(B-148) REpositioning of Medications IN Dementia (REMIND): Evaluating fitness for purpose of the SNDS French nationwide claims database

Background: Alzheimer's disease and related disorders (ADRD) cause pathological changes in the brain leading to progressive cognitive decline ≥10y before diagnosis and are major causes of disability. No curative or preventive treatments exist, underscoring the need for new drug discovery approaches.

Drug repurposing offers an opportunity to evaluate the benefit of drugs approved for other indications for ADRD. In REMIND, we will conduct 2 approaches to identify and evaluate candidates for ADRD prevention. First, we will focus on previously identified candidates targeting dysfunctional metabolic pathways that proceed or interact with the accumulation of ADRD lesions from the DREAM study. Second, as unknown mechanisms may drive ADRD progression, we will identify and evaluate new candidates and drug combinations using mechanism-agnostic approaches. Such research requires a large population with long follow-up. The SNDS (French nationwide claims database), covering 99% of the French population since 2006, represents a unique opportunity.

Objectives: To assess the feasibility of conducting drug repurposing studies for ADRD prevention in the SNDS.

Methods: Key parameters analyzed are ADRD ascertainment, follow-up length, DREAM drugs approval status, and prescription prevalence in 2020. Statistical power is estimated using an inclusion period of 2y, a 13y follow-up, and an age and sex adjusted ADRD incidence rate of 11.4/1000 person-years anticipated in the SNDS.

Results: ADRD is identifiable in the SNDS using algorithms based on hospital records, chronic disease status, and antidementia drug claims. These algorithms are expected to have strong specificity but reduced sensitivity (0.63%) in older populations, performing best in people 40y–69y.

DREAM drugs targeting 13 of 15 pathological pathways identified in DREAM are captured in the SNDS. These include widely prescribed drugs (e.g., amlodipine > 23 million users in 2020) and rarer ones (e.g., probenecid, 1,234 users).

The SNDS provides over 15y of uninterrupted follow-up for 68 million people. Sample size calculations indicate that ≥ 390 and ≥ 3,812 subjects are necessary to achieve sufficient power to detect hazard ratios ≤ 0.6 and ≤ 0.8, respectively.

Conclusions: The SNDS is an underutilized tool for identifying potential preventive therapeutics and has suitable follow-up, disease information, and drug delivery claims to conduct ADRD drug repurposing studies. SNDS enables target trial emulation to improve causal inference, simulating drug administration before symptom onset and possibly before pathological brain changes. Still, key challenges remain: reverse causation, confounding by indication, and active controls when combinations are studied.