Increased Risk of Alzheimer Disease-Associated Mortality in Nonobese vs Obese Metabolic Dysfunction-Associated...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized for its extrahepatic consequences, including emerging links to neurodegenerative disorders such as Alzheimer disease (AD). Whether AD mortality risk differs across MASLD phenotypes, remains unclear.

We analyzed adults from the Third National Health and Nutrition Examination Survey (1988-1994) with mortality follow-up through 2019 via the National Death Index. Participants were followed for AD mortality. Cumulative incidence was estimated using Kaplan-Meier methods. Cox proportional hazards models evaluated MASLD phenotypes and AD mortality, adjusting for age, sex, race/ethnicity, poverty-income ratio, body mass index, and smoking status.

Among 7125 adults, 1033 had nonobese MASLD and 817 had obese MASLD. At baseline, nonobese MASLD participants were older (mean age 60 ± 12 years), more likely male (59%), and more frequently White (46%) compared with obese MASLD (mean age 56 ± 13 years, 46% male, 37% White; P < .001). Age-standardized cumulative incidence of AD mortality was highest in nonobese MASLD (1.98%), followed by non-MASLD (1.81%) and obese MASLD (0.78%). In adjusted models, MASLD was not significantly associated with AD mortality overall. However, nonobese MASLD was independently associated with higher AD mortality compared with obese MASLD (adjusted hazard ratio 3.76; 95% confidence interval 1.19, 11.90; P = .024) and with the overall population (adjusted hazard ratio 1.49; 95% confidence interval 1.03, 2.16; P = .034).

Nonobese MASLD emerged as distinct high-risk metabolic phenotype associated with significantly higher AD mortality, independent of demographic, socioeconomic, and behavioral factors. These findings suggest that nonobese MASLD may reflect unique neuro-metabolic vulnerability and warrant further mechanistic investigation into pathways such as differential adiposity patterns, inflammation, and metabolic signaling. Targeted screening, improved risk stratification, and prospective studies are needed to better define and mitigate long-term cognitive risks in this understudied subgroup.