Vaccination Lowers the Risk of Alzheimer’s Disease


Jacob Schor, ND, FABNO

Friday is my hiking day.  I meet up with a local hiking group at a nearby church and we go somewhere together.  New Hampshire’s White Mountains are within easy reach, and there are numerous land trusts and conservation areas in Maine within easy drives for us to explore.  We go out year-round. In the colder months we rely on snowshoes, micro-spikes, and puffy down coats.  Come spring we’ll wear head nets and slather on bug repellent. The consensus is that cold is more tolerable than bugs or summer.  My fellow hikers are an interesting and hardy bunch; I am often left in awe by their past accomplishments and current endurance.  As a 70-year-old, I’m pretty much the youngest member of the group and can usually keep up.  Many are in their 80s and are showing few signs of wear.

The population of Maine has several distinguishing characteristics; one is that we are the oldest population in the country.  Median age in the state is 45.  Florida may be where everyone goes to retire but the population there is younger with a median age of 42.  Living here, I find myself much more aware that many people are experiencing neuro-cognitive decline as they age.  Sometimes it feels like there is an epidemic of Alzheimer’s disease going on.  I suppose this is partly true.

Alzheimer’s disease (AD) is a growing concern as populations in many countries get older and AD incidence increases.  Of course, my sense that AD incidence has increased may simply be that I’m hanging out with older people so more of them are showing symptoms. The data supports my sense.  In 2015 an estimated 50 million people suffered from AD worldwide and it was projected that nearly 75 million would be affected by 2050.1 In the US in 2007, approximately 5.4 million Americans were affected by AD.  American women over 65 are more likely to be diagnosed.2 By 2022 the number of Americans with Alzheimer’s had crept up to 6.5 million. This number is projected to reach 13.8 million by 2060.”3 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.”4

Whatever the case, I find that I’m much more aware of how big a problem this condition is for many people and their families.  This is likely why a series of recent studies have caught and held my attention so closely.  It seems that people who get routine vaccinations against influenza and other diseases have a substantially lower risk of developing Alzheimer’s disease.

Now we naturopathic doctors admittedly have a long history of being suspicious regarding the safety and the efficacy of vaccine therapies against disease.  To describe many of us as “vaccine hesitant” would be an understatement.  Thus, my reading of these new studies and accepting their findings comes with considerable reluctance but given the burden Alzheimer’s brings to so many lives, these new data deserve our careful consideration.

Perhaps the most recent study we should consider is one by Huo and Finkelstein published in January 2024.  They asked whether getting vaccinated against pneumococcal pneumonia altered risk of getting Alzheimer’s disease. Using a sophisticated database, they compared medical records of 14,392 people who received pneumococcal vaccines compared to those who had not.  Their analysis suggests that getting vaccinated lowered risk of developing AD by 63%.  (OR=0.37; 95%CI: 0.33-0.42; P-value < .0001).5

My first reaction on reading this is was that it is too good to be true.  The problem with that conclusion is that this wasn’t the first time such conclusions have been reported. This Huo and Finkelstein report is just one of a series of studies reporting similar outcomes in favor of vaccination.

“A growing literature supports a protective association between vaccines targeting an array of pathogens (e.g., influenza, pneumococcus, herpes zoster) and the risk of Alzheimer disease (AD).” Avram Bukhbinder 20236

The earliest study I’ve found like this is René Verreault et al from November 2001.  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 or influenza was associated with lower risk for Alzheimer’s disease [diphtheria odds ratio (OR) 0.41, tetanus OR 0.60, or influenza OR 0.75], compared to no exposure.7

Verreault hypothesized, “… that conventional infectious agents, in conjunction with changes in the immune system, play a role.” Viral and bacterial infections were already considered possible factors in developing AD.  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 more recently COVID-19.8-13 So, it makes sense then that preventing or decreasing microbe-caused inflammation might delay or reduce risk of Alzheimer’s.  Vaccines obviously lower risk of their targeted infections, but the often-underappreciated fact is they also trigger generalized immune activity and lower risk of infections in general.

Two Taiwanese studies document 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. Data was analyzed from 11,943 patients with CKD of whom 5,745 (48%) received influenza vaccination and the remaining 6,198 (52%) who had not. The adjusted hazard ratio (aHR) for dementia, which decreased 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.14

A second Taiwanese study reporting protective effect after influenza vaccine, published in 2020, had tracked patients diagnosed with chronic obstructive pulmonary disease (COPD).  These patients are particularly vulnerable to influenza infection.15 Also, a nationwide retrospective cohort study of older patients (≥60 years n=19,848), these patients were followed from 2001 to 2012 and were divided into four groups based on how many influenza vaccinations they received. Only 45% were vaccinated. The aHR of dementia was 0.68 comparing vaccinated with unvaccinated patients. Risk of dementia decreased with the increasing number of vaccinations received.  For patients who received 2-3 vaccinations, the aHR was 0.81 and for those received 4 vaccinations, the aHR decreased to 0.44.16

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 five large high-quality studies included 292,157 patients (mean age=75.5 ± 7.4 years; 46.8% females) and found that influenza vaccine was significantly associated with lower dementia risk.  After adjustment for potential confounders, relative risk was 0.71.17

A larger and rather compelling study led by Avram Bukhbinder and published in 2022 included almost 1 million participants. Bukhbinder reported a relative risk of AD with vaccination of 0.60 and an attributable relative risk of 0.034 of Alzheimer’s following influenza vaccination, in a nationwide sample of American adults aged 65 and above.18

A study by Antonios Douros et al from May 2023 requires special mention as their results contradict the rest of these studies reporting positive outcomes.  These researchers utilized a population-based cohort in the United Kingdom’s Clinical Practice Research Datalink. Surprisingly their results suggest that common vaccines were associated with an increased risk of dementia (OR, 1.38), compared with no exposure.19 These results were so unexpected and unexplained that even the study authors sought to find excuses for their results: “Unmeasured confounding and detection bias likely accounted for the observed increased risk.”20 Detailed analysis of possible sources for these errors have appeared in several publications.21 “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.”22

A recent paper from September 2023 by Harris, Ling, Bukhbinder et al, reminds us that it might not be the influenza vaccine in particular that bestows benefit but perhaps the general process of immunization that is responsible.  Their retrospective cohort 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 (HZ); 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.  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.  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 0.73.23

A review paper by Bukhbinder et al., from August 2023 provides an excellent summary of the studies up to that point and tackles the question of mechanisms of action that might explain why vaccination might protect against AD.24 Their paper mentions several studies that examined the effect of Bacillus Calmette-Guérin (BCG) vaccination and suggests BCG is responsible for numerous protective changes in cerebral chemistry.  Though it still feels surprising that vaccines can have this AD side effect, it is certainly plausible.

Bukhbinder’s paper also raises the question of whether the benefits observed in these studies might be the result of “the healthy-vaccinee bias.”  This is the simple notion that people who follow healthier lifestyles that are associated with lower risk of dementia (e.g., frequent exercise, better diet, etc.) are also more likely to get the routine vaccines suggested by their doctors. Bukhbinder suggests this concern will soon be eliminated because their group has a soon to be published study showing that high-dose vaccines are more effective than standard doses.  Evidence of such a dose response would discredit the healthy-vaccinee bias theory.25

An excellent two-part review on the history of vaccination and dementia by Chares Greenblatt and Richard Lathe was just published in January 2024.  These two authors single out the effects of BCG and point out its possible impact on AD: “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.”26,27

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.”  Rather vaccinations act as powerful stimulants to immune function.

Not a perfect solution, but Greenblatt and Lathe remind us that “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.”

We would all love to read more definitive evidence that this protective effect is true.  Normally we would stall adopting a controversial new therapy until there were randomized clinical trials confirming what is still mostly retrospective unrandomized evidence.  The problem is that setting such a trial would raise ethical qualms; we cannot randomly withhold an indicated medical treatment and give a placebo instead.

Given the current weight of evidence in support of these vaccinations for older patients,  for us to advocate against vaccination would require us to supply equally robust evidence to support that position.

References

  1. Prince M, Wimo A, Guerchet M, et al. World Alzheimer report 2015. The global impact of dementia: an analysis of prevalence, incidence, cost and trends. 2015
  2. P.V. Rabins, D. Blacker, B.W. Rovner, T. Rummans, L.S. Schneider, P.N. Tariot, et al., American Psychiatric Association practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. Second edition, Am. J. Psychiatr. 164 (12 Suppl) (2007) 5–56.
  3. ALZHEIMER’S ASSOCIATION REPORT 2022. https://doi.org/10.1002/alz.12638 https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.12638
  4. https://www.alz.org/alzheimers-dementia/facts-figures#:~:text=More%20than%206%20million%20Americans%20of%20all%20ages%20have%20Alzheimer’s,are%20age%2075%20or%20older.  Accessed March 9, 2024.
  5. 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 Jan 25;310:961-965.
  6. Bukhbinder AS, Ling Y, Harris K, Jiang X, Schulz PE. Do vaccinations influence the development of Alzheimer disease? Hum Vaccin Immunother. 2023 Aug 1;19(2):2216625.
  7. Verreault R, Laurin D, Lindsay J, De Serres G. Past exposure to vaccines and subsequent risk of Alzheimer’s disease. CMAJ. 2001 Nov 27;165(11):1495-8. PMID: 11762573; PMCID: PMC81665. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81665/
  8. Bornand D, Toovey S, Jick SS, Meier CR (2016) The risk of new onset depression in association with influenza –a population-based observational study. Brain Behav Immun 53, 131–137.
  9. Scherrer JF, Salas J, Wiemken TL, Hoft DF, Jacobs C, Morley JE (2021) Impact of herpes zoster vaccination on incident dementia: A retrospective study in two patient cohorts. PLoS One 16, e0257405. 
  10. Ou YN, Zhu JX, Hou XH, Shen XN, Xu W, Dong Q, Tan L, Yu JT (2020) Associations of infectious agents with Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis 75, 299–309.
  11. Muzambi R, Bhaskaran K, Smeeth L, Brayne C, Chaturvedi N, Warren-Gash C (2021) Assessment of common infections and incident dementia using UK primary and secondary care data: A historical cohort study. Lancet Healthy Longev 2, e426–e435. 
  12. Fink A, Doblhammer G, Tamguney G (2021) Recurring gastrointestinal infections increase the risk of dementia. J Alzheimers Dis 84, 797–806. 
  13. Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ (2021) 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: A retrospective cohort study using electronic health records. Lancet Psychiatry 8, 416–427. 
  14. 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 Mar;95(9):e2868. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782855/
  15. Mallia P, Johnston SL. Influenza infection and COPD. Int J Chron Obstruct Pulmon Dis. 2007;2(1):55-64.
  16. 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 Apr;68(4):838-845.
  17. Veronese N, Demurtas J, Smith L, Michel JP, Barbagallo M, Bolzetta F, Noale M, Maggi S. Influenza vaccination reduces dementia risk: A systematic review and meta-analysis. Ageing Res Rev. 2022 Jan;73:101534.
  18. 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.
  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 May 29;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 May 29;227(11):1227-1236.
  21. 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 May 29;227(11):1224-1226.
  22. January 9, 2023. Do Vaccines Raise or Lower Risk for Dementia? The Jury Remains Out.Neil M. Ampel, MD, reviewing Douros A et al. J Infect Dis 2022 Dec 21 Salmon DA et al. J Infect Dis 2022 Dec 21
  23. 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
  24. Bukhbinder AS, Ling Y, Harris K, Jiang X, Schulz PE. Do vaccinations influence the development of Alzheimer disease? Hum Vaccin Immunother. 2023 Aug 1;19(2):2216625.
  25. Bukhbinder AS, Ling Y, Harris K, Jiang X, Schulz PE. Do vaccinations influence the development of Alzheimer disease? Hum Vaccin Immunother. 2023 Aug 1;19(2):2216625.
  26. Greenblatt CL, Lathe R. Vaccines and Dementia: Part I. Non-Specific Immune Boosting with BCG: History, Ligands, and Receptors. J Alzheimers Dis. 2024 Feb 20.
  27. Greenblatt CL, Lathe R. Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia. J Alzheimers Dis. 2024 Feb 19.

Published April 20, 2024

About the Author

Jacob Schor, ND, now retired, had a general practice with a focus on naturopathic oncology in Denver, Colorado. He served as Abstract & Commentary Editor for the Natural Medicine Journal for several years (https://www.naturalmedicinejournal.com/) and posts blog articles on natural therapies,  nutrition, and cancer (https://drjacobschor.wordpress.com/). He was a board member of CoAND and past president of OncANP, and is someone who is happier outdoors than inside.