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Basic Science and Pathogenesis
Kenny Vetter1, Katherine A Murphy1, Yu Hou1
1University of Minnesota, Minneapolis, MN, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
Insomnia increases Alzheimer's disease (AD) risk, particularly in females with the ApoE4 genotype. Targeting orexin receptors may improve neuronal function in affected females, paving the way for precision medicine in AD treatment.
Area of Science:
- Neuroscience
- Genetics
- Sleep Medicine
Background:
- Alzheimer's disease (AD) prevalence is higher in females, with sleep disturbances and ApoE genotype influencing risk.
- Insomnia is a significant risk factor for AD development, disproportionately affecting females.
- Understanding the interplay of insomnia, sex, and ApoE genotype is crucial for targeted AD therapies.
Purpose of the Study:
- To investigate the sex- and ApoE genotype-dependent mechanisms of insomnia-induced Alzheimer's disease (AD).
- To identify potential therapeutic targets for AD by analyzing pathway interactions.
- To predict treatment responsiveness based on individual patient characteristics.
Main Methods:
- Utilized electronic health records (EHR) from The All of Us Research Program for population data.
- Analyzed human brain transcriptomics and single-nucleus RNA sequencing data (ROSMAP) to identify key AD-related genes.
- Tested dual orexin receptor antagonists (DORA) in mouse neuronal cultures (ApoE4 knock-in) measuring neuronal activity.
Main Results:
- Insomnia correlated with higher AD-related dementia risk in females but not males; increased mild cognitive impairment risk in both sexes.
- Orexin receptor 1 (HCRTR1), dysregulated in insomnia, was identified as a key driver in the AD brain network.
- HCRTR1 expression was elevated in ApoE4+ female MCI/AD brains, and DORA treatment enhanced neuronal activity in these cells.
Conclusions:
- A pathway linking insomnia, sex, and ApoE genotype in AD pathogenesis has been identified.
- Findings suggest potential for sex- and ApoE-specific treatment strategies for AD.
- This research supports the development of precision medicine approaches for Alzheimer's disease.
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