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Alzheimer’s disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed~ 50 000 common and rare functional genomic variants from 71 individuals of the ‘Paisa’pedigree, the world’s largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s–70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE* E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by~ 12 years (β= 11.74, 95% confidence interval (CI): 8.07–15.41, P= 6.31× 10− 8, P FDR= 2.48× 10− 3). Subsequently, to evaluate …