Description

This study seeks to identify additional rare variants and novel genes potentially contributing to AD. Whole exome sequencing was performed on 23 multi-generational families with an average of eight affected subjects. Exome sequencing was filtered for rare, nonsynonymous and loss-of-function variants. Alterations predicted to have a functional consequence and located within either a previously reported AD gene, a linkage peak (LOD>2), or clustering in the same gene across multiple families, were prioritized.  240 individuals (77 AD subjects, 4 individuals with mild cognitive impairment (MCI) and 159 unaffected relatives) from 23 families of European ancestry heavily affected with late-onset AD were utilized in this study.  99 individuals (77 AD patients, 4 individuals with MCI, and 18 unaffected relatives) from 23 AD extended families underwent WES.

Affected individuals meet the standard NINCDS-ADRDA criteria for AD and MCI. In addition, cognitive and neuropsychiatric data were collected on all affected individuals using the NCRAC LOAD battery, the Geriatric Depression Scale (GDS15), the Cornell Scale for Depression in Dementia (CSDD) and the Neuropsychiatric Inventory Questionnaire (NPIQ).

Principal Investigators

  • Margaret A. Pericak-Vance, Ph.D. — University of Miami Miller School of Medicine

Funding Sources

National Institutes of Health (R01 AG027944, R01 AG028786 to MAPV, R01 AG019085 to JLH, P20 MD000546); a joint grant from the Alzheimer’s Association (SG-14-312644) and the Fidelity Biosciences Research Initiative to MAPV; the BrightFocus Foundation (A2011048 to MAPV). NIA-LOAD Family-Based Study supported the collection of samples used in this study through NIH grants U24 AG026395 and R01 AG041797 and the MIRAGE cohort was supported through the NIH grants R01 AG025259 and R01 AG048927.

Publications

  • Cukier HN. Exome Sequencing of Extended Families with Alzheimer's Disease Identifies Novel Genes Implicated in Cell Immunity and Neuronal Function. Journal of Alzheimer's disease & Parkinsonism. 2017 Aug. PubMed link