Increased neuroplastic activity in the pathogenesis of Alzheimer’s disease
Published in Alzheimer's & Dementia, 2025
Recommended citation: Bolton, C. J., Zhang, P., Wilhoite, S. R., Moore, E. E., Houston, M. L., Pechman, K. R., Dumitrescu, L., Peterson, A., Khan, O. A., Liu, D., Gifford, K. A., Blennow, K., Hohman, T. J., Zetterberg, H. and Jefferson, A. L. (2025). "Increased neuroplastic activity in the pathogenesis of Alzheimer's disease." Alzheimer's & Dementia, 21(11), e70897. https://doi.org/10.1002/alz.70897
Introduction
We test the hypothesis that high levels of neuroplasticity in the context of Alzheimer’s disease (AD) risk factors are involved in AD pathogenesis by investigating interactions between cerebrospinal fluid (CSF) levels of growth-associated protein-43 (GAP-43) and AD risk factors (female sex, cerebrovascular risk, mild cognitive impairment, apolipoprotein E [APOE] $\varepsilon$4 genotype, amyloid positivity) on CSF biomarkers of AD pathology (amyloid beta 42/40[A$\beta$42/40], phosphorylated tau (p-tau)) and neurodegeneration (tau).
Methods
Baseline GAP-43 levels in 161 non-demented older adults were related to cross-sectional and longitudinal (mean follow-up = 4 years) CSF biomarkers of AD, adjusting for covariates, with GAP-43 $\times$ AD risk factor interaction terms.
Results
Higher GAP-43 was cross-sectionally related to all AD biomarkers (p-values < 0.0001) and predicted longitudinal reductions in A$\beta$42 (p < 0.0001). Associations were stronger in AD risk groups.
Discussion
We found strong support linking increased levels of neuroplasticity in the context of AD risk factors to the pathological cascade of AD over a 4-year mean follow-up period.
Highlights
- Cerebrospinal fluid growth-associated protein-43 (GAP-43) is associated with Alzheimer’s disease (AD) biomarkers cross-sectionally and longitudinally.
- GAP-43 interacts with AD risk factors to predict AD biomarkers.
- Increased neuroplastic activity may play a role in AD pathogenesis.