This study aims to evaluate the comparative risk of dementia/Alzheimer's disease onset between patients treated with medications that target specific metabolic pathways and patients treated with alternative medications for the same indication.

This is a non-randomized, non-interventional study that is part of the DREAM Study of Brigham and Women's Hospital. DREAM is led by Dr. Madhav Thambisetty, MD, PhD, Chief of the Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA) intramural research program. This study aims to evaluate the comparative risk of dementia/Alzheimer's disease onset between patients treated with medications that target specific metabolic pathways and patients treated with alternative medications for the same indication using healthcare claims data.

Please see https://drive.google.com/drive/folders/1VRjPaaelXFyBbA5gV6pwB\_ijSIMyIJ4N?usp=share\_link or Appendix A(https://drive.google.com/drive/folders/1OgKQlxsJi9UWRDd3Kbaux\_8adngoSnZY?usp=sharing) for full code and algorithm definitions.

Medicare timeframe: 2008 to 2019 (end of data availability).

Inclusion Criteria:

• 1. Aged >/= 65 years on the index date
• 2. Enrollment in Medicare Part A, B, and D with no HMO coverage for 365 days prior to and including cohort entry date
• 3. Diagnosis code for type 2 diabetes measured 365 days prior to drug initiation

Exclusion Criteria:

• 1. Prior history of dementia measured anytime prior to cohort entry date
• 2. Prior history of nursing home admission in the 365 days prior to the cohort entry date
• 3. Prior use of any GLP receptor agonists (semaglutide, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide) or DPP4 inhibitors
• 4. Prior use of Semaglutide or DPP4 inhibitors concomitantly on index date

This study will employ a new user, active comparator, observational cohort study design comparing semaglutide v DPP4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin). The patients will be required to have continuous enrollment during the baseline period of 365 days before initiation of study drugs (index date). Follow-up for the outcome (dementia) differs between analyses. Follow-up begins the day after drug initiation (analysis 1, 3, 4); 180 days after drug initiation (analysis 2).

Study cohort after 1:1 propensity score matching

'As-treated' follow-up approach - Median follow-up days of 98 (for Semaglutide) and 134 (for DPP4 Inhibitors)

Our study did not capture Serious Adverse Events.