Investigators for this study report the development and use of an innovative, powerful approach to identify functional variants that provide AD resilience to high-risk individuals. In this study, pedigrees were identified with a statistical excess of AD mortality that also included at least four AD high-risk resilient individuals. Linkage analysis was performed in these families and whole genome sequence (WGS) data from resilient individuals was used to interrogate identified linkage regions for candidate variants.  Finally, RAB10 and SAR1A was tested for biological impact in vitro. The results of this study suggest that RAB10 variants impact risk for AD and that RAB10 may represent a promising therapeutic target for AD prevention.

Researchers user the Utah Population Database (UPDB) to identify large pedigrees with an evidence of excess AD mortality (i.e., families with a higher number of AD deaths than expected).  Pedigrees with an excess of AD deaths were identified by comparing the observed (i.e., number of affected individuals in the pedigree) to the expected numbers of AD-affected individuals within the pedigree. The expected number of AD deaths was estimated using population-based, cohorts specific rates of AD death estimated from all Utah death certificates for individuals in the UPDB genealogy.

“AD resilient individuals” defined as individuals who are at least 75 years old, cognitively normal, and carry at least one APOE ε4 allele were included in this study.  AD deaths were identified by the inclusion of ICD codes for AD death in individual death certificates, where deaths were only considered an AD death if the death certificate included AD ICD codes (ICD9 331.0; ICD10 F00 or G30) as a primary or contributing cause-of-death.

An expert panel of neurologists, neuropsychologists, neuropsychiatrists, and a cognitive neuroscientist assigned final diagnoses of dementia following standard research protocols (e.g., NINCDS-ADRDA criteria for AD or NINCDS-AIREN criteria for vascular dementia).