Apathy as a Potential Mediator of the Association Between Poor Glycemic Status and Incident Cognitive Impairment and Self-Reported Alzheimer’s Disease and Related Dementias in Older Adults: The Health and Retirement Study

Background: Apathy is an increasingly recognized predictor of cognitive decline. Although both poor glycemic status and apathy have been independently linked to cognitive decline, whether apathy mediates the relationship between poor glycemic status and cognitive decline remains unclear. Methods: We used data from 4571 adults aged ≥60 years without baseline memory problems from the U.S. Health and Retirement Study. Glycemic status was measured using glycosylated hemoglobin (HbA1c). Apathy-like symptoms were derived from CES-D items, reflecting diminished positive affect and motivation. Outcomes included incident cognitive impairment and incident self-reported Alzheimer’s disease and related dementias (ADRD). Accelerated Failure Time models, adjusted for age, sex, and education, estimated associations between HbA1c and time to each outcome. Mediation was tested using a product-of-coefficients approach that incorporated survey weights. Results: Over a mean 8.89 (SD 4.7) years, 938 participants developed cognitive impairment. Higher HbA1c was associated with shorter time to cognitive impairment (TR = 0.85; 95% CI 0.79–0.91). After adjustment for apathy-like symptoms, the association was attenuated (TR = 0.87; 95% CI 0.81–0.92), indicating approximately 11% mediation. Over 9.2 (SD 4.6) years, 583 participants reported incident ADRD. Higher HbA1c was associated with shorter time to ADRD (TR= 0.91; 95% CI 0.85–0.97) that was attenuated (TR = 0.93; 95% CI 0.86–0.99), suggesting 20% mediation through apathy-like symptoms. However, the mediation effects attenuated after further adjustment for baseline cognition and vascular/lifestyle factors. Conclusions: Overall, poorer glycemic status was associated with accelerated onset of adverse cognitive events, with apathy-like symptoms as a potential mediator requiring confirmation in future studies.