Smith and Ashford present a compelling hypothesis on evolution of APOE alleles, namely that ɛ4 prevalence is mediated by immune selection pressure against enteric pathogens. While the ɛ3 allele is more prevalent today, it outcompetedɛ4 only relatively recently, as immune selection pressure for more effective immune responses to such pathogens was alleviated with transition to agrarian from hunter-gatherer lifestyles. Smith and Ashford’s hypothesis is intriguing in itself, but the implications for APOE ɛ4 function in Alzheimer’s disease are even more so and encourage greater focus on specific aspects of immunity in accounting for both ɛ4-mediated and general Alzheimer’s disease risk.
DolginE (2022) This is how an Alzheimer’s gene ravages the brain. Nature611, 649.
2.
PowellDS, KuoP-L, QureshiR, CoburnSB, KnopmanDS, PaltaP, GottesmanR, GriswoldM, AlbertM, DealJA, GrossAL (2021) The relationship of APOE ɛ4, race, and sex on the age of onset and risk of dementia. Front Neurol12, 735036.
3.
YassineHN, FinchCE (2020) APOE alleles and diet in brain aging and Alzheimer’s disease. Front Aging Neurosci12, 150.
4.
WhitwellJL, TosakulwongN, WeigandSD, Graff-RadfordJ, Ertekin-TanerN, MachuldaMM, DuffyJR, SchwarzCG, SenjemML, JackCR, LoweVJ, JosephsKA (2021) Relationship of APOE, age at onset, amyloid and clinical phenotype in Alzheimer disease. Neurobiol Aging108, 90–98.
5.
LiuCC, LiuCC, KanekiyoT, XuH, BuG (2013) Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat Rev Neurol9, 106–118.
6.
SmithCJ, AshfordJW (2023) Apolipoprotein ɛ4-associated protection against pediatric enteric infections is a survival advantage in pre-industrial populations. J Alzheimers Dis93, 907–918.
7.
PielFB, PatilAP, HowesRE, NyangiriOA, GethingPW, WilliamsTN, WeatherallDJ, HaySI (2010) Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat Commun1, 104.
8.
RaichlenDA, AlexanderGE (2014) Exercise, APOE genotype, and the evolution of the human lifespan. Trends Neurosci37, 247–255.
9.
KulminskiAM, ArbeevKG, CulminskayaI, UkraintsevaSV, StallardE, ProvinceMA, YashinAI (2015) Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: Insights on mechanisms from the Long Life Family Study. Rejuvenation Res18, 128–135.
10.
KulminskiAM, ShuL, LoikaY, NazarianA, ArbeevK, UkraintsevaS, YashinA, CulminskayaI (2020) APOE region molecular signatures of Alzheimer’s disease across races/ethnicities. Neurobiol Aging87, 141.e141–141.e148.
11.
TaoQ, AngTFA, DeCarliC, AuerbachSH, DevineS, SteinTD, ZhangX, MassaroJ, AuR, QiuWQ (2018) Association of chronic low-grade inflammation with risk of Alzheimer disease in ApoE4 carriers. JAMA Netw Open1, e183597.
12.
TaoQ, Alvin AngTF, Akhter-KhanSC, ItchapurapuIS, KillianyR, ZhangX, BudsonAE, TurkKW, GoldsteinL, MezJ, AloscoML, QiuWQ (2021) Impact of C-reactive protein on cognition and Alzheimer disease biomarkers in homozygous apolipoprotein E ɛ4 carriers. Neurology97, e1243–1252.
