An important question, presently unresolved, will be the distances along chromosomes over which linkage disequilibrium extends in older outbred populations such as we generally find in the United States. A fraction of these will alter encoded proteins and probably a smaller fraction will alter regulatory sequences, altering the expression of specific genes. Ultimately, these variations in DNA sequence will account for the inherited susceptibility to disease and other human traits. There are presently over 100,000 SNP's identified, many in genes lying in pathways implicated in disease. Studies testing variants in candidate genes can potentially identify susceptibility alleles in the general population.
Histology features deposits of beta amyloid, neuronal loss and neurofibrillary tangles.
Rare mendelian forms of early onset Alzheimer's disease have been identified as due to mutations in membrane proteins, presenillins 1 and 2, or in the amyloid precursor protein. These mutations all appear to increase the rate of deposition of beta amyloid. ApoE is known to be involved in cholesterol metabolism and is required for the normal uptake of one form of cholesterol by the liver. The common allelic variants present in most populations are ApoE2, ApoE3 and ApoE4. It appears that inheritance of ApoE4 acts quantitatively to reduce the age of onset of Alzheimer's disease, with each copy of ApoE4 reducing age of disease onset by about 8 years.