Cerebrospinal Fluid sTREM-2, GFAP, and β-S100 in Symptomatic Sporadic Alzheimer’s Disease: Microglial, Astrocytic, and APOE Contributions Along the Alzheimer’s Disease Continuum

Article type: Research Article

Authors: Bonomi, Chiara Giuseppina^a | Assogna, Martina^{a; b} | Di Donna, Martina Gaia^a | Bernocchi, Francesca^a | De Lucia, Vincenzo^a | Nuccetelli, Marzia^c | Fiorelli, Denise^c | Loizzo, Stefano^d | Mercuri, Nicola Biagio^e | Koch, Giacomo^{b; f} | Martorana, Alessandro^a | Motta, Caterina^{a; *}

Affiliations: [a] UOSD Centro Demenze, Policlinico Tor Vergata, University of Rome ‘Tor Vergata’, Rome, Italy | [b] Non Invasive Brain Stimulation Unit, IRCCS Santa Lucia, Rome, Italy | [c] Department of Experimental Medicine, University of Rome ‘Tor Vergata’, Rome, Italy | [d] Department of Cardiovascular, Endocrine-Metabolic and Ageing-Associated Diseases, Istituto Superiore di Sanità, Rome, Italy | [e] Neurology Unit, Policlinico Tor Vergata, University of Rome ‘Tor Vergata’, Rome, Italy | [f] Human Physiology Unit, Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy

Correspondence: [*] Correspondence to: Caterina Motta, MD, PhD, UOSD Centro Demenze, Policlinico Tor Vergata, University of Rome ‘Tor Vergata’, Viale Oxford, 81, 00133 Roma, Italy. Tel.: +39 06 20903137; Fax: +39 06 20903118; E-mail: [email protected].

Abstract: Background:Many transversal mechanisms act synergistically at different time-points in the cascade of Alzheimer’s disease (AD), since amyloid-β (Aβ) deposition, tau pathology, and neuroinflammation influence each other. Objective:We explored the contributions of microglia and astrocytes in patients with symptomatic sporadic AD stratified according to AT(N) system and APOE genotype. Methods:We compared the cerebrospinal fluid (CSF) levels of sTREM-2 and markers of astrocytic activation (GFAP; β-S100) from 71 patients with AD (23 A+T–,48 A+T+; 38 APOE ɛ3, 33 APOE ɛ4) and 30 healthy controls (HC). With multivariate analyses we investigated associations between glial biomarkers, Aβ42, and p-tau in all subgroups. Results:CSF sTREM-2 was higher in A+T+ [1.437 (0.264)] and A+T– [1.355 (0.213)] than in HC [1.042 (0.198); both p < 0.001]; GFAP and β-S100 were comparable across groups. Considering all patients, sTREM-2 positively associated with Aβ42 (p = 0.04) and p-tau (=0.016), with the first being present only in the A+T– subgroup (p = 0.023). GFAP positively associated with Aβ42 in all patients (p = 0.020) and in the A+T+ subgroup (p = 0.04). Stratifying by APOE, a positive association of sTREM-2 and p-tau was confirmed selectively in carriers of ɛ4 (p = 0.018). Finally, sTREM-2 positively correlated with β-S100 in all subgroups, and with GFAP in A+T+ (p = 0.042). Conclusion:Our results confirm the increase of CSF sTREM-2 in AD, which associates with reduced amyloidopathy in A+T– patients. Moreover, microglial activation seems to increase CSF tau levels in carriers of APOE ɛ4, is associated with astrocytic reactivity (GFAP) in A+T+, and likely leads the acquisition of a more neurotoxic astrocytic phenotype (β-S100).

Keywords: Alzheimer’s disease, Alzheimer’s disease continuum, astrocytes, β-S100, biomarkers, GFAP, microglia, soluble TREM-2

DOI: 10.3233/JAD-221010

Journal: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1385-1397, 2023