Table 1.

Peer-reviewed clinical trials associated with positive Alzheimer’s disease outcomes following treatment with antimicrobials

Antimicrobial(s)	On-target effect(s)	Off-target effect(s) on AD-associated processes	Clinical trial: Study population	Clinical trial: Treatment dosage	Clinical trial: Improved AD outcomes
Cycloserine	Broad-spectrum antibiotic [18]	Inhibits: PI3K/Akt pathway NO production Phosphorylation of LPS-induced ERK [19]	Probable AD patients (n = 91) Placebo-controlled Double-blind [20]	5, 15, or 50 mg 2 × daily (oral) 10-week duration [20]	Implicit memory performance of words repeated across trials [20]
			AD patients (n = 17) Placebo-controlled Double-blind [21]	50 or 100 mg 1 × daily 4-week duration [21]	ADAS-cog scores [21]
Doxycycline and Rifampin	Broad-spectrum antibiotic (both) [22, 23]	Enhances: PACAP receptors (Doxycycline) [24] Inhibits: Microglial inflammation (Rifampin) [25]	Probable AD and mild-to-moderate dementia patients (n = 101) Placebo-controlled Triple-blind [26]	200 and 300 mg (Doxycycline and Rifampin, respectively) 1 × daily (oral) 3-month duration [26]	Functional behavior at 3 months ADAS-cog score at 6 months [26]
Helicobacter pylori eradication regimen: Omeprazole, clarithromycin, and amoxicillin	Proton-pump inhibitor (Omeprazole) [27] Macrolide antibiotic (clarithromycin) [28] Broad-spectrum antibiotic (amoxicillin) [29]	Inhibits: TGF- β upregulation in vivo (amoxicillin) [30]	H. pylori-positive patients with AD (n = 56) Placebo-controlled Triple-blind [31]	In accordance to clinical standard practice in Europe  > 2-year follow-up period [31]	MMSE CAMCOG FRSSD [31]
Antiherpetic treatment: Either acyclovir, famciclovir, ganciclovir, idoxuridine, penciclovir, tromantadine, valacyclovir, or valganciclovir	Antiviral [20]		Herpes simplex virus type 1 and/or type 2 patients (n = 8362, ≥ 50 years old) Placebo-controlled Triple-blind [32]	Self-administered, as needed Until onset of dementia  > 10-year follow-up period [32]	Lower incidence of overall dementia (AD, vascular and other dementia) [32]
Sodium oligomannate (GV-971)	Inhibits Aβ fibrillization [33]	Inhibits: Gut dysbiosis Peripheral immune cells infiltration into the brain Neuroinflammation in animal models [33]	Probable AD patients (n = 818) Placebo-controlled Double-blind [34]	2 × daily (oral) 36-week duration [34]	ADAS-cog12 scores [34]
N-acetyl-L-cysteine (NAC)	Thiol antioxidant [35] Ameliorates psychiatric and neurological disorder-associated physiological processes [36, 37]	Broad-spectrum antibiotic [38–40]	Probable AD patients (n = 43) Placebo-controlled Double-blind [41]	50 mg/Kg/day  ≤ 6-month duration [41]	Letter fluency task Wechsler Memory Scale [41]
			Moderate to late-stage AD patients (n = 12) Placebo-controlled [42]	600 mg of NAC 2 × daily (oral)  ≤ 9-month duration [42]	Dementia Rating Scale scores [42]

Aβ Amyloid-beta, AD Alzheimer’s disease, ADAS-cog Alzheimer's Disease Assessment Scale-Cognitive subscale, ADLs Activities of Daily Living, CAMCOG Cambridge Cognitive Examination for the Elderly, CNS central nervous system, FRSSD Functional Rating Scale for Symptoms of Dementia, LPS lipopolysaccharides, MMSE Mini-Mental State Examination, NO nitric oxide, ERK extracellular signal-regulated kinase, PACAP pituitary adenylate cyclase-activating polypeptide, PI3K/Akt phosphoinositide 3-kinase/Akt