Dataset Information

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease.

ABSTRACT: Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-β burden. Leveraging rich multimodal data from a population-based sample of older adults, we found that this novel tau PRS was a strong surrogate of tau PET deposition and captured a significant proportion of the variance in tau PET levels as compared with amyloid PET burden, APOE (apolipoprotein E) ε4 (the most common risk allele for AD), and a non-APOE PRS of clinical case-control AD risk variants. In independent validation samples, the tau PRS was associated with cerebrospinal fluid phosphorylated tau levels in one cohort and with postmortem Braak neurofibrillary tangle stage in another. We also observed an association of the tau PRS with longitudinal cognitive trajectories, including a statistical interaction of the tau PRS with amyloid burden on cognitive decline. Although additional study is warranted, these findings demonstrate the potential utility of a tau PRS for capturing the collective genetic background influencing tau deposition in the general population. In the future, a tau PRS could be leveraged for cost-effective screening and risk stratification to guide trial enrollment and clinical interventions in AD.

SUBMITTER: Ramanan VK

PROVIDER: S-EPMC9109940 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease.

Ramanan Vijay K VK Heckman Michael G MG Lesnick Timothy G TG Przybelski Scott A SA Cahn Elliot J EJ Kosel Matthew L ML Murray Melissa E ME Mielke Michelle M MM Botha Hugo H Graff-Radford Jonathan J Jones David T DT Lowe Val J VJ Machulda Mary M MM Jack Clifford R CR Knopman David S DS Petersen Ronald C RC Ross Owen A OA Vemuri Prashanthi P

Acta neuropathologica 20220412 5

Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyo ...[more]

PMID: 35412102

Similar Datasets

Project description: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 Aβ pathology status (Aβ positives (n = 322), Aβ 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-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).ConclusionsPolygenic 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.

Dataset Information

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease.

Publications

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets