Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment

Neurodegenerative dementias including Alzheimer disease severely impair cognitive and social abilities and are a major cause of mortality with no causal treatment yet. 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⁺ T_H cells against synaptic proteins may play a role in dementia, given the profound changes of synaptic proteins in the disease. We investigated T_H 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_H 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 ('immune senescence'). Compared to the ubiquitously available Candida albicans antigen, synaptic autoantigen-specific T_H cell responses were strongly driven by IFNγ-producing T cells, expression of which markedly decreased with age. Patients with dementia had significantly less IL-17-producing synaptic autoantigen-specific T_H 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_H cells decline with age and are not a major driver of dementia development.