The spectrum of preclinical Alzheimer's disease pathology and its modulation by ApoE genotype

Sporadic Alzheimer's disease (AD) usually presents clinically after 65 years of age, but its pathological changes begin decades earlier. We examined for AD pathology in the postmortem brains of 431 of subjects aged 30–65 years not clinically characterized. Among 40–49 year olds, 15% showed diffuse amyloid β (Aβ) plaques, with a prevalence of 80% in ApoE4/E4, 42% in E4/E3, and <1% in E3/E3 subjects. Aβ deposits appeared after age 49 years in subjects with E3/E3 genotypes. Neuritic plaques first appeared after age 50 years and increased steadily with age in all genotypes. Insoluble Aβ42 levels were highest in parietal, temporal, and frontal lobes, but barely detectable in precuneus. Tau lesions were present in the hippocampus and entorhinal cortex in 7% of subjects aged <40 years and increased steadily with age reaching near 70% in the 60- to 65-year age group. In the locus coeruleus, tau lesions were present in 72% of subjects aged 31–40 years and 94% in the 41- to 50-year age group. Both Aβ and tau lesions are present in the brains of young individuals decades before the age of clinical onset of AD. Aβ lesions closely correlate with the ApoE4 allele and appear as the earliest event in the development of senile plaques.