Excerpt from Alzheimer Disease

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Background

Alzheimer disease (AD) is the most common cause of dementia, which is an acquired cognitive and behavioral impairment of sufficient severity to markedly interfere with social and occupational functioning.

AD affects approximately 5 million people in the United States and more than 30 million people worldwide. A larger number of individuals have decreased levels of cognitive impairment (eg, minimal cognitive impairment), which frequently evolves into a full-blown dementia, thereby increasing the number of affected persons. The prevalence of AD is expected to substantially increase in this century because it preferentially affects the elderly, who constitute the fastest growing age group in many, especially industrialized, countries. Statistical projections indicate that the number of persons affected by the disorder in the United States will nearly triple by the year 2050.

AD is also a major public health problem from the economic perspective. In the United States, the cost of caring for patients with AD was more than $110 billion per year in the early 1990s, and the average yearly cost per patient is about $45,000. Because methods for assessing the economic effects of neurodegenerative disorders are still in their infancy, these figures must be interpreted as underestimates.

Many excellent treatises on AD have reviewed important aspects of the disorder in considerable detail. This article is intended to be a comprehensive but not necessarily exhaustive review of AD.

Pathophysiology

The anatomic pathology of AD includes neurofibrillary tangles (NFTs); senile plaques (SPs) at the microscopic level; and cerebrocortical atrophy, which predominantly involves the association regions and particularly the medial aspect of the temporal lobe. In his original report on the disorder, Alois Alzheimer described the co-occurrence of NFTs and SPs, which is now universally accepted as a hallmark of the disease.

Although NFTs and SPs are characteristic of AD, they are not pathognomonic. In fact many other neurodegenerative conditions distinct from AD are characterized by NFTs (eg, progressive supranuclear palsy, dementia pugilistica) or SPs (eg, normal aging). Therefore, the mere presence of these lesions is not sufficient to diagnose AD. These lesions must be present in sufficient numbers and in a characteristic topographic distribution to fulfill the current histopathologic criteria for AD.

In addition to NFTs and SPs, many other lesions of AD have been recognized since Alzheimer's original papers were published. These include (1) the granulovacuolar degeneration of Shimkowicz; (2) the neuropil threads of Braak et al; and (3) neuronal loss and synaptic degeneration, which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder.

Some authorities believed that NFTs, when present in low densities and essentially confined to the hippocampus, were part of normal aging. However, the histologic stages for AD that Braak et al formulated includes an early stage in which a low density of NFTs is present in the entorhinal and perirhinal (ie, transentorhinal) cortices. Therefore, even small numbers of NFTs in these areas of the medial temporal lobe should be considered abnormal. The issue of whether these early changes should be considered part of minimal cognitive impairment (Kuljis, 1997) or the early stages of AD instead remains to be settled experimentally.

In contrast, the presence of even low numbers of NFTs in the cerebral neocortex is considered abnormal and indicates AD if associated with SPs in that location, with a specific topographic pattern. Granulovacuolar degeneration occurs almost exclusively in the hippocampus and has received less attention than neuropil threads, which are an array of dystrophic neurites diffusely distributed in the cortical neuropil, more or less independently of plaques and tangles. This lesion suggests neuropil alterations beyond those merely due to NFTs and SPs and indicates an even more widespread insult to the cortical circuitry than that visualized by studying only plaques and tangles.

Despite the wide distribution of these lesions in the cerebral cortex, the increasing consensus is that most patients with AD have a relatively consistent topographic pattern. NFTs are initially and most densely distributed in the medial aspect and in the pole of the temporal lobe; they affect the entorhinal cortex and the hippocampus most severely. As AD progresses, NFTs accumulate in most other cortical regions, beginning in high-order association regions and less frequently in the primary motor and sensory regions. SPs also accumulate primarily in association cortices and in the hippocampus. Plaques and tangles have relatively discrete and stereotypical patterns of laminar distribution in the cerebral cortex, which indicate predominant involvement of corticocortical connections, as many investigators have observed.

According to this formulation, the pathophysiologic mechanism underlying the clinical manifestations of AD is corticocortical disconnection due to the loss of medium-sized pyramidal neurons effecting such connections. However, multiple lines of evidence suggest that several classes of local circuit neurons are selectively lost throughout the cerebral cortex as well; these data demonstrate that the corticocortical disconnection is not the only alteration in cortical circuitry that mediates the symptoms of AD.

Frequency

United States

The lifetime risk of AD is estimated to be 1:4-1:2. More than 14% of individuals older than 65 years have AD, and the prevalence increases to at least 40% in individuals older than 80 years.

International

Prevalences similar to those in the United States have been reported in industrialized nations. Countries experiencing rapid increases in the elderly segments of their population have rates approaching those in the United States.

Mortality/Morbidity

• Second to only certain cancers and cardiovascular disease, AD is frequently considered a leading cause of death in the United States.
• The primary cause of death is intercurrent illness, such as pneumonia, in a patient who has experienced the debilitating effects of AD for many years.

Race

Some claim that AD affects certain ethnic and racial groups more severely than others, but more study is needed before reliable statements about racial predilections can be made.

Sex

AD affects both men and women. Many studies indicate that the risk of AD is significantly higher in women than in men. Some authorities have postulated that this difference is due to the loss of the neurotrophic effect of estrogen in postmenopausal women. Other factors may also influence this relative difference.

Age

The prevalence of AD increases with age.

• AD is most prevalent in individuals older than 60 years. Some forms of familial early-onset AD can appear as early as the third decade, but this represents a subgroup of the less than 10% of all familial cases of AD.
• More than 90% of cases of AD are sporadic and occur in individuals older than 60 years.
• Of interest, results of some studies of nonagenarians and centenarians suggest that the risk decreases in individuals older than 80 or 90 years. If so, age is not an unqualified risk factor for the disease, but further study of this matter is needed.

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