Association between polygenic risk score of Alzheimer's disease and plasma phosphorylated tau in individuals from the Alzheimer's Disease Neuroimaging Initiative

BackgroundRecent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer's disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181.MethodsData from the Alzheimer's Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n=818), after stratification on diagnostic status (CU (n=236), MCI (n=434), AD dementia (n=148)), and after stratification on A beta pathology status (A beta positives (n=322), A beta negatives (n=409)).ResultsAssociations between plasma p-tau181 and APOE PRSs (p=3e(-18)-7e(-15)) and non-APOE PRSs (p=3e(-4)-0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-beta (A beta)-positive and negative individuals (p=5e(-5)-1e(-3)), while the non-APOE PRSs were associated with plasma p-tau181 in A beta positives only (p=0.02).ConclusionsPolygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and A beta pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and A beta -positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.

Automated summary

The study revealed that polygenic risk for AD, including APOE, was associated with plasma p-tau181 regardless of diagnostic or A beta pathology status, while polygenic risk for AD beyond APOE was only linked to plasma p-tau181 in individuals with MCI and A beta positivity.