Role of astrogliosis in the relationship between cerebrovascular burden and Alzheimer's disease pathology. (20th December 2022)

• Record Type: Journal Article
• Authors: Ottoy, Julie; Kang, Min Su; Benedet, Andréa Lessa; Bezgin, Gleb; Lussier, Firoza Z; Ruthirakuhan, Myuri; McSweeney, Melissa; Pascoal, Tharick A; Ferrari‐Souza, João Pedro; Blennow, Kaj; Zetterberg, Henrik; Ashton, Nicholas J.; Gauthier, Serge; Black, Sandra E.; Rosa‐Neto, Pedro; Goubran, Maged
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 5
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.066546
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Cerebrovascular disease represents a common co‐pathology of Alzheimer's disease (AD) contributing to cognitive decline. While both vascular injury and AD pathology were previously linked to reactive astrocytes (astrogliosis), the interrelationship between these biomarkers remains unclear in AD. Here, we investigated potential effects of plasma glial fibrillary acidic protein (GFAP), an assumed marker of astrogliosis, on the relationship between vascular burden and AD pathology. Method: We enrolled 210 participants across the AD continuum, including 111 cognitively normal amyloid‐negative (CN Aβ‐), 37 CN Aβ+, and 62 MCI/AD Aβ+ (TRIAD). Amyloid‐β pathology was quantified through 18 F‐NAV4694‐PET standardized uptake value ratio (SUVR) in the AD‐signature regions, while tau pathology was quantified through 18 F‐MK6240‐PET SUVR in regions corresponding to Braak stages. Vascular burden was quantified as the log‐transform of white matter hyperintensity volume by intracranial volume (WMH). GFAP levels were log‐transformed. At baseline, we employed linear regression models to investigate the effects of WMH and GFAP on tau pathology. Longitudinally, we performed linear mixed effect modeling to investigate the effects of baseline WMH and GFAP on tau accumulation over time (613±252 days). All analyses were adjusted for baseline age, sex, APOE ‐ε4, and cortical Aβ. Last, we investigated a potential mediating effect of GFAP in the relationship between WMH and tau accumulation over time, using bias‐corrected bootstrapping with 5, 000 replications. Result: At baseline, GFAP ( P =0.001), but not WMH, was positively associated with tau in the lower Braak I‐II regions. Conversely, both GFAP and WMH were positively associated with tau in the higher Braak regions ( P <0.001), as was their interaction (WMH * GFAP; Braak III‐IV β=0.14±0.06, P =0.014; Braak V‐VI β=0.19±0.06, P =0.001). Longitudinally, baseline Aβ but not WMH or GFAP predicted tau accumulation ( P <0.001). Serial mediation analysis revealed a significant indirect effect of WMH→GFAP→cortical Aβ→Tau increases [95%CI 0.03, 0.29]. Conclusion: We observed an interaction effect between higher WMH volumes and plasma GFAP levels on tau pathology across the AD continuum. Furthermore, we observed an indirect effect of WMH volumes on tau accumulation over time through amyloidosis and plasma GFAP. These results may indicate that reactive astrogliosis, potentially secondary to vascular injury, may be a factor contributing to AD progression.