Cerebrospinal fluid soluble TREM2 is associated with accelerated AD‐related longitudinal neurodegeneration in preclinical Alzheimer’s disease
Authors: Stephenson Henry G. , Deming Yuetiva , Ewers Michael , Ma Yue , Van Hulle Carol A. , Koscik Rebecca Langhough , Jonaitis Erin M. , Ulland Tyler K. , Chin Nathaniel A. , Okonkwo Ozioma C. , Betthauser Tobey J , Asthana Sanjay , Kollmorgen Gwendlyn , Suridjan Ivonne , Wild Norbert , Carlsson Cynthia M. , Johnson Sterling C. , Blennow Kaj , Zetterberg Henrik , Bendlin Barbara B 
Published: June 2023

AbstractBackgroundCerebrospinal fluid (CSF) concentration of soluble TREM2 (sTREM2), a potential biomarker for microglial activation, is associated with attenuated longitudinal neurodegeneration and cognitive decline in Alzheimer’s disease (AD), but data in early disease are lacking. This study’s purpose was to use longitudinal volumetric imaging to assess the association of sTREM2 with age‐ and preclinical AD‐related grey matter (GM) changes.MethodCognitively unimpaired participants (N = 384; amyloid‐positive N = 82) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin ADRC clinical core studies with baseline CSF biomarker and subsequent longitudinal T1‐weighted magnetic resonance imaging data were analyzed. CSF sTREM2 and phosphorylated‐tau181/amyloid‐beta1‐42 ratio (pTau/Aβ42) were measured using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). T1‐weighted images were longitudinally registered to intra‐subject templates and segmented to create 58 GM regions of interest (ROIs) via the CAT12 longitudinal segmentation pipeline. Linear mixed‐effects models (random participant intercepts and age slopes) testing a three‐way interaction between time‐varying age, sTREM2, and pTau/Aβ42 to predict regional grey matter changes with all potential two‐way interactions and simple effects (adjusted for gender, years of education, intracranial volume, and head coil) were tested. In the event of a non‐significant three‐way interaction, the three‐way interaction was dropped and the model was reinterpreted. Statistical significance was considered at p < .05, uncorrected for multiple comparisons.ResultAge had a negative effect on regional GM volume across the brain and showed widespread interactions with pTau/Aβ42, indicative of accelerated decline with AD pathology. Negative three‐way interactions between sTREM2, pTau/Aβ42, and age were evident in the angular, supramarginal, lingual, and middle occipital gyri, predicting accelerated AD‐related longitudinal neurodegeneration with higher sTREM2 concentration. Negative two‐way interactions between pTau/Aβ42 and sTREM2 were evident in the supplementary motor cortex and superior frontal gyrus, indicating worse effects of AD‐pathology with higher sTREM2, regardless of age.ConclusionOverall, higher sTREM2 may be associated with accelerated AD‐related neurodegeneration over time in the context of preclinical AD, particularly in posterior ROIs. Higher sTREM2 and underlying microglial activation may denote individuals at higher risk of experiencing the deleterious effects of early AD pathology on the brain.