Alzheimer’s Risk May Be Influenced by Flu Shots

Older adults who received a high-dose inactivated influenza vaccine had a lower risk of incident Alzheimer’s disease dementia compared with those who received a standard-dose shot, U.S. claims data showed.

Compared with standard-dose shots, high-dose flu shots were associated with a lower risk for Alzheimer’s dementia in the first 25 months after vaccination, reported 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, the researchers wrote in Neurology. The relationship was stronger in women than in men.

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 8 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 — were 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.

Bukhbinder and co-authors analyzed data from 2014 to 2019 from IQVIA PharMetrics Plus for Academics, a U.S. healthcare claims database.

All standard-dose, nonadjuvanted, non-recombinant, inactivated flu vaccines approved in the U.S. during the study period for people 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 people 65 and older in December 2009.

Eligible participants were 65 and older with 2 or more years of continuous medical and prescription drug coverage and no previous indicators of cognitive impairment; they were followed for up to 3 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 3 years), using inverse probability weighting to adjust for confounding, emulate randomization, and mitigate selection bias.

In per-protocol analyses, participants were censored if they received any flu vaccines 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 years, and 57% were women.

Women who received a high-dose shot had a significantly lower risk of Alzheimer’s dementia from months 1 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 underestimated. The researchers also acknowledged that Alzheimer’s dementia has a long preclinical phase and the follow-up duration of up to 3 years is a limitation, although it was similar to other studies examining vaccination and dementia risk.

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