The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging

Clifford, K. P.; Prevot, T. D.; Sumitomo, A.; Bansal, Y.; Das, S.; Marcotte, M.; Zhou, R.; Yeung, J.; Ding, M.; Felsky, D.; Nieman, B.; Banasr, M.; Sibille, E.; Tomoda, T.; Nikolova, Y.

doi:10.64898/2026.10.27.762265

bioRxiv · 10.64898/2026.10.27.762265

The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging

Clifford, K. P.·Prevot, T. D.·Sumitomo, A.·Bansal, Y.·Das, S.·Marcotte, M.·Zhou, R.·Yeung, J.·Ding, M.·Felsky, D.·Nieman, B.·Banasr, M.·Sibille, E.·Tomoda, T.·Nikolova, Y.

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Abstract

The human extracellular-matrix-related FREM3 gene is strongly age-dependent, enriched in age-sensitive excitatory long-range-projecting neurons, and implicated in neurodegenerative diseases. To establish the first translationally relevant causal evidence for the role of FREM3 in brain structure and cognition, we developed an excitatory-neuron-specific Frem3 conditional knockout mouse model (Frem3-cKO) and computed genetically regulated expression of FREM3 (FREM3-GReX) in humans, enabling convergent neurostructural and cognitive characterizations. Frem3-cKO mice showed widespread lower global and regional brain volume in middle age vs young adulthood, consistent with drastic age-dependent volume loss absent in wildtype mice. These effects were strongest in cognitively relevant cortical regions and paralleled by lower cognitive performance. In humans, lower FREM3-GReX was associated with lower total surface area, which further mediated an indirect link to lower cognitive performance across multiple age-sensitive domains. We provide the first translationally relevant cross-species evidence supporting a key role for FREM3/Frem3 in maintaining brain and cognitive health across aging.

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Clifford, K. P., Prevot, T. D., Sumitomo, A., Bansal, Y., Das, S., Marcotte, M., Zhou, R., Yeung, J., Ding, M., Felsky, D., Nieman, B., Banasr, M., Sibille, E., Tomoda, T., Nikolova, Y.. 2026-10-28. The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging. https://doi.org/10.64898/2026.10.27.762265

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