Biomarkers of agitation in moderate‐to‐severe Alzheimer's disease patients enrolled in an RCT with nabilone: Biomarkers (non‐neuroimaging) / plasma/serum/urine biomarkers

Background Brain cholesterol metabolism, neuroinflammation, and oxidative stress are processes altered during Alzheimer’s disease (AD), which may impede endocannabinoid signaling, and thus worsen agitation. We assessed whether the brain cholesterol metabolite, cerebrocholesterol (Cchol), proinflammatory cytokine, tumor necrosis factor (TNF), and oxidative stress marker, 4‐hydroxynonenal (4‐HNE) were associated with agitation severity and response to nabilone. Method Serum Cchol, TNF and 4‐HNE, were collected from AD patients enrolled in a 14‐week, double‐blind cross‐over trial comparing 6 weeks of nabilone to placebo, at the start and end of each phase. We assessed the relationship between agitation (Cohen Mansfield Agitation Inventory (CMAI)) and baseline (BL) biomarker levels; the relationship between change in agitation and BL biomarker levels within each phase; and the relationship between change in agitation and change in biomarker levels within each phase. Exploratory analyses included adjustments for BL cognition (Mini‐Mental Status Exam (MMSE)), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation. Result Serum was collected from thirty‐eight participants (mean±SD age=87±10, 77% male, CMAI=68±18, MMSE=6.3±6.3). Cchol was not associated with CMAI cross‐sectionally or longitudinally, before and after adjusting for MMSE. However, BL Cchol was negatively correlated with BL CMAI IPA (F(1,36)=4.95, p=.03). In placebo only, lower BL Cchol was associated with increases in CMAI IPA (b=‐35.2, p=.02), and decreases in Cchol were associated with increases in CMAI IPA (b=‐20.94, p=.03). After adjusting for MMSE, BL TNF was positively correlated with BL CMAI (F(2,25)=3.69, p=.04), and predicted improvements in CMAI during nabilone only (b=‐1.14, p=.045). Decreases in TNF were associated with improvements in CMAI during nabilone only (b=1.12, p=.006). BL 4‐HNE was positively correlated with BL CMAI (F(1,35)=6.41, p=.02), and predicted worsening in CMAI during placebo only (b=0.01, p=.01). Changes in 4‐HNE were not associated with changes in CMAI in either phase. Conclusion Cchol, TNF, and 4‐HNE may be markers of agitation severity in AD. Though neither Cchol nor 4‐HNE predicted response to nabilone and did not change over time with nabilone, these markers may be associated with changes in agitation severity. Findings with TNF suggest that this marker predicts treatment response, and decreases with nabilone treatment.