APOE ε4 effects on hippocampal atrophy in the healthy elderly reflect future cognitive decline

Abstract

The APOE {varepsilon}4 allele is the primary genetic risk factor for late onset Alzheimers disease (AD). A cardinal problem in determining APOE {varepsilon}4s effect on cognition and brain structure in older individuals is dissociating prodromal changes - linked to increased AD risk - from potential phenotypic differences. To address this, we used cognitive and neuroimaging data from a large cohort of cognitively normal 69-86 year-olds with up to 8 yearly follow-ups to investigate cross-sectional and longitudinal differences between APOE {varepsilon}3/{varepsilon}3 homozygotes and {varepsilon}3/{varepsilon}4 heterozygotes. Although we found a significant age-by-genotype interaction in right hippocampal volume, once our analyses were conditionalised by future diagnosis to account for prodromal mild cognitive impairment (MCI) and AD, this effect was no longer observed. Likewise, longitudinally, rate of hippocampal atrophy was determined not by genotype, but by future diagnosis. Thus, we provide direct evidence in support of the prodromal hypothesis of APOE {varepsilon}4 on brain structure.