{
  "meta": {
    "title": "Kram: Mom's APOE E3/E4 family-report evidence audit — receipts",
    "page": "https://projectforty2.ai/kram/mom-apoe",
    "published": "2026-11-05",
    "last_checked": "2026-11-05",
    "timezone_label": "America/Denver",
    "genotype_audited": "APOE E3/E4",
    "personal_identifiers": "none (no name beyond the dedication, no date of birth, no lab IDs)",
    "breaktest": {
      "by": "Ford",
      "verdict": "pass_with_fixes",
      "fixes_applied": "2026-11-05"
    },
    "disclaimer": "Not medical advice. A map of evidence for families."
  },
  "authoritative_apoe_risk": [
    {
      "id": "belloy2023",
      "citation": "Belloy ME et al. APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry. JAMA Neurol. 2023;80(12):1284-1294.",
      "pmid": "37930705",
      "doi": "10.1001/jamaneurol.2023.3599",
      "url": "https://jamanetwork.com/journals/jamaneurology/fullarticle/2811630",
      "supports": "ε3/ε4 OR vs ε3/ε3 by ancestry: East Asian ~4.54, White/European ~3.46 (3.27–3.65), Black ~2.18, Hispanic ~1.90; 2–4.5× spans ancestries, not European alone"
    },
    {
      "id": "fortea2024",
      "citation": "Fortea J et al. APOE4 homozygosity represents a distinct genetic form of Alzheimer's disease. Nat Med. 2024;30(5):1284-1291.",
      "pmid": "38710950",
      "doi": "10.1038/s41591-024-02931-w",
      "url": "https://www.nature.com/articles/s41591-024-02931-w",
      "supports": "ε4/ε4 biology near-full penetrance framing; NOT about ε3/ε4 heterozygotes",
      "note": "PubMed title spelling 'homozygozity' matches record"
    },
    {
      "id": "framingham_myers1996",
      "citation": "Myers RH et al. Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham Study. Neurology. 1996;46(3):673-677.",
      "pmid": "8618665",
      "doi": "10.1212/wnl.46.3.673",
      "supports": "Framingham: 27% of ε3/ε4 developed AD by age 85 (vs 9% without ε4); most ε4 carriers do not develop dementia; low PPV of genotyping as screening"
    },
    {
      "id": "nia_genetics_factsheet",
      "citation": "National Institute on Aging. Alzheimer's Disease Genetics Fact Sheet.",
      "url": "https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/alzheimers-disease-genetics-fact-sheet",
      "supports": "APOE not deterministic; testing not routine for prediction; counseling/consumer caveats"
    },
    {
      "id": "alz_genetic_testing_ts",
      "citation": "Alzheimer's Association. Genetic Testing (topic sheet).",
      "url": "https://www.alz.org/getmedia/f4818e7f-287b-4e9e-be71-7e4879dd2e05/alzheimers-dementia-genetic-testing-ts.pdf",
      "supports": "Routine healthy-person risk testing not advised without counseling; APOE may inform treatment ARIA risk"
    },
    {
      "id": "pmc_apoe_testing_new_age",
      "citation": "Apolipoprotein E Genetic Testing in a New Age of Alzheimer Disease Clinical Practice.",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10783973/",
      "supports": "APOE testing mainly for amyloid-lowering treatment decisions after biomarkers"
    }
  ],
  "lifestyle_trials": [
    {
      "id": "fingers2015",
      "citation": "Ngandu T et al. FINGER. Lancet. 2015;385(9984):2255-2263.",
      "pmid": "25771249",
      "doi": "10.1016/S0140-6736(15)60461-5"
    },
    {
      "id": "pointer2025",
      "citation": "Baker LD et al. Structured vs Self-Guided Multidomain Lifestyle Interventions for Global Cognitive Function: The US POINTER Randomized Clinical Trial. JAMA. 2025;334(8):681-691.",
      "pmid": "40720610",
      "doi": "10.1001/jama.2025.12923",
      "url": "https://aaic.alz.org/releases-2025/us-pointer-study-results-announced.asp",
      "supports": "No untreated control. Structured beat self-guided by 0.029 SD/yr (95% CI 0.008–0.050, p=.008); no APOE4 interaction (p=.95). Scores rose in both arms.",
      "note": "Grade in audit: moderate for structured > self-guided; not strong causal prevention claim"
    },
    {
      "id": "mind2023",
      "citation": "Barnes LL et al. Trial of the MIND Diet for Prevention of Cognitive Decline in Older Persons. N Engl J Med. 2023;389:602-611.",
      "pmid": "37466280",
      "doi": "10.1056/NEJMoa2302368",
      "supports": "No significant cognitive difference vs calorie-aware control at 3 years"
    },
    {
      "id": "scarmeas2006_med",
      "citation": "Scarmeas N et al. Mediterranean diet and risk for Alzheimer's disease. Ann Neurol. 2006;59(6):912-921.",
      "pmid": "16622828",
      "note": "Observational; cited in report ref 35"
    },
    {
      "id": "scarmeas2009_activity",
      "citation": "Scarmeas N et al. Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009;302(6):627-637.",
      "pmid": "19671904",
      "note": "Report ref 31"
    }
  ],
  "aria_and_biomarkers": [
    {
      "id": "leqembi_label",
      "citation": "LEQEMBI (lecanemab-irmb) US prescribing information — DailyMed SPL setid 9d1ff786-e577-410a-a273-c4d7d0e4e975 (label updated July 21, 2026). ApoE ε4 testing recommendation and ARIA boxed warning.",
      "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d1ff786-e577-410a-a273-c4d7d0e4e975",
      "prior_url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761269s005lbl.pdf",
      "note": "Ford break-test: testing language unchanged vs Jan 2025 accessdata PDF; receipt pointed to current DailyMed v24 eff. 2026-07-21"
    },
    {
      "id": "kisunla_dailymed",
      "citation": "KISUNLA (donanemab-azbt) DailyMed / FDA label language on ApoE ε4 testing and ARIA.",
      "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=190352d4-ef62-4679-b4fa-e846e2766afa&type=display"
    },
    {
      "id": "ncbi_lecanemab_apoe",
      "citation": "Lecanemab Therapy and APOE Genotype. Medical Genetics Summaries. NCBI Bookshelf.",
      "url": "https://www.ncbi.nlm.nih.gov/books/NBK605938/"
    },
    {
      "id": "fda_ptau217_2025",
      "citation": "FDA Clears First Blood Test Used in Diagnosing Alzheimer's Disease (Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio). May 16, 2025.",
      "url": "https://www.fda.gov/news-events/press-announcements/fda-clears-first-blood-test-used-diagnosing-alzheimers-disease",
      "supports": "Of positive results, 91.7% had amyloid on PET/CSF; of negative results, 97.3% were amyloid-negative (share of pos/neg blood results matching PET/CSF — not sensitivity/specificity). Less than 20% indeterminate. Symptomatic adults ≥55 in specialized care; not screening."
    }
  ],
  "alzheimers_association_supplements": [
    {
      "id": "alz_alternative_treatments",
      "url": "https://www.alz.org/alzheimers-dementia/treatments/alternative-treatments",
      "supports": "No supplement proven to prevent/treat/cure AD; specific pages on CoQ10, ginkgo/GEM, huperzine, omega-3, phosphatidylserine"
    },
    {
      "id": "alz_dietary_supplements_statement_2023",
      "url": "https://www.alz.org/getmedia/b213d93c-122e-4a0b-9877-b9394211ae33/dietary-supplements-statement.pdf",
      "citation": "Alzheimer's Association Medical and Scientific Advisory Group. Dietary Supplements and Medical Foods. Reviewed January 2023."
    }
  ],
  "supplement_evidence": {
    "omega3_dha": [
      {
        "pmid": "20434961",
        "citation": "Yurko-Mauro K et al. MIDAS. Alzheimers Dement. 2010.",
        "role": "Report's positive DHA ARCD trial"
      },
      {
        "pmid": "21045096",
        "citation": "Quinn JF et al. ADCS DHA in Alzheimer disease. JAMA. 2010.",
        "role": "Null overall in mild-moderate AD"
      },
      {
        "pmid": "35415212",
        "citation": "Kang JH et al. Marine n-3 fatty acids and cognitive change among older adults in the VITAL randomized trial. Alzheimers Dement (N Y). 2022;8(1):e12288.",
        "doi": "10.1002/trc2.12288",
        "role": "VITAL-Cog: 1 g/day marine n-3, no cognitive benefit over 2–3 years in community-dwelling older adults"
      },
      {
        "pmid": "28114437",
        "citation": "Yassine HN et al. DHA × APOE4 stage review. JAMA Neurol. 2017.",
        "role": "Report ref 38"
      },
      {
        "pmid": "42315445",
        "citation": "Yassine HN et al. PreventE4 high-dose DHA. EBioMedicine. 2026;129:106316.",
        "doi": "10.1016/j.ebiom.2026.106316",
        "role": "PreventE4: primary endpoint CSF DHA/AA at 6 mo (engagement, incl. APOE4); cognition/MRI secondary, underpowered, no 24-mo difference; 38% dropout — not a simple failure"
      }
    ],
    "coq10": [
      {
        "pmid": "7495231",
        "citation": "Thomas SR et al. Coantioxidants make alpha-tocopherol an efficient antioxidant for LDL. Am J Clin Nutr. 1995.",
        "role": "Report ref 16 — lab chemistry, over-claimed for clinical CoQ10"
      },
      {
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9759150/",
        "citation": "Cochrane-related CoQ10 primary CVD prevention evidence limited"
      }
    ],
    "vitamin_k": [
      {
        "pmid": "15514282",
        "citation": "Geleijnse JM et al. Rotterdam Study menaquinone. J Nutr. 2004.",
        "role": "Report's 57% relative CHD mortality reduction (RR 0.43 upper tertile); dietary observational"
      },
      {
        "url": "https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/",
        "citation": "NIH ODS Vitamin K Health Professional Fact Sheet",
        "role": "Warfarin interaction; AI ~90–120 mcg/day context"
      }
    ],
    "pomegranate": [
      {
        "pmid": "11500191",
        "citation": "Aviram M, Dornfeld L. Pomegranate juice ACE and BP. Atherosclerosis. 2001.",
        "role": "Report ref 19"
      },
      {
        "pmid": "15158307",
        "citation": "Aviram et al. 3-year carotid stenosis pomegranate juice. Clin Nutr. 2004.",
        "role": "Report ref 20"
      },
      {
        "url": "https://www.lifeextension.com/magazine/2014/11/enhance-endothelial-health-how-pomegranate-protects-against-atherosclerosis",
        "role": "Report ref 21 magazine"
      }
    ],
    "pycnogenol_centella": [
      {
        "pmid": "25391252",
        "role": "Hu et al. Pycnogenol borderline endothelial study — report ref 22"
      },
      {
        "pmid": "24452082",
        "role": "Report ref 23 — correct PMID (was wrongly 26505327 = Belcaro Minerva Cardioangiol 2017)",
        "citation": "Belcaro G et al. Pycnogenol and Centella Asiatica for asymptomatic atherosclerosis progression. Int Angiol. 2014;33(1):20-6.",
        "wrong_pmid_was": "26505327"
      },
      {
        "pmid": "11666118",
        "role": "Cesarone Centella carotid plaque echogenicity RCT"
      }
    ],
    "lipids_botanicals": [
      {
        "pmid": "21495900",
        "role": "Akhtar amla — report ref 25"
      },
      {
        "pmid": "22746542",
        "role": "Rondanelli artichoke HDL 2013 — ref 28"
      },
      {
        "pmid": "30723511",
        "role": "Rondanelli artichoke 2019 — ref 29"
      },
      {
        "pmid": "24600231",
        "role": "Evans pantethine 2014 — ref 30"
      },
      {
        "pmid": "17976306",
        "role": "Report ref 26 theaflavin rat paper — orphaned/mismatched"
      }
    ],
    "phosphatidylserine": [
      {
        "pmid": "21103034",
        "role": "Kato-Kataoka soy PS Japan — ref 39"
      },
      {
        "pmid": "11201936",
        "role": "Schreiber open trial — ref 40"
      },
      {
        "url": "https://web.archive.org/web/20120817065242/http:/www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/ucm072999.htm",
        "role": "FDA qualified health claim — very limited evidence disclaimer"
      }
    ],
    "ginkgo_vinpocetine": [
      {
        "pmid": "19017911",
        "citation": "DeKosky ST et al. GEM. JAMA. 2008.",
        "role": "Null dementia prevention in adults ≥75, 120 mg BID, median 6.1 y (GEM) — omitted by report; strong negative scoped to that population/dose"
      },
      {
        "pmid": "21061003",
        "role": "Mashayekh ginkgo CBF pilot — report ref 44"
      },
      {
        "pmid": "15760651",
        "role": "Vinpocetine PET stroke — ref 41"
      },
      {
        "url": "https://www.fda.gov/food/information-select-dietary-supplement-ingredients-and-other-substances/vinpocetine-dietary-supplements",
        "role": "FDA vinpocetine dietary ingredient / pregnancy risk communications"
      },
      {
        "url": "https://www.cochrane.org/evidence/CD003119_insufficient-evidence-benefits-vinpocetine-people-dementia",
        "role": "Cochrane vinpocetine insufficient"
      }
    ],
    "sage": [
      {
        "pmid": "18350281",
        "role": "Scholey sage extract — ref 58"
      },
      {
        "pmid": "16205785",
        "role": "Kennedy sage mood — ref 56"
      },
      {
        "pmid": "27888449",
        "role": "Lopresti Salvia review — ref 57"
      }
    ],
    "lithium": [
      {
        "pmid": "22746245",
        "citation": "Nunes MA et al. Microdose lithium AD. Curr Alzheimer Res. 2013.",
        "role": "Small human study — report ref 47"
      },
      {
        "pmid": "26605788",
        "role": "Report ref 46 — article PMID (was wrongly 26678744 = correction notice)",
        "citation": "Nunes MA et al. Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease. PLoS ONE. 2015;10(11):e0142267.",
        "correction_notice_pmid": "26678744",
        "note": "26678744 is the Correction notice for the same article; cite 26605788 as the paper"
      },
      {
        "pmid": "24738557",
        "role": "Motoi lithium autophagy — ref 45"
      },
      {
        "pmid": "40770094",
        "citation": "Aron L et al. Lithium deficiency and the onset of Alzheimer's disease. Nature. 2025.",
        "doi": "10.1038/s41586-025-09335-x",
        "url": "https://www.nih.gov/news-events/nih-research-matters/lithium-levels-tied-alzheimers-disease-dementia",
        "nih_research_matters": {
          "url": "https://www.nih.gov/news-events/nih-research-matters/lithium-levels-tied-alzheimers-disease-dementia",
          "date": "2025-09-09",
          "supports": "Quotes Yankner group planning a clinical trial of lithium orotate; human dose/safety still needed"
        }
      }
    ],
    "colostrinin": [
      {
        "pmid": "12388930",
        "role": "Leszek long-term colostrinin — ref 49"
      },
      {
        "pmid": "19262960",
        "role": "Szaniszlo insights — ref 48"
      },
      {
        "pmid": "15004324",
        "citation": "Bilikiewicz A, Gaus W. Colostrinin in AD. J Alzheimers Dis. 2004.",
        "role": "Larger but limited Polish RCT"
      }
    ],
    "mag_threonate": [
      {
        "pmid": "20152124",
        "role": "Slutsky Neuron 2010 — ref 50"
      },
      {
        "pmid": "25213836",
        "role": "Li Mol Brain 2014 mouse — ref 51"
      },
      {
        "pmid": "24077207",
        "role": "Wang Pain Physician neuropathic pain — ref 52"
      },
      {
        "pmid": "26519439",
        "citation": "Liu G et al. MMFS-01 RCT. J Alzheimers Dis. 2016.",
        "role": "Human Magtein-containing product RCT not cited in report"
      }
    ],
    "huperzine": [
      {
        "pmid": "21502597",
        "citation": "Rafii MS et al. Phase II huperzine A. Neurology. 2011.",
        "role": "Primary 200 μg BID failed at wk 16; secondary 400 μg BID: +2.27 ADAS-Cog at wk 11 (p=0.001), ns at wk 16 (p=0.07) — omitted by report"
      },
      {
        "pmid": "17056129",
        "role": "Zhang review — ref 53"
      },
      {
        "url": "https://www.cochrane.org/evidence/CD005592_there-currently-insufficient-evidence-effects-huperzine-alzheimers-disease-ad",
        "role": "Cochrane insufficient"
      },
      {
        "url": "https://www.mskcc.org/cancer-care/integrative-medicine/herbs/huperzia-serrata",
        "role": "Cholinergic side effects / interactions monograph"
      }
    ]
  },
  "report_reference_problems": [
    {
      "ref": 1,
      "issue": "broken_url",
      "detail": "NIH news URL in report returns HTTP 404 as of 2026-11-05",
      "url_tried": "https://www.nih.gov/news-events/news-releases/nih-funded-research-provides-new-clues-how-apoe4-affects-alzheimers-risk"
    },
    {
      "ref": 13,
      "issue": "magazine_not_peer_reviewed_primary",
      "url": "https://www.lifeextension.com/magazine/2010/1/the-secret-behind-the-mediterranean-diet",
      "http_status_checked": 200
    },
    {
      "ref": 21,
      "issue": "magazine_not_peer_reviewed_primary",
      "url": "https://www.lifeextension.com/magazine/2014/11/enhance-endothelial-health-how-pomegranate-protects-against-atherosclerosis",
      "http_status_checked": 200
    },
    {
      "ref": 34,
      "issue": "magazine_not_peer_reviewed_primary",
      "url": "https://www.lifeextension.com/magazine/2016/4/how-to-delay-brain-aging-by-11-years",
      "http_status_checked": 200
    },
    {
      "ref": 16,
      "issue": "overclaimed_fit",
      "pmid": "7495231",
      "detail": "Lab LDL/tocopherol coantioxidant chemistry used to support clinical CoQ10 'first line of defense' dosing claim"
    },
    {
      "ref": 26,
      "issue": "orphaned_or_mismatched",
      "pmid": "17976306",
      "detail": "Theaflavin rat ischemia paper listed; artichoke body text cites 28-29 instead"
    },
    {
      "item": "ginkgo",
      "issue": "selective_omission",
      "detail": "Cites small CBF pilot; omits GEM null prevention RCT PMID 19017911"
    },
    {
      "item": "vitamin_K_dose",
      "issue": "observational_to_supplement_leap",
      "detail": "Geleijnse dietary menaquinone tertiles ≠ evidence for 2600 mcg/day multi-K supplement"
    },
    {
      "item": "DHA_APOE4",
      "issue": "outdated_optimism_vs_newer_trial",
      "detail": "Report leans on Yassine 2017 review; PreventE4 2026 showed no 24-month cognitive/MRI benefit despite CNS engagement"
    },
    {
      "item": "magnesium_L_threonate",
      "issue": "animal_evidence_for_human_claim",
      "detail": "Refs 50-52 animal/pain models; human MMFS-01 not cited"
    }
  ],
  "report_citations_verified_exist": {
    "method": "PubMed eutils title/author queries on 2026-11-05; Life Extension URLs HEAD/GET",
    "mostly_real_journal_articles": true,
    "note": "Existence ≠ appropriate support for clinical claims. See report_reference_problems.",
    "key_pmids_matched": {
      "2_Liu2013": "23296339",
      "5_Strittmatter1993": "8446617",
      "18_Geleijnse2004": "15514282",
      "36_YurkoMauro_MIDAS": "20434961",
      "38_Yassine2017": "28114437",
      "47_Nunes2013": "22746245",
      "58_Scholey2008": "18350281"
    }
  },
  "grades_table": [
    {
      "item": "Exercise + Med/MIND-style diet (multidomain)",
      "grade": "mixed-moderate (POINTER structured>self-guided, no untreated control)",
      "key": "PMID 25771249; 40720610; 37466280"
    },
    {
      "item": "Omega-3 / DHA",
      "grade": "weak (dementia prevention after VITAL-Cog + PreventE4)",
      "key": "PMID 35415212; 42315445"
    },
    {
      "item": "CoQ10",
      "grade": "no good evidence (AD)",
      "key": "alz.org alternative treatments"
    },
    {
      "item": "Vitamin K 2600 mcg",
      "grade": "weak + warfarin safety flag",
      "key": "PMID 15514282; ODS"
    },
    {
      "item": "Pomegranate",
      "grade": "weak",
      "key": "Aviram small studies"
    },
    {
      "item": "Pycnogenol + gotu kola",
      "grade": "weak",
      "key": "Belcaro/Cesarone"
    },
    {
      "item": "Amla / artichoke / pantethine",
      "grade": "weak-mixed (lipids)",
      "key": "small RCTs"
    },
    {
      "item": "Phosphatidylserine",
      "grade": "weak/mixed",
      "key": "FDA QHC disclaimer"
    },
    {
      "item": "Ginkgo",
      "grade": "strong negative (prevention in ≥75 at 120 mg BID / GEM)",
      "key": "PMID 19017911"
    },
    {
      "item": "Vinpocetine",
      "grade": "weak/insufficient",
      "key": "FDA; Cochrane"
    },
    {
      "item": "Sibelius sage",
      "grade": "weak",
      "key": "PMID 18350281"
    },
    {
      "item": "Lithium 300 mcg",
      "grade": "weak human + animal/mechanistic",
      "key": "PMID 22746245; 40770094"
    },
    {
      "item": "Colostrinin",
      "grade": "weak",
      "key": "PMID 15004324"
    },
    {
      "item": "Mg L-threonate",
      "grade": "animal→weak human",
      "key": "PMID 20152124; 26519439"
    },
    {
      "item": "Huperzine A",
      "grade": "weak/failed primary Phase 2 (200 μg BID); secondary 400 μg BID signal only",
      "key": "PMID 21502597"
    }
  ],
  "ford_breaktest_fixes_2026_11_05": [
    {
      "fix": "Belcaro report ref 23 receipt PMID 26505327 → 24452082",
      "verified": true
    },
    {
      "fix": "Nunes report ref 46 receipt PMID 26678744 (correction) → 26605788 (article)",
      "verified": true
    },
    {
      "fix": "One-page 2–4× European → ~3.5× European; 2–4.5× across ancestries (Belloy)",
      "verified": true
    },
    {
      "fix": "Myers 1996 PMID 8618665 cited for ~27% by 85",
      "verified": true
    },
    {
      "fix": "p-tau217 statistic wording + under 20% indeterminate",
      "verified": true
    },
    {
      "fix": "POINTER drop both-improved/Strong; 0.029 SD/yr structured>self-guided",
      "verified": true
    },
    {
      "fix": "PreventE4 primary CSF; cognition secondary/underpowered; 38% dropout; not failure",
      "verified": true
    },
    {
      "fix": "Closing imperative → evidence best supports",
      "verified": true
    },
    {
      "fix": "Huperzine 200 μg BID + 400 μg secondary signal",
      "verified": true
    },
    {
      "fix": "Ginkgo strong negative scoped to ≥75 / GEM dose",
      "verified": true
    },
    {
      "fix": "VITAL-Cog PMID 35415212 added",
      "verified": true
    },
    {
      "fix": "Leqembi receipt → DailyMed setid 9d1ff786… updated Jul 21 2026",
      "verified": true
    },
    {
      "fix": "Lithium NIH Research Matters 2025-09-09 receipt for planning-trial quote",
      "verified": true
    }
  ]
}