Are PPIs Linked With Increased Dementia Risk? The Latest Evidence Says No

David A. Johnson, MD


August 17, 2017

Tracking a Potential Link

Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.

When it comes to caring for patients who need proton pump inhibitors (PPIs), one of the most troubling things they can tell you is that they've stopped taking their medication because they saw the recent news linking their use to dementia. Let's shed some light on the facts surrounding these actual studies and what they show, so that you can give your patients proper guidance on the science rather than the accompanying media noise.

Dementia is a very common problem that we see as our patients age. It's estimated that approximately 36 million people worldwide live with dementia, with that number expected to double by 2030 and triple by 2050.[1]

Drug exposures do represent a concern in this area. We know that benzodiazepines and anticholinergics are linked with cognitive dysfunction and perhaps directly with dementia.[2,3] PPIs have been claimed to have an indirect link with dementia. The scientific hypothesis for this has been driven by animal model data, which suggest that PPIs may inhibit the degradation of amyloid fibrils, in particular, beta-amyloid, with its deposition increased as a result.[4] Human studies indicate that beta-amyloid is a possible marker for increased Alzheimer's disease risk.[5] The link is not quite that clear, however, as there are also data that PPIs may be protective against dementia-type related changes.

There is also some concern that PPIs may inhibit the vacuolar ATPase enzymes on the lysosomes in the microglia, which may decrease the degradation of these beta-amyloid plaques.[6]

The long story told short is that PPIs have been attributed to dementia, particularly Alzheimer's disease. Two German studies—a retrospective claims-based database analysis[7] and a cohort study[8]—have suggested a nominal association, and, I believe, received a disproportionate amount of attention.

New Data Call Link Into Question

What do we tell our patients?

The most recent news is that two studies have just emerged that are very reassuring and, to my mind, largely dismiss this association with cognitive deterioration.

Nurses' Health Study. The first of these studies[9] analyzed data from the Nurses' Health Study, which dates back to 1999 through 2013 and looks at nearly 40,000 nurses who were reevaluated every 2 years. This particular study selected out approximately 14,000 nurses who had a Cogstate assessment of their cognitive function. This is a well-validated instrument that looks at deterioration over time of cognitive function, which correlates with the development of dementia.

After correcting for multiple variables, the authors found that patients using PPIs tended to have worse risk categories: lower socioeconomic status and baseline educational level, and higher BMI, rate of comorbid diseases, diabetes, and other things attributable to vascular disease.

Lo and behold, there was no difference as it relates to the deterioration of cognitive function with PPI exposure, nor was it related to dose or duration. There was some semblance of a statistically relevant correlation between cognitive deterioration and the use of histamine H2-receptor antagonists. However, as this was not the study's primary intent, I caution you to limit your focus here to the PPIs.

Using a well-validated instrument and prospective evaluation over two decades, the Nurses' Health Study suggests that there is no deterioration of cognitive function associated with the PPI use, duration, or dose.

Finnish data. A separate Finnish study[10] was just published in the American Journal of Gastroenterology.

In Finland, there is a unique health data capture system, as everyone participates in the same type of process. When they have any cognitive dysfunction, they're also then straddled into an algorithm that leads to intensive evaluation of the diagnosis. They get a CT or an MRI and then are given a variety of cognitive function assessments before they are labeled as a patient with dementia or Alzheimer's disease, as defined by international standards of cognitive function.

This study had a unique way of looking at PPI exposure. Rather than in claims-based studies where they just see that you were prescribed this medication, in the Finnish study they could actually see if you purchased and picked up these medications. The authors adjusted for a lag latency of effect, which is a potential bias as patients may have been seen more frequently because they were sicker and therefore more likely to have had their symptoms identified. After applying a 3-year lag window between exposure and outcome, they found that there was no significant deterioration as it relates to the Alzheimer's disease and the exposure to PPIs, excluding the windows and the short-term exposure. Once again, there was no evident effect over the dose or duration of exposure.

Advice to Patients

A lot of my patients come in and say that they've stopped taking their PPI because they were concerned. Just today I saw somebody who expressed concern that they were losing their memory.

We now have two extremely well-designed studies that adjusted for stratification risks and used validated instruments to assess true Alzheimer's disease or cognitive dysfunction. The Finnish study in particular looked at over 70,000 patients with Alzheimer's disease. We have not seen any link between PPI exposure, dose, or duration and cognitive decline.

As noted, the animal data that first established this possible link were quite mixed on this to begin with, so the plausibility seems to fall apart rather quickly.

Use this as a window of opportunity to discuss these medications with your patients. I see too many patients take PPIs just because they have taken them forever. This is a chance to ask if they really need them. If they do, then they should take them. It is not about preventing Alzheimer's disease if you stop it, but rather about preventing or treating whatever other comorbid diseases you have as it relates to acid reflux or other acid-related conditions.

Reassuringly, the data are quite strong and support that there is no association between PPIs and the disease of dementia.

I am Dr David Johnson. Thank you again for listening.


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