Disentangling the role of adaptive immunity in Alzheimer’s disease

Abstract

Abstract Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, is characterized by progressive synaptic and neuronal loss, amyloid-β deposition, hyperphosphorylated tau accumulation, and chronic neuroinflammation, traditionally attributed primarily to the innate immune system. Increasing evidence, however, implicates the adaptive immune system as an active contributor to AD pathogenesis and progression. This emerging perspective has stimulated the development of immunomodulatory strategies aimed at mitigating cognitive decline and neuropathological hallmarks of the disease. In this review, we examine how adaptive immune responses change throughout the course of AD, integrating findings from both human studies and animal models while emphasizing the temporal dynamics of these alterations. We critically evaluate areas of consensus and controversy in the field, highlighting how differences in experimental models, disease stages, and methodological approaches contribute to divergent findings. Finally, we assess current therapeutic strategies targeting adaptive immunity, discussing their potential mechanisms of action and identifying key therapeutic windows and routes of administration that may maximize efficacy. By providing a comprehensive overview of adaptive immune involvement in AD, this review aims to inform the development of more precise and effective immunomodulatory interventions.