Neuropsychiatric symptoms, Alzheimer’s Disease and Cerebrospinal Fluid Cortisol and Dehydroepiandrosterone Sulfate: a Prospective Study

Abstract Background Neuropsychiatric symptoms (NPS) are important treatment targets in the management of dementia, can be present at very early stages of neurodegeneration, and are associated with more rapid clinical disease progression. Increased cortisol has been reported in Alzheimer’s disease (AD), and has been associated with cognitive decline. At the same time, cortisol is often referred to as the “stress hormone” and elevated cortisol output has been observed in association with depression and delirium. Dehydroepiandrosterone sulfate (DHEAS) has known anti‐glucocorticoid effects and may counter the effects of cortisol. Methods One hundred and twenty‐three participants with cognitive impairment (mild cognitive impairment or dementia, N=78) and with normal cognition (N=53) were included in a prospective study in a memory clinic setting. NPS were assessed using the Neuropsychiatric Inventory (NPI), CSF cortisol and DHEAS, as well as CSF AD biomarkers were obtained at baseline. NPS and cognitive performance were re‐assessed at follow‐up visits 18 and 36 months from baseline. We constructed linear regression models to examine the links between baseline NPS, AD pathology, and CSF cortisol and DHEA. We used repeated‐measures mixed ANCOVA models to examine the associations between the NPS changes over time, baseline CSF cortisol and DHEA, and AD pathology. Results Higher CSF cortisol was associated with more common (p<0.001) and more severe NPS at baseline after controlling for covariates (B=0.091[0.031;0.150], p=0.003; r=0.309), in particular with depression, anxiety, apathy/indifference. Elevated CSF cortisol was also associated with NPS worsening over time regardless of AD pathology (p=0.036, η 2 =0.207). Both associations remained significant after controlling for AD pathology status. CSF DHEAS was neither associated with NPS at baseline nor with their change over time. Conclusion Elevated CSF cortisol is associated with more severe NPS at baseline, as well as with more pronounced worsening over three years, independently of AD pathology status. Cortisol may predict the course of NPS in individuals with cognitive impairment. Our findings also suggest that interventions targeting the HPA axis may be helpful to treat neuropsychiatric symptoms of dementia.