Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau protein (p-tau). The disease progresses over decades, starting with an asymptomatic phase marked by biomarker evidence of AD pathology, followed by a clinical phase with evident symptoms, loss of independence, and eventually death. Early diagnosis and the identification of individuals at risk are crucial for effective management and the development of disease-modifying interventions. Peripheral biomarkers offer potential for predicting AD in asymptomatic individuals or those with mild cognitive impairment (MCI). Recent research highlights the immune system's role in AD progression. Observations of T cell adaptive immune responses in AD indicate these cells as potential active contributors in AD pathogenesis, a feature also seen in other neurodegenerative diseases like primary tauopathies and Parkinson’s disease. However, the role of the adaptive immune system as an early and specific biomarker for AD is underexplored. Preliminary studies show AD patients have specific subsets of peripheral Aβ-specific T cells with elevated expression of phosphorylated-protein kinase C-delta or -zeta, crucial for transcription factor activation and cytokine production. Increased levels of activated HLA-DR positive CD4(+) and CD8(+) T-cells in MCI and early AD patients, compared to healthy controls or patients with other dementias, suggest a pathology-specific T cell signature.
In this proposal, we hypothesize that early molecular changes in the AD continuum trigger a specific adaptive immune response, which can identify individuals that will experience steeper trajectories of cognitive decline. By investigating the role of antigen-specific T-cells as prognostic markers, we aim to enhance early diagnosis and tailor interventions for those most at risk, improving outcomes in AD patient management and treatment.