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O4–06–04: Late‐onset Alzheimer's disease neuropathology genomic screen identifies novel loci for neuritic plaque and other Alzheimer's neuropathology features
Author(s) -
Beecham Gary,
HamiltonNelson Kara,
Naj Adam,
Wang LiSan,
Martin Eden,
Mayeux Richard,
Haines Jonathan,
Farrer Lindsay,
Schellenberg Gerard,
PericakVance Margaret,
Montine Thomas
Publication year - 2013
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.2013.04.368
Subject(s) - neuropathology , genome wide association study , cerebral amyloid angiopathy , apolipoprotein e , senile plaques , alzheimer's disease , pathology , disease , psychology , biology , medicine , genetics , genotype , dementia , single nucleotide polymorphism , gene
lectins. Methods: Here, we explore the functional outcomes of genetic variation at the CD33 locus using: ex vivo immune profiling, pathologic and imaging characterization of human subjects, immunohistochemistry, as well as in vitro evaluations of monocyte function. Ex vivo immune profiling was performed on subjects from a number of cohorts: the Brigham and Women’s Hospital PhenoGenetic Project (n1⁄449), the Memory and Aging Project (MAP) (n1⁄460), the Religious Orders Study (ROS) (n1⁄491), and the Chicago Health and Aging Project (CHAP) (n1⁄424). Pathological studies were performed on 151 subjects from the ROS and MAP cohorts. 172 MAP subjects were used for the microglia immunohistochemistry studies. Imaging data was examined from two collections of older subjects: The Harvard Aging Brain study (n1⁄4122) and the AD Neuroimaging Initiative (n1⁄496). Monocyte function was analyzed using subjects from the PhenoGenetic Project. Results: We report that the risk allele, rs3865444 C is associated with: 1) greater cell surface protein expression of CD33 (in both old (p1⁄4.4.1 x 10) and young individuals (p1⁄42.2x10)), 2) diminished internalization of beta-amyloid peptide 142 (p1⁄40.001) and dextran (p1⁄40.003), 3) accumulation of fibrillar amyloid as measured by Pittsburgh Compound B in living subjects (p1⁄40.02), and 4) neuritic amyloid pathology (p1⁄40.01) as well as a pathologic diagnosis of AD in deceased subjects (p1⁄40.01). Further, we found that CD33 is expressed not only in circulating monocytes, but also in microglia/macrophages in the brain. There is also an increased proportion of activated microglia in the inferior temporal lobe of brains of subjects bearing the risk allele (p1⁄40.003). Conclusions: Thus, our functional dissection of the CD33 locus provides evidence that the CD33 molecule plays a role in amyloid biology.