statistical power for GWAS discovery.20 Furthermore, Alzheimer’s disease pathology can be found in cognitively normal individuals, who might develop the clinical manifestations of Alzheimer’s disease if they live long enough.2 Inclusion of young–old (60–69 years) or younger participants as controls in Alzheimer’s disease GWAS might lead to further confounding and reduced statistical power; the genetic aetiology of non–Mendelian early–onset Alzheimer’s disease dementia seems to be the same as in late–onset Alzheimer’s disease dementia,21 but individuals with earlier onset might have higher combined genetic and environmental risk. Rather than using age–matched case–control studies, use of the youngest possible cases with the oldest possible controls might substantially improve the discovery power of GWAS in late–onset diseases such as Alzheimer’s disease.22,23 Existing Alzheimer’s disease GWAS cohorts have generally included a minimum age restriction for cases, and have occasionally used young population controls, both practices that should be avoided in future recruitment if possible.
