Introduction Spatial navigation deficits are observed in Alzheimer's disease cross‐sectionally, but prediction of longitudinal clinical decline has been less examined. Methods Cognitive mapping (CM) was assessed in 95 participants and route learning (RL) was assessed in 65 participants at baseline. Clinical progression over an average of 4 to 5 years was assessed using the clinical dementia rating (CDR) scale. Relative predictive ability was compared to episodic memory, hippocampus, and cerebrospinal fluid biomarkers (phosphorylated tau/amyloid β 42 (ptau181/Aβ42) ratio). Results CM and RL were predictors of clinical progression (P’s < 0.032). All measures, except RL‐Learning remained predictors with episodic memory in models (P’s < 0.048). Only RL‐Retrieval remained a predictor when ptau181/Aβ42 was included (P < 0.001). CM interacted with hippocampus and ptau181/Aβ42 in prediction (P’s < 0.013). CM, RL, and episodic memory evidenced strong diagnostic accuracy (area under the curve (AUC) = 0.894, 0.794, and 0.735, respectively); CM tended to perform better than episodic memory (P = 0.056). Discussion Baseline spatial navigation performance may be appropriate for assessing risk of clinical progression.

Introduction: Associations of physical exercise with Alzheimer disease (AD) biomarkers and cognitive functioning have been observed cross-sectionally. However, the effects of exercise on longitudinal change in AD biomarkers have not been thoroughly investigated. The current study examined whether individuals with higher baseline exercise exhibited less longitudinal change in AD biomarkers and cognitive functioning, and whether APOE and/or brain-derived neurotrophic factor (BDNF) genotypes moderated the effects of exercise on longitudinal changes. Methods: Clinically normal individuals completed a questionnaire on physical exercise over the prior 10-year period at baseline. Ninety-five individuals had serial cerebrospinal fluid samples collected to examine Aβ42, ptau181 and total tau; 181 individuals underwent multiple assessments of amyloid positron emission tomography imaging with Pittsburgh Compound-B; 327 individuals underwent multiple cognitive assessments, including measures of episodic memory, executive functions, verbal fluency, and processing speed. Results: Greater exercise was associated with less steep decline in processing speed. Baseline exercise did not robustly impact longitudinal change for any other outcomes. Neither APOE nor BDNF genotype robustly moderated the effect of exercise on trajectories of AD biomarkers or cognitive decline. Interpretation: Results suggest that self-reported physical exercise may be limited as a moderator of changes in AD biomarkers.

INTRODUCTIONNeuronal health as a potential underlying mechanism of the beneficial effects of exercise has been understudied in humans. Furthermore, there has been limited consideration of potential moderators (e.g., cardiovascular health) on the effects of exercise.METHODSClinically normal middle‐aged and older adults completed a validated questionnaire about exercise engagement over a 10‐year period (n = 75; age 63 ± 8 years). A composite estimate of neuronal injury was formulated that included cerebrospinal fluid‐based measures of visinin‐like protein‐1, neurogranin, synaptosomal‐associated protein 25, and neurofilament light chain. Cardiovascular risk was estimated using the Framingham Risk Score.RESULTSCross‐sectional analyses showed that greater exercise engagement was associated with less neuronal injury in the group with lower cardiovascular risk (p = 0.008), but not the group with higher cardiovascular risk (p = 0.209).DISCUSSIONCardiovascular risk is an important moderator to consider when examining the effects of exercise on cognitive and neural health, and may be relevant to personalized exercise recommendations.Highlights We examined the association between exercise engagement and neuronal injury. Vascular risk moderated the association between exercise and neuronal injury. Cardiovascular risk may be relevant to personalized exercise recommendations.

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