Sex differences in memory impairments after traumatic brain injury: mechanisms and models.

Abstract

Traumatic brain injury (TBI) is a major cause of long-term cognitive impairment, with deficits in episodic memory among the most common and disabling consequences. Although biological sex is increasingly recognized as an important determinant of TBI outcomes, its role in shaping post-injury memory impairment remains incompletely understood. Findings from both clinical and preclinical studies are often inconsistent, and sex is frequently underrepresented in experimental designs. Clinical studies generally indicate that women experience worse cognitive outcomes after TBI, including more severe and persistent memory deficits and greater affective burden. In contrast, preclinical findings are more variable, with sex differences emerging in a domain-specific and context-dependent manner. Early animal studies often reported no significant sex differences, particularly in spatial memory tasks. More recent work reveals that males tend to show earlier and more widespread spatial learning impairments and greater vulnerability to anterograde memory deficits, while females more commonly exhibit delayed but persistent deficits in memory consolidation and retention. These behavioral differences are accompanied by sex-specific mechanisms. Altogether, sex differences in memory outcomes following TBI are complex, context-dependent, and shaped by both biological and methodological factors. Greater incorporation of sex as a biological variable in both clinical and preclinical research is essential. Moving toward a precision medicine framework, accounting for sex as a variable in therapeutic target selection and trial design will be important for optimizing cognitive recovery after TBI.