Atlas chapter 18 · Cognition

Maitake / Hen-of-the-Woods

Grifola frondosa

E3+ narrow+ — Supports the tested propositionR1 — the grade-owning Y10M cognition proposition currently rests on one small randomized, double-blind, placebo-controlled trial. No independent replication of the Y10M cognitive signal has yet been established. The study was funded by YUKIGUNI FACTORY Co., Ltd., which manufactured the test foods, and two authors were affiliated with the company's R&D department. This does not invalidate the trial, but independent replication must test both cohort reproducibility and investigative independence. Multiple outcomes, NK-cell analyses, strain comparisons within the same trial and further publications from the same programme are not counted as replication.

Proposition / claim: Y10M improved MoCA-J performance relative to placebo over 18 weeks in healthy Japanese adults aged 60-85; cognitive superiority over C5304 was not established.
Evidence owner: Y10M Grifola frondosa as administered in the 18-week study food intervention. The evidence owner includes the strain, food matrix, dose, duration, population and cognitive endpoint actually studied. The Y10M cognition signal does not automatically transfer to C5304, generic Maitake, other strains, powders, extracts or arbitrary commercial products.
Dominant uncertainty: Independent replication and direct cognitive strain superiority. Two distinct questions remain central: (1) will the Y10M cognitive signal replicate independently? (2) if it does, is Y10M's cognitive effect genuinely different from C5304?

Organism: Grifola frondosa
Tested intervention: Y10M Maitake incorporated into bread, providing 50 g of the assigned Y10M strain per day for 18 weeks. The broader three-arm study also included C5304 Maitake incorporated into matched study bread at 50 g/day, and placebo bread without Maitake.
Evidence target: Strain
Intervention description: A randomized, double-blind, placebo-controlled three-arm food intervention comparing Maitake strain Y10M, Maitake strain C5304 and placebo. Participants consumed study bread containing 50 g/day of their assigned Maitake strain, or matched placebo bread without Maitake, for 18 weeks. Y10M is the evidence-owning strain for the narrow placebo-relative cognition signal; C5304 is a comparator strain and must not be treated as equivalent merely because both belong to Grifola frondosa. One species can contain different evidence owners.
Population: Healthy Japanese adults aged 60-85 years, with screening MMSE scores of at least 24. 48 participants were randomized and 47 completed the 18-week intervention. Per-protocol completer groups: placebo n=14; Y10M n=16; C5304 n=17.
Comparator: Three-arm comparison: Y10M versus C5304 versus placebo bread without Maitake. For the grade-owning proposition, the key demonstrated comparator is Y10M versus placebo. For the unresolved strain-superiority proposition, the relevant direct comparison is Y10M versus C5304, which was tested but not shown to be significant.
Outcome: MoCA-J performance after 18 weeks, including post-intervention total score and change from baseline; other cognitive measures included MMSE and HDS-R. The Y10M group showed significant placebo-relative MoCA-J differences. C5304 did not show a significant placebo-relative MoCA-J difference. ANCOVA with Bonferroni-corrected pairwise testing did not establish significant Y10M-versus-C5304 cognitive superiority. Separately, Y10M and C5304 did show significant differences in CD69 expression for total NK cells and the NKdim subset; that immune biomarker strain difference does not establish cognitive strain superiority, and the reported positive association between CD69 changes and MoCA-J does not establish NK-cell activation as the causal mechanism.
Evidence maturity (E): E3+ narrow
Direction: + — Supports the tested proposition
Historical flag (H): Not specified at dossier level
Replication (R): R1 — the grade-owning Y10M cognition proposition currently rests on one small randomized, double-blind, placebo-controlled trial. No independent replication of the Y10M cognitive signal has yet been established. The study was funded by YUKIGUNI FACTORY Co., Ltd., which manufactured the test foods, and two authors were affiliated with the company's R&D department. This does not invalidate the trial, but independent replication must test both cohort reproducibility and investigative independence. Multiple outcomes, NK-cell analyses, strain comparisons within the same trial and further publications from the same programme are not counted as replication.
Claim Gap (CG): Claim ceiling: CG1 for Y10M-specific cognition wording. CG0 — In one small randomized trial, Y10M Maitake improved MoCA-J scores relative to placebo in healthy older Japanese adults. CG1 — Preliminary controlled evidence suggests Y10M Maitake may improve selected cognitive performance in older adults. CG2 — Maitake may support cognition. The strain identity has disappeared. CG3 — Maitake improves memory and prevents cognitive decline. Outcome and duration have expanded. CG4 — Maitake helps prevent dementia. The direct experiment no longer supports the claimed endpoint.
Evidence Transfer Vector: Transferred proposition: "Maitake prevents dementia in older adults." Vectors I / O / D / R / P. I — Intervention: Y10M → generic Maitake. O — Outcome: MoCA-J performance → dementia. D — Duration: 18 weeks → years. R — Replication: single small trial → preventive certainty. P — Population: healthy older Japanese adults → older adults generally.
Taxonomic Transfer Confidence: HIGH. Grifola frondosa taxonomy is not the principal transfer problem in this dossier; the main problem is strain and preparation identity. HIGH taxonomic transfer confidence must not be read as implying strain equivalence.
Intervention Transfer Confidence: Y10M → Y10M produced under equivalent conditions: POTENTIALLY HIGH with adequate preparation control. Y10M → C5304: LOW for cognitive equivalence until demonstrated. Y10M → generic commercial Maitake: LOW. One species. Different evidence owners.
Safety: S1. No participant discontinued because of adverse effects such as abdominal pain, palpitations or allergic reactions in the Y10M or C5304 groups, and measured physical and hematological parameters remained within standard ranges during the intervention. This is reassuring for this 18-week programme. It does not establish rare-event safety, long-term safety, safety in all populations, safety with medications, or safety for arbitrary Maitake preparations.
Conservation: C0/C+ — Maitake is readily cultivable and no clinical case for Y10M requires pressure on wild populations. Cultivation also supports strain maintenance, characterization, batch control and reproducibility. Cultivability does not imply clinical equivalence between strains or preparations.
Resolution zone: RZ-2-3 — a controlled human signal exists, but the priority is independent confirmatory replication with an adequately powered direct strain comparison. This is not a generic "more research needed" label.
Next best experiment: Run a larger, independently funded, randomized, double-blind, placebo-controlled three-arm trial: Y10M versus C5304 versus placebo. Prespecify the Y10M-versus-C5304 cognitive contrast as a key hypothesis and power the study adequately for that direct comparison. Use the same or a well-justified dose, a matched food matrix, and a longer duration where feasible. Prespecify one clearly defined primary cognitive endpoint. Retain NK-cell measures as secondary mechanistic outcomes rather than primary efficacy evidence. Characterize both strains and the finished study foods, including where feasible polysaccharide profiles, metabolomics, relevant candidate compounds and batch variability. The strain-superiority question must be built directly into the experiment rather than inferred afterward from one significant and one nonsignificant placebo comparison.
Primary references: Jogi EM, Kato MC, Masuda Y, Konishi M, Kuwabara N, Sato S, Nakagawa S, Yamasaki K, Aoki R, Ohno M, Ohata S, Kato S, Hashimoto M. Maitake Mushroom (Grifola frondosa) Enhances Cognitive Function in Healthy Older Japanese: A Randomized, Double-Blind, Placebo-Controlled Trial. J Nutr Sci Vitaminol (Tokyo). 2026;72(2):163-175. DOI: 10.3177/jnsv.72.163. PMID: 42055721. PMCID: none. Trial registration: UMIN000050636. ROLE: GRADE-OWNING / PRIMARY. Sole controlled clinical programme owning the Chapter 18 proposition. Three-arm randomized double-blind placebo-controlled 18-week food intervention; 85 screened, 48 randomized (19 male, 29 female), 47 completed (one withdrawal for foot surgery); per-protocol placebo n=14, Y10M n=16, C5304 n=17; 50 g/day of the assigned strain in two 55 g bread pieces; healthy Japanese adults aged 60-85 y with screening MMSE >=24, recruited in Kawamoto-machi, Shimane. ANCOVA adjusted for baseline value, age, sex and years of education with Bonferroni-corrected pairwise comparisons. MoCA-J total: Y10M vs placebo significant post-intervention (p=0.045) and on change from baseline (p=0.040); MoCA-J memory subscale change p=0.024 vs placebo; C5304 vs placebo not significant; no significant Y10M-versus-C5304 cognitive contrast reported. MMSE and HDS-R null on both post-intervention and change scores. Funded by YUKIGUNI FACTORY Co., Ltd.; two authors company-affiliated; test breads manufactured by Musashino Foods Co., Ltd.
Kuwabara N, Jogi EM, Kato M, Masuda Y, Konishi M, Yamasaki K, Ohata S, Kato S, Hashimoto M, Sato S, Nakagawa S. Application of ergosterol as a maitake mushroom intake biomarker. Ann Clin Biochem. 2026;63(1):83-87. DOI: 10.1177/00045632251357138. PMID: 40562565. PMCID: none. ROLE: PREPARATION / EXPOSURE VERIFICATION (same programme). Serum ergosterol confirms actual maitake ingestion in participants of the same bread-intervention programme; the primary trial states that Y10M ergosterol values were taken from this publication. SAME PARTICIPANT PROGRAMME AS THE PRIMARY TRIAL - NOT AN INDEPENDENT REPLICATION.
Nishihira J, Sato M, Tanaka A, Okamatsu M, Azuma T, Tsutsumi N, Yoneyama S. Maitake mushrooms (Grifola frondosa) enhances antibody production in response to influenza vaccination in healthy adult volunteers concurrent with alleviation of common cold symptoms. Funct Foods Health Dis. 2017;7(7):462-482. DOI: 10.31989/ffhd.v7i7.363. PMID: none (journal not indexed in PubMed). ROLE: CONTROLLED CORROBORATIVE (different proposition) + SAFETY CONTEXT. Human controlled evidence for a different strain (Gf433), different outcome (vaccine antibody response, cold symptoms) and different population; it does not test cognition and is not a replication of the Y10M cognition proposition.
Wesa KM, Cunningham-Rundles S, Klimek VM, Vertosick E, Coleton MI, Yeung KS, Lin H, Nimer S, Cassileth BR. Maitake mushroom extract in myelodysplastic syndromes (MDS): a phase II study. Cancer Immunol Immunother. 2015;64(2):237-247. DOI: 10.1007/s00262-014-1628-6. PMID: 25351719. PMCID: PMC4317517. ROLE: SAFETY (different preparation and population). Human exposure to a concentrated maitake beta-glucan extract in a clinical population; supports tolerability but concerns an extract, not the 50 g/day whole-mushroom food matrix, so its safety evidence does not transfer automatically to Y10M bread.
Zhang S, Tomata Y, Sugiyama K, Sugawara Y, Tsuji I. Mushroom Consumption and Incident Dementia in Elderly Japanese: The Ohsaki Cohort 2006 Study. J Am Geriatr Soc. 2017;65(7):1462-1469. DOI: 10.1111/jgs.14812. PMID: 28295137. ROLE: CONTEXT ONLY (observational). Population-level association between mushroom consumption generally and dementia incidence; not species-, strain- or preparation-specific and carries no controlled causal weight for Y10M.
Chen Z, Tang Y, Liu A, Jin X, Zhu J, Lu X. Oral administration of Grifola frondosa polysaccharides improves memory impairment in aged rats via antioxidant action. Mol Nutr Food Res. 2017;61(11):1700313. DOI: 10.1002/mnfr.201700313. PMID: 28752930. ROLE: MECHANISTIC / PRECLINICAL. Animal evidence for polysaccharide fractions; establishes biological plausibility only and cannot support any human claim rung.
Bai Y, Chen L, Chen Y, Chen X, Dong Y, Zheng S, Zhang L, Li W, Du J, Li H. A Maitake (Grifola frondosa) polysaccharide ameliorates Alzheimer's disease-like pathology and cognitive impairments by enhancing microglial amyloid-beta clearance. RSC Adv. 2019;9(64):37127-37135. DOI: UNVERIFIED. PMID: none located (journal not indexed in PubMed). ROLE: MECHANISTIC / PRECLINICAL. Mouse model evidence linking a maitake polysaccharide to microglial amyloid clearance; supports the immune-brain hypothesis the primary trial invokes but establishes nothing clinically.
Masuda Y, Inoue H, Ohta H, Miyake A, Konishi M, Nanba H. Oral administration of soluble beta-glucans extracted from Grifola frondosa induces systemic antitumor immune response and decreases immunosuppression in tumor-bearing mice. Int J Cancer. 2013;133(1):108-119. DOI: UNVERIFIED. PMID: UNVERIFIED. ROLE: MECHANISTIC / PRECLINICAL. Supports systemic immune activation by orally administered G. frondosa beta-glucans, the mechanistic bridge proposed for the NK-cell findings; not clinical evidence.
Fujiwara Y, Suzuki H, Yasunaga M, Sugiyama M, Ijuin M, Sakuma N, Inagaki H, Iwasa H, Ura C, Yatomi N, Ishii K, Tokumaru AM, Homma A, Nasreddine Z, Shinkai S. Brief screening tool for mild cognitive impairment in older Japanese: validation of the Japanese version of the Montreal Cognitive Assessment. Geriatr Gerontol Int. 2010;10(3):225-232. DOI: 10.1111/j.1447-0594.2010.00585.x. PMID: 20141536. ROLE: INSTRUMENT / CONTEXT. Validates MoCA-J as an MCI screening instrument in older Japanese adults; supports the outcome measure but not the intervention claim, and a screening-instrument change is not a dementia outcome.
Tabata T, Yamasaki Y, Ogura T. Comparison of Chemical Compositions of Maitake (Grifola frondosa (Fr.) S. F. Gray) Cultivated on Logs and Sawdust Substrate. Food Sci Technol Res. 2004;10(1):21-24. DOI: UNVERIFIED. PMID: none (journal not indexed in PubMed). ROLE: PREPARATION / STRAIN IDENTITY. Demonstrates that cultivation substrate materially changes maitake composition; constrains transfer from the trial material to other commercial maitake.
Koutrotsios G, Kalogeropoulos N, Stathopoulos P, Kaliora AC, Zervakis GI. Bioactive compounds and antioxidant activity exhibit high intraspecific variability in Pleurotus ostreatus mushrooms and correlate well with cultivation performance parameters. World J Microbiol Biotechnol. 2017;33(5):98. DOI: 10.1007/s11274-017-2262-1. PMID: 28421412. ROLE: PREPARATION / STRAIN IDENTITY (analogous genus). Documents large within-species, between-strain variation in cultivated edible fungi; supports the Atlas position that one species can contain different evidence owners, and is cited as an analogy, not as direct G. frondosa strain characterization.
Grifola frondosa (Dicks.) Gray - NCBI Taxonomy ID 5627 (Basidiomycota, Agaricomycetes, Polyporales); IUCN Global Fungal Red List preliminary assessment, Grifola frondosa, preliminary category Near Threatened (NT) A2c+3c+4c, proposed 2019, assessment not yet published. Accessed 27 August 2026. ROLE: TAXONOMIC + CONSERVATION. Species identity is stable and unambiguous; the only conservation signal located concerns wild European populations, whereas the trial material and commercial supply are cultivated (Japanese cultivated production reported in the tens of thousands of tonnes annually).
Source chapter: Chapter 18, The Fungal Evidence Atlas