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) . 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)||, |||
|Gingivitis||1.11 (1.02 to 1.20)|||
|Urinary tract infections||1.08 (1.06 to 1.10)|||
|Gastritis||1.06 (1.02 to 1.09)|||
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  and a Mendelian randomization study of alleles that affect 25(OH)D concentrations . 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 .
A recent feature in Nature outlined how researchers are studying how gut bacteria alter the brain . 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 .
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 .
William B. Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center
San Francisco, CA, USA
Disclosure: I receive funding from Bio-Tech Pharamacal, Inc. (Fayetteville, AR).
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