Multifactorial glial responses and their contributions to Alzheimer's disease continuum

Alzheimer's disease (AD) is the most common neurocognitive disorder. Various factors are intricately intertwined before clinical symptoms appear, although both amyloid-β peptide deposition and neurofibrillary tangle formation (i.e. pathological hallmarks of the AD brain) are established. Among such factors, glial responses have been increasingly recognized as important roles in the progression of these pathologies and viewed as one component of the AD continuum. However, the detailed molecular and cellular mechanisms of glial function underlying AD pathogenesis remain to be elucidated. Recent studies showed that peripheral immunity, gut microbiota or environmental factors influence brain pathophysiologies through communication with glial cells in the brain. This disease complexity makes understanding AD etiology difficult and hinders the development of effective therapeutic strategies to tackle this disease. Conversely, aged patients often suffer from multiple – not a single – diseases as multimorbidity, and AD pathogenesis might be related to pathologies caused by other diseases. Hence, investigating AD as a systemic disease has become critical for identifying therapeutic interventions. This review aimed to summarize current knowledge on AD research and share perspectives for understanding glial functions regarding AD pathophysiology.