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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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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