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, A beta 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 A beta (42) based) were calculated, APOE genotype was determined, and A beta 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 A beta misfolding were assessed through logistic regression and the ability of each genetic marker and A beta misfolding to predict Alzheimer's disease was determined. The Alzheimer's disease polygenic risk score and APOE epsilon 4 presence were associated to A beta misfolding (odds ratio, 95% confidence interval: per standard deviation increase of score: 1.25, 1.03-1.51; APOE epsilon 4 presence: 1.61, 1.04-2.49). No association was evident for the A beta polygenic risk score. All genetic markers were predictive of Alzheimer's disease diagnosis albeit much less so than A beta misfolding (areas under the curve: A beta polygenic risk score: 0.55; AD polygenic risk score: 0.59; APOE epsilon 4: 0.63; A beta misfolding: 0.84). Clinical Alzheimer's genetic risk was associated to early pathological changes (A beta misfolding) measured in blood, however, predicted Alzheimer's disease less accurately than A beta misfolding itself. Genetic predisposition may provide information regarding disease initiation, while A beta misfolding could be important in clinical risk prediction.

Automated summary

This study found that the polygenic risk score for Alzheimer's disease and the presence of the APOE ε4 gene were associated with Aβ misfolding, while the Aβ polygenic risk score was not. All genetic markers could predict Alzheimer's disease diagnosis, but Aβ misfolding had higher predictive accuracy than the other genetic markers.