Association Between Polygenic Risk Score and the Progression from Mild Cognitive Impairment to Alzheimer's Disease
Hongliang Liu1,2, Michael Lutz3, Sheng Luo4
1Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
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-PET and AV45-PET), 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 Aβ42 (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.
Insights
Polygenic risk scores (PRS) predict Alzheimer's disease (AD) progression in individuals with mild cognitive impairment (MCI). PRS also correlate with cognitive decline and key AD biomarkers, offering potential for early prediction.
Area of Science:
- Neuroscience
- Genetics
- Gerontology
Background:
- Mild cognitive impairment (MCI) is a complex condition with a significant risk of progressing to Alzheimer's disease (AD).
- Identifying predictive markers for AD progression in MCI patients is crucial for timely intervention.
Purpose of the Study:
- To evaluate the association between polygenic risk scores (PRS) and the time to AD progression from MCI.
- To assess PRS correlations with longitudinal cognitive changes and AD-related biomarkers (cerebrospinal fluid and imaging).
Main Methods:
- Constructed PRS using 40 independent non-APOE single nucleotide polymorphisms (SNPs) from Alzheimer's Disease Genome-Wide Association Studies (GWAS).
- Tested PRS association with MCI to AD progression in 767 MCI patients from ADNI and 1373 from NACC studies.
- Analyzed PRS association with cognitive scores, CSF biomarkers (tau, p-tau, Aβ42), and neuroimaging (amyloid PET, hippocampal volume).
Main Results:
- PRS significantly predicted MCI to AD progression in both ADNI (p=0.003) and NACC (p=0.009) cohorts.
- PRS correlated with increased cognitive impairment scores (ADAS-Cog), elevated tau/p-tau, and amyloid burden, but reduced hippocampal volume.
- Mediation analysis indicated Aβ42 partially mediates the effect of PRS on AD risk.
Conclusions:
- Polygenic risk scores are valuable predictors of AD progression and clinical changes following MCI diagnosis.
- PRS may aid in identifying MCI patients at higher risk for developing Alzheimer's disease.
More Related Videos
Related Concept Videos
01:26Alzheimer's Disease: Overview
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
01:11Genome-wide Association Studies-GWAS
GWAS does not require the identification of the target gene involved in...
01:18Polygenic Traits
01:22Alzheimer's Disease: Treatment
01:25Imaging Studies for Cardiovascular System VI: Calcium -Scoring CT