Age-Associated Memory Impairment and Cognitive Decline (AAMCD)

Multiple rodent studies demonstrate improved learning and memory in Morris water maze and passive avoidance paradigms, with reversal of scopolamine-induced amnesia comparable to rivastigmine. One open-label human study (n=30) showed 41-48% improvement in auditory memory and 32-45% improvement in visual memory after 2 months, though it lacked placebo control. Mechanistically linked to acetylcholinesterase inhibition, enhanced long-term potentiation (LTP) in hippocampus, and reduction of tau and amyloid precursor protein expression in rat brain.

In rodent models, P. olacoides extract consistently improved memory retrieval in step-down avoidance and object recognition tasks in both young and aged mice across multiple studies. Effects are mediated through acetylcholinesterase inhibition (15-33% in hippocampus) and serotonin 5-HT2A receptor modulation. No human cognitive trials exist.

In multiple rodent models, 7,8-DHF consistently improved spatial memory, long-term memory, and learning. Benefits observed in wildtype mice as well as models of alcohol-induced, sevoflurane-induced, and vascular dementia-related cognitive impairment, with effects mediated through TrkB/BDNF signaling.

A small 6-month RCT (n=30) of Persicaria minor extract (Biokesum® 500 mg/day) in older adults with mild cognitive impairment found significant improvement in visual memory (p=0.012) and increased right DLPFC brain activation. Two rodent studies demonstrated enhanced recognition and spatial memory in cerebral hypoperfusion and scopolamine-induced cognitive impairment models, with increased acetylcholine and GABA neurotransmitter expression.

Three RCTs in middle-aged to older adults (n=100, n=60, n=34) found MHBA (35 mg/day) significantly improved divided attention (SDMT, p=0.045), verbal fluency (p=0.034), Stroop test performance (p=0.019), and attention/executive function after single dose. Multiple animal studies show MHBA improves hippocampus-dependent memory via vagus nerve activation and norepinephrine release, with nicotinic acetylcholine receptor involvement.

Multiple RCTs show mixed results. Two industry-affiliated trials (n=71, 28 days; n=196, 28 days) found improved reaction time and working memory accuracy. A pilot (n=8) found reduced reaction time and fewer cognitive errors. However, the only independent RCT (n=72) found no cognitive benefit at 100mg or 300mg, and 100mg actually increased mental fatigue. A combination product trial (n=138, WCCE + phosphatidylserine) showed improved numeric working memory and picture recognition.

In rodent models, Clitoria ternatea root extract (100-300mg/kg) improved memory and learning in passive avoidance and Y-maze tests, with some studies reporting effects comparable to piracetam or Bacopa monnieri. The mechanism is attributed to acetylcholinesterase inhibition leading to increased acetylcholine levels, a well-characterized nootropic pathway. No human clinical trials exist.

In multiple rodent models (pole climbing, passive avoidance, active avoidance paradigms), ethanol extract of Evolvulus alsinoides significantly improved learning and memory, with effects comparable to piracetam. The extract also reversed scopolamine-induced amnesia in rats, suggesting cholinergic involvement.

Small Improvement

No effect

A small pilot crossover RCT in 20 older adults (aged 62-81) found that haskap berry extract at 200 mg and 400 mg anthocyanin doses significantly improved word recall and word recognition scores at 1.5 hours post-consumption compared to placebo.

Small Improvement

Small Improvement

Small acute human studies suggest sage extract modestly improves memory and attention, likely via cholinesterase inhibition. Related species S. lavandulaefolia may have stronger cognitive evidence; a review of plant extracts highlights sage among candidates for Alzheimer's disease intervention.

In AF64A-treated rats and mice with cholinergic deficits, oral coluracetam (1-10 mg/kg) significantly improved water maze learning and working memory deficits. Repeated administration produced long-lasting cognitive improvement persisting 24-72 hours after the last dose, suggesting durable changes to choline transporter regulation. No cognitive enhancement was observed in normal (non-impaired) animals.

In an animal study, salidroside ameliorated memory and emotional behavior in adult mice. Preclinical models of cognitive impairment suggest salidroside may improve learning and memory through antioxidant and anti-inflammatory mechanisms.

In a rat model, Anacyclus pyrethrum protected against seizure-induced cognitive impairment, increasing platform crossings and decreasing escape latency in spatial memory tests, possibly via enhanced cholinergic neurotransmission (PMID:23242789). No human data exists.

A small number of studies suggest Huperzine-A may enhance memory in healthy young adults, particularly procedural memory. Evidence is limited, derived from isolated Huperzine-A rather than whole clubmoss extract, and requires replication in larger controlled trials.

In a rat model, Danggui Shaoyao San (a traditional combination formula containing dong quai) improved colchicine-induced learning acquisition impairment. This represents a single preclinical study using a multi-herb combination formula, not dong quai alone, limiting attribution of effects.

In rodent studies, oleamide affected choline acetyltransferase activity and cognitive performance. However, FAAH-knockout mice showed disrupted working memory in water maze tasks with oleamide, suggesting dose- and context-dependent cognitive effects. Evidence is mixed and limited to animal models.

Two comprehensive reviews (Sharma et al. 2020; Middha et al. 2026) document neuroprotective effects of Acorus calamus active compounds through modulation of Nrf-2, NF-κB, PI3K/AKT, and Ras/MAPK signaling pathways in preclinical models, reducing oxidative stress associated with neurological dysfunction. Evidence remains limited to animal and in vitro studies with no direct human clinical trials on cognition.

C3G protected PC12 neuronal cells against apoptosis mediated by LPS-stimulated microglial activation. A 2019 review outlined neuroprotective effects in the central nervous system across multiple preclinical models. Anthocyanin-rich berry extracts containing cyanidin show some cognitive benefits in elderly populations, but effects may be attributable to the overall anthocyanin mixture rather than C3G specifically.

Animal studies suggest Codonopsis pilosula may enhance memory and exert neuroprotective effects, possibly through increased BDNF expression. Evidence is substantially weaker than for Panax ginseng, and no human trials exist for cognitive outcomes.

In rodent models, sunifiram (0.001-0.1 mg/kg) reversed scopolamine-induced amnesia in mouse passive avoidance tests and rat Morris water maze tests, with potency approximately 1,000 times greater than piracetam. It also reversed amnesia induced by the AMPA receptor antagonist NBQX. No human studies exist.

Limited human studies and animal data suggest magnesium L-threonate (Magtein) may enhance brain magnesium levels and cognitive function. However, this evidence pertains to the magnesium chelate, not isolated L-threonate. The comparative advantage over other bioavailable magnesium forms remains unestablished.

In mice, N. jatamansi extract (200mg/kg for 8 days) significantly improved learning and memory in elevated plus maze and passive avoidance tasks, reversing diazepam- and scopolamine-induced amnesia. In rats, 200mg/kg for 21 days prevented chronic restraint stress-induced learning and memory deficits in a radial arm maze. No human cognitive trials exist.

Preliminary evidence suggests a possible role for lutein and zeaxanthin in cognitive function in the elderly (PMID:23053547). A primate study (PMID:22780947) demonstrated that macular lutein and zeaxanthin concentrations are correlated with brain carotenoid levels, providing a plausible biological mechanism, but human intervention data remain very limited.

No effect

An open-label trial in 8 aging HIV patients found improved cognitive performance on the Trail Making Test-B after 12 weeks of GlyNAC supplementation. No placebo-controlled RCTs confirm this finding.

A single 12-week randomized, double-blind, placebo-controlled trial in 75 healthy adolescents found that 1.5 g/day of loquat leaf ethanol extract significantly improved total K-MMSE scores (p=0.043) and memory subscale scores (p=0.014) compared to placebo. No adverse events were reported.