Maladaptive aging trajectory in late-onset Alzheimer's disease

Dementia constitutes a significant public health crisis, accounting for one-third of deaths among the elderly and exceeding the combined mortality of breast and prostate cancers. Alzheimer's disease (AD), the predominant form of dementia (60–70%), primarily manifests as late-onset AD (LOAD), which constitutes over 95% of all AD cases. The risk of developing LOAD escalates dramatically with age, affecting approximately half of individuals over 85 years of age, thus positioning LOAD as a critical age-related medical challenge. The present study proposes a novel conceptual framework for understanding LOAD, positing it not merely as a discrete disease but rather as a maladaptive trajectory of brain aging, in which physiological aging processes progressively evolve into pathological states. This transition is driven by synergistic interactions between genetic susceptibility, environmental exposures, and aging-related mechanisms, with epigenetic alterations serving as a central dynamic mediator. This analysis demonstrates that genetic factors, aging, and environmental influences collectively regulate LOAD susceptibility through a multidimensional interplay: while genes directly drive pathological pathways, their expression is dynamically modulated by age and environmental context via epigenetic mechanisms. Deciphering these complex interactions provides crucial insights into LOAD pathogenesis. This reconceptualisation necessitates a paradigm shift in therapeutic strategy. Rather than focusing exclusively on amyloid-centric approaches, we advocate targeting core aging mechanisms to enhance brain resilience. The most promising interventions aim to counteract maladaptive cognitive decline by improving proteostasis, modulating epigenetic drivers, and suppressing chronic neuroinflammation. This would reposition healthy brain aging as the cornerstone of LOAD prevention and treatment.