Age-linked biological context shapes adaptive immunity in Alzheimer's disease

Alzheimer's disease (AD) is increasingly recognized as a neuroimmune disorder with protective or pathogenic adaptive immunity dependent on the biological context. This review synthesizes evidence from human studies, genetic analyses, mouse models, and clinical trials to examine how lymphocytes and humoral immunity influence AD. Human studies show T-cell accumulation in disease-relevant brain compartments, peripheral B-cell remodeling, endogenous anti-amyloid beta antibodies, and cytokine dysregulation. Complementary genetic studies implicate antigen presentation, lymphocyte regulation, immunoglobulin signaling, and immune checkpoints in AD susceptibility. The findings indicate that the consequences of adaptive immune engagement vary with age and disease stage and are further modified by sex, genetic context, and therapeutic modality. Adaptive immunity in AD is therefore dynamic rather than uniformly beneficial or detrimental. Age in particular emerges as a major determinant that biases immune responses from earlier regulatory states toward later maladaptive inflammation, providing a framework to reconcile conflicting findings and guide stage-aware immunomodulation.