23 March 2021
A forthcoming article in the Journal of Alzheimer’s Disease reported that having a burden of infectious disease was associated with a small increase in the risk of Alzheimer’s disease (AD) (OR, 1.05; 95% CI, 1.02 to 1.08) [1]. They found significantly increased associations for bacterial infections but not viral infections. A reasonable question is whether the associations are caused by the infection or are, perhaps, related to an underlying factor that is a risk for both the infections and AD. The underlying factor considered here is vitamin D status.
The evidence that risk of infections by the bacteria considered in that article are reduced by either vitamin D supplementation or higher 25-hydroxyvitamin D [25(OH)D] concentration are given in Table 1.
Table 1. Findings regarding vitamin D for bacterial diseases related to risk of AD.
| Infectious disease | Adjusted OR* | Observational study | Clinical trial | Mendelian randomization |
|---|---|---|---|---|
| Lyme disease | 1.26 (0.74 to 2.15) | none | none | none |
| Pneumonia | 1.11 (1.05 to 1.16) | [2], [3] | [2] | |
| Gingivitis | 1.11 (1.02 to 1.20) | [4] | ||
| Urinary tract infections | 1.08 (1.06 to 1.10) | [5] | ||
| Gastritis | 1.06 (1.02 to 1.09) | [6] |
*from [1]
There is also evidence that viral infections can also increase the risk of AD. A recent meta-analysis of individual participant data from randomized controlled trials found that vitamin D supplementation significantly reduced risk of acute respiratory tract infections, especially if baseline 25(OH)D concentration was
There is good evidence that higher vitamin D status reduces risk of AD from observational studies [10] and a Mendelian randomization study of alleles that affect 25(OH)D concentrations [11]. Thus, since there is reasonable evidence that vitamin D reduces risk of four of the bacteria associated with increased risk of AD as well as AD itself, finding an association between infections and AD is a necessary but not sufficient condition for a causal relationship.
To establish a causal relationship, one way would be to identify direct evidence that an infection affects the brain. For example, the bacterium associated with Lyme disease, Borrelia burgdorferi, was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls [12].
A recent feature in Nature outlined how researchers are studying how gut bacteria alter the brain [13]. The mechanisms could involve bacterial clumping and/or misfolded proteins as well as bacterial metabolites. A pioneer of such studies is Robert Friedland. His latest review is from 2020 [14].
Whether bacterial and viral diseases are causal risk factors for AD is probably less important than how risk of AD from bacterial and viral infections can be reduced. Based on the information in this letter, one approach seems to be to increase serum 25(OH)D concentrations to above 50 ng/mL, which can be achieved by supplementation with 5000 to 8000 IU/d [15].
William B. Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center
San Francisco, CA, USA
wbgrant@infionline.net
@wbgrant2
ORCID 0000-0002-1439-3285
Disclosure: I receive funding from Bio-Tech Pharamacal, Inc. (Fayetteville, AR).
REFERENCES
[1] Douros A, Santella C, Dell'Aniello S, Azoulay L, Renous C, Suissa S, Brassard P (2021) Infectious disease burden and the risk of Alzheimer’s disease: A population-based study. J Alzheimers Dis, doi: 10.3233/JAD-201534.
[2] Colak Y, Nordestgaard BG, Afzal S (2020) Low vitamin D and risk of bacterial pneumonias: Mendelian randomisation studies in two population-based cohorts. Thorax, doi: 10.1136/thoraxjnl-2020-215288.
[3] Lu D, Zhang J, Ma C, Yue Y, Zou Z, Yu C, Yin F (2018) Link between community-acquired pneumonia and vitamin D levels in older patients. Z Gerontol Geriatr 51, 435-439.
[4] Zhou X, Zhang P, Wang Q, Xia S, Ji N, Ding Y, Wang Q (2018) 25-Hydroxyvitamin D3 alleviates experimental periodontitis via promoting expression of cathelicidin in mice with type 2 diabetic mellitus. J Nutr Sci Vitaminol (Tokyo) 64, 307-315.
[5] Ali SB, Perdawood D, Abdulrahman R, Al Farraj DA, Alkubaisi NA (2020) Vitamin D deficiency as a risk factor for urinary tract infection in women at reproductive age. Saudi J Biol Sci 27, 2942-2947.
[6] El Shahawy MS, Hemida MH, El Metwaly I, Shady ZM (2018) The effect of vitamin D deficiency on eradication rates of Helicobacter pylori infection. JGH Open 2, 270-275.
[7] Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Janssens W, Jensen ME, Kerley CP, Laaksi I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S, Stelmach I, Trilok Kumar G, Urashima M, Camargo CA, Griffiths CJ, Hooper RL (2019) Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol Assess 23, 1-44.
[8] Dolatshahi M, Sabahi M, Aarabi MH (2021) Pathophysiological clues to how the emergent SARS-CoV-2 can potentially increase the susceptibility to neurodegeneration. Mol Neurobiol, doi: 10.1007/s12035-020-02236-2.
[9] Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF (2020) SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One 15, e0239252.
[10] Littlejohns TJ, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PH, Fried L, Kestenbaum BR, Kuller LH, Langa KM, Lopez OL, Kos K, Soni M, Llewellyn DJ (2014) Vitamin D and the risk of dementia and Alzheimer disease. Neurology 83, 920-928.
[11] Larsson SC, Traylor M, Markus HS, Michaelsson K (2018) Serum parathyroid hormone, 25-hydroxyvitamin D, and risk of Alzheimer's disease: a Mendelian randomization study. Nutrients 10, 1243.
[12] Miklossy J (2011) Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med 13, e30.
[13] Willyard C (2021) How gut microbes could drive brain disorders.Nature 590, 22-25.
[14] Friedland RP, McMillan JD, Kurlawala Z (2020) What are the molecular mechanisms by which functional bacterial amyloids influence amyloid beta deposition and neuroinflammation in neurodegenerative disorders? Int J Mol Sci 21, 1652.
[15] Kimball SM, Mirhosseini N, Holick MF (2017) Evaluation of vitamin D3 intakes up to 15,000 international units/day and serum 25-hydroxyvitamin D concentrations up to 300 nmol/L on calcium metabolism in a community setting. Dermatoendocrinology 9, e1300213.
Comments
Response to: The Relationship Between Infections and AD
We thank Dr. Grant for the interest in our study [1] and for the opportunity to clarify several points. Our study observed a small (5%) increase in the risk of Alzheimer’s disease (AD) associated with infectious disease burden, with the risk increasing gradually with longer time since first infection and peaking after 12-30 years (11%). Dr. Grant suggests that the underlying etiology for the observed association could be vitamin D status rather than infectious disease per se, arguing that vitamin D supplementation has been shown to reduce the risk of infection and also the risk of AD. Dr. Grant provides several references in support of the link between vitamin D status and the risk of specific infections, for which our study allegedly found an association with an increased risk of AD in infection-specific analyses. The references include ‘observational studies’, ‘clinical trials’, and ‘Mendelian randomization studies’. Moreover, Dr. Grant groups the infections included in our study based on etiology into ‘viral’ and ‘bacterial’.
First, we must clarify that our study was not designed to assess the potential role of vitamin D in the association between infectious disease burden and the risk of AD. One reason was that we did not have access to patients’ vitamin D levels, which precluded the possibility of vitamin D specific analyses.
Second, and although we are not experts in the field of vitamin D, we would like to mention that a brief review of the provided references does not necessarily support the ‘causal’ language used in Dr. Grant’s letter regarding the potential link between vitamin D status and the risk of AD. For example, the studies listed under “clinical trials” include a preclinical study conducted in diabetic mice (reference 4) and one one-arm intervention study comparing the rates of eradication treatment failure for Helicobacter pylori infection between patients with vitamin D deficiency and those without (reference 6). Of note, the analyses in the latter study were unadjusted, which probably introduced important confounding.
Third, we would like to clarify that the etiology-based classification proposed by Dr. Grant was not part of our study. Indeed, we specifically decided against separate analyses for ‘viral’ and ‘bacterial’ infections during the planning stage of the study, given the difficulty in estimating the causal pathogen for several of the infections of interest (e.g., pneumonia). The reason is that we did not have access to patient’s laboratory data.
Fourth, we must mention that the risk estimates shown by Dr. Grant refer to our infection-specific analyses for the outcome of overall dementia and not for the outcome AD. Of note, our infection-specific analyses on the risk of AD showed a positive association only for gastritis.
Overall, and while the potential role of vitamin D in the association between infection and AD is an interesting hypothesis that could be addressed by future research, our study was not designed to address this issue. Thus, no conclusions can be drawn in this regard.
Antonios Douros, MD, PhD, and Paul Brassard, MD, MSc
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