Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals.
J Alzheimers Dis
; 94(4): 1587-1605, 2023.
Article
in En
| MEDLINE
| ID: mdl-37482996
ABSTRACT
BACKGROUND:
Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan.OBJECTIVE:
In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways.METHODS:
PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample.RESULTS:
We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-ß, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded.CONCLUSION:
In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-ß, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-ß and tau, long before the onset of clinical symptoms.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Alzheimer Disease
/
Cognitive Dysfunction
Type of study:
Diagnostic_studies
/
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
J Alzheimers Dis
Journal subject:
GERIATRIA
/
NEUROLOGIA
Year:
2023
Type:
Article
Affiliation country:
United States