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P2‐133: ASSOCIATION OF OLFACTORY PERFORMANCE AND HIPPOCAMPAL VOLUME IN PERSONS AT RISK OF ALZHEIMER'S DEMENTIA
Author(s) -
LafailleMagnan MarieElyse,
Collins Louis,
Fonov Vladimir,
Fontaine David,
Etienne Pierre,
Poirier Judes,
Breitner John C.S.
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.05.808
Subject(s) - dementia , repeatable battery for the assessment of neuropsychological status , clinical dementia rating , audiology , psychology , alzheimer's disease , olfaction , montreal cognitive assessment , cognition , neuropsychology , disease , psychiatry , medicine , neuroscience
EOAD andw11% of EOAD overall, leaving the majority of genetic risk for this severe form of Alzheimer disease unexplained. Methods: To identify novel early-onset Alzheimer disease candidate genes we performed Whole-Exome Sequencing (WES) on 55 individuals in 19 Caribbean Hispanic EOAD families previously screened negative for APP, PSEN1, and PSEN2 to search for rare variants contributing to risk for EOAD. Variants were filtered for segregating, conserved and functional rare variants (MAF<0.1%) assuming both autosomal and X-linked dominant models. Filtered loci were examined for implication as AD candidate genes by comparison to: late-onset Alzheimer (LOAD) susceptibility genes, biologically relevant Alzheimer KEGG Pathway genes, candidate genes from 45WESed NH-White EOAD cases, and results of an Alzheimer’s Disease Genetics Consortium (ADGC) exome chip association study. Results: 2,225 variants in 1,531 genes passed our stringent filtering criteria, including 308 genes with rare segregating, conserved and functional variants in two or more families. Frameshift insertions-deletions in ABCA7 and HLA-DRB1, a nonframeshift deletion in RIN3, and missense variants in DSG2 and PICALM, all LOAD susceptibility genes, were discovered. 11 AD KEGG Pathway genes have variants, including LRP1, a gene involved in AD through its roles in cholesterol transport and b-amyloid modulation. 83 variant carrying genes are in 2+ Hispanic and 2+ Non-white Hispanic families, including the AD-relevant HLA-A (associated with earlier AD age-at-onset), CHST15 (a potential modulator or Abeta toxicity), and NOTCH4 (a presenelin pathway gene). Exome chip results showed the variant carrying gene MICA, which encodes the HLA-A gene and has been associated with LOAD in a small study, as having suggestive association (p1⁄49.10x10-4). One family has variants in both HLA-A and MICA. Conclusions: Exome sequencing of Hispanic EOAD pedigrees identified multiple rare segregating variants with potential roles in AD pathogenesis, several of which were shared in two or more families.