Table 2.

Early development of APOE-directed therapeutic approaches in human clinical trials.

Drug	Rationale	ID	Status	Design	Phase	Subjects	Dose/route/ duration	Primary outcome	Secondary outcomes	Results	Ref.
Bexarotene	Increase APOE levels	NCT02061878	Completed	Randomised, double-blind, placebo-controlled	1b	Healthy young (aged 21–49) APOE ε3/ε3 volunteers	225 mg BID PO × 5 days	Newly generated Aβ in CSF (SILK)	Fractional clearance rate of Aβ from CNS (SILK)	Poor bexarotene brain penetration (not detectable in >95% CSF samples), 25% increase in CSF APOE levels, marginally significant increase in newly synthesized APOE, no change in Aβ synthesis/clearance or levels	Ghosal et al. 2016⁸³
Bexarotene	Increase APOE levels	NCT01782742	Completed	Randomized double blind placebo-controlled	2	Moderate AD (MMSE 10–20) with positive baseline amyloid PET scan	150 mg BID PO × 4 weeks	Aβ burden in amyloid PET imaging	Cognition (MMSE, ADAS-Cog, CDR), behavior (NPI), ADL, serum Aβ40/42	Significant reduction in Aβ burden only in APOE ε4 non-carriers which correlated with increased serum Aβ42 levels, increased triglyceride plasma level in bexarotene group, no efficacy in clinical outcomes	Cummings et al. 2016⁸⁴
Probucol	Increase APOE levels	NCT02707458	Completed	Open label, dose finding	1 & 2	Cognitively intact at risk of AD by family history	Initial 600 mg QD PO, then individualized, 1 year of follow-up	Plasma probucol and CSF and plasma APOE levels	N.A.	N.A.	n.a.
CN-105	APOE mimetic	NCT03802396	Recruiting	Randomized double blind placebo-controlled	2	≥60 year-old undergoing major surgery	0.1 mg/kg vs 0.5 mg/kg vs 1 mg/kg IV Q6H × 4 days and 6 weeks of follow-up	Safety	CSF cytokine levels, change in cognition, post-operative delirium	N.A.	n.a.
Gene therapy (AAVrh.10hPOE2 vector)	Switch APOE4 to APOE2	NCT03634007	Recruiting	Open label, dose ranging	1	Symptomatic (any stage), APOE ε4/ε4, positive CSF biomarkers or amyloid PET scan	8×10¹⁰ GC/kg vs 2.5×10¹¹ GC/kg vs 8×10¹¹ GC/kg, single intracisternal, injection and 2 years of follow-up	Safety	Maximum dose tolerated	N.A.	n.a.

AAV = adeno-associated virus; AD = Alzheimer’s disease; ADAS-Cog = Alzheimer’s Disease Assessment Scale-Cognitive subscale; ADL = Activities of Daily Living; BID = bis in die (twice daily); CSF = cerebrospinal fluid; GC = genome copies; IV = intravenously; MMSE = Mini Mental State Examination; N.A. = not available. NPI = neuropsychiatric inventory; PET = positron emission tomography; PO = per os (orally); Q6H = quaque sexta hora (every 6 hours); QD = quaque die (once daily); SILK = stable isotope labelling kinetics.