Alzheimer β amyloid deposition enhanced by ApoE ε4 gene precedes neurofibrillary pathology in the frontal association cortex of nondemented senior subjects

To clarify how Alzheimer disease pathology develops in the brains of nondemented subjects. we examined the interrelations among the amounts and morphology of A beta deposition, neurofibrillary pathology, and apolipoprotein E (ApoE) genotype in the frontal association cortex of 101 autopsy brains from patients aged between 40 to 83. Senile plaque density correlated well with the logarithmic data of insoluble A beta measured by enzyme immunoassay (EIA). The amounts of A beta 42- EIA increased dramatically in the late preclinical stage, whereas the A beta 42+ plaque density increased in the early preclinical stage. Neurofibrillary pathology appeared only in the areas with severe A beta deposition and in subjects aged over 70. The ApoE epsilon4 allele enhanced the A beta deposition in presenile subjects. plaque-associated glial A beta was prominent in subjects with mild to moderate A beta deposition. The morphology of cerebral A beta deposition changed from diffuse plaques with small amounts of A beta in each plaque in the early preclinical stage to primitive/neuritic plaques with larger amounts of A beta in each plaque in the late preclinical stage. Our findings suggest that the prevention of A beta deposition in the late preclinical stage can be a rational therapeutic target, especially in elderly people with ApoE epsilon4 allele.