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

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 gene’s roles 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.