DOI: 10.1002/alz.081975 ISSN: 1552-5260

Astrocyte reactivity is associated with synaptic dysfunction across the aging and Alzheimer’s disease spectrum, whereas microglial reactivity is specifically associated with synaptic dysfunction related to cognitive impairment

Francieli Rohden, Pamela C.L. Ferreira, Bruna Bellaver, Cristiano Schaffer Aguzzoli, Carolina Soares, Guilherme Povala, João Pedro Ferrari‐Souza, Firoza Z Lussier, Hussein Zalzale, Sarah Abbas, Peter Charles Lemaire, Douglas Teixeira Leffa, Arlec Cabrera, Cécile Tissot, Joseph Therriault, Stijn Servaes, Jenna Stevenson, Nesrine Rahmouni, Andrea Lessa Benedet, Annie Cohen, Oscar L. Lopez, Nicholas J. Ashton, Thomas K Karikari, Henrik Zetterberg, Kaj Blennow, Diogo O. Souza, Eduardo R Zimmer, Pedro Rosa‐Neto, Tharick A. Pascoal
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Healthy synapses are the key to proper brain function, ensuring communication between neurons. Recent studies have associated synaptic dysfunction with Alzheimer’s disease (AD) proteins, however, little is known about the role of glial reactivity, another pathology closely linked to AD, in brain synaptic dysfunction (Figure 1).


We evaluated 123 individuals (67 cognitively unimpaired (CU) and 56 cognitively impaired (CI)) who had available Aß‐ and Tau‐PET as well as cerebrospinal fluid measures of glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), and presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). ANCOVA adjusted for clinical diagnosis, age, and sex was used to compare levels of CSF biomarkers; whereas linear regressions adjusted for age, sex, clinical diagnosis, and Aß/tau‐PET were used to test the associations between glial reactivity and synaptic markers.


Demographic information is shown in Table 1. Increased levels of GAP‐43, SNAP‐25, and Ng were observed in CI compared to CU individuals. CSF GFAP was highly associated with both presynaptic and postsynaptic biomarkers in CU and CI groups. CSF YKL‐40 was associated only with presynaptic biomarkers in both clinical groups. On the other hand, CSF sTREM2 showed an association with all synaptic markers but only in the CI group (Figure 2).


We found a heterogeneous association between synaptic markers and glial activation. The presence of GFAP+ astrocytes was associated with dysfunction of presynaptic/postsynaptic markers, whereas YKL‐40+ astrocytes specifically reflected presynaptic dysfunction across aging and AD spectrums. On the other hand, microglial activation reflected synaptic dysfunction associated with dementia symptoms. Our results support recent experimental observations suggesting that clarifying the heterogeneity of different glial cell phenotypes is crucial to advancing our understanding of the role of immune cells in cognitive decline.

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