Hallmarks of aging and Alzheimer's Disease pathogenesis: Paving the route for new therapeutic targets

Aging is the leading risk factor for Alzheimer's Disease (AD). Understanding the intricate interplay between biological aging and the AD pathophysiology may help to discover innovative treatments. The relationship between aging and core pathways of AD pathogenesis (amyloidopathy and tauopathy) have been extensively studied in preclinical models. However, the potential discordance between preclinical models and human pathology could represent a limitation in the identification of new therapeutic targets. This narrative review aims to gather the evidence currently available on the associations of β-Amyloid and Tau pathology with the hallmarks of aging in human studies. Briefly, our review suggests that while several hallmarks exhibit a robust association with AD pathogenesis (e.g., epigenetic alterations, chronic inflammation, dysbiosis), others (e.g., telomere attrition, cellular senescence, stem cell exhaustion) demonstrate either no relationship or weak associations. This is often due to limitations such as small sample sizes and study designs, being either cross-sectional or with short follow-up intervals, limiting the generalizability of the findings. Distinct hallmarks play varying roles in different stages of AD pathology, emphasizing the need for longitudinal studies with longer follow-up periods. Considering the intricate interconnections across the hallmarks of aging, future research on AD pathology should focus on multiple hallmarks simultaneously.