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

Excitatory-neuron-specific Frem3 conditional knockout mice show widespread lower global and regional brain volume in middle age versus young adulthood, with strongest effects in cortical regions linked to cognition.

• Why it matters: The study addresses the lack of translationally relevant causal evidence for how age-dependent FREM3 influences brain structure and cognitive aging.
• What they did: It created an excitatory-neuron-specific Frem3 conditional knockout mouse model (Frem3-cKO) and computed human genetically regulated expression of FREM3 (FREM3-GReX) to compare neurostructural and cognitive outcomes across species.
• The result: In humans, lower FREM3-GReX is associated with lower total surface area, which mediates an indirect link to lower cognitive performance across multiple age-sensitive domains.