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Generalized Psychophysiological Interaction (PPI) Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease
Published on: November 14, 2017
Genetic data and cognitively defined late-onset Alzheimer's disease subgroups
Shubhabrata Mukherjee1, Jesse Mez2, Emily H Trittschuh3,4
1Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA.
Molecular Psychiatry
|December 6, 2018
Summary
Identifying distinct Alzheimer's disease subgroups is key for personalized medicine. This study found that individuals with significant memory loss show a stronger association with the APOE ε4 allele, suggesting biologically distinct groups.
Area of Science:
- Neuroscience
- Genetics
- Gerontology
Background:
- Personalized medicine for late-onset Alzheimer's disease (AD) requires biologically coherent patient subgroups.
- Cognitive heterogeneity in AD suggests underlying biological differences.
Purpose of the Study:
- To categorize individuals with late-onset AD into biologically coherent subgroups based on cognitive performance.
- To identify genetic factors, including APOE and novel single-nucleotide polymorphisms (SNPs), associated with these subgroups.
Main Methods:
- Analysis of genome-wide SNP data from 2431 individuals across five AD studies (total n=4050).
- Cognitive assessment categorized participants into subgroups based on memory, executive function, visuospatial skills, and language.
- Comparison of genotype frequencies between AD subgroups and cognitively normal elderly controls, focusing on APOE and suggestive SNPs (p < 10^-5).
Main Results:
- A significant association was observed between the APOE ε4 allele and the subgroup with isolated substantial relative memory impairment (p = 1.5 x 10^-27).
- Thirty-three novel suggestive genetic loci (p < 10^-5) with extreme odds ratios were identified across subgroups, with consistent effect directions.
- No statistical evidence of heterogeneity was found for these novel loci across datasets.
Conclusions:
- Cognitively defined subgroups of late-onset AD are biologically coherent.
- Novel genetic loci associated with specific AD cognitive profiles have been nominated, offering targets for future research and personalized medicine.
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