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Natural Medicine Journal

April 3, 2024

Vaccination Lowers Risk of Alzheimer Disease?

Results from a retrospective study

Jacob Schor

ND, FABNO
Adults aged 65 years and more who received the pneumococcal vaccine had a lower risk of developing Alzheimer disease than those who did not.

Reference

Huo X, Finkelstein J. Pneumococcal vaccination lowers the risk of Alzheimer's disease: a study utilizing data from the IBM® MarketScan® Database. Stud Health Technol Inform. 2024;310:961-965.

Study Objective  

To assess whether pneumococcal vaccination is associated with a lower risk of Alzheimer disease (AD)

Key Takeaway

People who received pneumococcal vaccination had a significant and substantially lower risk of developing Alzheimer disease (AD) compared to people who did not receive the vaccination.

Design

This was a retrospective study using data obtained from the IBM MarketScan® commercial and Medicaid claims databases from 2013 to 2019. Investigators used this data to compare relative risk of AD in individuals who received pneumococcal vaccine with those who did not.

Investigators divided the data into two 3-year periods. The initial period, from September 1, 2013, to August 31, 2016, was called the “look-back period” during which the interventions occurred, in this case vaccination. The second period, which went from September 1, 2016, to August 31, 2019, would be, if this were a standard prospective trial, what we normally consider the follow-up period.

Investigators used the conditional logistic regression method to estimate the relationship between pneumococcal vaccination and the onset of AD.

Participants  

In the initial data, 142,874 people received the pneumococcal vaccine, and 14,392 did not. 

Exclusionary criteria included:

  1. Aged less than 65 years at the start of follow-up.
  2. Diagnosis of mild cognitive impairment (MCI), encephalopathy, or dementia from any cause during the look-back period. 
  3. Prescription for medications indicated for AD during the look-back period.
  4. Had influenza vaccine at any time during the entire follow-up period or look-back period.

Using a logistic regression model that accounted for all baseline characteristics, propensity score matching (PSM) generated matched sets of vaccinated and unvaccinated subjects to create 2 groups of 14,392 subjects, 1 group who had been vaccinated against pneumococcus and the other group who had not been.

Interventions  

The vaccine cohort was defined as individuals who received 1 dose of PCV13 (Prevnar13®) followed by 1 dose of PPSV23 (Pneumovax®) or 1 dose of PCV20 (Prevnar20®). The unvaccinated cohort was defined as subjects who did not receive any pneumococcal vaccine (eg, PCV13, PCV20, PPSV23) during the follow-up period. Neither group had received vaccination against influenza.

Study Parameters Assessed   

Investigators tracked numerous covariates that might affect risk of AD, including age, sex, and physical and psychiatric comorbidity (ie, asthma, atrial fibrillation or flutter, B12 deficiency, congestive heart failure, chronic obstructive pulmonary disease, hyperlipidemia, hypertension, ischemic heart disease, obesity, traumatic brain injury, type 2 diabetes, stroke, alcohol use disorder, anxiety disorder, depression, substance use disorder, and tobacco use).

Subjects were grouped by age: 65 to 74 years, 75 to 84 years, and 85 years and older. 

Primary Outcome Measure

Development of AD

Key Findings

Conditional logistic regression indicated that the people who received the pneumococcal vaccine had a significantly lower risk of developing AD as compared to the people who did not receive any pneumococcal vaccine (OR=0.37; 95% CI, 0.33–0.42; P<0.0001). The pneumococcal vaccine was associated with a 63% reduction in the risk of AD among US adults aged 65 and more. 

Transparency

The authors do not report any outside funding or disclosures to suggest conflicts of interest.

Practice Implications

These 2 authors, Xingyue Huo and Joseph Finkelstein, report that vaccination against pneumococcal pneumonia is associated with a subsequent 63% reduction in risk of developing AD. At first read, this feels like a radical idea, way too good to be true. As there are currently no effective pharmaceutical treatments for AD, the possibility that these findings are valid needs to be considered.  

Given the growing apprehension by the public in recent years regarding the safety of vaccinations, we might be tempted to ignore Huo and Finkelstein’s findings if it were not for the prior studies that have reported similar findings.

Actually, these current results do not come as a surprise; there has been a steady progression of published studies reporting similar significant associations between vaccination and reduced AD risk. As Avram Buhkbinder wrote in a 2023 review, “A growing literature supports a protective association between vaccines targeting an array of pathogens (eg, influenza, pneumococcus, herpes zoster [HZ]) and the risk of Alzheimer disease (AD).”1

Given the burden that AD places on individuals, their families, and communities, we are obligated to examine any avenue that might provide relief.

AD is a chronic disease of neurodegeneration characterized by cognitive decline and dementia. In recent years, this disease has become a growing concern worldwide as populations in many countries get older and incidence increases. Afflicted individuals become incapacitated, unable to provide for themselves or their families, and physically and financially dependent on others. It is not just the emotional suffering caused but also the financial burden that is to be reckoned with. 

In 2015 an estimated 50 million people suffered from AD worldwide, and it was projected that nearly 75 million would be affected by 2050.2 In the United States in 2007, approximately 5.4 million Americans were affected by AD. American women over 65 are more likely to be diagnosed.3 By 2022 the number of Americans with AD had crept up to 6.5 million. This number is projected to reach 13.8 million by 2060.”4 According to the Alzheimer's Association, “Deaths from Alzheimer’s have more than doubled between 2000 and 2019, while those from heart disease—the leading cause of death—have decreased.”5

The earliest study to come to my attention suggesting that vaccination might provide protection was published in November 2001 by René Verreault et al. They had analyzed data from 4,392 subjects participating in the Canadian Study of Health and Aging, a prospective cohort study on dementia. Five years after the study started, 3,682 participants were cognitively unimpaired and 183 were newly diagnosed with AD. Past exposure to vaccines against diphtheria or tetanus, poliomyelitis, and influenza was associated with lower risk for AD (diphtheria or tetanus OR=0.41; 95% CI, 0.27–0.62; OR=0.60, 95% CI, 0.37–0.99; and influenza OR=0.75, 95% CI, 0.54–1.04, respectively) compared to no exposure.6

Verreault noted that not knowing what causes AD made interpreting their findings more complicated. One hypothesis was “that conventional infectious agents, in conjunction with changes in the immune system, play a role.” Viral and bacterial infections were already thought to be possible contributing factors. The list of infectious diseases associated with increased risk of or speed of cognitive decline include influenza, pneumonia, herpes, periodontitis, urinary tract infections, gastrointestinal infections, sepsis, and Covid-19.7-12 It made sense then that preventing or decreasing microbe-caused inflammation could delay or reduce the risk of AD or other neurodegenerative diseases and that vaccines did trigger immune reactivity.

Two Taiwanese studies published more than a decade later documented vaccine effects on patients with specific illnesses. The first, published in 2016, from Ju-Chi Liu et al, examined the risks of developing chronic kidney disease (CKD), a disease associated with elevated risk of dementia. Taiwan has the highest rate of CKD in the world. Investigators used data from the national health database to seek out information from all the people in the country diagnosed with CKD between 2000 and 2007 (N=32,844). For 11,943 patients with CKD, investigators compared 5,745 (48%) who had received influenza vaccination with the remaining 6,198 (52%) who had not. The adjusted hazard ratio (aHR) for dementia in vaccinated patients compared with unvaccinated in all seasons was 0.64 (P<0.0001). Risk was even lower if the vaccine was received off-season.3 

A second Taiwanese study reporting protective effect after influenza vaccine, published in 2020, tracked patients diagnosed with chronic obstructive pulmonary disease (COPD). These patients are particularly vulnerable to influenza infection.14 This was also a nationwide retrospective cohort study of older patients (≥60 years, N=19, 848). The patients were followed from 2001 to 2012. These patients were divided into 4 groups based on how many influenza vaccinations they received. Only 45% were vaccinated. The aHR of dementia was 0.68 (95% CI, 0.62–0.74, P<0.001) comparing vaccinated with unvaccinated patients. Risk of dementia decreased with the increasing number of vaccinations received. For patients who received 2 to 3 vaccinations, the aHR was 0.81 (95% CI, 0.73–0.90), and for those who received 4 vaccinations, the aHR decreased to 0.44 (95% CI, 0.40–0.50).15

In 2022 a group of international researchers led by Nicola Veronese published a large meta-analysis of earlier studies. Their aggregated sample size, garnered from 5 large, high-quality studies, included 292,157 patients (mean age=75.5 ± 7.4 years; 46.8% females), and they found that influenza vaccine was significantly associated with lower dementia risk. After adjustment for potential confounders, relative risk was 0.71 (CI, 0.60–0.94).16

A larger and rather compelling study led by Avram Bukhbinder and published in 2022 is what some call “the landmark study,” and it included almost 1 million participants. Bukhbinder reported a relative risk of AD with vaccination of 0.60 (95% CI, 0.59–0.61) and an attributable relative risk of 0.034 (95% CI, 0.033–0.035) of AD following influenza vaccination, in a nationwide sample of American adults aged 65 years and above.

A study by Antonios Douros et al from May 2023 requires special mention, as their results provide the rare dissenting finding to this series of studies reporting positive results.

Bukhbinder’s group obtained data for their analysis from a company called Optum® Clinformatics® Data Mart (CDM). The company provides anonymous data gleaned from medical, pharmacy, and administrative insurance claims, along with laboratory result data. The CDM data used for this study covered 2009 through 2019. From this data, propensity score matching produced a sample of 935,887 flu-vaccinated vs unvaccinated matched pairs (average age 74 years, 57% female, with a median follow-up of 46 months). Of the flu-vaccinated patients, 5.1% (n = 47,889) developed AD during follow-up, while 8.5% (n = 79,630) of the flu-unvaccinated patients did. The RR was 0.60 (95% CI, 0.59–0.61), and absolute risk reduction (ARR) was 0.034 (95% CI, 0.033–0.035), corresponding to a number needed to treat of 29.4.17

Another study of interest was led by Kathleen Harris and published in September 2023. It also used propensity score matching to create a virtual cohort of matched patients who either did or did not receive vaccinations. In this study, instead of focusing on influenza vaccination, the researchers examined the data for impact of other vaccines, specifically vaccines against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster; or pneumococcus.

These vaccinations also turned out to be associated with reduced risk of AD.

People who received the Tdap/Td vaccine had an RR of 0.70 of AD compared to those not vaccinated (95% CI, 0.68–0.72). People vaccinated against herpes zoster had an RR of 0.75 (95% CI, 0.73–0.76) compared to the unvaccinated. The pneumococcal vaccine was also helpful (RR 0.73 [95% CI, 0.71–0.74].18

A study by Antonios Douros et al from May 2023 requires special mention, as their results provide the rare dissenting finding to this series of studies reporting positive results. This group of researchers utilized a population-based cohort of dementia-free individuals aged ≥50 years in the United Kingdom’s Clinical Practice Research Datalink between 1988 and 2018. Using a nested case-control approach, they matched each patient with dementia with 4 controls. Conditional logistic regression yielded confounder-adjusted odds ratios with 95% confidence intervals of dementia associated with common vaccines more than 2 years before the index date compared with no exposure during the study period. Surprisingly, their results suggest that common vaccines were associated with an increased risk of dementia compared with no exposure (OR, 1.38 [95% CI, 1.36–1.40]). Salmon et al comment, “Counter to the hypothesized protective effect of vaccines on dementia, Douros et al., found that exposure to common vaccines was associated with an increased risk of dementia (odds ratio [OR], 1.38 [95% confidence interval (CI), 1.36–1.40]) that was driven mainly by immunizations for influenza (1.39 [1.37–1.41]) and pneumococcal disease (1.12 [1.11–1.13]). Other routine immunizations were either not associated with dementia (tetanus and pertussis vaccines) or associated with a small decrease in the risk of dementia (shingles and diphtheria vaccines), with ORs slightly less than 1.”19

These results were so unexpected and unexplained that even the study authors sought to find an excuse for their results, writing, “Unmeasured confounding and detection bias likely accounted for the observed increased risk.”20 

The discrepancies in Douros and colleagues’ findings may have resulted from study design. Detailed analysis of possible sources of error have appeared in several publications,19 and these may account for the outcome. “As the authors and editorialists point out, unmeasured and confounding detection biases probably account for these results; for example, people with dementia may be more likely to be vaccinated due to caregivers’ concerns or because of residence in skilled nursing facilities,” writes Neil Sampel reviewing the Douros study.21

“Regardless of the specific study design, however, no observational study can eliminate the risk of confounding due to unmeasured characteristics,” Bukhbinder et al further comment.17

If there are confounders that exist to this degree, it suggests there are aspects to this relationship between vaccines and neurodegeneration of which we may be unaware.

A recent paper from September 2023 by Harris, Ling, Bukhbinder et al reminds us that it might not be the influenza vaccines in particular that bestow benefit but perhaps the general process of immunization that confers protection.

This was also a retrospective cohort study using Optum’s Clinformatics® Data Mart that calculated risks for developing AD among older adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster; or pneumococcus.

For the Tdap/Td vaccine, 7.2% (n= 8,370) of vaccinated patients and 10.2% (n = 11,857) of unvaccinated patients developed AD during follow-up; the RR was 0.70 (95% CI, 0.68–0.72). For the HZ vaccine, 8.1% (n = 16,106) of vaccinated patients and 10.7% (n = 21,417) of unvaccinated patients developed AD during follow-up; the RR was 0.75 (95% CI, 0.73–0.76). For the pneumococcal vaccine, 7.92% (n = 20,583) of vaccinated patients and 10.9% (n = 28,558) of unvaccinated patients developed AD during follow-up; the RR was 0.73 (95% CI, 0.71–0.74).18

A review paper by Bukhbinder et al, from August 2023, provides an excellent summary of the studies up until then and tackles the question as to how vaccination may provide such protection against AD.17 This paper mentions studies that examined the effect of bacillus Calmette-Guérin (BCG) vaccination on mice with AD-like pathology but not yet symptomatic, and suggest BCG vaccination accounts for numerous protective changes in their cerebral chemistry. While an attempt will not be made here to summarize the many possible mechanisms put forward to explain the vaccine effects, suffice to say, there are plausible explanations.

The paper also raises the question of whether the benefits observed in these mentioned studies might be the result of what is called “the healthy vaccinee bias.” This is the simple notion that people who follow healthier lifestyles associated with lower risk of dementia (eg, frequent exercise) are also more likely to get the routine vaccines suggested by their doctors. It is likely that doctors are more persistent at recommending vaccines to patients with other chronic diseases such as diabetes or hypertension, conditions associated with increased risk of AD. These recent studies that use insurance data to mine data may pose an unforeseen problem. To comply with HIPAA (Health Insurance Portability and Accountability Act) rules that data is made anonymous, not just the identity but many of the behavioral patterns and social behaviors are lost to analysis.

The authors suggest that this concern may be allayed shortly by a soon-to-be published study they are conducting in which they compare high-dose vaccines to standard doses and find that the former appear to have a greater impact on reducing AD. Such a dose response would discredit the healthy vaccinee bias.17

An excellent 2-part review on the history of vaccination and dementia by Chares Greenblatt and Richard Lathe was published in early 2024. They bring particular attention to the effects of BCG and point out its possible impact on AD, stating: “Five studies to date have determined that intravesical BCG administration, the standard of care for bladder cancer, is followed by a mean ~45% reduction in subsequent AD development in these patients.”22,23

While vaccinations may lower risk of AD, we should not confuse the issue and think of them as vaccinations against AD. As Greenblatt and Lathe point out: “protection is generally incomplete, and, as a rule of thumb only, rates of prevention/protection are often in the broad range of 10–50%, to be compared against COVID vaccines that protect against severe SARS-CoV-19 infection at ∼90%, diphtheria vaccine confers 97% protection, and tetanus vaccine is virtually 100% effective against tetanus.”23

So vaccination is not a perfect solution, but Greenblatt and Lathe remind us: “Even so, for diseases such as AD where we have no effective treatment, a success rate of even 10% would be a remarkable achievement and would undoubtedly outperform the marginal benefits obtained with other anti-AD therapeutics.”23

There are questions we would love answers to but which may prove hard to obtain. This is because setting up randomized clinical trials to solve them will be unethical. We cannot in good conscience randomize a trial in which we withhold a medically indicated therapy to half the participants enrolled, a therapy that is now suspected to reduce by half the threat of a serious disease; a therapy that is currently already recommended for disease prevention, just not the disease we are curious about. Thus, we must continue to rely on retrospective studies in which participants self-select whether to receive vaccination.

Is one vaccine better at AD prevention than another, or might they all have about the same degree of benefit? Would a variety of different vaccines over the years increase or decrease benefit?

When patients used to ask for my opinion about vaccinations, I often gave them the wrong answer, asking them in return, “Which would you rather have: this specific disease or the shot?” Perhaps the real question that we should be asking them now is whether they want AD or not. These recent findings may change how we weigh the pros and cons of vaccination.

Categorized Under

Jacob Schor

ND, FABNO

Jacob Schor, ND, FABNO, is a graduate of National College of Naturopathic Medicine (since renamed National University of Naturopathic Medicine), Portland, Oregon, and recently retired from his practice in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is a past member of the board of directors of the Oncology Association of Naturopathic Physicians and American Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician's Journal. In 2008, Dr Schor was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the past Abstracts & Commentary editor.

References

  1. Bukhbinder AS, Ling Y, Harris K, Jiang X, Schulz PE. Do vaccinations influence the development of Alzheimer disease? Hum Vaccin Immunother. 2023;19(2):2216625.
  2. M Prince, A Wimo, M Guerchet, GC Ali, YT Wu, M Prina. The global impact of dementia: an analysis of prevalence, incidence, cost and trends. World Alzheimer Report 2015 webpage. https://unilim.hal.science/hal-03495438/document. Accessed March 29, 2024.
  3. Rabins PV, Blacker D, Rovner BW, et al. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. Second edition. Am J Psychiatr. 2007;164(12 Suppl):5-56.
  4. Alzheimer’s Association. 2022 Alzheimer’s disease facts and figures. Alzheimer’s Association website. https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.12638. Accessed March 29, 2024.
  5. Alzheimer’s Association. Facts and figures. Alzheimer’s Association website. https://www.alz.org/alzheimers-dementia/facts-figures. Accessed March 9, 2024. 
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  7. Bornand D, Toovey S, Jick SS, Meier CR. The risk of new onset depression in association with influenza—a population-based observational study. Brain Behav Immun. 2016;53:131-137.
  8. Scherrer JF, Salas J, Wiemken TL, Hoft DF, Jacobs C, Morley JE. Impact of herpes zoster vaccination on incident dementia: a retrospective study in two patient cohorts. PLoS One. 2021;16:e0257405.
  9. Ou YN, Zhu JX, Hou XH, et al. Associations of infectious agents with Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2020;75:299-309.
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  11. Fink A, Doblhammer G, Tamguney G. Recurring gastrointestinal infections increase the risk of dementia. J Alzheimers Dis. 2021;84:797-806.
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  13. Liu JC, Hsu YP, Kao PF, et al. Influenza vaccination reduces dementia risk in chronic kidney disease patients: a population-based cohort study. Medicine (Baltimore). 2016;95(9):e2868.
  14. Mallia P, Johnston SL. Influenza infection and COPD. Int J Chron Obstruct Pulmon Dis. 2007;2(1):55-64.
  15. Luo CS, Chi CC, Fang YA, Liu JC, Lee KY. Influenza vaccination reduces dementia in patients with chronic obstructive pulmonary disease: a nationwide cohort study. J Investig Med. 2020;68(4):838-845.
  16. Veronese N, Demurtas J, Smith L, et al. Influenza vaccination reduces dementia risk: a systematic review and meta-analysis. Ageing Res Rev. 2022;73:101534.
  17. Bukhbinder AS, Ling Y, Hasan O, et al. Risk of Alzheimer’s disease following influenza vaccination: a claims-based cohort study using propensity score matching. J Alzheimers Dis. 2022;88(3):1061-1074.
  18. Harris K, Ling Y, Bukhbinder AS, et al. 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. J Alzheimers Dis. 2023;95(2):703-718.
  19. Salmon DA, Black S, Didierlaurent AM, Moulton LH. Commentary on “Common vaccines and the risk of dementia: a population-based cohort study”: science can be messy but eventually leads to truths. J Infect Dis. 2023;227(11):1224-1226.
  20. Douros A, Ante Z, Suissa S, Brassard P. Common vaccines and the risk of incident dementia: a population-based cohort study. J Infect Dis. 2023;227(11):1227-1236.
  21. Ampel NM. Do vaccines raise or lower risk for dementia? the jury remains out. NEJM Journal Watch website. https://www.jwatch.org/na55692/2023/01/09/do-vaccines-raise-or-lower-risk-dementia-jury-remains-out. Accessed March 29, 2024.
  22. Greenblatt CL, Lathe R. Vaccines and dementia: part I. non-specific immune boosting with BCG: history, ligands, and receptors. J Alzheimers Dis. 2024;98(2):343-360.
  23. Greenblatt CL, Lathe R. Vaccines and dementia: part II. efficacy of BCG and other vaccines against dementia. J Alzheimers Dis. 2024;98(2):361-372.

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