Effect of neuroinflammation markers on the relation between A, T and N: sex‐specific resilience or vulnerability?
Muge Akinci, Clara Vila‐Castelar, Eleni Palpatzis, Georgette Argiris, Gwendlyn Kollmorgen, Margherita Carboni, Kaj Blennow, Henrik Zetterberg, Carles Falcon, Juan Domingo Gispert, Marc Suarez‐Calvet, Eider M Arenaza‐Urquijo- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Sex‐specific vulnerability and resilience along the amyloid cascade may be partly explained by neuroinflammatory processes. Microglial activation may play a more important role in the development of Alzheimer’s disease (AD) in women than in men. We investigated the effect of sex and biomarkers of microglia and astrocytic activation on amyloid (A) and tau (T) burden, and neurodegeneration (N) in cognitively unimpaired (CU) older adults at increased AD risk.
Method
We included 397 CU participants (49‐73 years, 61.5% women) with the following available CSF biomarker data: Aβ42/40, p‐tau181, sTREM2, GFAP, and YKL40 measured with Roche NeuroToolKit or Elecsys® immunoassays. A subsample (n = 299) also had MRI‐based hippocampal volume data (ASHS segmentation). The outcomes of interest were A: Aβ42/40, T: p‐tau181, and N: hippocampal volume. Predictors included demographics and neuroinflammation markers. First, we tested the effect of sex and neuroinflammation markers on A, T, and N in the whole sample. Then, we tested the neuroinflammation*Aβ42/40 and neuroinflammation*p‐tau interactions on p‐tau and hippocampal volume, respectively. Finally, we looked at sex‐stratified models.
Result
Men were older, more often APOE‐ε4 carriers and showed higher GFAP levels (men>women). In the whole sample, neither sex nor neuroinflammation markers were associated with Aβ42/40. However, sex (women>men), higher sTREM2 and higher YKL40 were associated with higher p‐tau181 levels, and sex (women<men), lower sTREM2, and higher YKL40 were associated with lower hippocampal volume. Models including interaction terms showed a sex‐independent interaction of GFAP with Aβ42/40 and p‐tau181 on p‐tau181 and hippocampal volume, respectively, suggesting a role of astrocytic activation along the ATN pathway. Sex‐stratified analyses showed (1)
Conclusion
Pending replication with longitudinal measurements, our results suggest that microglial and astrocytic activation may play a sex‐specific role in downstream amyloid. While astrocytic activation moderates the associations between A, T and N in men and women, microglial activation might provide resilience to neurodegeneration only in women (Figure 1).