evaluation, neuropsychological assessment, and neuroimaging, leading to individually tailored interventions designed to optimize cognitive and functional abilities.

The current standard of treatment for mild to moderate Alzheimer's disease is cholinergic augmentation with a centrally acting cholinesterase inhibitor, but a number of new therapeutic options are under investigation. In addition, behavioral interventions can be effective at all stages of the disease to help maintain independence and minimize caregiver burden.