Journal Article

Biomarkers

Zhang, Panpan, Liu, Dandan, Blennow, Kaj, Zetterberg, Henrik, Hohman, Timothy J, Jefferson, Angela L, Peterson, Amalia Jo, Bolton, Corey J

2025

Overview

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-amyloid (Ab ), 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.

• Subject: Aged / Aged, 80 and over / Alzheimer Disease - cerebrospinal fluid / Amyloid beta-Peptides - cerebrospinal fluid / Biomarkers - cerebrospinal fluid / Cognitive Dysfunction - cerebrospinal fluid / Cross-Sectional Studies / Female / GAP-43 Protein - cerebrospinal fluid / Humans / Longitudinal Studies / Male / Neuropsychological Tests / Peptide Fragments - cerebrospinal fluid / tau Proteins - cerebrospinal fluid