{
  "cutoff": "2026-10-13",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "9802273",
      "year": "1998",
      "title": "Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial.",
      "doi": "10.1016/s0140-6736(98)03086-4",
      "url": "https://pubmed.ncbi.nlm.nih.gov/9802273/",
      "interpretation": "1998 SystEur reports a small randomized dementia-prevention signal for a BP regimen."
    },
    {
      "pmid": "18614402",
      "year": "2008",
      "title": "Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial.",
      "doi": "10.1016/S1474-4422(08)70143-1",
      "url": "https://pubmed.ncbi.nlm.nih.gov/18614402/",
      "interpretation": "2008 HYVET lowersBP but not significant dementia over its early-terminated horizon."
    },
    {
      "pmid": "26945371",
      "year": "2016",
      "title": "Influenza Vaccination Reduces Dementia Risk in Chronic Kidney Disease Patients: A Population-Based Cohort Study.",
      "doi": "10.1097/MD.0000000000002868",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26945371/",
      "interpretation": "2016 influenza/CKD observational protection extends beyond infection season."
    },
    {
      "pmid": "29244265",
      "year": "2018",
      "title": "Herpes Zoster and Dementia: A Nationwide Population-Based Cohort Study.",
      "doi": "10.4088/JCP.16m11312",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29244265/",
      "interpretation": "2018 Taiwanese HZ/antiviral associations motivate prevention hypotheses."
    },
    {
      "pmid": "30688979",
      "year": "2019",
      "title": "Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial.",
      "doi": "10.1001/jama.2018.21442",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30688979/",
      "interpretation": "2019 SPRINT separates positive MCI/composite outcomes from nonsignificant probable dementia."
    },
    {
      "pmid": "32213642",
      "year": "2020",
      "title": "Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline.",
      "doi": "10.1212/WNL.0000000000009277",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32213642/",
      "interpretation": "2020 ASPREE aspirin finds no cognitive/dementia benefit."
    },
    {
      "pmid": "35434253",
      "year": "2022",
      "title": "Reduced dementia incidence after varicella zoster vaccination in Wales 2013-2020.",
      "doi": "10.1002/trc2.12293",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35434253/",
      "interpretation": "2022 Welsh ordinary cohorts explicitly retain healthy-life-expectancy selection."
    },
    {
      "pmid": "35170873",
      "year": "2022",
      "title": "No evidence that herpes zoster is associated with increased risk of dementia diagnosis.",
      "doi": "10.1002/acn3.51525",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35170873/",
      "interpretation": "2022 UK overt-zoster/dementia association is null or inverse."
    },
    {
      "pmid": "35754275",
      "year": "2022",
      "title": "Potential Involvement of Varicella Zoster Virus in Alzheimer's Disease via Reactivation of Quiescent Herpes Simplex Virus Type 1.",
      "doi": "10.3233/JAD-220287",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35754275/",
      "interpretation": "2022 neural cultures demonstrate VZV–HSV1 reactivation with AD-like markers."
    },
    {
      "pmid": "39053634",
      "year": "2024",
      "title": "The recombinant shingles vaccine is associated with lower risk of dementia.",
      "doi": "10.1038/s41591-024-03201-5",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39053634/",
      "interpretation": "2024 product-transition analysis reports more dementia-diagnosis-free time after RZV."
    },
    {
      "pmid": "40175543",
      "year": "2025",
      "title": "A natural experiment on the effect of herpes zoster vaccination on dementia.",
      "doi": "10.1038/s41586-025-08800-x",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40175543/",
      "interpretation": "2025 Welsh birth-date natural experiment identifies a local live-vaccine causal signal."
    },
    {
      "pmid": "40267506",
      "year": "2025",
      "title": "Herpes Zoster Vaccination and Dementia Occurrence.",
      "doi": "10.1001/jama.2025.5013",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40267506/",
      "interpretation": "2025 Australian eligibility design corroborates a positive diagnosis contrast."
    },
    {
      "pmid": "40562756",
      "year": "2025",
      "title": "Lower risk of dementia with AS01-adjuvanted vaccination against shingles and respiratory syncytial virus infections.",
      "doi": "10.1038/s41541-025-01172-3",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40562756/",
      "interpretation": "2025 AS01-adjuvanted RSV/zoster cohorts suggest a possible immune pathway."
    },
    {
      "pmid": "40258956",
      "year": "2025",
      "title": "Blood pressure reduction and all-cause dementia in people with uncontrolled hypertension: an open-label, blinded-endpoint, cluster-randomized trial.",
      "doi": "10.1038/s41591-025-03616-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40258956/",
      "interpretation": "2025 randomized hypertension care lowers incident all-cause dementia."
    },
    {
      "pmid": "41579903",
      "year": "2026",
      "title": "Herpes zoster vaccination and incident dementia in Canada: an analysis of natural experiments.",
      "doi": "10.1016/S1474-4422(25)00455-7",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41579903/",
      "interpretation": "2026 Canadian eligibility contrasts extend geography while separate uptake and interaction limits remain."
    },
    {
      "pmid": "42296498",
      "year": "2026",
      "title": "Dementia Risk After Recombinant Herpes Zoster Vaccination in Older Adults With a Recent Skilled-Nursing Facility Stay : A Target Trial Emulation.",
      "doi": "10.7326/ANNALS-25-04689",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42296498/",
      "interpretation": "2026 nursing-facility RZV emulation retains residual negative-control confounding."
    },
    {
      "pmid": "42754179",
      "year": "2026",
      "title": "Natural experiments of herpes zoster vaccination: Quantifying the implied vaccine effectiveness against dementia.",
      "doi": "10.1016/j.bbi.2026.107021",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42754179/",
      "interpretation": "2026 quantitative reanalysis challenges implied causal magnitudes outside Wales."
    }
  ],
  "gaps": [
    "Resolve implausible international implied receipt effects and weak separate-survey first stages with individual-level local data.",
    "Direct preventive efficacy of recombinant vaccination rather than ordinary vaccinee cohorts.",
    "Biological onset versus delayed clinical diagnosis and competing-death effects.",
    "Prespecified age/product/sex boundaries with formal interaction tests.",
    "Separate infection suppression, heterologous immune effects and healthcare pathways.",
    "Drug-specific clinical prevention rather than class transfer from surrogate or observational successes."
  ],
  "decisive_experiment": "Combine an ethically designed randomized timing/product or vaccine-encouragement comparison within clinically permitted practice with adjudicated incident dementia, active comparators and competing-death analyses. Prespecify product, age and sex, assess baseline cognition and healthcare contacts, and separately reproduce eligibility estimates using individual uptake and counterfactual complier risks. A mechanistic substudy must distinguish viral reactivation from adjuvant immunity without replacing clinical endpoints."
}