A high-dose inactivated flu vaccine has been tied to a roughly 20% lower risk of Alzheimer’s dementia – within the first two years of vaccination – than a standard-dose risk, US researchers have written in the journal Neurology.
MedPage Today reports that according to Avram Bukhbinder, MD, a clinical fellow in Neurology at Massachusetts General Hospital in Boston, and colleagues, at 25 months, the minimum number needed to treat with the high-dose flu shot to prevent one additional case of Alzheimer's dementia was 185.2 in per-protocol analyses.
They added that the relationship was stronger in women than in men, according to the healthcare claims data they reviewed.
Per-protocol analyses indicated that the risk ratio (RR) for Alzheimer’s dementia after high- versus standard-dose flu shots ranged from 0.78 at month 1 to 0.89 at month 25.
“The findings show the higher dose had about a 20% reduction versus the standard-dose vaccination,” noted co-author Paul Schulz, MD, of the McGovern Medical School at UTHealth in Houston.
“It’s interesting that the RR reduction is greatest in the first few months, when the flu vaccine is also protective from the influenza virus.”
This analysis is the latest in a series of studies by the research team exploring the link between vaccines and Alzheimer’s dementia risk.
“Our first paper in 2022 found that influenza vaccination reduces the risk of Alzheimer’s by up to 40% (with six annual vaccinations) for up to eight years,” Schulz told MedPage Today. “After that, we wondered whether it was influenza-specific.”
That question led to a second paper in 2023, which showed that each of three vaccines – tetanus and diphtheria, with or without pertussis, herpes zoster (shingles), or pneumococcus – was tied to subsequent lower Alzheimer’s risk.
“This suggested that reducing Alzheimer’s risk is a general property of vaccinations and is not specific to the influenza vaccination,” Schulz said.
“The nagging question after these studies was whether we had a true finding versus a finding due to the ‘healthy survivor effect’ – in other words, whether people who get vaccinated might be healthier in general.”
To address that variable, the current study focused solely on older adults who received a flu shot. Other researchers have used a similar strategy of comparing two vaccinated groups to study relationships between dementia risk and different shingles vaccines, for example.
Database
Bukhbinder and his co-authors analysed data from 2014 to 2019 from IQVIA PharMetrics Plus for Academics, a US healthcare claims database.
All standard-dose, non-adjuvanted, non-recombinant, inactivated flu vaccines approved in the US during the study period for people aged 50 and older were grouped as standard vaccines. The only high-dose vaccine was a more concentrated formulation (Fluzone High-Dose) approved by the FDA for seniors in December 2009.
Eligible participants were 65 and older with two or more years of continuous medical and prescription drug coverage and no previous indicators of cognitive impairment; they were followed for up to three years after vaccination.
Incident Alzheimer’s dementia was defined through diagnostic codes or claims for one of four drugs used to treat Alzheimer’s symptoms: donepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon), or memantine (Namenda).
The researchers emulated a target trial using 21 sequential nested trials (one for each month of the flu vaccine season over three years), using inverse probability weighting to adjust for confounding, emulate randomisation, and mitigate selection bias.
In per-protocol analyses, participants were censored if they received any flu jabs during follow-up; estimates better reflected baseline dosage – high versus standard dose – without subsequent shots.
In intention-to-treat analyses, participants were not censored for additional flu shots, which may better mirror real-world experiences of annual vaccinations.
The high-dose group included 185 269 person-trials and the standard-dose group included 53 978 after weighting. Mean age in both groups was 74, and 57% were women.
Women who received a high-dose shot had a significantly lower risk of Alzheimer’s dementia from months one to 13 in per-protocol analyses. Among men, per-protocol results were not statistically significant, but in intention-to-treat analyses, the risk of Alzheimer’s dementia was lower after high-dose shots from months 17 to 24.
The study lacked mortality data, which may mean Alzheimer’s risk was under-estimated. The researchers also acknowledged that Alzheimer’s dementia has a long preclinical phase and the follow-up duration of up to three years is a limitation, although it was similar to other studies examining vaccination and dementia risk.
Study details
Risk of Alzheimer dementia after high-dose vs standard-dose influenza vaccination
Avram Samuel Bukhbinder, Yaobin Ling, Lauren Jhin et al.
Published in Neurology on 28 April 2026
Abstract
Background and Objectives
Previous studies, including large cohort analyses comparing vaccinated and unvaccinated adults, suggest that routine immunisations such as inactivated influenza vaccines (IIVs) may reduce Alzheimer dementia (AD) risk. Whether AD risk differs after high-dose IIV (H-IIV) vs standard-dose IIV (S-IIV) remains unexamined. We hypothesised that AD risk would be lower among adults ≥65 years after H-IIV compared with S-IIV.
Methods
This retrospective cohort study analysed data spanning 2014–2019 from IQVIA PharMetrics Plus for Academics, a US health care claims database. Eligible participants were ≥65 years with ≥2 years of continuous medical and pharmaceutical coverage and no previous diagnostic or pharmacotherapeutic indicators of cognitive impairment. Vaccinations were identified by name and Current Procedural Terminology codes. Participants were followed for up to three years post-vaccination. Incident AD was defined using International Classification of Diseases codes and AD medication dispenses (anticholinesterase inhibitors, memantine). We emulated a target trial using sequential nested trials to align eligibility, treatment assignment, and time-zero with vaccination dates, preventing immortal time bias. Inverse probability weighting adjusted for measured confounding, emulated randomisation, and mitigated selection bias. Effects were estimated as risk difference, number needed to treat (NNT), risk ratio; 95% CIs were obtained via bootstrapping. Secondary analyses examined potential effect modifiers such as sex.
Results
The H-IIV group included 120,775 unique participants (185,183 person-trials; mean age 74.4 years, SD 5.5; 57.3% female), and the S-IIV group included 44,022 participants (53,918 person-trials; mean age 73.0, SD 6.1; 56.4% female). H-IIV was associated with significantly lower AD risk during months 1–25 post-vaccination (minimum NNT = 185.2 at 25 months). After sex stratification, risk reduction persisted longer among women (months 1–13, minimum NNT = 416.7) than men (months 17–24, significant only in intention-to-treat analysis, minimum NNT = 232.6).
Discussion
High-dose influenza vaccination is associated with reduced AD risk compared with standard-dose vaccination in adults ≥65 years, with a stronger effect among women. Significant study limitations included duration of follow-up (≤3 years) and lack of sociodemographic, lifestyle, biomarker, and mortality data. Further research is needed to clarify whether the observed difference reflects protection against influenza infection or non-infection–related mechanisms.
Classification of Evidence
This study provides Class II evidence that treatment with H-IIV vs S-IIV was associated with decreased incident dementia in individuals ≥65 years of age captured in this US healthcare claims database.
See more from MedicalBrief archives:
More evidence flu jab may guard against Alzheimer’s – Texas cohort study
Flu and pneumonia vaccinations may reduce Alzheimer’s risk