A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology.

Ann Neurol
Authors
Keywords
Abstract

OBJECTIVE: Genome-wide association studies have linked variants in TREM2 (triggering receptor expressed on myeloid cells 2) and TREML2 with Alzheimer disease (AD) and AD endophenotypes. Here, we pursue a targeted analysis of the TREM locus in relation to cognitive decline and pathological features of AD.

METHODS: Clinical, cognitive, and neuropathological phenotypes were collected in 3 prospective cohorts on aging (n = 3,421 subjects). Our primary analysis was an association with neuritic plaque pathology. To functionally characterize the associated variants, we used flow cytometry to measure TREM1 expression on monocytes.

RESULTS: We provide evidence that an intronic variant, rs6910730(G) , in TREM1, is associated with an increased burden of neuritic plaques (p = 3.7 × 10(-4) ), diffuse plaques (p = 4.1 × 10(-3) ), and Aβ density (p = 2.6 × 10(-3) ) as well as an increased rate of cognitive decline (p = 5.3 × 10(-3) ). A variant upstream of TREM2, rs7759295(C) , is independently associated with an increased tau tangle density (p = 4.9 × 10(-4) ), an increased burden of neurofibrillary tangles (p = 9.1 × 10(-3) ), and an increased rate of cognitive decline (p = 2.3 × 10(-3) ). Finally, a cytometric analysis shows that the TREM1 rs6910730(G) allele is associated with decreased TREM1 expression on the surface of myeloid cells (p = 1.7 × 10(-3) ).

INTERPRETATION: We provide evidence that 2 common variants within the TREM locus are associated with pathological features of AD and aging-related cognitive decline. Our evidence suggests that these variants are likely to be independent of known AD variants and that they may work through an alteration of myeloid cell function.

Year of Publication
2015
Journal
Ann Neurol
Volume
77
Issue
3
Pages
469-77
Date Published
2015 Mar
ISSN
1531-8249
URL
DOI
10.1002/ana.24337
PubMed ID
25545807
PubMed Central ID
PMC4461024
Links
Grant list
U01 AG046152 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
P01 AG036694 / AG / NIA NIH HHS / United States
R01 AG043617 / AG / NIA NIH HHS / United States
K25AG41906 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01AG17917 / AG / NIA NIH HHS / United States
U01AG46152 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01AG30146 / AG / NIA NIH HHS / United States
R01AG11101 / AG / NIA NIH HHS / United States
R01AG15819 / AG / NIA NIH HHS / United States
P01AG036694 / AG / NIA NIH HHS / United States
P30AG10161 / AG / NIA NIH HHS / United States
R01 AG011101 / AG / NIA NIH HHS / United States
R01AG43617 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States