Drugs that are frequently prescribed for older individuals (and not-so-old individuals) often come with unintended and undesirable side-effects. Cholesterol-lowering statins are a good example of a nearly ubiquitous drug with some potentially alarming consequences (including increased risk for type 2 diabetes). Prescription antacids are another example be they proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs). PPIs are associated with increased risk for kidney disease as well as heart attack and cardiovascular disease. Recent research has found yet another disturbing link with long-term antacid use: increased risk for dementia.
The findings have been mixed on this issue so let’s take a look at some of the relevant studies. In a German study of over 3000 community-dwelling subjects age 75 or older compared to subjects not taking PPIs those taking PPIs had a significantly increased risk for any form of dementia including Alzheimer’s disease. In another much larger study out of Germany (n=73679 individuals age 75 or older) regular use of PPIs was associated with increased risk of developing dementia after adjusting for age sex polypharmacy and comorbidities as potential confounders. Even while acknowledging the need for further research in this area the study authors wrote “The avoidance of PPI medication may prevent the development of dementia.”
Of course these are just associations for now and not definitive causal links. But it’s not difficult to entertain the possibility—possibly even the likelihood—that long-term impairment of nutrient absorption could have adverse effects on cognitive function. Robust stomach acid with the proper pH is a key step in healthy digestion. When this is compromised—as antacid drugs are deliberately intended to do—the liberation of vitamins and minerals from foods is reduced which over the long term may result in nutrient insufficiencies and outright deficiencies. The potential consequences of this run the gamut including increased risk for bone fractures B12 deficiency C. diff infection community acquired pneumonia and deficiencies of critical minerals such as magnesium and iron. Considering the brain’s high requirement for micronutrients for proper structural maintenance of neurons and proper ion gradients it doesn’t seem terribly far-fetched that long term disruption of healthy digestion via years of antacid use could have grave implications for cognitive function.
Even so some studies have failed to find an association between PPI or H2RA use and increased risk for dementia. In a longitudinal observational study of individuals age 50 or older with either normal cognition or mild cognitive impairment (MCI) at baseline both continuous and intermittent use of PPIs were associated with decreased risk for decline in cognition as well as progression from MCI to Alzheimer’s disease.
The most recent study to question the link between long term PPI use and dementia was a prospective cohort of over 3000 non-demented individuals age 65 and older. Participants were screened every 2 years for a mean follow-up of 7.5 years. Out of 3484 participants 827 (23.7%) developed dementia of which 670 (19%) were diagnosed with possible or probable Alzheimer’s. When separated by duration of PPI use the incidence of dementia appeared to increase with longer duration of use:
|Duration of PPI Use||Hazard Ratio||95% Confidence Interval|
|1 year||0.89||0.65 - 1.18|
|3 years||0.99||0.75 - 1.30|
|5 years||1.13||0.82 - 1.56|
The authors concluded “Proton pump inhibitor use was not associated with dementia risk even for people with high cumulative exposure.” However there does appear to be at least a trend toward increased risk for dementia with increased duration of PPI use. And while a mean of 7.5 years of follow-up sounds like a long time it’s possible that in some individuals the unintended effects of these drugs might take even longer to manifest themselves particularly if—as might be the case for slowly occurring micronutrient insufficiencies—it takes a longer period of time for the full impact to be felt. Let’s not forget that many older individuals have been taking PPIs and other types of antacids for far longer than 7.5 years.
A separate study investigating the association between H2RA use and reduced risk for dementia found that H2RAs were not protective against dementia. Compared to no PPI use or light use (1-3 years duration) risks of developing dementia or Alzheimer’s in those in the highest exposure category (greater than 3 years of PPI use >1080 standard daily doses) were as follows:
|Duration/exposure of H2RA Use||Hazard Ratio||95% Confidence Interval|
|Dementia||1.28||0.95 - 1.72|
|Alzheimer’s Disease||1.41||1.00 - 1.97|
So it seems that H2RA use doesn’t confer any protection against developing dementia or Alzheimer’s disease but whether or not these drugs actually increase risk needs further definitive research.
Considering the well-documented risks of long-term antacid use the potential for even a mild contribution to increased risk for dementia suggests that dietary and lifestyle interventions may be warranted before these drugs are prescribed. (And it should be noted that many individuals with signs and symptoms of GERD or excessive stomach acid actually have too little acid and may benefit from HCl supplementation rather than from suppression of what little acid they do produce.) Patients who do find the drugs essential for symptom relief should be evaluated periodically for micronutrient status and cognitive function.