The heritability of blood‐based biomarkers related to risk of Alzheimer's disease in a population‐based sample of early old‐age men

Abstract

INTRODUCTIONDespite their increased application, the heritability of Alzheimer's disease (AD)–related blood‐based biomarkers remains unexplored.METHODSPlasma amyloid beta 40 (Aβ40), Aβ42, the Aβ42/40 ratio, total tau (t‐tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (μ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them.RESULTSAdditive genetics explained 44% to 52% of Aβ42, Aβ40, t‐tau, and NfL. The Aβ42/40 ratio was not heritable. Aβ40 and Aβ42 were genetically near identical (rg = 0.94). Both Aβ40 and Aβ42 were genetically correlated with NfL (rg = 0.35 to 0.38), but genetically unrelated to t‐tau.DISCUSSIONExcept for Aβ42/40, plasma biomarkers are heritable. Aβ40 and Aβ42 share mostly the same genetic influences, whereas genetic influences on plasma t‐tau and NfL are largely unique in early old‐age men. The absence of genetic associations between the Aβs and t‐tau is not consistent with the amyloid cascade hypothesis.

Cross-sectional study of plasma phosphorylated Tau 217 in persons without dementia

“…To our knowledge, only one twin study – not including p-tau217 – has investigated the heritability of blood-based AD biomarkers. 4 We found that age and APOE genotype, but not ADPRS (based on cases having clinical diagnosis of AD), were significant predictors of continuous p-tau217 levels but also AD pathology as indicated by abnormal levels of plasma p-tau217 using published cut-offs for amyloid and tau positivity. 1 For the ADPRS, we chose to use the score based on Lambert et al (2013).…”

“…Only one twin study has investigated the heritability of AD plasma biomarkers and found that about half of the variance in beta-amyloid (Aβ)42 and Aβ40 was explained by additive genetic effects whereas Aβ42/40 had zero heritability; also plasma total tau had 50% heritability. 4 However, twin studies have not investigated the heritability of plasma p-tau217 despite its promise as an accurate cost-effective biomarker of both amyloid and tau positivity. 1 The large case-control genome-wide association studies (GWAS) of AD have indicated over 80 loci.…”