Alzheimer Disease:

Author: Heather S Anderson, MD, Assistant Professor, Staff Neurologist, Department of Neurology, Alzheimer and Memory Center, University of Kansas Medical Center


Introduction:
Background
Alzheimer disease (Alzheimer’s disease, AD), the most common cause of dementia, is an acquired cognitive and behavioral impairment of sufficient severity that markedly interferes with social and occupational functioning. Alzheimer disease is a major public health problem from the economic perspective. In the United States, the cost of caring for patients with dementia was $144 billion per year in 2009, and the average yearly cost for healthcare and long-term care services per patient was about $33,007 in 2004, the most recent data available.1


Alzheimer disease affects approximately 5.3 million people in the United States.1 A larger number of individuals have decreased levels of cognitive function (eg, mild cognitive impairment) that frequently evolve into a full-blown dementia, thereby increasing the number of affected persons. By 2030, an estimated 7.7 million Americans aged 65 and older will have Alzheimer disease.2 Statistical projections indicate that the number of persons affected by the disorder in the United States could range from 11-16 million by the year 2050.2
This article is intended to be a comprehensive, but not necessarily exhaustive, review of Alzheimer disease.

For related information:

•Alzheimer's Disease Resource Center
•Alzheimer's Disease: Slideshow

Pathophysiology
The anatomic pathology of Alzheimer disease 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. NFTs and SPs were described by Alois Alzheimer in his original report on the disorder in 19073 ; they are now universally accepted as a hallmark of the disease.

Although NFTs and SPs are characteristic of Alzheimer disease, they are not pathognomonic. NFTs are found in several other neurodegenerative disorders, including progressive supranuclear palsy and dementia pugilistica. SPs may occur in normal aging. Therefore, the mere presence of these lesions is not sufficient to diagnose Alzheimer disease. These lesions must be present in sufficient numbers and in a characteristic topographic distribution to fulfill the current histopathologic criteria for Alzheimer disease.

In addition to NFTs and SPs, many other lesions of Alzheimer disease 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 al4 ; 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 Alzheimer disease that Braak et al formulated include an early stage in which a low density of NFTs is present in the entorhinal and perirhinal (ie, transentorhinal) cortices.4 Therefore, even small numbers of NFTs in these areas of the medial temporal lobe may be abnormal.

In contrast, there is consensus that the presence of even low numbers of NFTs in the cerebral neocortex with concomitant SPs is characteristic of Alzheimer disease. Granulovacuolar degeneration occurs almost exclusively in the hippocampus. 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.

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 Alzheimer disease progresses, NFTs accumulate in many 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.


Frequency
United States
The lifetime risk of Alzheimer disease 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
Prevalence of Alzheimer disease 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
•In the United States, Alzheimer disease is frequently considered a leading cause of death. In 2006, Alzheimer disease was the seventh leading cause of death5 ; however, Alzheimer disease as an underlying cause of death is frequently underreported6 .
•The primary cause of death is intercurrent illness, such as pneumonia, in a patient who has become severely demented from Alzheimer disease. Patients lose the ability to walk and swallow. Difficulty swallowing may lead to aspiration pneumonia.
Race
Alzheimer disease and other dementias are more common in African-Americans compared to whites. According to the Alzheimer's Association, in the population aged 71 and older, African-Americans are almost 2 times as likely to have Alzheimer disease and other dementias than whites (21.3% of African-Americans vs 11.2% of whites). The number of Hispanic patients studied in this age group was too small to determine the prevalence of dementia in this population.

In individuals age 65 and older, 7.8% of whites, 18.8% of African-Americans, and 20.8% of Hispanics have Alzheimer disease or other dementias, and the prevalence of Alzheimer disease and other dementias is higher in older versus younger age groups.1
Sex
Alzheimer disease affects both men and women; however, Plassman et al found the risk of developing Alzheimer disease to be significantly higher in women than in men, primarily due to the higher life expectancy in women compared with men.7



Age
The prevalence of Alzheimer disease increases with age.



•Alzheimer disease is most prevalent in individuals older than 60 years. Some forms of familial early-onset Alzheimer disease can appear as early as the third decade, but this represents a subgroup of the less than 10% of all familial cases of Alzheimer disease.
•More than 90% of cases of Alzheimer disease are sporadic and occur in individuals older than 60 years.
•Of interest, results of some studies of nonagenarians and centenarians suggest that the risk may decrease in individuals older than 90 years. If so, age is not an unqualified risk factor for the disease, but further study of this matter is needed.
•Savva et al found that the association between the pathological features of Alzheimer disease and dementia (eg, neuritic plaques, diffuse plaques, tangles) is stronger in younger old persons (ie, age 75 years) than in older old persons (ie, 95 years). These results were achieved by assessing 456 brains donated to the population-based Medical Research Council Cognitive Function and Ageing Study from persons 69-103 years of age at death. These results demonstrate that the relationship between cerebral atrophy and dementia persist into the oldest ages, but the strength of association between pathological features of Alzheimer disease and clinical dementia diminished. It is important to take age into account when assessing the likely effect of interventions against dementia on the population.8
Clinical
History
Patients with Alzheimer disease most commonly present with insidiously progressive memory loss, to which other spheres of cognitive impairment are added over several years. After memory loss occurs, patients may also have language disorders (eg, anomia) and impairment in their visuospatial skills and executive functions.

The National Institutes of Health-Alzheimer's Disease and Related Disorders Association (NIH-ADRDA), the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision, Text Revision (DSM-IV-TR), and the Consortium to Establish a Registry in Alzheimer's Disease (CERAD) have formulated several clinical guidelines for the diagnosis of AD. The NIH-ADRDA criteria for the diagnosis of AD require the finding of a slowly progressive memory loss of insidious onset in a fully conscious patient. AD cannot be diagnosed in patients with clouded consciousness or delirium. Toxic metabolic conditions and brain neoplasms must also be excluded as potential causes of the patient's dementia.

The main focus of these diagnostic guidelines consists of verifying the initial finding of mild, slowly progressive memory loss, that additional spheres of cognition are also compromised, and that other possible causes for dementia (eg, cerebrovascular disease, cobalamin deficiency, syphilis, thyroid disease) are ruled out with a combination of clinical examination and ancillary radiologic and laboratory tests. These guidelines are widely believed to be 90-95% accurate (as histopathologically verified) when followed carefully, and they are important not only for routine management but also for selecting and enrolling patients in therapeutic trials.

Substantially less common, but biopsy or autopsy-proven, presentations include right parietal lobe syndrome, progressive aphasia, spastic paraparesis, and impaired visuospatial skills, which is subsumed under the visual variant of Alzheimer disease.


Physical
The earliest evidence of Alzheimer disease is the onset of chronic, insidious memory loss that is slowly progressive over several years. This loss may be associated with slowly progressive behavioral changes. Patients with mild Alzheimer disease usually have somewhat less obvious executive, language, and/or visuospatial dysfunction. In atypical presentations, dysfunction in cognitive domains other than memory may be most apparent. In later stages, many patients develop extrapyramidal dysfunction.

Initial mental status testing should include evaluation of attention and concentration, recent and remote memory, language, praxis, executive function, and visuospatial function. Brief standardized examinations such as the Mini-Mental Status Examination are less sensitive and specific than longer batteries specifically tailored to individual patients. Nonetheless, screening exams have a role, particularly as a baseline.

A complete neurologic exam is performed to look for signs of other diseases that could cause dementia such as Parkinson disease or multiple strokes.



Causes
The cause of Alzheimer disease is unknown. Several investigators now believe that converging risk factors, which include advancing age, lipoprotein E epsilon 4 genotype, obesity, insulin resistance, vascular factors, dyslipidemia, hypertension, and inflammatory markers9,10,11,12 trigger a pathophysiologic cascade that, over decades, leads to Alzheimer pathology and dementia.

Familial forms of Alzheimer disease account for less than 7% of all cases of Alzheimer disease, with most cases being sporadic (ie, not inherited). Mutations in genes coding for 3 proteins unequivocally cause Alzheimer disease. These genes (for amyloid precursor protein [APP, on chromosome 21], for presenilin I [on chromosome 14], and for presenilin II [on chromosome 1]) all lead to a relative excess in the production of the stickier 42-amino acid form of the beta-amyloid peptide over the less sticky 40-amino acid form.

This beta-pleated peptide is postulated to have neurotoxic properties and to lead to an incompletely understood cascade of events resulting in neuronal death, synapse loss, and the formation of neurofibrillary tangles (NFTs) and senile plaques (SPs) among other lesions. Nonetheless, mutations accounting for less than half of all cases of early-onset Alzheimer disease have been found. Other than the ApoE epsilon 4 genotype, no polymorphisms in other genes have been consistently found to be associated with late-onset Alzheimer disease.

Considerable attention has been devoted to elucidating the composition of NFTs and SPs to find clues about the molecular pathogenesis and biochemistry of Alzheimer disease. Since the time of Alois Alzheimer, SPs have been known to include a starchlike (or amyloid) substance, usually in the center of these lesions, which is surrounded by a halo or layer of degenerating (dystrophic) neurites and reactive glia (both astrocytes and microglia).

One of the most important advances in recent decades has been the chemical characterization of this amyloid protein, the sequencing of its amino acid chain, and the cloning of the gene encoding its precursor protein (on chromosome 21). These advances have provided a wealth of information about the mechanisms underlying amyloid deposition in the brain, including information about the familial forms of Alzheimer’s disease. Although the amyloid cascade hypothesis has gathered the most research dollars, other interesting hypotheses have been proposed, including the mitochondrial cascade hypothesis.13
Attention has also been devoted to the mechanisms leading to the development of NFTs, the main constituent of which is the microtubule-associated protein tau that is hyperphosphorylated and that accumulates in the perikarya of large and medium pyramidal neurons. Somewhat surprisingly, mutations of the tau gene result not in Alzheimer disease but in some familial cases of frontotemporal dementia.