To investigate mortality trends due to Alzheimer's disease (AD) and psychoactive substance use (PASU) among White adults (> 25 years) in the United States from 1999 to 2020.

AD due to PASU represents a growing public health concern, associated with cognitive, behavioral, and social dysfunction, particularly in Whites. Nevertheless, the mortality trends due to AD and PASU remain underexplored.

Mortality data for white adults (≥ 25 years) were obtained from CDC wonder database using ICD 10 codes F10-19 (PASU) and G30 (AD). Results were presented as crude (CMR) and age adjusted mortality rates (AAMR) per 100,000 population, with Jointpoint regression used to calculate annual percentage changes (APCs) with 95% confidence intervals (CI).

From 1999 to 2023, we obtained 62,894 deaths among White adults with PASU and AD. Overall, the AAMR increased from 0.15 in 1999 to 1.98 in 2023, surging remarkably from 1999 to 2005 (APC: 48.27*) continued to rise until 2020 (APC: 5.30*), followed by a non-significant decline from 2020 to 2023 (APC: -4.60) [AAPC of 13.30* (95% Cl, 10.57-16.10)].  mortality trends for individuals with both PASA and AD increased from 2005 to 2012, contrasting from mortality rates for AD alone [APC: -2.37*]). Males consistently exhibited higher mortality rates (1.70) compared to females (1.13). Regionally, the Midwest had the highest AAMR (1.67), followed by South (1.30) and Northeast (0.94), with non-metropolitan areas showing a higher AAMR (1.67) than metropolitan areas (1.14).State specific AAMR ranged between Washington and California (3.87 vs 0.21 respectively). Highest CMR was recorded in adults aged above 85 years (25.25).

Mortality rates from AD and PASU have risen from 1999 to 2020 followed by stability until 2023, with evident disparities across demographic and geographic lines, underscoring the need for targeted interventions to reduce deaths in high-risk groups.