. Author manuscript; available in PMC: 2021 Dec 1.

Published in final edited form as: Nat Rev Neurol. 2020 Sep 16;16(12):661–673. doi: 10.1038/s41582-020-0397-4

Table 1 |.

Priority candidates from the 2018–2019 Delphi consensus

Drug classes	Proposed candidates	Proposed mechanism of action	Summary of evidence	Remaining work required
*Shortlisted candidates*
ROCK inhibitors	Fasudil	Reduction in Aβ levels in vitro through the Dkk1-driven Wnt–PCP pathway⁷²; reduction in inflammation⁷⁰; prevention of synaptic damage⁷¹ and impaired dendritic arborization⁶⁹	Strong and consistent evidence of synaptic protection, reduction in amyloid and cognitive benefits in a range of in vivo animal models of AD^67,71,72; several studies have shown acceptable safety in people with pulmonary hypertension and ischaemic heart disease^74,136,137; only one very small study in MCI and AD, which found better scores on the verbal fluency test, Mini-Mental State Examination and activities of daily living with fasudil treatment than with nimodipine; the full study has not been published in English⁷⁵	A well-powered RCT among participants with AD or MCI is needed to evaluate the effect of fasudil on cognitive function
AChE inhibitors	Phenserine	Suppression of IL-1β production; reduction in glutamate-induced excitotoxicity; protection against oxidative stress; reduction in Aβ levels; increase in production of BDNF; inhibition of APP and α-synuclein synthesis; and anti-apoptosis action on pre-programmed cell death pathway¹⁹	Several preclinical studies showed that phenserine reduces APP levels in cultured cells and in the brain of animal models^83–87; phase II studies of phenserine showed good tolerability and demonstrated some indication of cognitive benefit, although the study was under-powered to properly examine cognitive function⁷⁸	Further studies are needed to verify the potential mechanism of action in humans; these studies need to have adequate power to measure cognitive benefits
Antiviral drugs	Acidovir, pencidovir, valaciclovir and foscarnet	In vitro evidence suggests that HSV can accelerate the accumulation of amyloid^97–99 and promote abnormal tau phosphorylation^100–102; antiviral drugs might mitigate these effects	A post-mortem case–control study in carriers of APOE ε4 found that AD was more common among individuals who had HSV than in those who did not⁹⁵; an epidemiological study also showed that a cohort of persons with HSV had a higher risk of developing dementia than those without HSV¹⁰⁴; recent large-scale studies suggest that the association between HSV and dementia is mitigated or reversed by antiviral therapy^94,104	At least two small RCTs in a combined total of 163 individuals with AD are in progress^138,139, but a well-powered RCT is needed
*Non-shortlisted compounds*
DMARDs	Methotrexate, chloroquine phosphate, proguanil hydrochloride, cyclosporine, cyclophosphamide, hydroxychloroquine sulfate and sodium aurothiomalate	The potent anti-inflammatory actions of this class of agents might be a potential mechanism of action, but this has not been clarified in preclinical studies	A population-based retrospective cohort study found that participants using DMARDs had a modestly reduced risk of dementia compared with participants not using DMARDs¹⁸; a double-blind RCT in 168 individuals with mild AD over 18 months showed that hydroxychloroquine did not prevent cognitive decline¹⁰⁷ compared with placebo; an open-label trial in ten individuals with AD treated with hydroxychloroquine showed that CSF levels of Aβ did not change after treatment¹⁴⁰ (reviewed elsewhere¹⁰⁷)	More robust preclinical studies are needed to establish mechanism of action; high-powered RCTs are also needed to confirm findings from observational studies
ACE inhibitors	Captopril, ramipril, lisinopril and perindopril	Reduction in amyloid deposition and tau hyperphosphrylation¹⁴¹; protection against oxidative stress^109,142; reduction in blood pressure	Evidence of benefit inconsistent across studies¹⁴³	Although there is some supportive preclinical evidence, the epidemiological evidence is fairly weak; RCTs, several of which are already ongoing, are needed to distinguish between the effect of hypertension control and the specific effects of ACE inhibitors

Aβ, amyloid-β; ACE, angiotensin-converting enzyme; AChE, acetylcholinesterase; AD, Alzheimer disease; APP, amyloid precursor protein; BDNF, brain-derived neurotrophic factor; CSF, cerebrospinal fluid; DMARDs, disease-modifying antirheumatic drugs; HSV, herpes simplex virus; MCI, mild cognitive impairment; RCT, randomized clinical trial; ROCK, rho kinase.