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bioRxiv · 10.64898/2026.09.16.752098

A self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer's disease

Lin, D.·Atkinson, J. R.·Wu, W.·Chen, M.·Jayasekara, S.·Segal, B. M.·Ma, A.·Gao, J.
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Abstract

Microglia are key drivers of Alzheimer's disease (AD), and TREM2, one of the strongest genetic risk factors, enables the disease-associated microglia (DAM) state required for plaque engagement. How TREM2 sustains this protection, and why it falters as disease advances, remain unclear. Using proteomics, single-cell transcriptomics, and in vivo metabolic labeling, we show that plaque-associated microglia mount a TREM2-dependent anabolic program coupling nascent protein synthesis to mitochondrial biogenesis. This program, not the DAM signature, marks phagocytically competent microglia; its loss is associated with proteostatic overload and mitochondrial dysfunction. Unexpectedly, this anabolic program is self-limiting, peaking at low amyloid burden and declining as burden rises. This decline is conserved in humans: across 523 donors, anabolic capacity tracks TREM2 but falls at advanced Braak stage even as DAM signature keeps rising. Thus, anabolic capacity, rather than activation state, marks microglial resilience in AD, and sustained stimulation of phagocytosis by anti-amyloid antibodies risks biosynthetic exhaustion and self-limiting efficacy.

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Lin, D., Atkinson, J. R., Wu, W., Chen, M., Jayasekara, S., Segal, B. M., Ma, A., Gao, J.. 2026-09-20. A self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer's disease. https://doi.org/10.64898/2026.09.16.752098

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