Proton Pump Inhibitors and Risk of Mild Cognitive Impairment and Dementia

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d4455208e170">Background/Objective</h5> <p id="P1">Controversy exists over whether proton pump inhibitors (PPIs) increase risk for dementia. This study examined the risk associated with PPIs on conversion to mild cognitive impairment (MCI), dementia, and specifically Alzheimer’s disease (AD). </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d4455208e175">Design</h5> <p id="P2">Observational, longitudinal study.</p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d4455208e180">Setting</h5> <p id="P3">Tertiary academic Alzheimer Disease research centers funded by the National Institute on Aging. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d4455208e185">Participants</h5> <p id="P4">Research volunteers ≥ 50 years old with 2 to 6 annual visits. Eight hundred and eighty four were taking PPIs at every visit, 1,925 took PPIs intermittently, whereas 7,677 never reported taking PPIs. All had baseline normal cognition or MCI. </p> </div><div class="section"> <a class="named-anchor" id="S5">  </a> <h5 class="section-title" id="d4455208e190">Analytic Plan</h5> <p id="P5">Multivariable Cox regression analyses evaluated the association between PPI use and annual conversion of baseline normal cognition into MCI or dementia, or annual conversion of baseline MCI into dementia, controlling for demographics, vascular comorbidities, mood, and anticholinergics and histamine-2 receptor antagonists. </p> </div><div class="section"> <a class="named-anchor" id="S6">  </a> <h5 class="section-title" id="d4455208e195">Results</h5> <p id="P6">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 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. </p> </div><div class="section"> <a class="named-anchor" id="S7">  </a> <h5 class="section-title" id="d4455208e200">Conclusion</h5> <p id="P7">PPIs were not associated with greater risk of dementia or of AD, in contrast to recent reports. Study limitations include reliance on self-reported PPI use and the lack of dispensing data. Prospective studies are needed to confirm these results in order to guide empirically based clinical treatment recommendations. </p> </div>

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The Alzheimer's Disease Centers' Uniform Data Set (UDS): the neuropsychologic test battery.

Sandra Weintraub, David Salmon, Nathaniel Mercaldo … (2009)

The neuropsychologic test battery from the Uniform Data Set (UDS) of the Alzheimer's Disease Centers (ADC) program of the National Institute on Aging consists of brief measures of attention, processing speed, executive function, episodic memory, and language. This paper describes development of the battery and preliminary data from the initial UDS evaluation of 3268 clinically cognitively normal men and women collected over the first 24 months of utilization. The subjects represent a sample of community-dwelling, individuals who volunteer for studies of cognitive aging. Subjects were considered "clinically cognitively normal" based on clinical assessment, including the Clinical Dementia Rating scale and the Functional Assessment Questionnaire. The results demonstrate performance on tests sensitive to cognitive aging and to the early stages of Alzheimer disease in a relatively well-educated sample. Regression models investigating the impact of age, education, and sex on test scores indicate that these variables will need to be incorporated in subsequent normative studies. Future plans include: (1) determining the psychometric properties of the battery; (2) establishing normative data, including norms for different ethnic minority groups; and (3) conducting longitudinal studies on cognitively normal subjects, individuals with mild cognitive impairment, and individuals with Alzheimer disease and other forms of dementia.

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Long-term anticholinergic use and the aging brain.

Babar Khan, Kathleen Callahan, Dwayne Campbell … (2013)

Older Americans are facing an epidemic of chronic diseases and are thus exposed to anticholinergics (ACs) that might negatively affect their risk of developing mild cognitive impairment (MCI) or dementia. To investigate the association between impairment in cognitive function and previous AC exposure. A retrospective cohort study. Primary care clinics in Indianapolis, Indiana. A total of 3690 older adults who have undergone cognitive assessment and had a 1-year medication-dispensing record. Cognitive function was measured in two sequential steps: a two-step screening process followed by a formal diagnostic process for participants with positive screening results. Three patterns of AC exposure were defined by the duration of AC exposure, the number of AC medications dispensed at the same time, and the severity of AC effects as determined by the Anticholinergic Cognitive Burden list. Compared with older adults with no AC exposure and after adjusting for age, race, gender, and underlying comorbidity, the odds ratio for having a diagnosis of MCI was 2.73 (95% confidence interval, 1.27-5.87) among older adults who were exposed to at least three possible ACs for at least 90 days; the odds ratio for having dementia was 0.43 (95% confidence interval, 0.10-1.81). Exposure to medications with severe AC cognitive burden may be a risk factor for developing MCI. Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

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The Proton-Pump Inhibitor Lansoprazole Enhances Amyloid Beta Production

Nahuai Badiola, Víctor Alcalde, Albert Pujol … (2013)

A key event in the pathogenesis of Alzheimer’s disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.