Apolipoprotein E and GFAP showed negative regional association with amyloid-β (especially amyloid-β₄₀) accumulation in both sporadic and familial Alzheimer's disease.
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.
EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of 5 Familial Alzheimer's disease (5xFAD) mutations.
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).
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.
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).
Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women.
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.
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.
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.
In this study, we generated amyloid precursor protein/apoE knockout (APP/apoE<sup>KO</sup>) and APP/glial fibrillary acidic protein (GFAP)-apoE<sup>KO</sup> mice (the AD mice model used in this study was based on the APP-familial Alzheimer disease overexpression) to investigate the role of apoE, derived from astrocytes, in AD pathology and cognitive function.
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.