Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age

Abstract

Objective: To study the prevalence and age dependency of senile plaques (SP) and neurofibrillary tangles (NFT), the brain changes characteristic of Alzheimer disease (AD), and their association with apolipoprotein E (APOE) genotypes in a community-dwelling normal population.

Methods: This neuropathological study used both silver staining and A beta immunohistochemistry in brain tissue microarrays, including SP coverage and NFT counts from frontal cortex and hippocampus, and APOE genotyping, and was performed on a consecutive prospective series of 603 subjects (aged between 0 and 97 years) of an unselected population living outside of institutions. Cases were subjected to autopsy following sudden or unexpected out-of-hospital death, covering 22.1% of the mortality of Tampere, Finland and its surroundings. None died of AD, although 22 (3.7%) were demented and 10 (1.7%) had memory problems.

Results: Of the series, 30.8% had SP, and 42.1% had NFT; these occurred more commonly among females and showed a strong relationship with age. Both changes had already appeared at around 30 years of age, reaching an occurrence of almost 100% in the oldest. SP were more frequent in APOE epsilon 4-carriers compared with noncarriers in every age group except the oldest (>90 years). The difference was most evident during the ages 50 to 59 years, where 40.7% of epsilon 4-carriers had SP, compared with 8.2% in noncarriers (odds ratio, 8.39; 95% confidence interval, 2.55-27.62). The difference in NFT prevalence between APOE genotypes was not statistically significant in any age group.

Interpretation: The brain changes associated with AD may already begin developing early in middle age, especially among APOE epsilon 4 carriers.