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Background  Recent 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.    Methods  Data 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 Aβ pathology status (Aβ positives ( n  = 322), Aβ negatives ( n  = 409)).    Results  Associations 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-β (Aβ)-positive and negative individuals ( p  = 5e −5 –1e −3 ), while the non- APOE  PRSs were associated with plasma p-tau181 in Aβ positives only ( p  = 0.02).    Conclusions  Polygenic risk for AD including  APOE  was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond  APOE  was associated with plasma p-tau181 only in MCI and Aβ-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.

alzheimer's research and therapy

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