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

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, Aβ 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 Aβ₄₂ based) were calculated, APOE genotype was determined, and Aβ 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 Aβ misfolding were assessed through logistic regression and the ability of each genetic marker and Aβ misfolding to predict Alzheimer's disease was determined. The Alzheimer's disease polygenic risk score and APOE ε4 presence were associated to Aβ 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 Aβ polygenic risk score. All genetic markers were predictive of Alzheimer's disease diagnosis albeit much less so than Aβ misfolding (areas under the curve: Aβ polygenic risk score: 0.55; AD polygenic risk score: 0.59; APOE ε4: 0.63; Aβ misfolding: 0.84). Clinical Alzheimer's genetic risk was associated to early pathological changes (Aβ misfolding) measured in blood, however, predicted Alzheimer's disease less accurately than Aβ misfolding itself. Genetic predisposition may provide information regarding disease initiation, while Aβ misfolding could be important in clinical risk prediction.