Higher neuroplasticity marker linked to faster cognitive decline in women only

Older women whose cerebrospinal fluid carries higher levels of a protein that signals neuroplastic activity show faster decline in language, executive function, and visuospatial tasks, as well as functional abilities, over a mean 6.4-year follow-up, while men with the same protein signature do not, according to a study published in Alzheimer's Research & Therapy. The finding, drawn from the Vanderbilt Memory and Aging Project cohort, suggests that differential responses to neuroplasticity in aging, possibly driven by estrogen, could help explain long-recognized sex differences in cognitive decline.

The protein in question is growth associated protein-43, or GAP-43, a fluid marker of neuroplasticity. The research team, led by Corey J. Bolton and Amalia J. Peterson with colleagues including Timothy J. Hohman and Angela L. Jefferson, investigated the interaction of sex with GAP-43 on cognitive and functional decline, noting that estrogen may play a key role in neuroplasticity. The study's background notes that as women age and estrogen levels decline, high levels of neuroplasticity may be unsustainable.

To test that idea, the investigators turned to the Vanderbilt Memory and Aging Project. They enrolled 161 community-dwelling older adults, free of clinical dementia or stroke, with an average age of 72 years and 31 percent women. Each participant underwent a fasting lumbar puncture so researchers could analyze cerebrospinal fluid levels of GAP-43 in batch, alongside a comprehensive neuropsychological assessment at study entry. Participants were then tracked over a mean follow-up period of 6.4 years, allowing the team to relate baseline GAP-43 both to cognition and daily functioning at a single point in time and to the slope of change over the years that followed.

The analyses adjusted for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)-ε4 status, modified Framingham Stroke Risk Profile, and cognitive status. Analyses adjusted for baseline age, sex, education, race and ethnicity, apolipoprotein E ε4 status, a modified Framingham Stroke Risk Profile score, and cognitive status, so that the GAP-43 signal could not simply be attributed to known vascular or genetic risk factors. Follow-up models then formally tested whether GAP-43 interacted with sex in shaping cognitive and functional trajectories.

The cross-sectional results showed associations at baseline. At baseline, higher GAP-43 was associated with worse language performance, with a standardized effect of β = -0.0005 and p = 0.04, and worse visuospatial function, β = -0.0004 and p = 0.005. Higher levels also corresponded to greater functional impairment in everyday abilities, β = 0.002 and p = 0.003. Notably, however, GAP-43 did not interact with sex on any of these cross-sectional outcomes; the sex-specific pattern emerged only when the researchers examined change over time.

The longitudinal picture differed. Across the full sample, higher baseline GAP-43 predicted faster decline on language, executive function, and visuospatial tasks, with p-values below 0.02, as well as faster deterioration in functional abilities, β = 0.0006 and p = 0.007. But when the interaction with sex was modeled, the association differed by sex. GAP-43 interacted with sex on longitudinal trajectories of many cognitive measures, including language, processing speed, executive functioning, and visuospatial tasks, with p-values below 0.05, and on functional abilities with p = 0.005. Stratified by sex, GAP-43 was associated with faster decline in women, with p-values below 0.02, but not in men, where p-values exceeded 0.26.

In practical terms, the same cerebrospinal fluid concentration of this neuroplasticity marker was associated with faster decline only in women in this cohort. The authors interpret this as evidence that higher GAP-43 levels, indicating increased neuroplasticity, relate to longitudinal decline in cognition and functional abilities exclusively in women among community-dwelling older adults free of dementia.

The estrogen hypothesis offers a possible explanation for these results. The study's background notes that estrogen may play a key role in neuroplasticity, and that as women age and estrogen levels decline, high levels of neuroplasticity may be unsustainable. Differential responses to neuroplasticity in aging, possibly driven by estrogen, could therefore help explain the long-recognized sex differences in cognitive decline, the researchers conclude.

Several cautions temper the interpretation. The cohort is modest in size, at 161 participants with only 31 percent women, and all participants were community-dwelling older adults without clinical dementia or stroke at entry, so the findings may not generalize to clinical populations. The study measured GAP-43 at a single baseline time point, and the analysis is observational, meaning it identifies associations rather than proving that neuroplastic activity causes decline. The article was released as an accepted, peer-reviewed manuscript shared early for faster access, citable under a permanent DOI, with a final version of record to follow. Even so, the sex-specific interaction was assessed in models adjusting for baseline age, sex, education, race/ethnicity, APOE-ε4 status, modified Framingham Stroke Risk Profile, and cognitive status, and emerged across multiple cognitive domains.

Subject of Research: Sex-specific associations between the neuroplasticity marker GAP-43 and cognitive and functional decline in older adults

Article Title: Increased neuroplastic activity is associated with cognitive decline in women but not men over an average 6-year follow-up period

Article References: Bolton, C. J., Zhang, P., Liu, D., Gaynor, L. S., Pechman, K. R., Hohman, T. J., Zetterberg, H., Jefferson, A. L., & Peterson, A. J. (2026). Increased neuroplastic activity is associated with cognitive decline in women but not men over an average 6-year follow-up period. Alzheimer's Research & Therapy. https://doi.org/10.1186/s13195-026-02094-5

Image Credits: AI Generated

DOI: 10.1186/s13195-026-02094-5

Keywords: GAP-43, neuroplasticity, Alzheimer's disease, cognitive decline, estrogen, cerebrospinal fluid, sex differences, Vanderbilt Memory and Aging Project, longitudinal study, biomarker, aging brain, women's brain health