Genetic predisposition, Aß misfolding in blood plasma, and Alzheimer's disease.

ABSTRACT

Alzheimer's disease is highly heritable and characterized by amyloid plaques and tau tangles in the brain. The aim of this study was to investigate the association between genetic predisposition, Aß misfolding in blood plasma, a unique marker of Alzheimer associated neuropathological changes, and Alzheimer's disease occurrence within 14 years. Within a German community-based cohort, two polygenic risk scores (clinical Alzheimer's disease and Aß42 based) were calculated, APOE genotype was determined, and Aß misfolding in blood plasma was measured by immuno-infrared sensor in 59 participants diagnosed with Alzheimer's disease during 14 years of follow-up and 581 participants without dementia diagnosis. Associations between each genetic marker and Aß misfolding were assessed through logistic regression and the ability of each genetic marker and Aß misfolding to predict Alzheimer's disease was determined. The Alzheimer's disease polygenic risk score and APOE ε4 presence were associated to Aß misfolding (odds ratio, 95% confidence interval per standard deviation increase of score 1.25, 1.03-1.51; APOE ε4 presence 1.61, 1.04-2.49). No association was evident for the Aß polygenic risk score. All genetic markers were predictive of Alzheimer's disease diagnosis albeit much less so than Aß misfolding (areas under the curve Aß polygenic risk score 0.55; AD polygenic risk score 0.59; APOE ε4 0.63; Aß misfolding 0.84). Clinical Alzheimer's genetic risk was associated to early pathological changes (Aß misfolding) measured in blood, however, predicted Alzheimer's disease less accurately than Aß misfolding itself. Genetic predisposition may provide information regarding disease initiation, while Aß misfolding could be important in clinical risk prediction.