Genetic aspects of Alzheimer disease

Abstract

Alzheimer disease is the most common cause of dementia and represents a major public health problem. The neuropathologic findings of amyloid-beta plaques and tau containing neurofibrillary tangles represent important molecular clues to the underlying pathogenesis. Genetic factors are well recognized, but complicated. Three rare forms of autosomal-dominant early-onset familial Alzheimer disease have been identified and are associated with mutations in amyloid precursor protein, presenilin 1, and presenilin 2 genes. The more common late-onset form of Alzheimer disease is assumed to be polygenic/multifactorial. However, thus far the only clearly identified genetic risk factor for Alzheimer disease is Apo lipoprotein E. The epsilon4 allele of Apo lipoprotein E influences age at onset of Alzheimer disease, but is neither necessary nor sufficient for the disease. The search continues for the discovery of additional genetic influences.

Figure 1

Normal adult brain (top) compared with Alzheimer brain (bottom) showing marked diffuse cortical atrophy and ventricular enlargement.

Figure 2

Microscopic neuropathology of Alzheimer’s disease showing a neuritic plaque (lower left hand corner) and neurofibrillary tangles (upper right hand corner).

Figure 3

Molecular Aspects of the APP gene and protein showing the sites of cleavage by α, β and γ; secretases, production of the Aβ peptide (upper right) and sites of several disease causing mutations (bottom line).