Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease

APOE e4 has long been associated with increased risk and earlier age of onset for sporadic AD^{1,2,17,18,19,20}. A rare variant on the APOE e3 allele was found to delay onset of MCI by three decades in a PSEN1 E280A carrier²¹, yet the evidence linking the more common e2 and e4 variants has been mixed^5,6,22. Our findings in over 1,000 participants from a single kindred show an added effect of APOE genotype in carriers of the PSEN1 E280A mutation for ADAD, such that APOE e4+ PSEN1 mutation carriers had accelerated onset of age-related cognitive decline compared to APOE e4− PSEN1 mutation carriers. The age-related trajectory of clinical impairment diverged between APOE e4+ and e4− PSEN1 mutation carriers around age 44, approximately the median age of onset of mild cognitive impairment in this kindred⁴. Our results are consistent with a prior study reporting a detrimental effect of APOE…