Polygenic Risk Score Effectively Predicts Risk of Depression Onset in Alzheimer’s Disease

Abstract Introduction: Depression is a common, though heterogenous, comorbidity in late-onset Alzheimer’s Disease (LOAD) patients. In addition, individuals with depression are at greater risk to develop LOAD. In previous work, we demonstrated shared genetic etiology between depression and LOAD. Collectively, this evidence suggested interactions between depression and LOAD. However, the underpinning genetic heterogeneity of depression co-occurrence with LOAD is largely unknown.Methods: Major Depressive Disorder (MDD) genome wide association study (GWAS) summary statistics were used to create polygenic risk scores (PRS). The Religious Orders Society and Rush Memory and Aging Project (ROSMAP) and National Alzheimer’s Coordinating Center (NACC) datasets were utilized to assess the PRS performance in predicting depression onset in LOAD patients.Results: The developed PRS showed marginal results in standalone models for predicting depression onset in both ROSMAP (AUC=0.540) and NACC (AUC=0.534). Full models, with baseline age, sex, education, and APOEε4 allele count, showed improved prediction of depression onset (ROSMAP AUC: 0.606, NACC AUC: 0.583). In time-to-event analysis, standalone PRS models showed significant effects in ROSMAP (P=0.0051), but not in NACC cohort. Full models showed significant performance in predicting depression in LOAD for both datasets (P<0.001 for all).Discussion: This study provided new insights into the genetic factors contributing to depression onset in LOAD and advanced our knowledge of the genetics underlying the heterogeneity of depression in LOAD. The developed PRS accurately predicted LOAD patients with depressive symptoms, thus, has clinical implications including, diagnosis of LOAD patients at high-risk to develop depression for early anti-depressant treatment.

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Association Between Polygenic Risk Score and the Progression from Mild Cognitive Impairment to Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210700 ◽

2021 ◽

pp. 1-13

Author(s):

Hongliang Liu ◽

Michael Lutz ◽

Sheng Luo ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Risk Scores ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Increased Risk ◽

Risk Of Progression ◽

Clinical Changes

Background: Mild cognitive impairment (MCI) is a heterogeneous condition and MCI patients are at increased risk of progression to dementia due to Alzheimer’s disease (AD). Objective: In this study, we aim to evaluate the associations between polygenic risk scores (PRSs) and 1) time to AD progression from MCI, 2) changes in longitudinal cognitive impairment, and 3) biomarkers from cerebrospinal fluid and imaging. Methods: We constructed PRS by using 40 independent non-APOE SNPs from well-replicated AD GWASs and tested its association with the progression time from MCI to AD by using 767 MCI patients from the ADNI study and 1373 patients from the NACC study. PRSs calculated with other methods were also computed. Results: We found that the PRS constructed with SNPs that reached genome-wide significance predicted the progression from MCI to AD (beta = 0.182, se = 0.061, p = 0.003) after adjusting for the demographic and clinical variables. This association was replicated in the NACC dataset (beta = 0.094, se = 0.037, p = 0.009). Further analyses revealed that PRS was associated with the increased ADAS-Cog11/ADAS-Cog13/ADASQ4 scores, tau/ptau levels, and cortical amyloid burdens (PIB and AV45), but decreased hippocampus and entorhinal cortex volumes (p < 0.05). Mediation analysis showed that the effect of PRS on the increased risk of AD may be mediated by Aβ 42 (beta = 0.056, SE = 0.026, p = 0.036). Conclusion: Our findings suggest that PRS can be useful for the prediction of time to AD and other clinical changes after the diagnosis of MCI.

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Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.08.013 ◽

2017 ◽

Vol 14 (2) ◽

pp. 205-214 ◽

Cited By ~ 41

Author(s):

Carlos Cruchaga ◽

Jorge L. Del-Aguila ◽

Benjamin Saef ◽

Kathleen Black ◽

Maria Victoria Fernandez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Score ◽

Early Onset ◽

Late Onset ◽

Polygenic Risk Score ◽

Polygenic Risk

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

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00754-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Anna Zettergren ◽

◽

Jodie Lord ◽

Nicholas J. Ashton ◽

Andrea L. Benedet ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Studies ◽

Amyloid Β ◽

Total Sample ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Tau Pathology ◽

Polygenic Risk

Abstract 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.

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Associations between Alzheimer’s disease polygenic risk scores and hippocampal subfield volumes in 17,161 UK Biobank participants

10.1101/2020.10.24.20218925 ◽

2020 ◽

Author(s):

Heidi Foo ◽

Anbupalam Thalamuthu ◽

Jiyang Jiang ◽

Forrest Koch ◽

Karen A. Mather ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Layer ◽

Community Dwelling ◽

Granule Cell Layer ◽

Risk Scores ◽

Uniform Structure ◽

Polygenic Risk Score ◽

Uk Biobank ◽

Polygenic Risk

AbstractHippocampal volume is an important biomarker of Alzheimer’s disease (AD), and genetic risk of AD is associated with hippocampal atrophy. However, the hippocampus is not a uniform structure and has a number of subfields, the associations of which with age, sex, and polygenic risk score for AD (PRSAD) have been inadequately investigated. We examined these associations in 17,161 cognitively normal UK Biobank participants (44-80 years). Age was negatively associated with all the hippocampal subfield volumes and females had smaller volumes than men. Higher PRSAD was associated with lower volumes in the bilateral whole hippocampus, hippocampal-amygdala-transition-area (HATA), and hippocampal tail; right subiculum; left cornu ammonis (CA)1, CA4, molecular layer, and granule cell layer of dentate gyrus (CG-DG), with associations being greater on the left side. Older individuals (median age 63 years, n=8984) showed greater subfield vulnerability to high PRSAD compared to the younger group (n=8177), but the effect did not differ by sex. The pattern of subfield involvement in relation to the PRSAD in community dwelling healthy individuals sheds additional light on the pathogenesis of AD.

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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Nature Communications ◽

10.1038/s41467-021-22491-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Itziar de Rojas ◽

Sonia Moreno-Grau ◽

Niccolo Tesi ◽

Benjamin Grenier-Boley ◽

Victor Andrade ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Stratification ◽

Risk Score ◽

Disease Risk ◽

Age At Onset ◽

Risk Scores ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Study Results

AbstractGenetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

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