Finally, it was recently shown that the epsilon 4 allele of apolipoprotein E (ApoE) gene, which has been mapped to chromosome 19, is associated with an increased risk of developing the disease in late onset FAD families and sporadic cases.
Evidence of linkage of ApoE and ApoCII to FAD was examined by maximum-likelihood methods, using three models and assuming autosomal dominant inheritance: (1) age-dependent penetrance, (2) extremely low (1%) penetrance, and (3) age-dependent penetrance corrected for sporadic Alzheimer disease (AD).
Recent findings suggest that the presence of APOE 4 is associated with an increased risk for both familial Alzheimer's disease and late-onset Alzheimer's disease.
In none of the FAD families analysed was there a significant effect of the ApoE genotype on the age of onset with the exception of one of the two mutated EOFAD families in which the epsilon 2 allele delayed the age of onset.
Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women.
Besides familial Alzheimer's disease (AD), the genetic susceptibility has also been found in sporadic cases of AD, mostly related to the apolipoprotein E polymorphism.
Using the polymerase chain reaction, we analyzed the segregation of the ACT and ApoE polymorphisms in familial Alzheimer's disease (FAD) patients carrying mutations in Presenilin (PS) and APP genes and in both early onset (EO) and late onset (LO) FAD patients without known mutations.
Thus, we conclude that among the reported genetic risk factors, ApoE epsilon4 is the only definite risk factor for both FAD and AD, and the VLDLR polymorphism might be associated with AD cases in Japanese.
The epsilon4 allele of the apolipoprotein E gene on chromosome 19 is a susceptibility factor for AD, and in a small number of AD families, dominant mutations with high penetrance are operating in genes on chromosomes 1, 14 and 21.
However, in siblings with the same APOE genotype, a wide range of onset was seen, indicating that unknown genetic or environmental factors affect the expression of AD.
For the more common sporadic forms of AD, increased risk has been associated with a number of genes; the most important of which is the epsilon4 allele of apolipoprotein E. Two recent studies, one clinical and one using postmortem material, now show increased risk for AD associated with certain polymorphisms in the genes encoding the alpha and beta isoforms of interleukin-1 (IL-1).
In addition, polymorphisms in three other genes (among others), apolipoprotein E (apoE), alpha2-macroglobulin (alpham), and the low density lipoprotein receptor-related protein (LRP), are implicated to contribute to AD pathogenesis.
Insights into factors underlying causes of familial Alzheimer's disease (AD), such as mutant forms of beta-amyloid precursor protein and presenilins, and those conferring increased risk of sporadic AD, such as isoforms of apolipoprotein E and polymorphisms of alpha2-macroglobulin, have been rapidly emerging.
Recent genome-wide scanning studies have revealed the existence of a new locus on chromosome 12, which, together with inheritance of the epsilon4 allele of apolipoprotein E gene, on chromosome 19, represent the most important genetic factors associated with an increased risk of developing the disease in late onset FAD families.
This paper further reviews the mechanisms associated with AD causation for APOE and other candidate genes and implications for the development of prevention strategies.