Genetic analysis of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) in a population-based cohort of the oldest old

Abstract Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common proteinopathy in the oldest old that is associated with cognitive decline. Although the genetic basis of LATE-NC remains largely unknown, TMEM106B, GRN, and APOE loci are frequently implicated. Here, we examined nine previously reported LATE-NC risk loci (ARHGEF28, APOE, GRN, KAZN, LHX1, TPCN1, TMEM106B, UNC13C, and WWOX) in a population cohort of 262 individuals from the Vantaa 85+ study. We also tested whether Alzheimer’s disease polygenic risk score without APOE was associated with LATE-NC. Using ordinal logistic regression models, GRN rs5848 (OR = 2.45, 95% CI: 1.71–3.52, adjusted p = 5.75×10⁻6), APOE ε4 dose (OR = 1.73, 95% CI:1.07-2.80, adjusted p = 0.030) and KAZN rs72643142 (OR = 2.38, 95% CI: 1.38–4.11, adjusted p = 0.0048) were associated with higher LATE-NC stage. Additionally, Alzheimer’s disease polygenic risk score without APOE was associated with LATE-NC after adjusting for age, sex, Alzheimer’s disease pathology and APOE ε4 dose (OR = 1.36, 95 % CI: 1.06-1.75, adjusted p = 0.027). Our findings contribute to the understanding of LATE-NC genetics and suggest shared biological processes between LATE-NC and Alzheimer’s disease.