Cerebral beta-amyloid deposition is augmented by the -491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E epsilon4 allele.

The apolipoprotein E epsilon4 allele (APOE, gene; apoE, protein) is widely accepted as a risk factor for Alzheimer's disease (AD). Our previous studies found that APOEepsilon4 promotes AD pathogenesis by fostering the early deposition of the amyloidogenic peptide Abeta in the aging brain. Recent reports suggest that polymorphisms in the upstream promoter region of APOE differentially affect the production of apoE and also may have an important influence on the probability of developing AD. In this study, we asked whether APOE promoter -491 (A/T) variants interact with APOE polymorphisms to modulate the degree of beta-amyloid- and tau-related pathology in the medial temporal lobe of the non-demented elderly. Our results confirm that APOEepsilon4 is associated with increased formation of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles in the medial temporal lobe. We also found that homozygosity for A at position -491 of the APOE promoter (-491AA) correlates with increased Abeta17-24 and Abeta42 deposition in APOEepsilon4-positive cases, but not in cases lacking the epsilon4 allele. In comparison, Abeta burden is significantly less in epsilon4 carriers with the -491AT and -491TT promoter allelotypes. There was no effect of -491 polymorphisms on Abeta40 deposition (which is relatively sparse in the non-demented elderly), on the number of activated microglia, or on the amount of neurofibrillary tangles. We conclude that the amyloidogenic effects of apoE4 are exacerbated by polymorphisms in the APOE promoter that enhance apoE production.

Activated microglia do not mediate the early deposition of Abeta in carriers of the apolipoprotein Eepsilon4 allele.

Activated microglia are a prominent component of the senile plaques in end-stage Alzheimer's disease, but whether microglia contribute to the initiation of the lesions remains unknown. In a previous postmortem study of non-demented elderly cases, we found that amyloidogenesis is advanced by at least 10 years in carriers of the apoEepsilon4 allele. To determine whether microglia are involved in the initial stages of beta-amyloid pathogenesis and whether apoE genotype influences microglial activation, we quantified HLA-DR-immunoreactive microglia in the medial temporal lobe of 229 non-demented humans of various APOE genotypes who had died between 50 and 91 years of age. Our results show that the number of HLA-DR-immunoreactive microglia increases with advancing age in both the gray matter and the white matter. In contrast to amyloid plaques and neurofibrillary tangles, there is no significant correlation between apoE genotype and density of microglia, although apoEepsilon4 homozygotes tended to have more microglia than did other apoE groups. In sections double-immunostained for Abeta and activated microglia, activated microglia were associated with dense-cored plaques but not with diffuse plaques, suggesting that microglial activation is a relatively late event in the genesis of beta-amyloid. Activation of microglia thus appears not to be the initial impetus for Abeta-deposition in the elderly.

Apolipoprotein E4 promotes the early deposition of Abeta42 and then Abeta40 in the elderly.

The apolipoprotein Eepsilon4 allele (ApoEepsilon4) is associated with a selective increase in deposition of the 40-amino acid form of the beta-amyloid peptide (Abeta40) in endstage Alzheimer's disease. To determine how apoE genotype affects the early events in beta-amyloid pathogenesis, we analyzed the medial temporal lobes of 244 elderly persons who were not clinically demented using antibodies selective for the C termini of Abeta40 and Abeta42. We found that: (1) the number of both Abeta42- and Abeta40-positive senile plaques increase with age; (2) Abeta42 appears at younger ages, and in more amyloid deposits, than does Abeta40 in all ApoE groups; (3) when compared at similar ages, older persons with ApoEepsilon4 are more likely to have Abeta42- and Abeta40-immunoreactive deposits than are persons without ApoEepsilon4; (4) Abeta40-containing plaques arise at least a decade later than do Abeta42 plaques, and are seldom found in the medial temporal lobe of older persons lacking ApoEepsilon4; and (5) in the absence of overt Alzheimer's disease, cerebral amyloid angiopathy is rare in the elderly, but in our sample was significantly augmented in ApoEepsilon4 homozygotes. We conclude that ApoEepsilon4 hastens the onset of Abeta42 deposition in the senescent brain, which in turn fosters the earlier evolution of fibrillar, Abeta40-positive plaques, thereby increasing the risk of Alzheimer's disease.