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Autoimmune mechanisms have been increasingly considered to contribute to disease progression, e.g. by enhancing protein misfolding or pro-inflammatory immune responses. Understanding this contribution may lead to novel treatment options beyond removing neurodegeneration-associated proteins. We hypothesized that CD4<jats:sup>+<\/jats:sup> T<jats:sub>H<\/jats:sub> cells against synaptic proteins may play a role in dementia, given the profound changes of synaptic proteins in the disease. We investigated T<jats:sub>H<\/jats:sub> cell frequencies and phenotypes after antigen-reactive T cell enrichment (ARTE) using three important synaptic antigens known to play a role in cognitive function, N-Methyl-D-Aspartate receptor (NMDAR), Leucine-rich, glioma inactivated 1 (LGI1) and metabotropic glutamate receptor 5 (mGluR5). Our data revealed that synaptic autoantigen-specific T<jats:sub>H<\/jats:sub> cells occurred in all cohorts and were similarly frequent in patients with dementia and sex- and age-matched controls. However, they were significantly reduced compared to young healthy subjects, indicating strong age-related effects (\u2018immune senescence\u2019). Compared to the ubiquitously available Candida albicans antigen, synaptic autoantigen-specific T<jats:sub>H<\/jats:sub> cell responses were strongly driven by IFN\u03b3-producing T cells, expression of which markedly decreased with age. Patients with dementia had significantly less IL-17-producing synaptic autoantigen-specific T<jats:sub>H<\/jats:sub> cells than aged healthy controls. This first direct ex vivo quantitative and qualitative analysis of circulating T cells autoreactive to three synaptic autoantigens in dementia shows no correlation with cognitive impairment. It suggests that synaptic autoantigen-specific T<jats:sub>H<\/jats:sub> cells decline with age and are not a major driver of dementia development.<\/jats:p>","DOI":"10.1186\/s12979-025-00516-w","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T07:13:17Z","timestamp":1750317197000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment"],"prefix":"10.1186","volume":"22","author":[{"given":"Julius","family":"Hoffmann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-Luise","family":"Machule","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob","family":"Kreye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"St\u00f6ffler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e9ter","family":"K\u00f6rtvelyessy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Buthut","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"R\u00f6\u00dfling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Bacher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Scheffold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harald","family":"Pr\u00fcss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"516_CR1","doi-asserted-by":"publisher","unstructured":"Collaborators GBDDF. 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