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

The APOE ε4 allele is the primary genetic risk factor for late onset Alzheimer’s disease (AD). A cardinal problem in determining APOE ε4’s 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 ε3/ε3 homozygotes and ε3/ε4 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 ε4 on brain structure.