Insomnia, Depression, and Medication Effects on Mild Cognitive Impairment to Dementia Progression: A Nationwide TriNetX Cohort Study
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PROJECT SUMMARY/ABSTRACT Annually, up to 15% of patients with mild cognitive impairment (MCI) progress to Alzheimer’s disease and related dementias (ADRD)—debilitating and incurable conditions with limited treatments—and, cumulatively, as many as 80% progress within six years. The economic impact is substantial, with total social costs projected to be $707 billion in 2024 and rising as the population ages. Identifying modifiable risk factors is crucial, as delaying ADRD onset by five years could prevent ~1 million cases in the next decade. Insomnia and major depressive disorder (MDD) are key modifiable risk factors independently linked to ADRD. Yet, two major gaps remain: 1) few studies have evaluated their combined effect on MCI-to-ADRD progression, despite their frequent co- occurrence (59% of MDD patients have insomnia, which increases depression risk by 2.6 times); and 2) the influence of contemporary prescribing patterns for insomnia and MDD on progression remains unclear. While antidepressants and sedative-hypnotics may relieve symptoms, medications such as benzodiazepines and some non-benzodiazepine hypnotics have been associated associated with worsened cognition. MCI remains markedly underdiagnosed—only ~8% of expected cases are documented—leaving more than 90% undetected. Nevertheless, a documented MCI diagnosis provides a pragmatic “early-warning” stage for surveillance and prevention. This R21 proposal will: 1) examine the combined effect of insomnia and MDD on progression to ADRD among patients with MCI; 2) assess how real-world prescribing patterns, and their changes over time, influence MCI-to-ADRD progression; and 3) test whether associations vary by age, race, and sex. We will assess progression using longitudinal electronic health records linked to matched claims for ~7.8 million patients across 35 health care organizations, with 2011–2013 eligibility and 11–14 years of follow-up. The proposed research will generate preliminary evidence on the safety of pharmaceutical treatments, inform treatment algorithms, and lay the foundation for future interventions that enable clinicians and patients to engage in shared decision-making.
