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).