Proton pump inhibitors and dementia: A nationwide population-based study.

INTRODUCTION: Proton pump inhibitors (PPIs) may increase dementia risk. However, it is currently unknown whether timing of exposure or age at dementia diagnosis influence the risk. METHODS: We assessed associations between cumulative PPI use and dementia at different ages in a nationwide Danish cohort of 1,983,785 individuals aged 60 to 75 years between 2000 and 2018. RESULTS: During follow-up, there were 99,384 all-cause dementia incidences. Incidence rate ratio (IRR) of dementia with PPI ever-use compared with never-use was 1.36 (95% CI, 1.29 to 1.43) for age 60 to 69 years at diagnosis, 1.12 (1.09 to 1.15) for 70 to 79 years, 1.06 (1.03 to 1.09) for 80 to 89 years, and 1.03 (0.91 to 1.17) for 90+ years. Longer treatment duration yielded increasing IRRs. For cases below 90 years, increased dementia rate was observed regardless of treatment initiation up to >15 years before diagnosis. DISCUSSION: Regardless of timing of treatment initiation, PPI use was associated with increased dementia rate before age 90 years. Dementia rates increased with younger age at diagnosis. HIGHLIGHTS: After following 1,983,785 individuals for a median of 10 years, 99,384 developed dementia PPIs were used by 21.2% of cases and 18.9% of controls PPI use was associated with increased dementia rate regardless of time of treatment onset Magnitude of associations increased with younger age at diagnosis PPI use was not associated with dementia occurring after age 90 years.

Mapping morbidity 10 years prior to a diagnosis of young onset Alzheimer's disease.

INTRODUCTION: Early symptoms in young onset Alzheimer's disease (YOAD) may be misinterpreted, causing delayed diagnosis. This population-based study aimed to map morbidity prior to YOAD diagnosis. METHODS: In a register-based incidence density matched nested case-control study, we examined hospital-diagnosed morbidity for people diagnosed with YOAD in Danish memory clinics during 2016-2020 compared to controls in a 10-year period. Conditional logistic regression produced incidence rate ratios (IRRs). RESULTS: The study included 1745 cases and 5235 controls. YOAD patients had a higher morbidity burden in the year immediately before dementia diagnosis, for certain disorders up to 10 years before. This was especially evident for psychiatric morbidity with the highest increased IRRs throughout the entire period and IRR 1.43 (95% confidence interval 1.14-1.79) in the 5-10-years before dementia diagnosis. DISCUSSION: YOAD patients display a different pattern of morbidity up to 10 years prior to diagnosis. Awareness of specific alterations in morbidity may improve efforts toward a timely diagnosis. HIGHLIGHTS: Retrospective, nested case-control study of young onset Alzheimer's disease (YOAD). YOAD cases had a higher morbidity burden than controls. YOAD cases had a higher psychiatric morbidity burden up to 10 years before diagnosis. Altered morbidity patterns could serve as an early warning sign of YOAD.

Hospital-diagnosed sleep disorders and incident dementia: a nationwide observational cohort study.

BACKGROUND AND PURPOSE: Several smaller, community-based studies have suggested a link between sleep disorders and dementia with a focus on sleep as a modifiable risk factor for dementia. Studies on neurodegenerative diseases are prone to reverse causation, and few studies have examined the association with long follow-up time. Our aim was to explore the possible association between sleep disorders and late-onset dementia in an entire population. METHODS: In a nationwide cohort with 40-year follow-up, associations between hospital-based sleep disorder diagnoses and late-onset dementia were assessed. Incidence rate ratios (IRR) were calculated using Poisson regression. RESULTS: The cohort consisted of 1,491,276 people. Those with any sleep disorder had a 17% higher risk of dementia (IRR 1.17, 95% confidence interval [CI] 1.11-1.24) compared to people with no sleep disorder, adjusted for age, sex, calendar year, highest attained educational level at age 50, and somatic and psychiatric comorbidity. The risk of dementia was significantly increased 0-5 years after sleep disorder diagnosis (IRR 1.35, 95% CI 1.25-1.47), whilst the association after 5 years or more was non-significant (1.05, 95% CI 0.97-1.13). CONCLUSIONS: Our findings show an increased short-term risk of dementia following a hospital-based sleep disorder diagnosis, whilst weaker evidence of a long-term risk was found. This could potentially point towards sleep disorders as an early symptom of dementia. Further research is needed to distinguish sleep disorders as an early symptom of dementia, a risk factor, or both.

Hospital readmissions following infections in dementia: a nationwide and registry-based cohort study.

INTRODUCTION: We aimed to investigate readmission risks following infections in dementia, identify the types of infections behind the risks, and highlight the reasons for readmissions. METHODS: Acute inpatient hospital admissions for infections in Danish residents were included from 1 January 2000, or age 65 years. Primary outcomes were 7-day readmissions risk ratios (RRs; risk following infection index admissions of people with dementia relative to those without dementia), risks by infection site, and reasons for readmission. Secondary outcomes were 30- and 90-day readmission risks. Competing risk of death was estimated. RESULTS: Seven-day readmission RR was increased in all age groups and was highest in the youngest patients (women RR: 1.37, 95% confidence interval [CI] 1.22-1.53; men RR: 1.23, 95% CI 1.12-1.35). RRs decreased with increasing age and longer follow-up. The most notable common readmissions were for infections and dehydration in dementia. CONCLUSIONS: We conclude that there is a substantially increased readmission risk in people with dementia than in those without dementia, particularly within 7 days, and for the youngest in the cohort. Readmission risks were higher for infection index admissions than for admissions for causes other than infection, and readmissions were mostly due to infections. Our findings highlight the burden of infections in people with dementia and call for in-depth investigations of determinants related to readmission risks, to inform public policy and identify avenues for interventions that can decrease or prevent potentially avoidable readmissions.

Antiherpetic medication and incident dementia: Observational cohort studies in four countries.

BACKGROUND AND PURPOSE: Several epidemiological studies from Taiwan, all using the same data resource, found significant associations between herpes virus infection, antiherpetic medication, and subsequent dementia. We conducted a multicenter observational cohort study using health registry data from Wales, Germany, Scotland, and Denmark to investigate potential associations between antiherpetic medication and incident dementia, and also to comprehensively investigate such associations broken down according to medication type and dose, type of herpes virus, and dementia subtype. METHODS: A total of 2.5 million individuals aged 65 years or more were followed up using linked electronic health records in four national observational cohort studies. Exposure and outcome were classified using coded data from primary and secondary care. Data were analyzed using survival analysis with time-dependent covariates. RESULTS: Results were heterogeneous, with a tendency toward decreased dementia risk in individuals exposed to antiherpetic medication. Associations were not affected by treatment number, herpes subtype, dementia subtype, or specific medication. In one cohort, individuals diagnosed with herpes but not exposed to antiherpetic medication were at higher dementia risk. CONCLUSIONS: Short-term antiherpetic medication is not markedly associated with incident dementia. Because neither dementia subtype nor herpes subtype modified the association, the small but significant decrease in dementia incidence with antiherpetic administration may reflect confounding and misclassification.

Neonatal vitamin D levels and cognitive ability in young adulthood.

PURPOSE: Intelligence has a strong influence on life capability, and thus, identifying early modifiable risk factors related to cognitive ability is of major public health interest. During pregnancy, vitamin D is transported from the mother to the fetus through the placenta in the form of 25-hydroxyvitamin D (25(OH)D). Levels of 25(OH)D have in some studies been associated with childhood neurodevelopment; however, results from all studies are not in agreement. We investigated if neonatal 25(OH)D3 concentrations were associated with Børge Priens IQ test score (BPP) in young adulthood. METHODS: In this nested cohort study, 25(OH)D3 concentrations were measured in dried blood spots from 818 newborns. We followed the children for their IQ BPP test scores in the Danish Conscription Register, which holds information on test results from the BPP test on individuals who have been recruited for Danish mandatory military draft board examination. Using general linear models, we investigated the crude and adjusted relationship between quintiles of 25(OH)D3 concentrations and BPP IQ test results. RESULTS: The study population consisted of 95.8% men, with a mean age of 19.4 years. The median and range of the neonatal 25(OH)D3 levels were 26.2 nmol/L (0-104.7 nmol/L). The overall Wald test did not show an association between neonatal 25(OH)D3 levels and BPP IQ scores (p = 0.23); however, individuals within the 3rd (BPP IQ = 101.0, 98.0-103.9) and 4th (BPP IQ = 101.2, 99.1-104.3) quintiles had slightly higher BPP IQ scores than individuals from the first quintile (BPP IQ = 97.6, 94.6-100.6). CONCLUSIONS: Our results support the hypothesis that individuals with the lowest levels of neonatal vitamin D might have slightly lower BPP. However, more studies are needed with larger study populations to confirm our results.

Assistive technology designed to support self-management of people with dementia: user involvement, dissemination, and adoption. A scoping review.

BACKGROUND: Assistive technology is advocated as a key solution to the need for support among people living with dementia. There is growing awareness of the benefits of user involvement in the design and test of these technologies and the need to identifying applicable and effective methods for implementation. The aim of this review was to explore and synthesize research addressing assistive technology designed to be used by people with dementia for self-management. Further research aims were to explore if and how user involvement, dissemination, and adoption of assistive technology were addressed. METHOD: Electronic databases were searched using specified search terms. Key publications and grey literature sources were hand-searched. Materials published until year end 2018 were included. The results were summarized according to the research aims. RESULTS: Eleven papers derived from eight studies were included. The studies presented data from prototype design and testing, and the review showed great variation in study scope, design, and methodology. User involvement varied from extensive involvement to no user involvement. Methods for adoption also varied widely and only targeted prototype testing. None of the studies addressed dissemination. CONCLUSION: The results of this review underline the need for well-designed high-quality research into all the aspects that are essential to deliver applicable, effective, and sustainable assistive technology to support self-management of people with dementia. There is a need for evidence-based methods to promote and qualify user involvement, dissemination, and adoption. The results also point to the need for standardized outcome measures and standards for conducting and reporting research to improve its quality and impact.

Risk of Major Types of Dementias Following Hospital-Diagnosed Infections and Autoimmune Diseases.

Background: Population-based studies have shown an increased risk of dementia after infections, but weaker links were reported for autoimmune diseases. Evidence is scarce for whether the links may be modified by the dementia or exposure subtype. Objective: We aimed to investigate the association between infections and/or autoimmune diseases and rates of major types of dementias in the short- and long terms. Methods: Nationwide nested case-control study of dementia cases (65+ years) diagnosed in Denmark 2016-2020 and dementia-free controls. Exposures were hospital-diagnosed infections and autoimmune diseases in the preceding 35 years. Two groups of dementia cases were those diagnosed in memory clinics (MC) and those diagnosed outside memory clinics (non-memory clinic cases, NMC). Results: In total, 26,738 individuals were MC and 12,534 were NMC cases. Following any infection, the incidence rate ratio (IRR) for MC cases was 1.23 (95% CI 1.20-1.27) and 1.70 for NMC cases (1.62-1.76). Long-term increased rates were seen for vascular dementia and NMC cases. IRRs for autoimmune diseases were overall statistically insignificant. Conclusions: Cases with vascular dementia and not Alzheimer's disease, and a subgroup of cases identified with poorer health have increased long-term risk following infections. Autoimmune diseases were not associated with any type of dementia. Notably increased risks (attributed to the short term) and for NMC cases may indicate that immunosenescence rather than de novo infection explains the links. Future focus on such groups and on the role of vascular pathology will explain the infection-dementia links, especially in the long term.

Prescription medication use in the 10 years prior to diagnosis of young onset Alzheimer's disease: a nationwide nested case-control study.

BACKGROUND: Patients with young onset Alzheimer's disease (YOAD) face long diagnostic delays. Prescription medication use may provide insights into early signs and symptoms, which may help facilitate timely diagnosis. METHODS: In a register-based nested case-control study, we examined medication use for everyone diagnosed with YOAD in a Danish memory clinic during 2016-2020 compared to cognitively healthy controls. Prescription medication use were grouped into 13 overall categories (alimentary tract and metabolism, blood and blood forming organs, cardiovascular system, dermatologicals, genitourinary system and sex hormones, systemic hormonal preparations, antiinfectives for systemic use, antineoplastic and immunomodulating agents, musculo-skeletal system, nervous system, antiparasitic products, respiratory system, and sensory organs). Further stratifications were done for predetermined subcategories with a use-prevalence of at least 5% in the study population. Conditional logistic regression produced odds ratios, which given the use of incidence-density matching is interpretable as incidence rate ratios (IRRs). The association between prescription medication use and subsequent YOAD diagnosis was examined in the entire 10-year study period and in three time-intervals. RESULTS: The study included 1745 YOAD cases and 5235 controls. In the main analysis, several overall categories showed significant associations with YOAD in one or more time-intervals, namely blood and blood forming organs and nervous system. Prescription medication use in the nervous system category was increased for YOAD cases compared to controls already 10->5 years prior to diagnosis (IRR 1.17, 95% CI 1.05-1.31), increasing to 1.57 (95% CI 1.39-1.78) in the year preceding diagnosis. This was largely driven by antidepressant and antipsychotic use, and especially prominent for first-time users. CONCLUSIONS: In this study, medication use in several categories was associated with YOAD. Onset of treatment-requiring psychiatric symptoms such as depression or psychosis in mid-life may serve as potential early indicators of YOAD.

Healthcare utilization prior to a diagnosis of young-onset Alzheimer's disease: a nationwide nested case-control study.

OBJECTIVE: Our aim was to identify changes in healthcare utilization prior to a young-onset Alzheimer's disease diagnosis. METHODS: In a retrospective incidence density matched nested case-control study using national health registers, we examined healthcare utilization for those diagnosed with young-onset Alzheimer's disease in Danish memory clinics during 2016-2018 compared with age- and sex-matched controls. Negative binomial regression analysis produced contact rate ratios. RESULTS: The study included 1082 young-onset Alzheimer's disease patients and 3246 controls. In the year preceding diagnosis, we found increased contact rate ratios for all types of contacts except physiotherapy. Contact rate ratios for contacts with a general practitioner were significantly increased also > 1-5 and > 5-10 years before diagnosis. The highest contact rate ratios were for psychiatric emergency contacts (8.69, 95% CI 4.29-17.62) ≤ 1 year before diagnosis. INTERPRETATION: Results demonstrate that young-onset Alzheimer's disease patients have increased healthcare utilization from 5 to 10 years prior to diagnosis. Awareness of specific alterations in health-seeking behaviour may help healthcare professionals provide timely diagnoses.

Hospital-Diagnosed Infections, Autoimmune Diseases, and Subsequent Dementia Incidence.

Importance: Systemic inflammation has been suggested to explain reported associations between infections and dementia. Associations between autoimmune diseases and dementia also suggest a role for peripheral systemic inflammation. Objective: To investigate the associations of infections and autoimmune diseases with subsequent dementia incidence and to explore potential shared signals presented by the immune system in the 2 conditions. Design, Setting, and Participants: This nationwide, population-based, registry-based cohort study was conducted between 1978 and 2018 (40-year study period). All Danish residents born 1928 to 1953, alive and in Denmark on January 1, 1978, and at age 65 years were included. Persons with prior registered dementia and those with HIV infections were excluded. Data were analyzed between May 2022 and January 2023. Exposures: Hospital-diagnosed infections and autoimmune diseases. Main Outcomes and Measures: All-cause dementia, defined as the date of a first registered dementia diagnosis after age 65 years in the registries. Poisson regression with person-years at risk as an offset variable was used to analyze time to first dementia diagnosis. Results: A total of 1 493 896 individuals (763 987 women [51%]) were followed for 14 093 303 person-years (677 147 [45%] with infections, 127 721 [9%] with autoimmune diseases, and 75 543 [5%] with dementia). Among individuals with infections, 343 504 (51%) were men, whereas among those with autoimmune diseases, 77 466 (61%) were women. The dementia incidence rate ratio (IRR) following any infection was 1.49 (95% CI, 1.47-1.52) and increased along with increasing numbers of infections in a dose-dependent manner. Dementia rates were increased for all infection sites in the short term, but not always in the long term. The dementia IRR following any autoimmune disease was 1.04 (95% CI, 1.01-1.06), but no dose-dependent increase was observed, and only a few autoimmune conditions showed increased IRRs for dementia. Conclusions and Relevance: These findings may point toward a role for infection-specific processes in the development of dementia, rather than general systemic inflammation, as previously hypothesized. Assessing these 2 conditions in a single setting may allow for additional insights into their roles in dementia and for hypotheses on possible underlying mechanisms.

Reduced dementia incidence after varicella zoster vaccination in Wales 2013-2020.

Introduction: Chronic infection with herpes viruses is a potential contributing factor to the development of dementia. The introduction of nationwide shingles (varicella zoster) vaccination in Wales might therefore be associated with reduced incident dementia. Methods: We analyzed the association of shingles vaccination with incident dementia in Wales between 2013 and 2020 using retrospectively collected national health data. Results: Vaccinated individuals were at reduced risk of dementia (adjusted hazard ratio: 0.72; 95% confidence interval: 0.69 to 0.75). The association was not modified by a reduction in shingles diagnosis and was stronger for vascular dementia than for Alzheimer's disease. Vaccination was also associated with a reduction in several other diseases and all-cause mortality. Discussion: Our study shows a clear association of shingles vaccination with reduced dementia, consistent with other observational cohort studies. The association may reflect selection bias with people choosing to be vaccinated having a higher healthy life expectancy.

Dementia identified as a risk factor for infection-related hospital contacts in a national, population-based and longitudinal matched-cohort study.

The aim of this study was to investigate the association between incident dementia and rates of infection-related hospital contacts. We conducted a registry- and population-based matched-cohort study of all Danish residents who were born in or before 1950, included from 1 January 2000 or their 65th birthday (whichever came later), who were alive and resided in Denmark at the start of the study, excluding those who had received a dementia diagnosis before 1 January 2000 or their 65th birthday (n = 1,712,100). A total of 129,660 people (403,744 person years) with incident dementia were matched with 297,476 people (1,918,784 person years) without dementia. Incidence rate ratios (IRRs) of infection-related hospital contacts were calculated using Poisson regression, by infection type, sex and age. The IRR for any infection-related contact in dementia was 1.5, was highest for nervous and urinary system infections and sepsis, decreased with increasing age and was higher in men. More people with than without dementia had contacts five years before the index date. Our findings show that dementia is a risk factor for infection-related hospital contacts and infections might be an early sign of dementia.

The Copenhagen Primary Care Laboratory Pregnancy (CopPreg) database.

PURPOSE: The Copenhagen Primary Care Laboratory Pregnancy (CopPreg) database was established based on data from The Danish Medical Birth Register and the Copenhagen Primary Care Laboratory (CopLab) database. The aim was to provide a biomedical and epidemiological data resource for research in early disease programming (eg, parental clinical biomarker levels and pregnancy/ birth outcomes or long-term health in the offspring). PARTICIPANTS: The cohort consisted in total of 203 608 women (with 340 891 pregnancies) who gave birth to 348 248 children and with 200 590 related fathers. In this paper, we focused on women and fathers who had clinical test requisitions prior to and during pregnancy, and on all children. Thus, the cohort in focus consisted of 203 054 pregnancies with requisitions on 147 045 pregnant women, 39 815 fathers with requisitions during periconception and 65 315 children with requisitions. FINDINGS TO DATE: In addition to information on pregnancy and birth health status and general socio-demographic data, over 2.2 million clinically relevant test results were available for pregnancies with requisitions, over 1.5 million for children and over 600 000 test results were available for the fathers with requisitions during periconception. These were ordered by general practitioners in the primary care setting only and included general blood tests, nutritional biomarkers (macronutrients and micronutrients) and hormone tests. Information on tests related to infections, allergies, heart and lung function and sperm analyses (fathers) were also available. FUTURE PLANS: The CopPreg database provides ready to use and valid data from already collected, objectively measured and analysed clinical tests. With several research projects planned, we further invite national and international researchers to use this vast data resource. In a coming paper, we will explore and discuss the indication bias in our cohort.

A systematic literature review of the relation between iron status/anemia in pregnancy and offspring neurodevelopment.

BACKGROUND: The fetal brain starts developing early and animal studies have suggested that iron plays several roles for the development, but results from epidemiological studies investigating associations between gestational iron and offspring neurodevelopment are inconsistent. OBJECTIVE: To systematically examine results from observational studies and RCTs on gestational iron and offspring neurodevelopment, with focus on the importance of four domains: iron status indicators, exposure timing, neurodevelopmental outcomes, and offspring age. METHODS: PRISMA guidelines were followed. Embase, PsychInfo, Scopus, and The Cochrane library were searched in September 2017 and February 2018. Overall, 3307 articles were identified and 108 retrieved for full-text assessment. Pre-specified eligibility criteria were used to select studies and 27 articles were included;19 observational and 8 RCTs. RESULTS: Iron status in pregnancy was associated with offspring behavior, cognition, and academic achievement. The direction of associations with behavioral outcomes were unclear and the conclusions related to cognition and academic achievement were based on few studies, only. Little evidence was found for associations with motor development. Observed associations were shown to persist beyond infancy into adolescence, and results depended on iron status indicator type but not on the timing of exposure. CONCLUSION: We conclude that there is some evidence that low pregnancy iron, possibly particularly in the 3rd trimester, may be associated with adverse offspring neurodevelopment. As most previous research used Hemoglobin, inferring results to iron deficiency should be done with caution. No conclusions could be reached regarding associations beyond early childhood, and supplementation with iron during pregnancy did not seem to influence offspring neurodevelopment.

Associations between vitamin D status in pregnancy and offspring neurodevelopment: a systematic literature review.

CONTEXT: Vitamin D plays an important role in the development of the brain, which is one of the earliest fetal organs to develop. Results from epidemiological studies investigating associations between maternal levels of vitamin D during pregnancy and offspring neurodevelopment are mixed and inconclusive. OBJECTIVE: This systematic review of studies that examined vitamin D levels in pregnancy and offspring neurodevelopment used 3 specific domains-timing of exposure during pregnancy trimesters, neurodevelopmental outcomes, and offspring age at assessment of outcomes-to determine whether vitamin D status in pregnancy is associated with offspring neurodevelopment. DATA SOURCES: A search of the Embase, PsychInfo, Scopus, and The Cochrane Library databases in September 2017 and February 2018 identified 844 articles, of which 46 were retrieved for full-text assessment. STUDY SELECTION: Eligibility criteria were used to select studies. All authors examined the studies, and consensus was reached through discussion. Results were divided according to the 3 domains. DATA EXTRACTION: Authors examined the studies independently, and data from eligible studies were extracted using a modified version of the Cochrane data collection form. Using the modified Downs and Black checklist, 2 authors assessed the quality of the studies independently and were blinded to each other's assessment. Consensus was reached upon discussion and with the involvement of the third author. RESULTS: Fifteen observational studies were included. Vitamin D in pregnancy was associated with offspring language and motor skills in young children. Associations persisted into adolescence, and results were not dependent on the timing of vitamin D exposure during pregnancy. No supplementation studies were identified. CONCLUSIONS: There is some evidence that low vitamin D status in pregnancy is associated with offspring language and motor development, particularly in young children. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42017078312.