Alzheimer’s Disease

Huperzine-A, the primary active alkaloid from Huperzia serrata, has multiple RCTs and a Cochrane review showing cognitive benefits in Alzheimer's patients via acetylcholinesterase inhibition. However, these trials used isolated Huperzine-A rather than whole clubmoss extract, warranting a lower grade for the whole herb. One animal study using Japanese H. serrata extract demonstrated amelioration of scopolamine-induced cognitive impairment in mice.

In rodent models, Convolvulus pluricaulis extracts protect against cerebral ischemia-reperfusion injury (reducing lipid peroxidation and increasing SOD, catalase, glutathione), attenuate 3-nitropropionic acid-induced neurotoxicity relevant to Huntington's disease, and reduce tau and amyloid precursor protein expression in a scopolamine-induced Alzheimer's model. A Drosophila study confirmed rescue of tau-induced neurotoxicity and lifespan extension in a transgenic Alzheimer's fly model.

In rodent models of Parkinson's and Alzheimer's disease, longan flower, aril, and polysaccharide extracts consistently attenuated neurotoxicity, improved learning and memory, increased BDNF expression, reduced amyloid-beta and phosphorylated-tau, and enhanced microglial phagocytosis via RAS/MEK/ERK and PI3K/Akt/mTOR pathways. No human studies on cognition exist.

In AD mouse models, 7,8-DHF reversed memory deficits, reduced BACE1 and beta-amyloid levels, increased dendritic spine density, and reversed oxidative stress and mitochondrial dysfunction. Consistent neuroprotective effects observed across multiple AD rodent models including scopolamine-induced and ICV-STZ sporadic AD models.

Limited human studies in dementia patients showed modest cognitive benefits. Preclinical studies demonstrated idebenone protects against amyloid beta toxicity in cortical neurons (PMID:32925607). Nootropic use in cognitively healthy individuals is not supported by human evidence.

A Chinese Phase 3 RCT (n=818, 36 weeks) found a statistically significant improvement in ADAS-Cog12 scores (-2.15 points vs placebo, p<0.0001), but secondary endpoints (CIBIC+, ADCS-ADL) were not significant. A Phase 2 RCT (n=242, 24 weeks) did not reach significance on the primary ADAS-Cog12 endpoint (p=0.30 for 900mg). A small RCT (n=72, 48 weeks) reported improvements comparable to donepezil. A meta-analysis of 3 RCTs (n=1,108) favored GV-971 on ADAS-Cog12 but not other scales. Graded C rather than B due to inconsistent primary endpoint results across trials, failure to meet secondary endpoints, early termination of the global Phase 3 replication trial, and non-renewal of China's conditional approval in 2024.

In APP/PS1 transgenic Alzheimer's mice, hederagenin (25–50 mg/kg/day for 2 months) improved cognitive performance in Morris water maze, object recognition, and Y-maze tests while promoting amyloid-beta degradation via PPARα/TFEB-mediated autophagy. Additional studies in SH-SY5Y cells and C. elegans models confirmed reduced Aβ deposition, decreased oxidative damage via PI3K/Akt and PTPN1 signaling.

Moderate Improvement

A large prospective cohort study (Rush Memory and Aging Project, n=921, mean age 81) found that highest vs. lowest quintile of dietary flavonol intake was associated with reduced Alzheimer's dementia risk (HR 0.52, 95% CI 0.33-0.84). Kaempferol showed the strongest association (HR 0.49), followed by myricetin and isorhamnetin (both HR 0.62). Interestingly, quercetin alone did not reach significance.

A community-based epidemiological study of 575 deceased participants (Rush Memory and Aging Project) found that higher pelargonidin intake was associated with reduced amyloid-beta accumulation and fewer phosphorylated tau tangles in brain tissue, particularly among those without APOE e4 risk factor. Preclinical studies also show pelargonidin restores amyloid-beta-induced deficits in animal models.

Multiple preclinical studies demonstrate salidroside protects neurons against ischemia, polyglutamine toxicity, and oxidative damage in cell and animal models. Mechanisms include HSC70/BDNF signaling activation, antioxidant activity, and reduced neuroinflammation via MAPK/NF-kB pathways.

In rodent models, mulberry fruit extract enhanced memory via induction of nerve growth factor (PMID:23182412). Two studies in Alzheimer's disease mouse models showed the extract alleviated cognitive impairment by promoting amyloid-β clearance and inhibiting neuroinflammation (PMID:32488469), and reduced amyloid-β oligomer-induced cognitive disturbance and oxidative stress (PMID:34387016).

In rodent models, Anacyclus pyrethrum reduced oxidative stress markers, restored antioxidant enzyme activity, and may reduce amyloid-beta accumulation via Bcl-2/Bax modulation (PMID:31710948). A 2023 in vitro study confirmed anti-Alzheimer enzyme inhibitory activity of akarkara root-derived metabolites through bioassay-guided fractionation (PMID:37978514).

In 5xFAD transgenic Alzheimer's mice, A. iwayomogi extract improved cognitive function in Morris Water Maze tests, reduced amyloid-beta burden, and suppressed glial overactivation via AKT/autophagy-lysosomal pathways (n=12-18/group). Separately, the isolated compound yomogin (5 mg/kg) suppressed LPS-induced neuroinflammation in mice by inhibiting JNK/ERK/p38 MAPK phosphorylation (n=5/group). All preclinical.

In preclinical models, P. olacoides extract protected rat hippocampal slices from oxygen-glucose deprivation, reduced brain lipid peroxidation and free radical production in aged mice, and prevented amyloid-beta(1-42)-induced cognitive impairment and amyloid deposits in a mouse Alzheimer's model. All studies from a single research group.

In vitro and animal studies suggest myricetin may protect against neurodegeneration by modifying amyloid-beta conformation, interfering with secretase activity, and reducing post-ischemic brain damage. Identified as a candidate molecule for Alzheimer's disease research, but no human data exist.

In transgenic Alzheimer's mouse models, 5-month NR supplementation reduced microglial activation, suppressed NLRP3 inflammasome, decreased DNA damage and cellular senescence, and improved cognitive function and synaptic plasticity via the cGAS-STING pathway (Hou et al., 2021). Additional preclinical and review evidence supports NAD+ precursors for neurodegeneration, but no human trials have tested cognitive endpoints in Alzheimer's patients.

No effect

A small open-label human trial evaluated safety and target engagement of two OAA doses in Alzheimer's patients (Vidoni et al. 2021). The study demonstrated safety and some evidence of target engagement but was designed as a safety/biomarker study, not an efficacy trial. Supported by preclinical evidence of OAA-mediated neuroprotection and mitochondrial biogenesis in brain tissue.

In vitro enzyme assays demonstrate palmatine inhibits acetylcholinesterase with IC50 of 0.62 μM (second only to berberine at 0.47 μM among protoberberine alkaloids) and butyrylcholinesterase at IC50 3.32-6.84 μM. Two independent studies confirm sub-micromolar AChE inhibitory potency, a mechanism relevant to Alzheimer's disease therapeutics, though no in vivo or human data exist.

Polymethoxyflavones (nobiletin, tangeretin) found in orange peel show neuroprotective effects in rodent models of Alzheimer's and Parkinson's disease and are able to cross the blood-brain barrier. No controlled human trials have been conducted to date.

In Drosophila Alzheimer's disease models, jatamansinol extended lifespan, improved locomotor activity, enhanced learning and memory, and reduced both tau and amyloid-beta protein levels. In rat models, N. jatamansi extract reversed reserpine-induced orofacial dyskinesia and catalepsy, suggesting anti-parkinsonian potential. All evidence is preclinical.

No effect