Alzheimer's Disease
Population Genetics
Genetic etiologies for some forms of Alzheimer’s disease have been found, and specific genes that influence vulnerability have been identified (Table 6-5). A review of epidemiologic studies, however, is remarkable in that it does not show high heritability of the disorder. This observation is partly attributable to multiple environmental and genetic etiologic factors. It is also related to the variable age at onset for the condition. Early-onset causes are more likely to be heritable and may be determined by single genes. Late-onset cases are more likely to be multifactorial. Important genetic factors in late-onset cases may be obscured by the fact that mortality from other causes decreases familial aggregation.
Family Studies
Most of the relatives of late-onset Alzheimer’s probands will have died of other causes before passing the age of risk. For example, in one study, 60% of 125 autopsy-confirmed Alz-heimer’s probands did not have an affected first- degree relative. However, the risk to siblings of pro-bands (with an affected parent) whose age at onset was less than 70 years is close to 50%. The risk to first-degree relatives at age 90 has been estimated to be 40%. Another study reported that first-degree relatives of demented subjects with amnesia, apraxia, and aphasia have a corrected lifetime risk of close to 50% for Alzheimer’s disease at age 90, compared to 7% for relatives of control subjects (ie, demented subjects without agraphia).
Twin Studies
A total of 81 twin pairs, in which at least one member was affected by Alz-heimer’s disease, have been reported in the literature. In these pairs, the MZ concordance rate (approximately 45%) is not different from the DZ concordance rate (approximately 35%).
Linkage Studies
One study reported linkage of familial Alzheimer’s disease to RFLP markers on chromosome 21. The peak LOD score of 4.25 suggested a causative gene near these markers. Subsequently, several studies identified isolated, rare cases of familial Alzheimer’s disease in which a point mutation in the gene for amyloid precursor protein was found in ill pedigree members. These studies suggest that abnormalities in this gene are sufficient to cause the disease. Amyloid is a proteinaceous material that accumulates in the extracellular space of the brain in persons with Alzheimer’s disease. Another cause of early-onset familial Alzheimer’s disease is a gene on chromosome 14. Other familial cases are linked to a gene on chromosome 1. The genes on chromosomes 1 and 14 both code for proteins called presenilins. These proteins appear to be highly homologous; they may metabolize any bound precursor protein.
Many families with late-onset Alzheimer’s disease show linkage to a region of chromosome 19 that codes for apolipoprotein E (ApoE), which is also implicated in cardiovascular illness. One copy of the E4 allele will increase an individual’s risk fourfold compared to individuals with the more common form, E2. Two copies of E4 increase risk by a factor of 12. It is not yet clear whether E4 is a risk factor for all ethnic groups or just for certain populations. The molecular mechanisms for the Alzheimer’s disease vulnerability genes are the subject of intense investigation. There is reason to suspect that all of the causative genes may have an effect on accumulation of amyloid.
