High-Dose Flu Vaccine Linked to Lower Claims-Defined Dementia Risk

Key Takeaways

• Among older adults in a US claims setting, high-dose inactivated influenza vaccination was associated with significantly lower claims-defined Alzheimer dementia risk than standard-dose vaccination.
• In women, the lower-risk association spanned a longer reported window than the significant signal in men.
• In men, significantly lower risk appeared only in the intention-to-treat analysis.

For older adults receiving inactivated influenza vaccine, whether high- and standard-dose formulations are followed by different Alzheimer dementia outcomes remains a clinical question. Dementia identified through health care claims may reflect recorded diagnoses or treatment, rather than a confirmed underlying disease process. Investigators compared recipients of the two formulations from their vaccination dates to assess subsequent claims-defined outcomes.

Investigators retrospectively compared US adults aged 65 years or older in IQVIA PharMetrics Plus for Academics claims. The high-dose versus standard-dose inactivated influenza vaccine comparison included 120,775 unique high-dose recipients and 44,022 standard-dose recipients. Vaccines were identified by name and Current Procedural Terminology (CPT) codes. Sequential nested target-trial emulation aligned eligibility and vaccination time zero; recipients were not randomized. Inverse probability weighting addressed measured confounding. Incident claims-defined Alzheimer dementia was identified by diagnosis codes or dispensing of anticholinesterase inhibitors or memantine.

Compared with standard-dose recipients, high-dose recipients had significantly lower incident claims-defined Alzheimer dementia risk during months 1–25 after vaccination. The minimum estimated number needed to treat (NNT) was 185.2 at month 25. That NNT is an observational estimate, not a randomized treatment effect.

Sex-stratified findings followed different time courses. Among women, lower risk was reported during months 1–13 after vaccination. Among men, lower risk during months 17–24 was statistically significant only in the intention-to-treat analysis. Neither association establishes a preventive effect.

Follow-up extended no more than three years, and the investigators identified unavailable sociodemographic, lifestyle, biomarker, and mortality data as limitations. A diagnosis code or relevant medication dispensing can identify an outcome in claims but cannot establish biomarker-confirmed Alzheimer disease. Weighting for measured confounding does not eliminate the possibility of unmeasured differences between vaccine recipients. Consequently, the observed difference cannot establish that high-dose influenza vaccination prevents Alzheimer disease.

The investigators characterized the association between high-dose rather than standard-dose inactivated influenza vaccination and lower incident claims-defined dementia risk among older US adults as Class II evidence.

Clinician Questions

Which older adults were eligible for the influenza vaccine dose comparison of Alzheimer dementia?

In US IQVIA PharMetrics Plus for Academics claims from 2014–2019, adults aged 65 years or older receiving high- or standard-dose inactivated influenza vaccine needed at least two years of continuous medical and pharmaceutical coverage and no prior diagnostic or pharmacotherapeutic indicators of cognitive impairment.

Why do person-trial counts exceed recipient counts in the high-dose versus standard-dose flu vaccine comparison?

In the Alzheimer dementia comparison using sequential nested target-trial emulation, the high-dose group contributed 185,183 person-trials and the standard-dose group 53,918 person-trials. A person-trial represents trial participation, not necessarily a different person; arm-specific unique-recipient counts cannot simply be added to obtain a necessarily unduplicated overall cohort. These counts do not establish how many recipients, if any, switched vaccine groups.

Does the high-dose influenza vaccine association with Alzheimer dementia reflect influenza protection or another mechanism?

Investigators said more research is needed to determine whether the difference in claims-defined Alzheimer dementia risk between high- and standard-dose inactivated influenza vaccine recipients reflects protection against influenza infection or a non-infection-related mechanism. Neither explanation was established.

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