APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology

The e 4 allele of apolipoprotein E ( APOE ) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of e 4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71-90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE e 3/ e 4 controls carried a stop -gain affecting e 4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that e 4 drives AD risk through the gain of abnormal function and support e 4 knockdown as a viable therapeutic option.