A high-dose influenza vaccine was associated with a lower risk of Alzheimer's dementia in adults aged 65 and older, with women showing a stronger signal, raising fresh questions about whether stronger vaccine responses could help protect the aging brain.
Study: Risk of Alzheimer Dementia After High-Dose vs Standard-Dose Influenza Vaccination. Image Credit: Only_NewPhoto / Shutterstock
In a recent study published in the journal Neurology, researchers found that older adults who received a high-dose influenza vaccine (H-IIV) had a significantly lower incidence of Alzheimer's dementia than those who received a standard-dose formulation (S-IIV). The effects lasted up to 25 months after vaccination in the per-protocol analysis and up to 28 months in the intention-to-treat analysis. The association was more pronounced in women, suggesting potential sex-specific benefits.
A growing body of evidence suggests that routine vaccination may help reduce AD risk in older adults. Previous cohort studies have linked influenza vaccination to a lower incidence of dementia. Some studies report up to 40% risk reduction over four years among vaccinated individuals. However, it remains unclear whether enhanced formulations, such as high-dose vaccines, offer greater protection than standard-dose options. Evidence from herpes zoster vaccines shows stronger dementia risk reduction with more immunogenic formulations, particularly in women. These findings underscore the need to assess whether similar effects extend to influenza vaccines.
About the study
In the present study, researchers examined whether high-dose influenza vaccines reduce AD risk compared with standard-dose vaccines in adults aged 65 years and older.
The team analyzed data from the IQVIA PharMetrics Plus for Academics (PMPA) database spanning August 2014 to July 2019. The cohort included individuals with at least two years of continuous insurance coverage and no prior diagnoses or treatments indicative of cognitive impairment or dementia. The investigators identified influenza vaccination status using vaccine names and corresponding Current Procedural Terminology (CPT) codes in administrative claims.
To ascertain incident AD, the researchers used International Classification of Diseases (ICD) codes, supplemented by pharmacy claims for US FDA-approved symptomatic treatments. Individuals with incident AD had at least one AD-related diagnostic code (AD, senile dementia, or unspecified dementia) or a relevant medication prescription. The inclusion of senile and unspecified dementia codes was intended to reduce false negatives, although it may also have misclassified some non-AD dementias as AD. The team defined the influenza season as the period from August to February. They followed the participants over a period of three years post-vaccination.
To strengthen causal inference, the investigators applied target trial emulation (TTE) across 21 sequential monthly cohorts and used inverse probability of treatment weighting (IPTW) based on propensity scores to balance baseline characteristics between the high-dose and standard-dose groups. They estimated both per-protocol (PP) and intention-to-treat (ITT) effects. Estimates included risk differences (RD), risk ratios (RR), and number needed to treat (NNT). The models adjusted for demographics, comorbidities, medication use, and healthcare utilization.
Secondary analyses explored effect modification by sex and prior vaccination history. In addition, they evaluated alternative outcomes, including mild cognitive impairment (MCI), repeated annual vaccination exposure, and adjuvanted versus standard-dose formulations. A series of sensitivity analyses tested robustness. These included stricter diagnostic criteria, exclusion of nonspecific dementia codes, alternative medication-based definitions, variation in follow-up duration, lag-period analyses to reduce reverse causality, and restriction to medication-adherent individuals. The team also evaluated negative-control outcomes to assess residual confounding.
Results
The high-dose vaccination group comprised 120,775 individuals (mean age, 74 years; 57% women; 185,183 person-trials). The standard-dose vaccination group comprised 44,022 individuals (mean age, 73 years; 56% women; 53,918 person-trials). Participants were followed for a mean of 14-15 months in the PP analysis and 19 months in the ITT analysis.
Researchers found that high-dose vaccination was associated with a significantly lower risk of incident Alzheimer's dementia than standard-dose vaccination, particularly during the first 25 months after vaccination. In the PP analysis, the maximum risk difference reached 0.0054 at 25 months, corresponding to an NNT of 185. In the ITT analysis, the effect persisted up to 28 months, with a maximum risk difference of 0.0037 (NNT, 270).
Sex-stratified analyses revealed stronger and earlier benefits in women, with significantly reduced risk in the first 13 months (NNT, 417) in the PP analysis and through 17 months in the ITT analysis. In comparison, significant reductions emerged later in men, between 17 and 24 months in the ITT analysis (NNT, 233), while PP results in men were not statistically significant. Sustained annual high-dose vaccination over three years was also associated with further reductions in risk for Alzheimer's dementia outcomes, with effects observed up to 27 months (NNT, 294).
Sensitivity analyses generally supported the primary findings. Stricter case definitions and lag-period analyses continued to show reduced risk after high-dose vaccination, with one analysis reporting an NNT of 148 at 28 months. Broader outcomes, including all-cause dementia, also showed reductions in risk. However, results were attenuated or nonsignificant when using highly restrictive definitions or medication-only criteria, likely because fewer cases were identified. Negative-control analyses showed no association, supporting the robustness of the observed effect.
However, secondary analyses of MCI produced more mixed results. In ITT analyses using some MCI definitions, H-IIV was associated with an increased risk of incident MCI compared with S-IIV, whereas stricter MCI definitions were not significant. PP results for MCI were also mostly nonsignificant, except for one broader definition that showed increased risk during months 13 to 24.
Conclusions
The findings suggest that high-dose influenza vaccines are associated with a lower risk of Alzheimer's dementia than standard-dose vaccination among older adults. However, these findings should be interpreted cautiously due to short follow-up, claims-based diagnoses, and limited sociodemographic, lifestyle, and biomarker data. The study also used a US commercial claims database, which may limit generalizability to adults in traditional Medicare, uninsured populations, or other settings.
Further prospective studies with longer follow-up, diverse populations, and biomarker-confirmed outcomes are needed to validate these findings. Future research should also investigate whether the association is driven by reduced influenza burden or broader immunologic mechanisms, including trained immunity and reduced neuroinflammation. Because this was a retrospective, claims-based target-trial emulation rather than a randomized trial, the results should be interpreted as associative rather than definitively causal.
Severe infections linked to higher dementia risk independent of coexisting illnesses