Genetic risk for Alzheimer’s disease, and differential trajectories in circulating blood biomarkers in UK Biobank (n=17,817)
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Understanding pathways from genetic variation to cognitive impairment is critical for dementia prevention, risk stratification and the development of treatments. While genetic risk factors for dementia are known to associate with cross-sectional differences in biomarkers (e.g. lipids) in healthy people, potential influence over longitudinal trajectories is not understood.We leveraged genetic, general health and two-wave biomarker data from n = 17,817 UK Biobank participants. The outcomes were change in 26 common circulating blood biomarkers including inflammatory, cardiometabolic and lipid families. The presence of apolipoprotein ( APOE ) e4 ‘risk’ and e2 ‘protective’ alleles were tested separately versus ‘neutral’ e3e3 genotype, as were associations of non- APOE polygenic risk for Alzheimer’s disease. Biomarker change values were corrected for baseline levels, age, deprivation, sex, timepoint interval, smoking history, medication history, deprivation, genotyping chip and 10 genetic principal components (fully-adjusted).The average interval between assessments was 4.30 years (standard deviation; SD = 0.92). For e4 (versus e3e3), four associations were significant: accelerated change in total cholesterol, apolipoprotein b (ApoB) and low-density lipoprotein (LDL) each in the direction of poorer health (standardized β range = 0.021 SDs to 0.036 more change relative to e3e3), and c-reactive protein protectively (β = -0.059; all P < 0.001). For e2 allele presence, there were three significant associations: change in ApoB, total cholesterol and LDL in protective directions (β range = -0.057 to -0.090). There were no APOE genotypic interactions with baseline age, sex, or medication history, nor significant findings associated with non- APOE (Alzheimer’s disease) polygenic risk. APOE e genotype significantly modifies particularly lipid trajectories across time – most strongly ApoB levels. This adds nuance to lipids as a dementia risk factor, and, clinically, suggests more frequent lipid assessments in e4 carriers in that context. Our findings provide a plausible partial biological explanation for APOE’s progressive influence on neurocognitive health.
