Controversy Continues Regarding PPI Use and Dementia

Q&A

Dr Goldstein is Professor in the department of neurology at Emory University School of Medicine.

Following last year’s study in JAMA Neurology, which linked proton pump inhibitors (PPIs) with cognitive decline and dementia, patients and clinicians grew concerned about the popular medications that treat heartburn, gastroesophageal reflux disease, and peptic ulcers-to no surprise. It is estimated that globally about 35 million people have dementia, and this number is expected to more than double in the next 20 years. This staggering number of affected people will have a huge impact on both a societal and personal level. The only alternative seems to be prevention.

PPIs are very effective in treating gastric-acid related disorders, so many question whether stopping use of PPIs is this the best course of action. Critics argue that the study was flawed, because it did not adjust for enough confounders. Others agree that more research is needed before making grand changes in patient care. Meanwhile, new research contradicts previous results. So how should clinicians counsel their patients?

Neurology Times invited esteemed neuropsychiatrist and dementia expert Felicia C Goldstein, PhD, to share an update on PPIs and dementia. Her latest research may have clinicians further questioning this link and resulting clinical implications.

Neurology Times (NT): What does current research show about the association between PPI use and dementia?

Dr. Goldstein: There is controversy concerning whether PPI use is associated with an increased risk of dementia. Two studies conducted in Germany in persons 75 years and older found that PPI use increased the risk of dementia and Alzheimer disease (AD).

In a multicenter German Study of Aging, Cognition, and Dementia in Primary Care Patients Haenisch and colleagues¹ enrolled 3076 persons who underwent a brief cognitive screening battery and were judged to be dementia free at baseline. Compared with non-PPI users, the researchers found an increased risk of both dementia and specifically Alzheimer disease over a follow-up period of 6 years.

Another investigation by the same group² examined the claims data diagnoses of 73,679 persons aged 75 years and older. The risk of incident dementia was greater in persons taking PPI medications.

More recently, however, conflicting findings were reported by Booker and colleagues³ who reviewed medical record information from a database in Germany of patients aged 70 to 90 years with or without a diagnosis of dementia. PPI use was associated with a decreased risk of incident dementia.

Against this background of conflicting findings concerning whether PPI use is a risk factor for dementia, my colleagues and I addressed this question in persons enrolled in the National Alzheimer Coordinating Center database consisting of 33 nationwide NIH-NIA supported Alzheimer Disease Centers.⁴ We evaluated the association between PPI use and the annual conversion (follow-up of 2 to 6 years) of persons with normal cognition at baseline into mild cognitive impairment (MCI) or dementia, or the annual conversion of persons with MCI at baseline into dementia. All analyses controlled for demographics (age, race, gender, education), vascular comorbidities (self-reported hypertension, diabetes, heart disease, transient ischemic attack/stroke), mood (depression), and anticholinergic and histamine-2 receptor antagonist use.

Of 10,486 eligible participants, 884 (8.4%) reported always using PPIs, 1925 (18.4%) reported intermittent use, and 7677 (73.2%) reported never using PPIs at any annual follow-up. Continuous (always vs never) PPI use was associated with a decreased risk of decline in cognitive function (HR 0.78, 95% CI 0.66-0.93, P = .005) and a decreased risk of conversion to MCI or dementia due to AD (HR 0.82, 95% CI 0.69-0.98, P = .026). Intermittent use was also associated with decreased risk of decline in cognitive function (HR 0.84, 95% CI 0.76-0.93, P = .001), and risk of conversion to MCI or dementia due to AD (HR 0.82, 95% CI 0.74-0.91, P = .001). This reduced risk was found for persons with either normal cognition or MCI.

NT: What was different about this new study and what were its limitations?

Dr. Goldstein: We believe there are strengths as well as limitations of our study over earlier research. In terms of strengths, unlike the previous samples, our participants received a comprehensive neuropsychological battery of measures, and their cognitive status was diagnosed by a team of experienced clinicians at academic medical centers. We also had a broader age range of participants who were aged 50 years and older as opposed to being in their 70s. This allowed us to examine whether there were differential associations between PPI use and age in younger participants compared with those aged older than 75 years.

In a subgroup analysis, we did not observe a detrimental impact of PPI use in the oldest-old. Importantly, we controlled for histamine-2 receptor medications that are used to treat gastric-acid related disorders and have been found in one study to be associated with an increased risk for cognitive impairment.⁵

Despite these strengths, however, limitations in our research also exist. Dispensing data concerning dosage and schedule of PPI use were not available in the database, nor were they reported in other studies. Another limitation in our study concerns the reliance on self-report, which could have led to misclassification bias due to persons forgetting about medications. All studies, including ours, lacked information on compliance with PPIs.

NT: What would be the ideal follow-up study to address these issues and help further clarify the link between PPIs and dementia?

Dr. Goldstein: A randomized, prospective clinical trial is necessary before firm conclusions can be made regarding the effects of PPIs on cognition. Ideally, such a study would include the collection of cerebrospinal fluid biomarkers for Alzheimer disease since increased beta amyloid levels have been observed in an amyloid cell model and in mice after PPI treatment.⁶

NT: In the meantime, how should neurologists counsel patients about PPI use? Are some PPIs “safer” than others?

Dr. Goldstein: There is, of course, a quality of life issue, in that PPIs are used to treat the extreme discomfort associated with gastric-acid related disorders. Given the fact that the jury is still out on PPI use and the risk for incident cognitive impairment and dementia, patients need to weigh the benefits of these medications against the largely unknown future risks. As with all medications, patients and their significant others should be alert for adverse effects and use these medications on an as-needed basis.

References:

1. Haenisch B, von Holt K, Wiese B, et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eu Arch Psychiatry Clin Neurosci. 2015;265:419-428.

2. Gomm W, Von Holt K, Thome F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73:410-416.

3. Booker A, Jacob LE, Rapp M, et al. Risk factors for dementia diagnosis in German primary care practices. Int Psychogeriatr. 2016;28:1059-1065.

4. Goldstein FC, Steenland K, Zhao L, et al. Proton pump inhibitors and risk of mild cognitive impairment and dementia. J Am Geriatr Soc. June 7, 2017; Epub ahead of print.

5. Boustani M, Hall KS, Lane KA, et al. The association between cognition and histamine-2 receptor antagonists in African Americans. J Am Geriatr Soc. 2007;55:1248-1253.

6. Badiola N, Alcalde V, Pujol A, et al. The proton-pump inhibitor lansoprazole enhances amyloid beta production. PLoS One. 2013;8:e58837.