Older adults given the high-dose flu shot had slightly fewer Alzheimer's diagnoses than those given the standard one

Several large studies have found that older people who get vaccines, including the yearly flu shot, are diagnosed with dementia less often than people who skip them. In an earlier study, the same team linked having at least one flu shot to a 40% lower risk of Alzheimer's disease over four years. But comparing vaccinated with unvaccinated people is tricky: people who get their shots also tend to be healthier, richer and more careful about their health in many other ways.

This study asks a narrower question that avoids part of that problem. Since 2010, adults aged 65 and over in the United States can get a high-dose flu vaccine, which contains more of the viral proteins the immune system learns to recognize and protects older people better against flu than the standard shot. If flu itself, or the inflammation that comes with it, adds to the risk of dementia, then the stronger vaccine might go with fewer dementia diagnoses than the standard one. Comparing two groups that both chose to be vaccinated makes them more alike than comparing vaccinated with unvaccinated people.

What they did

The researchers, at UTHealth in Texas, used a large US database of health-insurance claims: records of doctor visits, diagnoses, vaccines and prescriptions. They included people aged 65 and over with at least two years of insurance records and no sign of memory problems or dementia, and no prescription for an Alzheimer's drug.

They used target trial emulation: they wrote down how an ideal trial would be run and then reproduced it as closely as possible with the existing records. In each month of three flu seasons (2016 to 2019), people who got a flu shot that month entered a new "trial", in the high-dose or the standard-dose group. That gave 120,775 people in the high-dose group (average age 74) and 44,022 in the standard-dose group (average age 73); about 57% were women. A statistical weighting made the two groups similar in age, illnesses, medicines, other vaccines and how often they saw a doctor.

People were followed for up to three years. A new case of Alzheimer's dementia was counted when the records showed a diagnosis of Alzheimer's, senile or unspecified dementia, or a prescription for one of the Alzheimer's drugs.

What they found

• Slightly lower risk after the high-dose shot. From the first month to month 25 after vaccination, the risk of an Alzheimer's diagnosis was lower in the high-dose group. The largest difference was about half a percentage point at 25 months. Put another way, about 185 people would need the high-dose rather than the standard shot for one fewer diagnosis in that time.
• Clearer in women. In women, the lower risk lasted from month 1 to month 13 in the main analysis. In men, a difference showed up only in one of the two ways of counting (months 17 to 24).
• Repeated shots. People who kept getting the high-dose vaccine every season also had a lower risk than those who kept getting the standard one, for up to 27 months.
• A sanity check passed. The vaccine type made no difference to a set of unrelated painful conditions such as appendicitis, which argues against the result being only a sign of healthier people choosing the high-dose shot.

What to keep in mind

• Observational. Nobody was assigned a vaccine at random. The weighting balances what the records show, but not things like income, education, exercise or health awareness, which the database lacks.
• Several checks weakened the result. When the team counted only diagnoses that named Alzheimer's (leaving out "senile" and "unspecified" dementia), or only prescriptions, the difference disappeared. It largely disappeared among people who had no flu shot in the two years before. In a smaller subgroup of people who reliably took their cholesterol medicine, the estimate pointed the same way but was no longer statistically clear, which the team reads as a hint that "healthy-vaccinee bias" may have played a part.
• Possible early cases. When the first month after the shot was left out, no difference appeared in months 1 to 7. The authors say the early part of the effect may reflect dementia that was already there but not yet diagnosed, or differences in how closely people were checked.
• Short follow-up, missing data. Alzheimer's develops over decades, and the study followed people for at most three years. The database had no death records, and only 5% of its members were 65 or older, mostly with private supplemental insurance, so the results may not apply to everyone.
• Claims are not diagnoses. Dementia is often coded imprecisely in insurance records, so some cases counted as Alzheimer's were probably other kinds of dementia.

Why it matters

The flu vaccine is already recommended every year for older adults to prevent flu and its complications. This study does not show that the high-dose shot prevents Alzheimer's. It adds a small, fragile signal that a stronger flu vaccine goes with slightly fewer dementia diagnoses in the following two years. The authors call for longer, prospective studies with proper memory testing and biomarkers to find out whether the link is real, and if so whether it comes from preventing flu infections or from some other effect on the aging immune system.