The surprising relationship between vaccinations and Alzheimer’s disease

Receiving routine vaccinations against common infections like tetanus, shingles, and pneumonia may offer an unexpected benefit: a reduced risk of developing Alzheimer’s disease later in life. A study published in the Journal of Alzheimer’s Disease in 2023 found that older adults who received these vaccines were less likely to be diagnosed with Alzheimer’s disease compared to their unvaccinated peers over an eight-year period. This research adds to a growing body of evidence suggesting that vaccinations could play a role in protecting against this devastating brain disease.

Alzheimer’s disease is a devastating brain disorder that gradually destroys memory and thinking skills. It is the most common cause of dementia, a general term for a decline in mental ability severe enough to interfere with daily life. In Alzheimer’s disease, brain cells are damaged and eventually die, leading to a progressive and irreversible loss of cognitive function. While the exact causes of Alzheimer’s are not fully understood, it is known that the disease involves complex changes in the brain that disrupt normal brain processes.

There is a growing theory that infections might play a role in the development of Alzheimer’s. The idea is that infections can cause inflammation in the brain, and this inflammation could contribute to the brain cell damage seen in Alzheimer’s. Vaccines are designed to prevent infections. Therefore, the researchers wanted to investigate whether receiving routine vaccines against infections like tetanus, diphtheria, shingles, and pneumonia might reduce the risk of Alzheimer’s disease.

They reasoned that if vaccines can prevent or lessen the severity of infections, they might also reduce the associated brain inflammation and, consequently, lower the chances of developing Alzheimer’s. They also considered that vaccines could have other effects on the immune system that might be beneficial in protecting against Alzheimer’s, independent of preventing specific infections.

To conduct this study, the research team used a large database of health insurance records from a company called Optum. This database contains anonymized information on medical treatments, prescriptions, and hospital visits for millions of people across the United States who have health insurance through their employer or Medicare Advantage.

The researchers looked at data from 2009 to 2019. They first identified a group of people aged 65 and older at the start of the study period. To ensure they were studying the development of new cases of Alzheimer’s, they excluded anyone who had already been diagnosed with dementia, mild memory problems, or any condition affecting the brain, or who were already taking medications for Alzheimer’s disease, before the study officially began. This left them with a large group of individuals to follow over time.

The study then examined who among these individuals received vaccinations for tetanus and diphtheria (with or without pertussis), shingles, or pneumonia during the follow-up period, which lasted from 2011 to 2019. The researchers used specific codes in the insurance records to identify when a person received each type of vaccine. For the tetanus and diphtheria vaccine, they included both the combined vaccine that also protects against pertussis, and the version without pertussis. For shingles, they looked at both types of shingles vaccines available in the United States: an older, less potent vaccine called Zostavax, and a newer, more effective vaccine called Shingrix. For pneumonia, they examined two types of pneumococcal vaccines: PCV13 and PPSV23.

Next, the researchers needed to determine who in their study group developed Alzheimer’s disease during the follow-up period. They used a combination of diagnosis codes for Alzheimer’s disease and related dementias, as well as records of prescriptions for medications commonly used to treat Alzheimer’s, such as donepezil and memantine. To increase the accuracy of identifying true Alzheimer’s cases, they required individuals to have at least two Alzheimer’s diagnoses, or one diagnosis plus a prescription, or at least two prescriptions within a 12-month period. This approach helped to minimize the chance of mistakenly identifying someone as having Alzheimer’s based on a single error in their medical records.

To make sure they were comparing similar groups of people, the researchers used a statistical technique called propensity score matching. This method helps to balance out differences between people who get vaccinated and those who do not. For example, people who choose to get vaccinated might be generally healthier or more proactive about their health than those who do not. To address this, the researchers considered a wide range of factors that could influence both vaccination status and Alzheimer’s risk.

These factors included age, sex, race, geographic region, number of healthcare visits, and presence of various pre-existing health conditions like asthma, heart problems, diabetes, and depression. They also accounted for use of certain medications and whether individuals had received other routine vaccinations, like the flu vaccine. By statistically matching vaccinated individuals with unvaccinated individuals who had similar characteristics across these factors, the researchers aimed to isolate the specific effect of vaccination on Alzheimer’s risk, rather than just reflecting other health or lifestyle differences.

After carefully analyzing the data, the researchers found that vaccination against tetanus and diphtheria was associated with a 30% lower risk of developing Alzheimer’s disease. Similarly, receiving a shingles vaccine was linked to a 25% reduction in Alzheimer’s risk, and pneumococcal vaccination was associated with a 27% lower risk. These findings were statistically significant, meaning they were unlikely to be due to chance.

The researchers also conducted further analyses to see if different types of shingles and pneumococcal vaccines had varying effects. They found that both types of shingles vaccines, Zostavax and Shingrix, were associated with a reduced risk of Alzheimer’s, but the newer Shingrix vaccine showed a much stronger protective effect. For pneumococcal vaccines, both PCV13 and PPSV23 were linked to similar reductions in Alzheimer’s risk.

To further ensure their results were not simply due to healthier individuals being more likely to get vaccinated, the researchers performed a sensitivity analysis. They repeated their main analyses focusing only on people who were consistently taking statin medications, which is another indicator of health-conscious behavior. Even within this group of individuals who were likely already health-conscious, the protective associations between vaccination and reduced Alzheimer’s risk remained, strengthening the confidence in the main findings.

In a seperate article in Human Vaccines and Immunotherapeutics, the researchers explained there are several possible ways that vaccines might reduce the risk of Alzheimer’s disease, and these mechanisms are not necessarily mutually exclusive. One key idea is that vaccines reduce the burden of infections. Infections, both those that directly affect the brain (like herpes zoster, which causes shingles) and those that occur elsewhere in the body, can trigger inflammation. This inflammation is thought to potentially worsen or speed up the processes that lead to Alzheimer’s. By preventing infections, vaccines could reduce this inflammatory burden and thus lower Alzheimer’s risk.

Another potential mechanism involves how vaccines might influence the immune system’s response to Alzheimer’s-related changes in the brain. Alzheimer’s disease is characterized by the buildup of abnormal proteins, like amyloid, in the brain. Vaccines might somehow enhance the immune system’s ability to clear away these harmful proteins, preventing them from accumulating and causing damage.

Alternatively, even if vaccines don’t directly reduce the amount of these proteins, they might modulate the brain’s immune response to them. In Alzheimer’s, the brain’s immune response to these abnormal proteins can sometimes be overactive and damaging, causing “collateral damage” to healthy brain tissue. Vaccines could potentially help to refine this immune response, making it more effective at clearing harmful substances while minimizing damage to healthy brain cells.

Finally, researchers are exploring the concept of “trained immunity.” Vaccines might “train” the innate immune system, which is the body’s first line of defense against pathogens, to be more generally effective and less prone to harmful inflammation as we age. This broader strengthening of the immune system could offer protection against a range of age-related diseases, including Alzheimer’s.

For the influenza vaccine specifically, there’s even a hypothesis about “cross-reactivity.” This idea suggests that there might be a similarity between some components of the flu virus and the amyloid proteins involved in Alzheimer’s. Vaccination against the flu could, in this case, trigger an immune response that also offers some protection against amyloid buildup in the brain, although this mechanism is thought to be more unique to the flu vaccine compared to the others studied.

While the study provides compelling evidence, it is important to acknowledge its limitations. The study used insurance claims data, which may not capture all instances of vaccination, particularly if someone paid for a vaccine without using their insurance. Furthermore, because this was a retrospective study, looking back at existing data, it cannot definitively prove that vaccines cause a reduction in Alzheimer’s risk. It only shows an association.

There might be other unmeasured factors that influence both vaccination and Alzheimer’s risk that the researchers were unable to account for, even with their careful statistical matching. For example, the study could not fully account for lifestyle factors like diet, exercise, or education level, which could also play a role. Additionally, the newer Shingrix vaccine has only been available for a relatively short time, so the follow-up period for studying its long-term effects on Alzheimer’s risk was limited.

Future research is needed to confirm these findings and to better understand the underlying mechanisms. Ideally, prospective studies, which follow people forward in time and track their vaccination status and development of Alzheimer’s disease, would provide even stronger evidence. Animal studies could also be helpful in exploring how vaccines might influence brain processes related to Alzheimer’s. It will also be important to investigate whether specific types of vaccines, or vaccination at certain ages, are more effective in reducing Alzheimer’s risk. Understanding why and how these vaccines might be protective could open up new avenues for Alzheimer’s prevention and treatment.

The study, “The Impact of Routine Vaccinations on Alzheimer’s Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using Propensity Score Matching,” was authored by Kristofera Harris, Yaobin Ling, Avram S. Bukhbinder, Luyao Chen, Kamal N. Phelps, Gabriela Cruz, Jenna Thomas, Yejin Kim, Xiaoqian Jiang, and Paul E. Schulz.