Phase: IIa RCT (randomized, controlled, blinded outcome assessment)
Population:
- N = 120 patients with MCI or early AD (Clinical Dementia Rating 0.5-1.0)
- Age 60-85 years
- Presence of ≥2 CVMS risk factors (circadian disruption, metabolic syndrome, vascular dysfunction)
Duration: 12 months treatment, 12 months follow-up
¶ Arm 1: Standard of Care (Control)
- Acetylcholinesterase inhibitor (donepezil/galantamine)
- Lifestyle counseling
- Circadian optimization:
- Morning bright light therapy (30 min, 10,000 lux at 7-9 AM)
- Melatonin 1-3 mg at bedtime
- Sleep hygiene protocol
- Metabolic targeting:
- Metformin 500-1000 mg BID (if not contraindicated)
- Dietary counseling (time-restricted eating)
- Vascular targeting:
- Low-dose aspirin 81 mg daily
- Blood pressure management (target <130/80)
- LDL management (target <70 mg/dL)
- Cognitive: ADAS-Cog13 change from baseline at 12 months
- CVMS composite score:
- Circadian: actigraphy-assessed sleep efficiency
- Metabolic: HbA1c, fasting insulin
- Vascular: QSM MRI (brain iron), flow-mediated dilation
- Brain amyloid PET (if available)
- CSF biomarkers (Aβ42/40, tau, neurofilament light)
- Incident dementia conversion rate
- Quality of life (QoL-AD)
Based on the Circadian-Vascular-Metabolic Syndrome hypothesis:
- Each intervention targets one component of the CVMS triad
- Combined therapy may show synergy (similar to PMID 41889929 showing multimodal circadian improves both sleep AND metabolic parameters)
- All interventions are repurposed, well-characterized, and low-cost
- Primary: Mixed-effects model for repeated measures
- Sample size: 60 per arm provides 80% power to detect 2.5-point ADAS-Cog difference (α=0.05, two-sided)
- Multiplicity adjustment for primary and key secondary endpoints
- MCI due to AD or mild AD (CDR 0.5-1.0)
- Age 60-85
- ≥2 CVMS risk factors:
- Circadian disruption: ESS >10 OR sleep efficiency <80%
- Metabolic syndrome: ≥3 NCEP criteria OR HOMA-IR >2.5
- Vascular dysfunction: history of CVD OR white matter hyperintensities on MRI
- Stable AD medication ≥3 months
- Moderate-severe AD (CDR >1)
- Active neurological disease (stroke, Parkinson's)
- Contraindications to metformin, aspirin, or bright light
- Shift workers (circadian disruption expected)
- All interventions are off-patent and low-risk
- Metformin has actual cardiovascular benefits
- Bright light therapy widely used for depression/circadian disorders
- Early stopping rules for safety
- CVMS therapy shows 2.5-4 point improvement on ADAS-Cog vs control
- CVMS composite score improves significantly in active arm
- Biomarkers show reduced neurodegeneration markers in active arm
Experiment designed: 2026-03-30 by Slot 13
Task ID for Orchestra: to be created