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Patients with sporadic AD (<jats:italic>s<\/jats:italic>AD) from a genetic isolate in the extremes of the AOO distribution were whole\u2010exome genotyped. Single\u2010 and multi\u2010locus linear mixed\u2010effects models were used to identify functional variants modifying AOO. A<jats:italic>posteriori<\/jats:italic>enrichment and bioinformatic analyses were applied to evaluate the non\u2010random clustering of the associate variants to physiopathological pathways involved in AD. We identified more than 20 pathogenic, genome\u2010wide statistically significant mutations of major modifier effect on the AOO. These variants are harbored in genes implicated in neuron apoptosis, neurogenesis, inflammatory processes linked to AD, oligodendrocyte differentiation, and memory processes. 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