AbstractBackgroundHypertension and diabetes have each been associated with an increased risk of progression to Alzheimerâs disease (AD) dementia. Here, we investigated their combined impact on progression from cognitively normal to clinicallyâdiagnosed AD.MethodCognitively normal individuals from the National Alzheimerâs Coordinating Center were identified as having neither hypertension nor diabetes (HTNâ/DMâ), hypertension without diabetes (HTN+/DMâ), or hypertension with diabetes (HTN+/DM+). The presence of HTN and DM were based on their diagnosis from recent medical history or medication use. This study investigated whether HTN+/DMâ or HTN+/DM+ were predictors of progression to clinicallyâdiagnosed AD compared to HTNâ/DMâ. In a subgroup analysis with postâmortem data, we investigated whether HTN+/DMâ, and HTN+/DM+ were predictors of progression to clinically diagnosed AD due to underlying ADâ and/or vascular neuropathology.ResultThis study included N = 11074 cognitively normal individuals (mean age: 71.7 (9.0), MMSE: 28.9 (1.4), male: N = 3818 (34%)). Approximately 7% (N = 830) progressed to clinicallyâdiagnosed AD, and the average duration of followâup was 5.2 (3.6) years. Fortyâtwo percent (N = 4608) were HTNâ/DMâ, 45% (N = 5034) were HTN+/DMâ, and 13% (N = 1432) were HTN+/DM+. Both HTN+/DMâ (hazard ratio (HR): 1.24 (1.17â1.32), p<.001), and HTN+/DM+ (HR: 1.31 (1.19â1.44), p<.001) were significant predictors of progression to clinicallyâdiagnosed AD. Subgroup analyses with postâmortem data (N = 919) demonstrated that compared to HTNâ/DMâ, those with HTN+/DMâ had a higher risk of progressing to clinicallyâdiagnosed AD with underlying cerebrovascular disease (CVD) neuropathology (HR: 1.54 (1.17â2.03), p = .002), whereas those with HTN+/DB+ had a higher risk of progression to clinicallyâdiagnosed AD with underlying AD (HR: 2.10 (1.16â3.79), p = .01) and cerebral amyloid angiopathy (CAA) neuropathology (HR: 1.52 (1.09â2.12), p = .01).ConclusionThese findings demonstrate that underlying CVD neuropathology contributes to the risk of clinicallyâdiagnosed AD in individuals with HTN+/DMâ, while both AD and CAA neuropathology contributes to the risk of clinicallyâdiagnosed AD in individuals with HTN+/DM+. This suggests that individuals with HTN+/DMâ and HTN+/DM+ vary phenotypically and may warrant the need for different treatment strategies to reduce the future risk of AD.