Assessment of Quantitative Biological Phenotypes as Potential Endophenotypes for Alzheimer's Disease (AD)

Another line of research in our laboratory is the study of AD genetics using biologically relevant endophenotypes including neuroimaging, pathology and neuropsychometric variables. We can apply these approaches both in the assessment of variants in known AD candidate genes as well as in novel gene/variant discovery.

In our laboratory, effect of genetic variants on biological phenotypes such as neuroimaging and cognitive variables are assessed. Variants with significant effects on these biological phenotypes are also analyzed for association with AD risk.

To exemplify our approach, we have recently assessed variables in a candidate gene for cognition and AD risk, KIBRA, which was identified by others to influence memory in a genome-wide association study (GWAS) of cognition. We genotyped 15 single nucleotide polymorphisms (SNPs) in >2500 LOADs vs. >2800 controls, including African-Americans. We found significant as well as suggestive evidence of AD risk in a number of our series. We also assessed episodic memory in a subset of these subjects that constituted four cognitively normal Caucasian and two African-American series, collectively composed of >2000 subjects; and identified significant associations in one of the series. We found KIBRA to be overexpressed in the temporal cortex but not cerebellum of AD brains.

These results provide additional support for KIBRA as a cognition and AD risk gene, but also highlight the multifactorial complexity of its genetic associations. Importantly, they provide an example of the endophenotype approach utilized in our laboratory that combines the strength of our large AD case-control series, with the cross-sectional and longitudinal collection of rich endophenotypes, such as cognition and gene expression.

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