APOEε2 is associated with milder clinical and pathological Alzheimer disease

ObjectiveThe Alzheimer disease (AD) APOE epsilon 4 risk allele associates with an earlier age at onset and increased amyloid- deposition, whereas the protective APOE epsilon 2 allele delays the onset and appears to prevent amyloid- deposition. Yet the clinical and pathological effects of APOE epsilon 2 remain uncertain because of its relative rarity. We investigated the effects of APOE epsilon 2 and epsilon 4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients. MethodsWe studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOE epsilon 3/epsilon 3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination). ResultsCompared to APOE epsilon 3/epsilon 3, APOE epsilon 2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOE epsilon 4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (epsilon 2>epsilon 3>epsilon 4). Mediation analysis suggests that this is largely explained through effects on pathology. InterpretationEven when adjusted for age at onset, symptom duration, and other demographic variables, APOE epsilon 2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOE epsilon 3 and epsilon 4 alleles, suggesting a relative neuroprotective effect of APOE epsilon 2 in AD. Ann Neurol 2015;77:917-929