Abstract
Brain Behav Immun. 2026 Jan 26:106468. doi: 10.1016/j.bbi.2026.106468. Online ahead of print.
ABSTRACT
Heightened TREM2-dependent microglial activation is thought to protect against the negative effects of Alzheimer's disease (AD) neuropathology, but data in preclinical disease and in the context of aging are lacking. This study examined the association of longitudinal hippocampal atrophy and memory composite scores with baseline sTREM2 in the cerebrospinal fluid (CSF) in two large, well-characterized samples of elderly individuals. It was hypothesized that higher sTREM2 would be associated with slower atrophy and cognitive decline and that this effect would be stronger in those with higher AD neuropathology. Linear mixed effects models predicting hippocampal volume and cognitive decline tested interactions between sTREM2 and time (years since baseline) to see whether higher sTREM2 was associated with slower atrophy and cognitive decline, controlling for pTau181 and its interaction with time. A three-way interaction between pTau181, sTREM2, and time was then added to determine whether AD pathology moderated effects of sTREM2. Results showed that higher sTREM2 was associated with slower hippocampal atrophy and cognitive decline independently of pTau181 levels. Further analysis showed that cognitive effects were moderated by AD pathology levels such that beneficial effects of sTREM2 were stronger at higher levels of AD pathology, though this effect was very small, and the interaction between sTREM2 and time remained significant. These findings suggest that higher TREM2-dependent microglial activation, as indexed by sTREM2, may indicate subtle resilience not just to the effects of AD but to age-related neurodegeneration more broadly.
PMID:41605308 | DOI:10.1016/j.bbi.2026.106468
UK DRI Authors
