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bioRxiv · 10.64898/2026.06.27.735015

Neuroticism is linked to cognitive decline and increased risk of Alzheimer's disease through dysregulation of excitatory neurons

Sharma, S.·Comandante-Lou, N.·Ma, Y.·Fujita, M.·Bennett, D. A.·Zammit, A. R.·De Jager, P.
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Abstract

INTRODUCTIONNeuroticism is an established risk factor for Alzheimers disease (AD), yet the molecular mechanisms linking this personality trait to neurodegeneration remain poorly understood. METHODSWe leveraged single-nucleus RNA-sequencing data from longitudinal cohort studies of cognitive aging (n = 655) to investigate the mechanisms mediating the association between neuroticism and AD. RESULTSWe identified two genes associated with neuroticism, both of which are downregulated in excitatory neurons: ADRA1B and LY6E-DT. In addition, we found that neuroticism is associated with enrichment of a specific excitatory neuron subpopulation: Exc.12. Further analysis revealed that Exc.12 partially mediates the relationship between neuroticism and AD, accounting for 12.2% of the total effect. DISCUSSIONThe dysregulation of excitatory neurons may represent a key cellular change that links neuroticism to AD.

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Sharma, S., Comandante-Lou, N., Ma, Y., Fujita, M., Bennett, D. A., Zammit, A. R., De Jager, P.. 2026-06-29. Neuroticism is linked to cognitive decline and increased risk of Alzheimer's disease through dysregulation of excitatory neurons. https://doi.org/10.64898/2026.06.27.735015

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