High-Dose Influenza Vaccination Linked to Lower Alzheimer Dementia Risk in Older Adults

High-dose inactivated influenza vaccination (H-IIV) was associated with a lower risk of incident Alzheimer dementia (AD) compared with standard-dose influenza vaccination (S-IIV) among adults aged 65 years and older, according to findings from a retrospective cohort analysis published in Neurology. In the study, which analyzed US claims data from the IQVIA PharMetrics Plus for Academics database between 2014 and 2019, investigators found that recipients of high-dose influenza vaccines experienced significantly lower cumulative risk of AD over the first 25 months after vaccination compared with those receiving standard-dose vaccines.¹

Senior author Paul E. Schulz, MD, Director of the Memory Disorders and Dementia Clinic at the University of Texas Health Science Center in Houston, and colleagues evaluated 120,775 unique participants in the H-IIV group (185,183 person-trials; mean age, 74.4 years; 57.3% women) and 44,022 participants in the S-IIV group (53,918 person-trials; mean age, 73.0 years; 56.4% women).¹

Using a target trial emulation approach to minimize biases common in observational research, investigators followed patients for up to 3 years after vaccination and assessed incident AD based on diagnostic codes or prescriptions for approved AD therapies, including donepezil, galantamine, rivastigmine, and memantine.¹

Study Findings

Compared with standard-dose vaccination, high-dose influenza vaccination was associated with significantly reduced AD risk from months 1 through 25 in the per-protocol analysis. The largest statistically significant effect occurred at month 25, corresponding to a risk difference of 0.0054 and a number needed to treat of approximately 185.¹

Similar findings were observed in intention-to-treat analyses, with a reduced risk of AD observed through 28 months of follow-up. Sex-stratified analyses suggested that the protective association was more sustained among women than men. In per-protocol analyses, reduced AD risk was observed from months 1 through 13 among women, whereas men showed significant reductions only in intention-to-treat analyses from months 17 through 24.¹

Potential Biological Mechanisms

Although the study did not evaluate mechanisms directly, the authors proposed several possible explanations for the observed association. Among them, researchers noted that enhanced influenza vaccines, including high-dose formulations, may provide stronger protection against infection, potentially reducing systemic inflammation and subsequent neuroinflammatory processes that contribute to neurodegeneration.¹

Alternative explanations include immune-mediated effects unrelated to infection prevention, such as trained immunity, modulation of age-related immune dysfunction (including inflammaging and immunosenescence), or alterations in neuroinflammatory responses to AD pathology.¹

Previous observational studies have similarly suggested that influenza vaccination may reduce dementia risk overall, including research showing approximately 40% lower risk of AD among vaccinated adults compared with unvaccinated individuals over a 4-year period.²

Limitations

Investigators noted several limitations, including follow-up duration that was limited to 3 years, which may not fully capture long-term dementia risk. Additionally, the claims database lacked information on sociodemographic factors, lifestyle variables, biomarker data, and mortality, all of which could influence dementia risk. Because dementia diagnoses were identified through administrative claims, some cases of non-Alzheimer dementias may have been misclassified as AD.

Despite these limitations, the findings provide Class II evidence that high-dose influenza vaccination is associated with a reduced risk of incident dementia compared with standard-dose vaccination among adults aged 65 years and older.¹

The authors concluded that additional research is needed to determine whether the observed effect reflects improved protection against influenza infection or broader immune-mediated mechanisms influencing neurodegenerative disease risk.¹

Related Research

This is not the first time vaccine use has been investigated for potential health benefits beyond infection prevention. AD is the leading cause of dementia and presents a major public health concern. Although prevention strategies remain a priority, the potential role of vaccination in reducing dementia risk is still incompletely understood. In a published review, adult vaccinations, particularly against herpes zoster, influenza, pneumococcus, and tetanus-diphtheria–acellular pertussis, were associated with a lower risk of dementia.3 Research on vaccinations and dementia risk was highlighted at the 18th Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held December 1 to 4, 2025, in San Diego, California.

At the meeting, 1 presentation described evidence from natural experiments supporting clinical trials of herpes zoster vaccination across populations without cognitive impairment, with mild cognitive impairment, and with established dementia.⁴ Another presentation, a phase 2 study, reported that in adults with type 1 diabetes, multidose Bacille Calmette-Guérin (BCG) immunotherapy was associated with a statistically significant reduction in plasma p-tau217 over 5 years.⁵ Additionally, a separate presentation showed that intradermal BCG vaccination induced transcriptional and metabolic reprogramming of central nervous system myeloid cells, consistent with trained immunity mechanisms relevant to neuroinflammation and AD pathology.⁶

At the 2025 CTAD Conference, Pierre Tariot, MD, director of Banner Alzheimer’s Institute, spoke with NeurologyLive® about an emerging area of interest focused on the broader, non–pathogen-specific effects of vaccines. He noted that data presented at the meeting included epidemiologic observations and translational findings suggesting potential associations between certain vaccinations and dementia-related outcomes. Tariot added that several presentations also addressed population-level trends as well as underlying biological pathways and biomarker changes relevant to neurodegeneration, reflecting growing interest in immunologic strategies as a potential area for future investigation in AD and related disorders.

REFERENCES
1. Bukhbinder AS, Ling Y, Jhin L, et al. Risk of Alzheimer Dementia After High-Dose vs Standard-Dose Influenza Vaccination. Neurol. 2026;106(8);e:214782. doi:10.1212/WNL.0000000000214782
2. Bukhbinder AS, Ling Y, Hasan O, et al. Risk of Alzheimer’s disease following influenza vaccination: a claims-based cohort study. JAlzheimers Dis . 2022;89(1):1-11.
3. Maggi S, Fulöp T, De Vita E, et al. Association between vaccinations and risk of dementia: a systematic review and meta-analysis. Age Ageing. 2025;54(11):afaf331. doi:10.1093/ageing/afaf331
4. Xie M, Eyting M, Bommer C, et al. The effect of herpes zoster vaccination at different stages of the dementia disease course: implications for defining the study population of clinical trials. Presented at: CTAD 2025; December 1-4; 2025. San Diego, CA. OC01.
5. Hashiguchi S, Hayashi H, Kartsounis N, et al. Impact of BCG immunotherapy on plasma P-tau217 in patients with Type 1 diabetes at risk of Alzheimer’s disease: a five-year, phase II, randomized, controlled trial. Presented at: CTAD 2025; December 1-4, 2025; San Diego, CA. LB29.
6. Arnold S, Kodali M, Li Z, et al. Impact of BCG immunotherapy on plasma P-tau217 in patients with type 1 diabetes at risk of Alzheimer’s disease: a five-year, phase II, randomized, controlled trial. Presented at: CTAD 2025; December 1-4, 2025; San Diego, CA. P264.