APOE loss‐of‐function variants: Compatible with longevity and associated with resistance to Alzheimer’s Disease pathology

• DOI: 10.1002/alz.082628
• Publication Date: 2023-12-25T15:25:40Z
• Authors: Yann Le Guen; Augustine Chempar...; Sunny Chen; Lesley Leong; John John Gorzynski; Guangxue Xue; Michael E Belloy; Nandita Kasireddy; Andres Peña Tauber; Kennedy Williams; Thomas S. Wingo; James J. Lah; Suman Jayadev; Chadwick M Hales; Elaine R Peskind; Daniel D Child; C Dirk Keene; Cong Le; Euan Ashley; Chang‐En Yu; Michael D Greicius
• Keywords: Loss function; Apolipoprotein E; Null allele

Abstract Background The ε4 variant of APOE is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). It remains unclear if protein increases AD through a gain abnormal function, or whether it functions less well than ε3 protein. Framed bluntly: Would knocking down in an carrier increase decrease risk? Method We searched whole‐exomes and whole‐genomes from ∼47,000 older controls cases Disease Sequencing Project (ADSP) looking early loss‐of‐function variants on . Five 26,605 carried while only one 20,856 did ( Figure.1A/B ). reasoned that does not function as ε3, then either should have ε4‐like impact risk. However, inherently detrimental, ε4, specifically, protective effect. Result Loss was seen two cognitively healthy homozygotes, last assessed at ages 82 88. This suggests ε3/null effective genotype strong driver Subject 6‐nominally ε3/ε4 but effectively ε4/null ‐developed symptoms 75 died 87 with autopsy‐confirmed AD, age‐at‐onset similar to typical (μ = 73.5y), later ε4/ε4 69.7y). loss result phenotype, Subjects 3 5. most illustrative phenotypes are 1 2 who nominally ε3/null. 79, normal levels amyloid tau cerebrospinal fluid 76, 2/3rds amyloid‐positive by 75. 90, same year, had no pathology, deposits cerebral blood vessels, making him prominent outlier compared 1700 individuals NACC Figure.1C Conclusion Taken together, these results provide human genetics evidence yet available support hypothesis drives reducing be expected reduce