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Desai et al1 investigated whether engaging in physical activity moderated the association between concentrations of plasma neurofilament light chain (NfL) and cognitive function over time in adults aged 65 years or older who participated in the well-characterized Chicago Health and Aging Project. In their study, Desai et al1 included 1158 participants, of whom 695 (60%) were African American and 463 (40%) were White (mean [SD] age, 77.4 [6.0] years). Physical activity was self-reported, and cognitive performance was routinely assessed. Participants were stratified by baseline NfL concentration (low [ 25.5 pg/mL] vs high [>25.5 pg/mL]). The results showed that adults with a high NfL level, indicating neuronal damage and/or neurodegeneration, and low physical activity (0 minutes per week) were more likely to experience global cognitive decline, including declines in MiniMental State Examination scores, compared with those with low NfL levels and medium (>0 to 150 minutes/week) or high ( 150 minutes/week) physical activity. Results were similar for episodic memory and perceptual speed. Their findings suggest that engaging in physical activity may mitigate at least some of the harmful effects of neuronal damage through unknown mechanisms. These results are consistent with those of a previous study that stratified groups based on low vs high levels of plasma total tau, also a marker of neuronal damage and/or neurodegeneration.2 Owing to a rapidly aging global population, the number of people affected by dementia is expected to increase substantially during the coming decades, with most of the increase expected in lowand middle-income countries. The World Health Organization reports that by 2030, 17% of the world’s population will be age 60 years or older.3 By 2050, the population of those 60 years or older will double, of whom two-thirds will be living in lowand middle-income countries. Intensive research efforts have been forged to delineate the underlying causes of dementia, and it is well-established that an intricate combination of genetic and lifestyle factors contributes. In the latest report by the Lancet Commission, it was stated that up to 40% of dementia cases can be prevented with appropriate management of modifiable risk factors.4 These risk factors are similar to those that have been identified for cardiovascular disease. One of these factors is physical inactivity, which may be associated with diminished cognitive reserve and increased metabolic (eg, obesity, diabetes) and vascular (eg, hypertension) risk.5 The multidomain World-Wide Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGERS) focuses on lifestyle factors in dementia prevention.6 These lifestyle factors include physical activity, cognitive training, dietary counseling, social activities, and monitoring and management of vascular and metabolic risk factors. However, studying the mechanism whereby these lifestyle factors may influence the underlying biology of dementia through the use of biomarkers has been limited to analyses of cerebrospinal fluid (obtained via an invasive and logistically challenging procedure) and/or brain imaging (usually costly, with limited access globally). The rapid development of blood-based biomarkers reflecting pathophysiological processes in the nervous system has been one of the major scientific achievements of the 21st century. One of these, NfL, a biomarker of neuroaxonal injury, is an analytically robust, dynamic cross-disease biomarker that reflects both acute neuronal injury and neurodegeneration. In patients with Alzheimer disease (AD), higher levels of plasma NfL7 are observed, and longitudinally measured increases in NfL8 are associated with cognitive deterioration and neurodegeneration. These features pave the way to study NfL in epidemiological studies. In addition to the Chicago Health and Aging Project, other population-based studies, such as the Rotterdam Study, have reported that a higher + Related article