A stronger flu shot might do more than prevent infection. New research suggests it could modestly lower Alzheimer’s risk, especially in older women, offering fresh insight into brain health and prevention.
Study: Risk of Alzheimer Dementia After High-Dose vs Standard-Dose Influenza Vaccination. Image credit: Galina Sharapova/Shutterstock.com
Dementia affects ~57 million people worldwide, and is incurable, highlighting the need for low-cost preventive strategies. A recent study in Neurology sought to determine whether high-dose influenza vaccines are associated with a reduced risk of Alzheimer’s dementia compared with standard-dose vaccines, and to uncover sex-dependent differences in effect.
Enhanced IIVs may be linked to greater protection
Prior research by these authors demonstrated that one or more doses of inactivated influenza vaccines (IIVs) were linked to a 40 % lower risk of Alzheimer’s dementia (AD) over the next four years. However, that study did not distinguish between standard-dose and immunologically enhanced IIVs.
Building on this earlier work, the authors hypothesized that enhanced IIVs may offer greater protection against AD than standard formulations.
Immunologically enhanced vaccines could plausibly reduce AD risk through both antimicrobial and nonantimicrobial mechanisms. For example, their greater effectiveness in preventing influenza may reduce the risk of severe infection and associated systemic inflammation, which in turn could lower neuroinflammation and neurodegeneration.
Additional pathways may include nonspecific immunological effects of vaccination or modulation of neuroinflammatory processes. These effects could help resolve early pathological changes linked to AD and protect against their progression.
Supporting this hypothesis, previous research has shown that the recombinant herpes zoster vaccine is associated with a lower risk of dementia compared to the live attenuated version, with stronger effects observed in women. This finding suggests that immunologically enhanced vaccines and their effects may vary by sex.
The current study assessed the effect of IIVs on AD risk among older adults (aged 65 years or above), comparing high-dose (H-IIV) with standard-dose (S-IIV) vaccines. The researchers used a target trial emulation (TTE) design, which uses observational data to fill in the data fields of a specified protocol for a hypothetical randomized trial. These are then adjusted to minimize the risk of selection and immortal-time biases, but the findings remain observational and cannot establish causality.
Lower AD risk after H-IIV compared to S-IIV
The risk of new AD appearing over 25 months of follow-up was about 0.54 percentage points lower (maximum risk difference) with the H-IIV than the S-IIV in the per-protocol analysis, indicating a modest absolute effect size despite statistical significance.
Women who received the H-IIV had a lower AD risk over the next 13 months. About 417 women would need to receive H-IIV to avert one new case of AD. Among men, no significant difference was observed in the primary per-protocol analysis, although a lower risk was seen in the intention-to-treat analysis during later follow-up, indicating sex-dependent differences in immunity. Previous studies suggest that older women tend to have greater immunity to influenza and higher nonspecific effects than males of the same age.
The risk of mild cognitive impairment (MCI) increased from 13-24 months of follow-up in some analyses (particularly the ICD-or-medication definition), but not with stricter case definitions, perhaps because of the high misclassification bias arising from MCI misdiagnosis in routine practice. To illustrate, over 92 % of MCI cases are not documented in claims data, while one study showed that MCI was coded as dementia in half the cases in a Medicare database.
When the effect of seasonal revaccination was observed in this cohort, incident AD risk was reduced after H-IIV for 27 months. Here, 294 people would need to receive the vaccine to avert a single new case of AD. This may tentatively suggest a benefit from regular revaccination, although the duration of effect was only slightly longer than in the primary analysis.
There was no significant difference in risk between adjuvanted and standard IIV in the primary (per-protocol) analysis, though a lower AD risk was observed in the intention-to-treat analysis at later time points. Additional analyses supported these findings.
Study design reduces bias but cannot prove causality
The study used a large US claims database to conduct the TTE. It compared high- and standard-dose IIVs rather than vaccinated versus unvaccinated, thus reducing bias and improving comparability between groups. The trial design avoided follow-up loss and protocol non-adherence.
Misclassification bias is probable for both MCI and AD. This study included both senile and unspecified dementia under AD, in an attempt to adjust for this. Their exclusion reduced the number of AD cases by 80 %. Moreover, the AD risk with either IIV type did not differ. This may reflect either a broader protective effect of IIV on dementia or misclassification of AD.
Since S-IIV is associated with higher mortality compared to H-IIV, due to lower protective efficacy against influenza, missing mortality data could underestimate the AD risk associated with S-IIV.
The limited follow-up period, the lack of socioeconomic and lifestyle data, and the underrepresentation of seniors in this sample are other limitations.
Mechanisms linking vaccination and neurodegeneration remain unclear
Given the prolonged preclinical phase of AD, longitudinal studies with diverse samples, using objective cognitive markers, are required to help map the long-term effect of influenza vaccination on neurological and cognitive health. The underlying mechanisms also need to be uncovered. Studies should also clarify whether such measures are effective once MCI symptoms have begun.
Such research could inform strategies to reduce the burden of Alzheimer’s disease.
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