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, rs6910730G, 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, rs7759295C, 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 rs6910730G 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.