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Poster D in Poster Session D: Wednesday, August 5, 2:00 – 3:45 pm, Kimmel Center, Shorin & Rosenthal Rooms

Neuroticism contributes to cognitive decline and Alzheimer’s disease through dysregulation of excitatory neurons

Sneha Sharma¹, Natacha Comandante-Lou¹, Yiyi Ma¹, Masashi Fujita¹, David A. Bennett², Andrea Zammit², Philip L. De Jager¹; ¹Columbia University, ²Rush University Medical Center

Presenter: Sneha Sharma

Neuroticism is an established risk factor for Alzheimer’s disease (AD), yet the pathways linking this personality trait to neurodegeneration remain unclear. Leveraging longitudinal clinical data and single-nucleus RNA-sequencing of the human brain, we investigated the mechanisms underlying the relationship between neuroticism and AD. We identified two genes associated with neuroticism, both of which were downregulated in excitatory neurons: ADRA1B and LY6E-DT. Altered expression of these genes was associated with enrichment of a specific subpopulation of excitatory neurons, Exc.12. We found that Exc.12 mediates the relationship between neuroticism and AD. Notably, this mediation effect was independent of classic Aβ and tau disease pathology. In summary, framing neurodegeneration through the lens of neuroticism highlights the dysregulation of excitatory neurons as a contributor to cognitive decline and AD.

Topic Area: Development, Individual Differences & Clinical Populations