APOE ε2 Linked to Milder Alzheimer’s Pathology, Cognitive Impairment

Tau tangles
Tau tangles
Compared with APOE ε4, APOE ε2 seems to have an indirect effect on cognition by influencing AD pathology.

WASHINGTON — The APOE ε2 allele, when compared with the ε3 and ε4 alleles, is associated with milder Alzheimer’s disease pathology postmortem and less severe antemortem cognitive impairment, results from a large autopsy cohort indicate. The APOE ε2 allele was previously linked to a lower risk of Alzheimer’s.

The APOE ε2 allele does not appear to have a direct effect on cognition, but rather an indirect effect by influencing Alzheimer’s pathology, as it is associated with delays in age of onset and may prevent amyloid-β deposition. Conversely, the APOE ε4 allele is associated with an earlier age of onset and increased plaque deposition, increasing the risk of Alzheimer’s by three to four times with one copy.  The study results were presented at the American Academy of Neurology 2015 Annual Meeting.

Alberto Serrano-Pozo, MD, PhD, of Massachusetts General Hospital in Boston, and colleagues collected data from 793 patients from the National Alzheimer’s Coordinating Center (NACC) autopsy cohort. The sample included only one patient (0.1%) with ε2/ε2 genotype, 40 (5%) with ε2/ε3, 339 (42.7%) with ε3/ε3, 320 (40.3%) with ε3/ε4, and 93 (11.7%) with ε4/ε4.

Compared with APOE ε3/ε3 genotype, APOE ε2 was associated with lower Braak neurofibrillary tangles (NFT) stages and possibly fewer neuritic plaques, but no direct effect on cerebral amyloid angiopathy (CAA) severity. APOE ε4 was associated with more neuritic plaques and CAA, but had no effect on Braak NFT stage.

Analyses of cognitive performance based on last clinical exam using the Clinical Dementia Rating Sum and the Mini-Mental State Examination showed ε2 scoring higher than ε3, and ε3 scoring higher than ε4, which after mediation analysis was largely attributed to the genotype’s effects on Alzheimer’s pathology.


  1. Serrano-Pozo A et al. Abstract S16.005. APOEε2 Is Associated With Milder Clinical and Pathological Alzheimer’s Disease. Presented at: American Academy of Neurology Annual Meeting 2015; April 18-25, 2015. Washington, D.C.