A TREM1 variant alters the accumulation of Alzheimer‐related amyloid pathology. Issue 3 (March 2015)

• Record Type: Journal Article
• Authors: Replogle, Joseph M.; Chan, Gail; White, Charles C.; Raj, Towfique; Winn, Phoebe A.; Evans, Denis A.; Sperling, Reisa A.; Chibnik, Lori B.; Bradshaw, Elizabeth M.; Schneider, Julie A.; Bennett, David A.; De Jager, Philip L.
• Is Part Of: Annals of neurology. Volume 77:Issue 3(2015:Mar.)
• Page Start: 469
• Page End: 477
• Publication Date: 2015-03
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24337
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24337-sec-0001" sec-type="section"> <title>Objective</title> <p>Genome‐wide association studies have linked variants in <italic>TREM2</italic> (triggering receptor expressed on myeloid cells 2) and <italic>TREML2</italic> with Alzheimer disease (AD) and AD endophenotypes. Here, we pursue a targeted analysis of the <italic>TREM</italic> locus in relation to cognitive decline and pathological features of AD.</p> </sec> <sec id="ana24337-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="ana24337-sec-0003" sec-type="section"> <title>Results</title> <p>We provide evidence that an intronic variant, rs6910730<sup>G</sup>, in <italic>TREM1</italic>, is associated with an increased burden of neuritic plaques (<italic>p</italic> = 3.7 × 10<sup>−4</sup>), diffuse plaques (<italic>p</italic> = 4.1 × 10<sup>−3</sup>), and Aβ density (<italic>p</italic> = 2.6 × 10<sup>−3</sup>) as well as an increased rate of cognitive decline (<italic>p</italic> = 5.3 × 10<sup>−3</sup>). A variant upstream of <italic>TREM2</italic>, rs7759295<sup>C</sup>, is independently associated with an increased tau tangle density (<italic>p</italic> = 4.9 × 10<sup>−4</sup>), an increased burden of neurofibrillary tangles (<italic>p</italic> = 9.1 × 10<sup>−3</sup>), and an increased rate of cognitive decline (<italic>p</italic> = 2.3 × 10<sup>−3</sup>). Finally, a cytometric analysis shows that the <italic>TREM1</italic> rs6910730<sup>G</sup> allele is associated with decreased TREM1 expression on the surface of myeloid cells (<italic>p</italic> = 1.7 × 10<sup>−3</sup>).</p> </sec> <sec id="ana24337-sec-0004" sec-type="section"> <title>Interpretation</title> <p>We provide evidence that 2 common variants within the <italic>TREM</italic> 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. Ann Neurol 2015;77:469–477</p> </sec> </abstract>