Distinct factors drive the progression of tau pathology in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. The primary histopathological markers for AD diagnosis are extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs), featured by aggregation of hyperphosphorylated and truncated tau proteins. Emerging evidence shows that tau pathology, rather than amyloid-β deposition, exhibits a stronger correlation with brain atrophy and cognitive decline in AD, emphasizing its pivotal role in disease progression. However, the molecular mechanisms of tau propagation in the brain are incompletely understood, and there is no effective therapy to halt tau pathology propagation in AD. In this review, we summarize current knowledge on the multifactorial triggers of tau pathology in AD in the aspects of (1) physiological or pathological driving factors, (2) different types of brain cells and (3) key regulatory proteins that steer tau aggregation and spread. Based on these findings, we also critically evaluate the current and potential therapeutic strategies against tau pathology in AD. Together, this review provides a comprehensive understanding of tau pathology regulation and highlights promising strategies for therapeutic intervention.