The Interaction of Sex and Neuroplasticity in the Pathogenesis of Alzheimer's Disease

TL;DR

Higher levels of a brain protein linked to neuroplasticity are associated with increased Alzheimer's pathology and faster cognitive decline in women, but not in men.

Contribution

This study reveals sex-specific effects of neuroplasticity on Alzheimer's biomarkers and cognitive decline.

Findings

Higher GAP-43 levels are linked to increased tau pathology and worse cognitive performance in women.

GAP-43 interacts with sex to influence longitudinal cognitive decline, with effects seen only in women.

Elevated baseline GAP-43 predicts faster decline in cognition and AD biomarkers over time.

Abstract

Women are at an increased risk of dementia due to Alzheimer's disease (AD) compared to men, a difference due in part to the role of female sex hormones. Estrogen, in particular, plays 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 a marker of neuroplasticity, growth‐associated protein‐43 (GAP‐43), on AD biomarkers and cognitive decline.

Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n = 161, 72±6 years, 31% female) underwent fasting lumbar puncture and comprehensive neuropsychological assessment at study entry and serially over a mean 6.4‐year follow‐up period. Cerebrospinal fluid (CSF) levels of GAP‐43, b‐amyloid1‐42 (Ab1‐42), tau, and phosphorylated‐tau (p‐tau) were analyzed in batch. Linear regression models related baseline CSF GAP‐43 cross‐sectionally and longitudinally to CSF biomarkers and cognition adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)‐e4 status, modified Framingham Stroke Risk Profile, and cognitive status. Follow‐up models assessed GAP‐43 x sex interactions on AD biomarkers and cognitive outcomes.

In cross‐sectional analyses, higher GAP‐43 was associated with higher levels of all CSF AD biomarkers (p‐values<0.0001), worse language performance (b=‐0.0005, p = 0.04) and worse visuospatial performance (b=‐0.0004, p = 0.005). GAP‐43 interacted with sex on CSF tau and p‐tau levels (p‐values<0.0001) such that associations were stronger in females compared to males. In longitudinal analyses, higher baseline GAP‐43 was associated with declining Ab42 levels (b=‐0.01, p <0.0001) and declining performance in tasks of language, executive function, and visuospatial abilities (p‐values<0.02), indicating greater AD pathology and declining cognition. GAP‐43 interacted with sex on longitudinal language, processing speed, executive functioning, and visuospatial performance trajectories (p‐values<0.05), such that significant associations were found in women (p‐values<0.02) but not men (p‐values>0.26).

In this cohort of community‐dwelling older adults, we found higher baseline levels of GAP‐43, indicating increased neuroplasticity, are related to cross‐sectional increases in tau pathology, especially in women, and longitudinal decline in cognition, exclusively in women. Findings suggest that differential responses to neuroplasticity in aging could help explain long‐recognized sex differences in tau pathology and cognitive decline.