24S-Hydroxycholesterol Is Associated with Agitation Severity in Patients with Moderate-to-Severe Alzheimer's Disease: Analyses from a Clinical Trial with Nabilone

J Alzheimers Dis. 2019;71(1):21-31. doi: 10.3233/JAD-190202.


Background: Agitation is a prevalent and difficult-to-treat symptom of Alzheimer's disease (AD). The endocannabinoid system (ECS) has been a target of interest for the treatment of agitation. However, ECS signaling may interact with AD-related changes in brain cholesterol metabolism. Elevated brain cholesterol, reflected by reduced serum 24-S-hydroxycholesterol (24S-OHC), is associated with reduced membrane fluidity, preventing ligand binding to cannabinoid receptor 1.

Objective: To assess whether 24S-OHC was associated with agitation severity and response to nabilone.

Methods: 24S-OHC was collected from AD patients enrolled in a clinical trial on nabilone at the start and end of each phase. This allowed for the cross-sectional and longitudinal investigation between 24S-OHC and agitation (Cohen Mansfield Agitation Inventory, CMAI). Post-hoc analyses included adjustments for baseline standardized Mini-Mental Status Exam (sMMSE), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation (physical aggression and nonaggression, and verbal aggression).

Results: 24S-OHC was not associated with CMAI scores cross-sectionally or longitudinally, before and after adjusting for baseline sMMSE. However, 24S-OHC was associated with greater CMAI IPA scores at baseline (F(1,36) = 4.95, p = 0.03). In the placebo phase only, lower 24S-OHC at baseline was associated with increases in CMAI IPA scores (b = -35.2, 95% CI -65.6 to -5.0, p = 0.02), and decreases in 24S-OHC were associated with increases in CMAI IPA scores (b = -20.94, 95% CI -57.9 to -4.01, p = 0.03).

Conclusion: 24S-OHC was associated with agitation severity cross-sectionally, and longitudinally in patients with AD. However, 24S-OHC did not predict treatment response, and does not change over time with nabilone.

Keywords: Alzheimer’s disease; behavioral symptoms; biomarkers; geriatric psychiatry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged, 80 and over
  • Alzheimer Disease / complications
  • Alzheimer Disease / psychology*
  • Anti-Anxiety Agents / therapeutic use*
  • Cross-Sectional Studies
  • Dronabinol / analogs & derivatives*
  • Dronabinol / therapeutic use
  • Female
  • Humans
  • Hydroxycholesterols / blood*
  • Hydroxycholesterols / metabolism
  • Longitudinal Studies
  • Male
  • Psychomotor Agitation / blood
  • Psychomotor Agitation / drug therapy*
  • Psychomotor Agitation / metabolism
  • Treatment Outcome


  • Anti-Anxiety Agents
  • Hydroxycholesterols
  • nabilone
  • 24-hydroxycholesterol
  • Dronabinol