Abstract / Summary
Women are disproportionately affected by Alzheimer’s disease compared to men, a difference that may be partly explained by the role of female sex hormones. Estrogen, in particular, may play a key role in neuroplasticity. However, as women age and estrogen levels decline, high levels of neuroplasticity may be unsustainable. This study investigates the interaction of sex with growth associated protein-43 (GAP-43), a fluid marker of neuroplasticity, on cognitive and functional decline. Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke ( n = 161, 72 ± 6 years, 31% female) underwent a fasting lumbar puncture and comprehensive neuropsychological assessment at study entry and over a mean 6.4-year follow-up period. Cerebrospinal fluid (CSF) levels of GAP-43 were analyzed in batch. Linear regression models related baseline CSF GAP-43 cross-sectionally and longitudinally to cognitive and functional measures adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E ( APOE )-ε4 status, modified Framingham Stroke Risk Profile, and cognitive status. Follow-up models assessed GAP-43 x sex interactions on cognitive and functional outcomes. In cross-sectional analyses, higher GAP-43 was associated with worse language (β=-0.0005, p = 0.04) and visuospatial function (β=-0.0004, p = 0.005) and greater functional impairment (β = 0.002, p = 0.003). GAP-43 did not interact with sex on any cross-sectional outcomes. In longitudinal analyses, higher baseline GAP-43 was associated with faster decline on language, executive function, and visuospatial tasks ( p -values < 0.02) as well as functional abilities (β = 0.0006, p = 0.007). GAP-43 interacted with sex on longitudinal trajectories of many cognitive measures, including language, processing speed, executive functioning, and visuospatial tasks ( p -values < 0.05) as well as functional abilities ( p = 0.005), such that GAP-43 was associated with faster decline in women ( p -values < 0.02) but not men ( p -values > 0.26). In community-dwelling older adults free of dementia, we found higher GAP-43 levels, indicating increased neuroplasticity, related to longitudinal decline in cognition and functional abilities, exclusively in women. These findings suggest that differential responses to neuroplasticity in aging, possibly driven by estrogen, could help explain long recognized sex differences in cognitive decline.