Table 1.
Studies / publications investigating a potential association between PPI uptake and the incidence and progression of dementia (in chronological order).
| Studies / Publications | Study Design / Data Origin | Country | Study Group Sizes / Characteristics | Types of Dementia / Parameters Investigated | Potential Confounders Considered / Limitations | Conclusions |
|---|---|---|---|---|---|---|
| Haenisch et al. (2015) | Longitudinal, multicenter cohort study in elderly primary care patients (German Study on Aging, Cognition and Dementia in Primary Care Patients, AgeCoDe). | Germany | 3,327 community-dwelling persons aged ≥ 75 years. | AD and non-AD related dementias. | Age, sex, education, ApoE4 allele status, polypharmacy, comorbidities, i.a. depression, diabetes, ischemic heart disease, and stroke. | Patients receiving PPI medication had a significantly increased risk of any dementia. |
| Akter et al. (2015) | Computerized neuropsychological testing using the Cambridge Neuropsychological Test Automated Battery. | Bangladesh | Sixty volunteers of either gender (age range 20-26 years). | Visual memory, executive functions, working memory, planning and strategy development, speed of response, and sustained attention. | Short-term PPI adminstration, limited sample size. | Significant impairment in visual memory, attention, executive function, and working and planning function upon PPI uptake. |
| Gomm et al. (2016) | Prospective cohort study using observational data from 2004 to 2011, derived from the largest German statutory health insurer (Allgemeine Ortskrankenkassen, AOK). | Germany | 73,679 participants, aged ≥ 75 years, free of dementia at baseline. | AD and non-AD related dementias. | Analysis was adjusted for potential confounding factors, including age, sex, comorbidities, and polypharmacy. | Patients receiving regular PPI medication had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication. |
| Wijarnpreecha et al. (2016) | Literature search performed in the MEDLINE and EMBASE database from inception to April 2016. | See related original studies / databases | See related original studies / databases. | See related original studies / databases. | See related original studies / databases. | Increased risk of dementia among PPI users. |
| Booker et al. (2016) | Case-control study including German primary care patients with first diagnosis of dementia (all-cause) during the index period (01/2010-12/2014). | Germany | 11,956 cases (initial diagnosis of dementia, all causes) and the 11,956 controls (without dementia), aged 70-90 years. Participants were matched on the basis of age, sex, type of health insurance, and physician. | AD (Alzheimer's disease (G30)) and related dementias (vascular dementia (F01) and unspecified dementia (F03)). | Diabetes, lipid metabolism, stroke incl. Transient Ischemic Attack (TIA), Parkinson's Disease (PD), intracranial injury, coronary heart disease, Mild Cognitive Impairment (MCI), mental and behavioral disorders due to alcohol use. Related medication was also assessed. | PPIs were associated with a decreased risk of developing dementia. |
| Goldstein et al. (2017) | Observational, longitudinal study, data from National Alzheimer’s Coordinating Center (NACC) database from 33 Alzheimer's Disease Centers from September 2005 through September 2015 (NIH-NIA supported). | USA | 10486 persons aged ≥ 50 years (all had baseline normal cognition (n = 7,404) or MCI (n = 3,082)). | AD | Demographic characteristics, vascular comorbidities, metabolic disorders, mood, polypharmacy, i.a., use of anticholinergics and antihistamines, reliance on self-reported PPI use and lack of dispensing data. | PPIs were not associated with greater risk of dementia or of AD. Continuous or intermittent PPI use was associated with lower risk of decline in cognitive function and lower risk of conversion to MCI or AD. This lower risk was found for persons with normal cognition or MCI. |
| Taipale et al. (2017) | A Finnish nationwide nested case-control study (MEDALZ). Data were derived from a Finnish nationwide health-care register, including Special Reimbursement Register, Prescription Register, Hospital Discharge Register. | Finland | Community- dwelling individuals with newly diagnosed AD during 2005-2011 (n = 70,718), and up to four age-, sex-, and region of residence-matched comparison individuals for each case (n = 282,858) | AD | Cardiovascular diseases (hypertension, coronary artery disease, chronic heart failure, chronic arrhythmias), diabetes, stroke, depression, polypharmacy. | PPI use was not associated with risk of AD with 3-year lag window applied between exposure and outcome. Longer duration of use was not associated with risk of AD. Higher dose use was not associated with an increased risk. In conclusion, no clinically meaningful association between PPI use and risk of AD was detected. The results for longer duration of cumulative use or use with higher doses did not indicate dose-response relationship. |
| Lochhead et al. (2017) | Prospectively collected data on medication use and other potential risk factors from the Nurses' Health Study II (NHS II, based on self-administered computerized neuropsychological test battery). | USA | 13,864 female participants (aged 50–70 years). | Assessment of cognitive function. | Education level, comorbidities (smoking status, alcohol consumption, cardiovascular diseases, metabolic disorders, BMI, etc.), polypharmacy. | The study results do not support the suggestion that PPI use increases dementia risk. |
| Batchelor et al. (2017) | Systematic review (meta-analysis) according to the PRISMA statement (registered on PROSPERO). | See related original studies / databases | Relevant studies were identified in Medline, EMBase, Cochrane Central Register of Controlled Trials (CENTRAL), PSYCinfo, Scopus, Web of Science and ClinicalTrials.gov. Eleven studies were included (with four studies investigating PPI use and dementia and seven studies exploring PPI use and acute cognitive impairment). | AD, non-AD dementias and acute cognitive impairment (see also related original studies / databases). | Familiy history of dementia, hypertension, diabetes, physical exercise, air pollution, intestinal microbiota, aluminium containing medications and medication in general (see also related original studies / databases). | The interpretation of the reported association between PPI treatment and dementia is hampered by methodological aspects and potential bias. The latter require future longitudinal studies. |
| Tai et al. (2017) | Population-based retrospective cohort study using the Taiwan National Health Insurance (NHI) claims database-National Health Insurance Research Database (NHIRD). | Taiwan | Patients initiating PPI therapy between January 2000 and December 2003 without a prior history of dementia. Analysis of data of 15726 participants aged >40 years. PPI users (n = 7,863), non- PPI users (n = 7,863). | AD and non-AD dementias. | Comorbidities included, i.e., diabetes mellitus, hypertension, hyperlipidemia, peripheral vascular disease, ischemic heart disease, depression, and ischemic stroke. Potential confounding drugs included anticoagulants, NSAIDs, antiplatelet agents, antidiabetic agents, antihypertensives, and statins. | An increased risk for dementia was identified among the Asian PPI users. Cumulative PPI use was significantly associated with dementia. |
| Gray et al. (2018) | Prospective population-based cohort study (Kaiser Permanente Washington, an integrated healthcare delivery system in Seattle, Washington). | USA | Individuals aged ≥ 65 years without dementia at study entry (n = 3,484). | AD and non-AD dementias. | Demographic characteristics (age at study entry, sex, years of education), medical history (cardiovascular disorders, metabolic diseases), health behaviors (BMI, smoking behavior, exercise, mood disorders), functional measures and medications. | PPI use was not associated with dementia risk, even for people with high cumulative exposure. |
| Imfeld et al. (2018) | A case-control analysis on the UK-based Clinical Practice Research Datalink (CPRD) through a license from the UK Medicines and Healthcare products Regulatory Agency (MHRA). | UK | 41,029 patients aged ≥ 65 years with newly diagnosed AD, vascular dementia or unspecified dementia between 1998 and 2015. | AD, vascular dementia and unspecified dementia. | Age, sex, calendar time, general practice, and number of years of recorded history were matched between groups. Comorbidities and co-medications at or within the year prior to the index date were considered. Covariates include arterial hypertension, diabetes mellitus, coronary heart disease, atrial fibrillation, stroke, depression, and polypharmacy (i.a., of platelet aggregation inhibitors, anticoagulants, NSAIDs, SSRIs, SNRIs). | Long-term PPI use was not associated with an increased risk of developing AD or VaD. |
| Hwang et al. (2018) | A population-based longitudinal study using the Korean National Health Insurance Corporation claims database merged with national health examination data for 2002-2013. | Republic of Korea | The study cohort included 70,529 individuals who were free of dementia in 2007. Incident dementia was assessed throughout follow-up until 2013. 1,297 participants developed dementia during the study period. | AD and non-AD dementias. | Covariates included pulmonary diseases, renal diseases, liver diseases, metabolic disorders. | PPI use was not associated with an increased risk of dementia. PPI use was not associated with increased risk. |
| Li et al. (2019) | Meta-analysis to determine potential association of PPI use and risk of dementia among older people. | See related original studies / databases | Studies were identified in PubMed, EMBASE, and Cochrane Library databases from inception to February 2018. Cohort studies that had identified a risk of dementia or AD among PPI users compared with non- PPI users were considered. Quality of studies was catagorized via the Newcastle-Ottawa Scale (NOS). Six cohort studies were selected. | See related original studies / databases. | See related original studies / databases. | No significant association between PPI intake and risk of dementia or AD could be detected. |
| Song et al. (2019) | Meta-analysis to investigate the risk of dementia and AD among PPI users. | See related original studies / databases | Relevant studies were identified in PubMed, Web of Science, EMBase and ScienceDirect. Ten independent studies with 642,305 participants were included. | See related original studies / databases. | See related original studies / databases. | PPI intake does not increase the risk of dementia and AD. |
| Torres-Bondia et al. (2020) | A community-based retrospective cohort study based on data available from 1st January 2002 to 31st December 2015 in the Catalan health service (CatSalut) system. | Catalonia / Spain | PPI users (n = 36,360) and non-users (n = 99,362) aged ≥ 45 years. A lag window of 5 years was considered between the beginning of the PPI treatment and the diagnosis of dementia. | AD and non-AD dementias. | Age, sex, hypertension, diabetes and dyslipidaemia were considered as confounding variables. | PPI use was not associated with the risk of AD. A weakly but significantly increased risk of non-AD dementias was observed among PPI users. A higher dose of PPIs was not associated with an increased risk of either AD or non-AD dementias. An increased risk of AD and non-AD dementias was detected in users of two types of PPIs compared with one type PPI users. |
| Cooksey et al. (2020) | Large-scale, multi-centre, population-based study using electronic health-data from the Secure Anonymised Information Linkage (SAIL) Databank, Wales (UK) from 1999 to 2015. | UK | 183,968 persons who had ever been prescribed PPIs, aged ≥ 55 year, compared to 131,110 non-PPI exposed individuals. | AD and non-AD dementias. | Personal characteristics (e.g., age, sex, smoking status, obesity, alcohol consumption), confounding comorbidities (diabetes, cardiovascular disease, depression, anxiety, head injury, hypertension, high cholesterol, vitamin-B12 deficiency), concomitant medications (anxiolytics, anti-depressants, anticoagulants, antiplatelets, statins, hormone replacement therapy (HRT), vitamin-B12 supplements, iron and antihypertensives). | No association between PPI use and increased dementia risk was detected. |
| Desai et al. (2020) | Meta-analysis to investigate a potential association between PPI use and the risk of dementia. | See related original studies / databases | Literature search in PubMed, Embase, Google Scholar, and Cochrane for studies investigating the risk of cognitive decline and dementia among PPI users versus non-PPI users in prospective studies. | See related original studies / databases. | Retrospective database linkage studies, case reports, case series, editorials, uncontrolled cohort studies, cross-sectional studies, and review articles were excluded. | No significant relationship between PPI use and dementia in prospective studies with at least a 5-year follow-up. |
| Khan et al. (2020) | Meta-analysis to investigate a potential association between PPI intake and the risk of dementia. | See related original studies / databases | Literature / study search in MEDLINE, EMBASE, ISI Web of Science, and Cochrane databases, up to February 2019. Quality categorisation of observational studies was assessed using the Newcastle-Ottawa scale and the GRADE approach. Eleven studies were included comprising 642,949 individuals. | See related original studies / databases. | See related original studies / databases. | No evidence for an association between PPI use and increased risk of dementia. |
| Zhang et al. (2020) | Meta-analysis to investigate a potential association between PPI intake and the risk of dementia. | See related original studies / databases | Literature search in English and Chinese databases from origination to December 2018. Six studies were considered, including a total of 166,146 participants. | See related original studies / databases. | See related original studies / databases. Exclusion criteria included animal experimental models, systematic review articles, letters, meta-analyses, comments, case reports; duplicated studies, studies without possibility to retrieve or calculate data of interest. | Result show a significant increase in dementia risk with PPI use. Subgroup analyses revealed a significant association between PPI use and the risk of dementia in Europe and among participants aged ≥ 65 years. |
| Chen et al. (2020) | Population-based retrospective cohort study using the Taiwan National Health Insurance (NHI) claims database-National Health Insurance Research Database (NHIRD). | Taiwan | Patients aged ≥ 65 years with cumulative PPI use between January 2000 and December 2005 (PPI user cohort n = 6,584; PPI non-user cohort, n = 6,584). | AD and non-AD dementias. | Covariates included sex, age, comorbidities (e.g. diabetes mellitus, hyperlipidemia, coronary artery disease, stroke, depression) and comedication (e.g. NSAIDs, anti-hypertensives, anti-diabetic agents, statins, aspirin, and anti-depressants). | PPI users exhibited a significantly elevated risk of dementia compared to PPI non-users. |
| Wu et al. (2020) | Population-based propensity score matched retrospective cohort study using Taiwan's National Health Insurance (NHI) Research Database. | Taiwan | Patients aged ≥ 40 years with PPIs use between 2000 and 2010 (PPI user cohort compared to PPI non-user cohort, n = 2,583 each). | AD and non-AD dementias. | Covariates considered: age, sex, hypertension, diabetes mellitus, coronary artery disease, hyperlipidaemia, stroke, asthma, chronic renal failure, depression. | No association between PPI uptake and a risk of developing dementia was detected. |
| Collin et al. (2021) | Wisconsin Registry for Alzheimer’s Prevention study. | USA | Questionnaires on medical history, blood samples and neuropsychological assessments from n = 1,573 individuals over a 10–15 year period. | AD and non-AD dementias. | Covariates included gender, antihypertensive drug use, physical activity, cigarette use, APO ε4 carrier status, H2RA use, heart disease, diabetes, depression, anxiety, lung disease. | PPI use was not associated with memory decline in a sample of subjects with familial risk factors for dementia. |
| Ahn et al. (2020) | Population-based cohort Study of Health in Pomerania (SHIP). | Germany | Participants aged 21 - 89 years, n = 2653 (baseline examinations 1997-2001, follow-up examination 2002-2006 and 2008-2012). | Brain volume (MRI), estimated brain age and cognitive function (Verbal Learning and Memory Test, VLMT; Nuremberg Age Inventory, NAI). | Multiple regression used to adjust confounding factors, e.g. age, sex, BMI, cognitive function-altering medications and further medication, socio-demographic variables, income, educational level, smoking experience, alcohol consumption, diabetes and cerebrovascular pathologies. | No relationship between PPI use and brain aging was detected. |
| Thunell et al. (2021) | Meta-analysis / scoping review to identify drug classes (including PPIs) associated with increasing or decreasing risk for AD or related dementias | See related original studies / databases | Systematic search using PubMed, SCOPUS, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for all published studies on humans from January 2008 till August 2018. | See related original studies / databases. | See related original studies / databases. | Twelve observational and four review studies examining PPIs were considered and exhibited mixed findings. Five of the 12 studies described increased risk of dementia or cognitive decline, two reported neuroprotective benefits, and five were inconclusive. |
Note: Relevant publications are listed including information about study design/data origin, country, study group characteristics (number of participants), types of dementia investigated, consideration of potential confounding factors and conclusions. Publications suggesting an association of PPI use and increased risk of dementias are highlighted in red. Those studies or meta-analyses reporting no increased risk of dementias upon PPI use or a neuroprotective effect are highlighted in blue. Neutral publications are listed in black.