The risk of developing Alzheimer’s disease (AD) may be significantly lowered after vaccination with the high-dose influenza vaccine, a new study of more than 200,000 older adults showed.
Older individuals who received a high-dose flu vaccine had a 55% lower risk for AD, compared to the 40% risk reduction among those who received the standard dose.
This reduction in risk persisted for up to 25 months post-vaccination, and the higher dose was associated with stronger protective effects among women.
The findings add to previous research by the investigators which showed the standard dose was associated with a lower risk of developing AD, highlighting that the higher dose vaccine may confer even greater protection.
The study was published online on April 1 in Neurology.
Does Dose Matter?
AD is the most common form of dementia, affecting over 7 million older adults. Modifiable risk factors for dementia include physical inactivity, smoking, hypertension, and hearing impairment.
Growing evidence suggests that adult vaccinations— such as the influenza vaccine — may be associated with a reduced risk for dementia. As the immune system naturally declines with age, older adults face a higher risk for flu-related complications.
For this reason, a high-dose influenza vaccine, which is approximately four times more potent than the standard formulation, is recommended by the CDC for individuals aged 65 years or older.
In 2022, a nationwide study of adults aged 65 years or older conducted by Paul Schulz, MD, professor of neurology at McGovern Medical School at UTHealth in Houston, showed that the influenza vaccine was associated with a significantly decreased risk for AD.
The inspiration for the current study, also led by Schulz, came when local public health department officials invited him to discuss his research on flu vaccines and incident AD risk.
“We went through the findings, and they asked if there was a difference with different dosages; I was confused,” Schulz, who is also director of the Neurocognitive Disorders Center at UTHealth Houston Neurosciences in Houston, said in a news release.
“I was stunned that, as a physician, I didn’t know a higher dose was offered,” Schulz added.
Novel Research
In what the investigators note is the first study of its kind, they assessed whether the higher flu dose was associated with a reduced risk for AD among older adults using a target trial emulated design.
All participants were aged 65 years or older and had no previous signs of cognitive impairment or dementia. The study included 120,775 older adults (mean age, 74 years; 57% women) who had received the high-dose vaccine and 44,022 of their counterparts (mean age, 73.0 years; 56% women) who received the standard dose.
AD was identified using International Statistical Classification of Diseases and Related Health Problems codes and records of dispensed AD medications.
Participants were followed for up to 3 years after vaccination.
A total of 21 sequential trials were emulated to capture variation across the months of the influenza seasons from 2016 to 2019. The analyses were adjusted for a range of potential confounders, including comorbidities, history of routine adult vaccinations, medication use, and demographic covariates.
Logistic regression models were used to calculate propensity scores for each person-trial. Propensity scores were then weighted to balance baseline covariates between those receiving the high-dose or standard dose vaccine.
Intention-to-treat (ITT) effects were estimated based on participants’ initial treatment assignment, regardless of whether they adhered to it. Per-protocol (PP) effects were estimated among participants who followed the treatment as intended.
The number needed to treat (NNT) was estimated for each month during the follow-up period. Risk ratio and risk difference were also estimated.
The researchers conducted multiple secondary analyses to identify effect differences by sex, evaluate AD risk after seasonal vaccination over 3 years, and compare AD risk between standard vaccination and adjuvanted vaccination.
Various sensitivity analyses were also performed to address potential outcome misclassification, reverse causality and further sex-dependent effects.
Higher Dose, Lower Risk
Compared to the standard dose, the risk for incident AD was significantly lower among those who had received the high-dose flu vaccine, with protective effects up to 25 months and 28 months in the PP and ITT analysis, respectively.
In the PP analysis, the maximum risk difference was 0.0054, with a NNT of 185. In the ITT analysis, the risk difference was 0.0037, with a NNT of 270.
Women who received the high dose had a significantly lower risk for incident AD up to 13 months post-vaccination, corresponding to a NNT of 417.
The PP analysis results were not statistically significant among men but in the ITT analysis, the high-dose vaccine was associated with a lower risk for AD from months 17-24. Sensitivity analyses showed the effects of the high-dose vaccine persisted longer among women.
Sustained high-dose vaccinations were associated with a lower risk for AD, corresponding to a NNT of 294.
There were no significant effect differences between the standard vaccine and adjuvanted flu vaccine in the PP analysis. However, in the ITT analysis, AD risk was significantly lower among those who received the adjuvant.
Future research should aim to understand the pathways for the potential dose-dependent effects from the influenza vaccine, the investigators noted.
“Understanding the mechanisms through which influenza vaccines and immunogenic enhancements influence AD pathology and presentation could inform the targeted interventions and public health strategies to mitigate the growing population burden of AD,” the investigators wrote.
Limitations of the study included the relatively short duration of follow-up duration and lack of mortality data.
The authors reported no targeted funding and no relevant disclosures.