Immune cells and inflammation as mechanisms underlying cognitive dysfunction and Alzheimer’s disease–related dementia

Alzheimer’s disease-related dementias (ADRD) are progressive neurodegenerative disorders and the most common cause of dementia worldwide. Despite extensive research into their underlying molecular and cellular mechanisms, therapeutic options remain limited. Current pharmacological treatments offer only modest symptomatic relief and may slow progression in early stages. More recently, anti-amyloid monoclonal antibodies, including aducanumab and donanemab, have been developed to target amyloid-β pathology; however, their clinical benefits remain limited, with marginal effects on progression primarily in prodromal Alzheimer’s disease (AD). These outcomes have prompted a shift toward identifying disease modifying strategies beyond amyloid accumulation. Neuroinflammation and immune dysregulation have emerged as critical contributors to ADRD pathogenesis. Resident central nervous system (CNS) immune cells, such as microglia and astrocytes, along with peripheral immune cells drive disease initiation and progression through sustained inflammatory signaling, altered immune surveillance, and impaired clearance of pathological proteins. Furthermore, neurovascular unit dysfunction, including blood–brain barrier breakdown and vascular inflammation, further exacerbates immune cell infiltration, promotes neuroinflammatory cascades, and accelerates neuronal injury. This review examines molecular and cellular mechanisms that may independently or synergistically interact with established ADRD risk factors to influence disease onset, severity, and progression. These mechanisms include peripheral immune cell signaling and CNS infiltration, neurovascular dysfunction, microglial activation, astrocyte reactivity, and increased BBB permeability. Multiple inflammatory cytokines and signaling pathways, including IL-1β, IL-6, and NLRP3, represent potential modifiable therapeutic targets. Although FDA approved IL 6 and IL 1 inhibitors could be repurposed for ADRD, their involvement in complex CNS and systemic processes may limit their use. Clarifying these interconnected pathways may advance our understanding of ADRD pathophysiology and support development of neuroimmune and neurovascular disease modifying therapies before substantial amyloid accumulation.