Alzheimer β Amyloid Deposition Enhanced by ApoE ɛ4 Gene precedes Neurofibrillary pathology in the Frontal Association Cortex of Nondemented Senior Subjects

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Abstract
To clarify how Alzheimer disease pathology develops in the brains of nondemented subjects, we examined the interrelations among the amounts and morphology of Aβ 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 Aβ measured by enzyme immunoassay (EIA). The amounts of Aβ42-EIA increased dramatically in the late preclinical stage, whereas the Aβ42+ plaque density increased in the early preclinical stage. Neurofibrillary pathology appeared only in the areas with severe Aβ deposition and in subjects aged over 70. The ApoE ɛ4 allele enhanced the Aβ deposition in presenile subjects. plaque-associated glial Aβ was prominent in subjects with mild to moderate Aβ deposition. The morphology of cerebral Aβ deposition changed from diffuse plaques with small amounts of Aβ in each plaque in the early preclinical stage to primitive/neuritic plaques with larger amounts of Aβ in each plaque in the late preclinical stage. Our findings suggest that the prevention of Aβ deposition in the late preclinical stage can be a rational therapeutic target, especially in elderly people with ApoE ɛ4 allele.

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