Pharmacoepidemiologic Study of Proton Pump Inhibitors and Alzheimer's Disease Risk - PROJECT SUMMARY Alzheimer’s disease and related dementias (ADRD) are prevalent, devastating, and costly conditions. As awareness increases, more at-risk individuals are actively engaging in strategies to delay disease onset and progression (e.g., adopting a healthier lifestyle) and addressing underlying medical conditions, including carefully managing medications. Concerns about medication use in older adults have grown, particularly regarding the potential link between proton pump inhibitors (PPIs) and dementia risk, as highlighted by a recently conducted survey of physicians and patients. PPIs are essential medications for treating gastroesophageal reflux associated with erosive esophagitis and peptic ulcer disease, as well as for preventing complications such as upper gastrointestinal bleeding. Therefore, the prescription and appropriate use of PPIs are highly significant for public health and patients’ quality of life. Preliminary evidence on biological mechanisms, including vitamin B12 deficiency and elevated amyloid-𝛽 levels in the brains of mice, supports the hypothesis that PPI use may influence cognitive function. In response to concerns expressed by physicians and patients, we aim to conduct a comprehensive investigation utilizing four ongoing studies in the United States. These include population- based cohorts of middle-aged and older adults, a clinical-pathological study incorporating autopsy data, and a randomized clinical trial on nutrition and cognition. Our objective is to better understand the association between PPI use and the risk of ADRD. Additionally, we aim to assess a potential alternative to PPI medications for the treatment of acid-related gastrointestinal disorders, such as histamine-2 receptor antagonists (H2RAs), with a focus on their impact on cognition and ADRD risk. Ultimately, we aim to address the following objectives to provide answers to specific questions relevant to patients and healthcare providers. Aim 1: To investigate the association between PPIs and H2RAs use, cognitive decline, and the risk of ADRD in middle-aged and older adults. If PPIs are associated with an increased risk of ADRD, how does the use of H2RAs compare? Aim 2: To evaluate the role of PPIs and H2RAs in the association between dietary and supplemental intake of vitamin B12 and plasma levels of vitamin B12. If the increased risk of ADRD is linked to the impact of PPIs on vitamin B12 levels, could supplementation with B12 mitigate the risk? Aim 3: To study the association of long-term PPIs and H2RAs use with dementia-related brain pathologies, including postmortem amyloid-𝛽 accumulation. If the mechanism by which PPIs influence ADRD risk involves elevated amyloid-𝛽 levels, should we propose assessing plasma amyloid-𝛽42/40 in individuals requiring long-term PPI use? PPIs are among the most widely dispensed drug classes in the US—with omeprazole alone dispensed more than 50 million times in 2022—and this study will provide evidence that will guide physician and patient decision-making regarding managing acid-related gastrointestinal disorders, particularly in individuals at risk for cognitive impairment.
