Moving Beyond Outcome-Based Exercise Studies in Cognitive Aging: A Mechanism-Informed Narrative Review of...

Exercise training is frequently examined in relation to cognitive and brain health in aging populations. Yet many exercise-cognition studies remain difficult to interpret mechanistically because cognitive outcomes are often assessed without sufficient alignment with exercise dose, biological endpoints, or participant vulnerability. This mechanism-informed narrative review argues that future research in cognitive aging should move beyond outcome-based interpretation alone and more explicitly connect the exercise stimulus with cerebrovascular endpoints, supportive biological markers, baseline vulnerability, and cognitive or translational outcomes. The review treats cerebrovascular endpoints, including cerebral blood flow, cerebrovascular reactivity, endothelial function, vascular compliance, and neurovascular coupling, as primary mechanistic anchors because they are closely related to vascular cognitive vulnerability and are more proximal to biological adaptation than cognitive test scores alone. Immune-inflammatory markers, blood-brain barrier-related indicators, myokines, neurotrophic factors, and exercise-induced circulating factors are considered supportive endpoints because they may clarify broader biological responsiveness when selected according to a clear hypothesis. The review also considers how exercise modality, delivered dose, adherence, baseline fitness, vascular risk, cognitive status, sex, comorbidity, and recovery capacity may shape responder heterogeneity. The purpose of this review is to develop a mechanism-informed framework for interpreting exercise-cognition studies in aging by aligning the delivered exercise stimulus, participant vulnerability, biological responsiveness, and cognitive or translational outcomes. Based on this synthesis, we propose a five-layer endpoint framework that positions cerebrovascular measures as primary mechanistic anchors and supportive biological markers as hypothesis-dependent contextual endpoints. Its distinct contribution is to integrate these elements within a single interpretive structure rather than considering exercise exposure, biological responses, participant characteristics, and cognitive outcomes as separate domains. Rather than serving as a clinical prescription model or formal reporting guideline, the framework is intended to improve hypothesis-endpoint alignment and the mechanistic interpretation of exercise-cognition studies in aging.