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In a recent study published in the Journal of Alzheimer’s Disease, researchers assessed the risk of incident Alzheimer’s disease (AD) development among individuals who received influenza vaccines in the United States (US).

Study: Risk of Alzheimer’s Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. Image Credit: LightField Studios/Shutterstock

Previous studies have reported a lower risk of developing dementia after vaccination against influenza among veterans and particular individuals with critical and chronic medical disorders. However, the impact of influenza vaccinations on incident AD risk among elder US individuals is not well characterized.

About the study

In the present nationwide retrospective cohort study, researchers compared AD development risks among recipients and non-recipients of intramuscularly administered influenza vaccines.

A large US claims database of the Optum Clinformatics® data mart (CDM) was used for the analysis. The study participants were aged ≥ 65 years and did not have dementia. Cohorts of influenza vaccine recipients and non-recipients were created using propensity-score matching (PSM). The study look-back and the follow-up periods were between 1 September 2009 and 31 August 2015 and between 1 September 2015 and 31 August 2019, respectively.

Individuals included in the study had ≥1 and ≥2 influenza vaccination records with international classification of diseases (ICD) codes in the look-back and follow-up periods, respectively. The two cohorts were matched for demographic parameters, medication use, and the presence of comorbidities. Individuals were excluded from the study if they were aged <65 years at the commencement of the follow-up period, if they were diagnosed with mild cognitive impairment (MCI), dementia, or encephalopathy, and if they were on AD medications (such as galantamine, donepezil, memantine, or rivastigmine).

Individuals who received intranasal influenza vaccinations were also excluded since the intranasal vaccine formulation has been recommended for individuals aged <50 years and the mechanism of action is substantially different from the intramuscular formulation. Incident AD development was considered in case of >2 AD-related records (such as ICD code for AD diagnosis or pharmacy claims for the abovementioned four AD medications). The absolute risk reductions (ARR) and relative risks (RR) were determined to evaluate the impact of influenza vaccines on AD risks in the period of follow-up.  

The primary analysis involved the assessment of influenza vaccinations in the follow-up period as a binary exposure as zero vaccination vs. ≥1 vaccination for influenza. The secondary analysis considered the total count of influenza vaccinations in the look-back study period. Primary analysis data were analyzed on the basis of the average treatment effect in the treated (ATT) values of influenza vaccinations on AD risk and secondary analysis data was analyzed by a time-to-event analysis.

In addition, sensitivity analyses were performed by removing ICD codes for senile and unspecific dementias and expanding the study outcome from incident AD to ADRD (AD and related dementias). Further, the impact of varying the look-back and follow-up period durations to two years and eight years, respectively, and considering individuals ≥75 years (when follow-up commenced) on the ATT values were assessed. Furthermore, Cox-type competing-risk regression modeling was used for estimating the impact of the number of influenza vaccinations on the cumulative incidence function (CIF) for AD during the follow-up period and the subdistribution hazard ratios (sHRs) were calculated.

Results

A total of 1,185,611 influenza-vaccinated and 1,170,868 influenza-unvaccinated individuals were identified which were sorted into 935,887 matched pairs of influenza vaccine recipients and non-recipients by PSM. The mean age of the individuals was 73.7 years, most (56.9%) of them were women and were followed up for a median of 46 months. Of the matched individuals, 47,889 (5.1%) of the influenza vaccine recipients and 79,630 (8.5%) of non-recipients developed incident AD in the follow-up period.

The RR, ARR, and the number needed to treat (NNT) values were 0.6, 0.034, and 29.4, respectively. In the sensitivity analyses, excluding senile and unspecific dementia ICD codes resulted in ARR and RR values of 0.02 and 0.65, respectively. The corresponding values obtained on including all ADRD codes were 0.033 and 0.60, respectively.

The sHR values for the number of intramuscular influenza vaccinations and for the time-influenza-vaccination interactions were 0.8 and 1.006, respectively. Similar to the primary ATT analysis with matched sample data, the secondary time-to-event analysis with unmatched sample data demonstrated a negative correlation between influenza vaccination and AD risk.

Overall, the study findings showed that influenza vaccination was associated with a 40% lower risk of incident AD development among US individuals aged ≥65 years; however, the underlying mechanisms for this apparent immune protection warrants further research. The association between influenza vaccination and the rate of symptom progression among patients with pre-existing Alzheimer’s dementia must also be assessed.

Aviram S. Bukhbinder, the study’s first author said,

We found that flu vaccination in older adults reduces the risk of developing Alzheimer’s disease for several years. The strength of this protective effect increased with the number of years that a person received an annual flu vaccine – in other words, the rate of developing Alzheimer’s was lowest among those who consistently received the flu vaccine every year. Future research should assess whether flu vaccination is also associated with the rate of symptom progression in patients who already have Alzheimer’s dementia.”

Moreover, Paul. E. Schulz, MD, the study’s senior author concluded,

Since there is evidence that several vaccines may protect from Alzheimer’s disease, we are thinking that it isn’t a specific effect of the flu vaccine. Instead, we believe that the immune system is complex, and some alterations, such as pneumonia, may activate it in a way that makes Alzheimer’s disease worse. But other things that activate the immune system may do so in a different way — one that protects from Alzheimer’s disease. Clearly, we have more to learn
about how the immune system worsens or improves outcomes in this disease
.”

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