The changing epidemiology of infection-associated mortality in Alzheimer's disease in the United States, 1999-2024.

BACKGROUND: Infections are major immediate causes of death in patients with Alzheimer's disease, trends across infection subtypes remain poorly characterized. We examined temporal trends, demographic geographic disparities, COVID-19-era patterns, projected infection-associated mortality in United States, 1999-2024. METHODS: Using CDC Multiple Cause of Death database, infection-associated AD deaths were classified into six subtypes. AAMRs and temporal trends were estimated using joinpoint regression. Kitagawa decomposition assessed demographic age-specific contributions to sex disparities, Bayesian Structural Time Series models projected burden through 2034. RESULTS: Among 2,342,153 AD-related deaths, 308,045 (13.2%) were infection-associated. Overall infection-associated AAMR declined by 57.6% (AAPC -3.72% per year), diverging from rising AD mortality. Respiratory infections showed the steepest decline (AAMR -68.3%) with improvements across all regions and urbanization strata. By contrast, genitourinary infections were the only subtype with rising burden-absolute deaths increased 75.1%, rural AAMR rose 73.1% over 1999-2020, and central trend-continuation projections suggest a possible further increase, particularly over the near-term horizon, although uncertainty becomes substantial in the longer term. Kitagawa decomposition showed that the female excess in genitourinary mortality was attributable to higher age-specific female rates rather than to population age structure-uniquely among the subtypes examined (cumulative risk effect +11,337; 47.4% of the female excess; cumulative female deaths exceeding male by 170%); the increase in this risk component over time was directionally consistent but of model-dependent statistical significance. Mortality was overwhelmingly concentrated in the oldest age stratum ( ≥ 85-year rate 2,516-fold that of < 65 years). During the COVID-19 era, overall infection-associated AD mortality fell below pre-pandemic projections, with genitourinary infections showing the smallest cumulative deficit of any subtype. Hispanic individuals had the highest AAMR by 2024, while Non-Hispanic Black individuals maintained elevated septicemia mortality throughout. CONCLUSION: Although infection-associated AD mortality declined substantially, a growing genitourinary infection burden widened across sex, rural, and racial strata, with trend-continuation projections suggesting a possible further increase, particularly over the near-term horizon. These findings, combined with external clinical evidence on infection prevention, suggest that targeted measures-including CAUTI prevention, sex-specific bladder health programs, and rural infection prevention investment-merit priority attention as baby boomers enter peak AD risk.