Alzheimer’s & Dementia | August 1, 2024

Schauer SP, Cho CH, Novikova G, Roth GA, Lee J, Sharma AD, Foley AR, Ng C, Shen P, Choi M, Ma TP, Phu L, Budayeva HG, Cheung TK, Lalehzadeh G, Imperio J, Ngu H, Etxeberria A, Liang Y, Rezzonico MG, Dourado M, Huang K, Lai Z, Hokom M, Pandya NJ, Newton D, Abdel-Haleem AM, Chan P, Lee D, Tassew NG, Sangaraju D, O’Connor D, Hötzel I, Stark KL, Chou C, Foreman O, Easton A, Wildsmith KR, Sperinde G, Rose CM, Friedman BA, Fuji RN, Weimer RM, Meilandt WJ, Sadekar S, Nugent AA, Biever A.

Alzheimers Dement. 2024 

https://doi.org/10.1002/alz.13921

Abstract

INTRODUCTION

Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease-modifying therapeutics for Alzheimer’s disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials.

METHODS

We conducted multi-omic analyses on paired non-human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell–derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays. We immunostained microglia to characterize proliferation and clustering.

RESULTS

We report CSF soluble TREM2 (sTREM2) and CSF chitinase-3-like protein 1 (CHI3L1/YKL-40) as PD biomarkers for the TREM2 agonist hPara.09. The respective reduction of sTREM2 and elevation of CHI3L1 in brain and CSF after TREM2 agonist treatment correlated with transient microglia proliferation and clustering.

DISCUSSION

CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism and can be used as clinical PD biomarkers to monitor TREM2 activity in the brain.