High cholesterol levels change the association of biomarkers of neurodegenerative diseases with dementia risk: Findings from a population‐based cohort

Abstract Introduction This study assessed whether in a population with comorbidity of neurodegenerative and cerebrovascular disease (mixed pathology) the association of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau181 (p‐tau181) with dementia risk varied depending on levels of total cholesterol and apolipoprotein E ( APOE ) ε4 genotype. Methods Plasma biomarkers were measured using Simoa technology in 768 participants of a nested case‐control study embedded within an ongoing population‐based cohort. Logistic and spline regression models, and receiver operating characteristic curves were calculated. Results The strength of the association between GFAP and NfL with risk of a clinical diagnosis of dementia changed depending on cholesterol levels and on APOE ε4 genotype. No significant association was seen with p‐tau181. Discussion In individuals with mixed pathology blood GFAP and NfL are better predictors of dementia risk than p‐tau181, and their associations with dementia risk are amplified by hypercholesterolemia, also depending on APOE ε4 genotype. HIGHLIGHTS Cholesterol levels changed the association of blood biomarkers with dementia risk. Blood biomarkers seem to perform differently in community‐ and clinic‐based cohorts. Neurofilament light chain might be a biomarker candidate for dementia risk after stroke.