Aluminium and fluoride in drinking water in relation to later dementia risk.

BACKGROUND: Environmental risk factors for dementia are poorly understood. Aluminium and fluorine in drinking water have been linked with dementia but uncertainties remain about this relationship. AIMS: In the largest longitudinal study in this context, we set out to explore the individual effect of aluminium and fluoride in drinking water on dementia risk and, as fluorine can increase absorption of aluminium, we also examine any synergistic influence on dementia. METHOD: We used Cox models to investigate the association between mean aluminium and fluoride levels in drinking water at their residential location (collected 2005-2012 by the Drinking Water Quality Regulator for Scotland) with dementia in members of the Scottish Mental Survey 1932 cohort who were alive in 2005. RESULTS: A total of 1972 out of 6990 individuals developed dementia by the linkage date in 2012. Dementia risk was raised with increasing mean aluminium levels in women (hazard ratio per s.d. increase 1.09, 95% CI 1.03-1.15, P < 0.001) and men (1.12, 95% CI 1.03-1.21, P = 0.004). A dose-response pattern of association was observed between mean fluoride levels and dementia in women (1.34, 95% CI 1.28-1.41, P < 0.001) and men (1.30, 95% CI 1.22-1.39, P < 0.001), with dementia risk more than doubled in the highest quartile compared with the lowest. There was no statistical interaction between aluminium and fluoride levels in relation with dementia. CONCLUSIONS: Higher levels of aluminium and fluoride were related to dementia risk in a population of men and women who consumed relatively low drinking-water levels of both.

The effect of age on the FCSRT-IR and temporary visual memory binding.

ABSTRACTBackground:Cognitive markers of early Alzheimer's disease (AD) should be sensitive and specific to memory impairments that are not associated with healthy cognitive aging. In the present study, we investigated the effect of healthy cognitive aging on two proposed cognitive markers of AD: the Free and Cued Selective Reminding Task with Immediate Recall (FCSRT-IR) and a temporary visual memory binding (TMB) task. METHOD: Free recall and the cost of holding bound information in visual memory were compared between 24 younger and 24 older participants in a mixed, fully counterbalanced experiment. RESULTS: A significant effect of age was observed on free recall in the FCSRT-IR only and not on the cost of binding in the TMB task. CONCLUSIONS: Of these two cognitive markers, the TMB task is more likely to be specific to memory impairments that are independent of age.

Environmental risk factors for dementia: a systematic review.

BACKGROUND: Dementia risk reduction is a major and growing public health priority. While certain modifiable risk factors for dementia have been identified, there remains a substantial proportion of unexplained risk. There is evidence that environmental risk factors may explain some of this risk. Thus, we present the first comprehensive systematic review of environmental risk factors for dementia. METHODS: We searched the PubMed and Web of Science databases from their inception to January 2016, bibliographies of review articles, and articles related to publically available environmental data. Articles were included if they examined the association between an environmental risk factor and dementia. Studies with another outcome (for example, cognition), a physiological measure of the exposure, case studies, animal studies, and studies of nutrition were excluded. Data were extracted from individual studies which were, in turn, appraised for methodological quality. The strength and consistency of the overall evidence for each risk factor identified was assessed. RESULTS: We screened 4784 studies and included 60 in the review. Risk factors were considered in six categories: air quality, toxic heavy metals, other metals, other trace elements, occupational-related exposures, and miscellaneous environmental factors. Few studies took a life course approach. There is at least moderate evidence implicating the following risk factors: air pollution; aluminium; silicon; selenium; pesticides; vitamin D deficiency; and electric and magnetic fields. CONCLUSIONS: Studies varied widely in size and quality and therefore we must be circumspect in our conclusions. Nevertheless, this extensive review suggests that future research could focus on a short list of environmental risk factors for dementia. Furthermore, further robust, longitudinal studies with repeated measures of environmental exposures are required to confirm these associations.

Semantic Harmonization of Alzheimer's Disease Datasets Using AD-Mapper.

Background: Despite numerous past endeavors for the semantic harmonization of Alzheimer's disease (AD) cohort studies, an automatic tool has yet to be developed. Objective: As cohort studies form the basis of data-driven analysis, harmonizing them is crucial for cross-cohort analysis. We aimed to accelerate this task by constructing an automatic harmonization tool. Methods: We created a common data model (CDM) through cross-mapping data from 20 cohorts, three CDMs, and ontology terms, which was then used to fine-tune a BioBERT model. Finally, we evaluated the model using three previously unseen cohorts and compared its performance to a string-matching baseline model. Results: Here, we present our AD-Mapper interface for automatic harmonization of AD cohort studies, which outperformed a string-matching baseline on previously unseen cohort studies. We showcase our CDM comprising 1218 unique variables. Conclusion: AD-Mapper leverages semantic similarities in naming conventions across cohorts to improve mapping performance.

Participating in innovative medicines initiative funded neurodegenerative disorder projects-An impact analysis conducted as part of the NEURONET project.

The European Commission's Innovative Medicines Initiative (IMI) has funded many projects focusing on neurodegenerative disorders (ND) that aimed to improve the diagnosis, prevention, treatment and understanding of NDs. To facilitate collaboration across this project portfolio, the IMI funded the "NEURONET" project between March 2019 and August 2022 with the aim of connecting these projects and promoting synergies, enhancing the visibility of their findings, understanding the impact of the IMI funding and identifying research gaps that warrant more/new funding. The IMI ND portfolio currently includes 20 projects consisting of 270 partner organizations across 25 countries. The NEURONET project conducted an impact analysis to assess the scientific and socio-economic impact of the IMI ND portfolio. This was to better understand the perceived areas of impact from those directly involved in the projects. The impact analysis was conducted in two stages: an initial stage developed the scope of the project, defined the impact indicators and measures to be used. A second stage designed and administered the survey amongst partners from European Federation of Pharmaceutical Industries and Associations (EFPIA) organizations and other partners (hereafter, referred to as "non-EFPIA" organizations). Responses were analyzed according to areas of impact: organizational, economic, capacity building, collaborations and networking, individual, scientific, policy, patient, societal and public health impact. Involvement in the IMI ND projects led to organizational impact, and increased networking, collaboration and partnerships. The key perceived disadvantage to project participation was the administrative burden. These results were true for both EFPIA and non-EFPIA respondents. The impact for individual, policy, patients and public health was less clear with people reporting both high and low impact. Overall, there was broad alignment between EFPIA and non-EFPIA participants' responses apart from for awareness of project assets, as part of scientific impact, which appeared to be slightly higher among non-EFPIA respondents. These results identified clear areas of impact and those that require improvement. Areas to focus on include promoting asset awareness, establishing the impact of the IMI ND projects on research and development, ensuring meaningful patient involvement in these public-private partnership projects and reducing the administrative burden associated with participation in them.

Data sharing in neurodegenerative disease research: challenges and learnings from the innovative medicines initiative public-private partnership model.

Efficient data sharing is hampered by an array of organizational, ethical, behavioral, and technical challenges, slowing research progress and reducing the utility of data generated by clinical research studies on neurodegenerative diseases. There is a particular need to address differences between public and private sector environments for research and data sharing, which have varying standards, expectations, motivations, and interests. The Neuronet data sharing Working Group was set up to understand the existing barriers to data sharing in public-private partnership projects, and to provide guidance to overcome these barriers, by convening data sharing experts from diverse projects in the IMI neurodegeneration portfolio. In this policy and practice review, we outline the challenges and learnings of the WG, providing the neurodegeneration community with examples of good practices and recommendations on how to overcome obstacles to data sharing. These obstacles span organizational issues linked to the unique structure of cross-sectoral, collaborative research initiatives, to technical issues that affect the storage, structure and annotations of individual datasets. We also identify sociotechnical hurdles, such as academic recognition and reward systems that disincentivise data sharing, and legal challenges linked to heightened perceptions of data privacy risk, compounded by a lack of clear guidance on GDPR compliance mechanisms for public-private research. Focusing on real-world, neuroimaging and digital biomarker data, we highlight particular challenges and learnings for data sharing, such as data management planning, development of ethical codes of conduct, and harmonization of protocols and curation processes. Cross-cutting solutions and enablers include the principles of transparency, standardization and co-design - from open, accessible metadata catalogs that enhance findability of data, to measures that increase visibility and trust in data reuse.

The Innovative Medicines Initiative neurodegeneration portfolio: From individual projects to collaborative networks.

The IMI public-private partnership between the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA) was launched in 2008 with an initial budget of €2 billion. Aiming to accelerate the development of innovative medicines for areas of unmet clinical need, the IMI has committed over €380 million to projects on neurodegenerative disorders (NDD), catalyzing public-private collaborations at scale and at all stages of the R&D pipeline. Because of this vast investment, research on neurodegenerative diseases has made enormous strides in recent decades. The challenge for the future however remains to utilize this newly found knowledge and generated assets to develop better tools and novel therapeutic strategies. Here, we report the results of an integrated programme analysis of the IMI NDD portfolio, performed by the Neuronet Coordination and Support Action. Neuronet was launched by the IMI in 2019 to boost synergies and collaboration between projects in the IMI NDD portfolio, to increase the impact and visibility of research, and to facilitate interactions with related initiatives worldwide. Our analysis assessed the characteristics, structure and assets of the project portfolio and identifies lessons from projects spanning preclinical research to applied clinical studies and beyond. Evaluation of project parameters and network analyses of project partners revealed a complex web of 236 partnering organizations, with EFPIA partners often acting as connecting nodes across projects, and with a great diversity of academic institutions. Organizations in the UK, Germany, France and the Netherlands were highly represented in the portfolio, which has a strong focus on clinical research in Alzheimer's and Parkinson's disease in particular. Based on surveys and unstructured interviews with NDD research leaders, we identified actions to enhance collaboration between project partners, by improving the structure and definition of in-kind contributions; reducing administrative burdens; and enhancing the exploitation of outcomes from research investments by EU taxpayers and EFPIA. These recommendations could help increase the efficiency and impact of future public-private partnerships on neurodegeneration.

Digital Support Platform: a qualitative research study investigating the feasibility of an internet-based, postdiagnostic support platform for families living with dementia.

OBJECTIVES: To establish the feasibility of the Digital Support Platform (DSP), an internet-based, postdiagnostic tool designed for families living with a diagnosis of dementia. DESIGN: Qualitative methods using normalisation process theory as an analysis framework for semistructured interview transcriptions. SETTING: A community care setting in the South-East Scotland. PARTICIPANTS: We interviewed 10 dyads of people with Alzheimer's, vascular or mixed dementia (PWD), and their family carers, who had been given and had used the DSP for at least 2 months. RESULTS: Our analysis revealed that the DSP was predominantly understood and used by the carers rather than PWD, and was used alongside tools and methods they already used to care for their relative. The DSP was interpreted as a tool that may be of benefit to those experiencing later stages of dementia or with physical care needs. Carers stated that the DSP may be of benefit in the future, reflecting a disinclination to prepare for or anticipate for future needs, rather than focus on those needs present at the time of distribution. PWD spoke positively about an interest in learning to use technology more effectively and enjoyed having their own tablet devices. CONCLUSIONS: The DSP was not wholly appropriate for families living with dementia in its early stages. The views of carers confirmed that postdiagnostic support was valued, but emphasised the importance of tailoring this support to the exact needs and current arrangements of families. There may be a benefit to introducing, encouraging, providing and teaching internet-enabled technology to those PWD who do not currently have access. Training should be provided when introducing new technology to PWD.

The effect of funding sources on donepezil randomised controlled trial outcome: a meta-analysis.

OBJECTIVE: To investigate whether there is a difference in the treatment effect of donepezil on cognition in Alzheimer disease between industry-funded and independent randomised controlled trials. DESIGN: Fixed effects meta-analysis of standardised effects of donepezil on cognition as measured by the Mini Mental State Examination and the Alzheimer's Disease Assessment Scale-cognitive subscale. DATA SOURCES: Studies included in the meta-analyses reported in the National Institute for Health and Care Excellence (NICE) technical appraisal 217 updated with new studies through a PubMed search. ELIGIBILITY CRITERIA: Inclusion criteria were double-blind, placebo-controlled trials of any length comparing patients diagnosed with probable Alzheimer disease (according to the NINCDS-ADRDA/DSM-III/IV criteria) taking any dosage of donepezil. Studies of combination therapies (eg, donepezil and memantine) were excluded, as were studies that enrolled patients with a diagnosis of Alzheimer disease associated with other disorders (eg, Parkinson's disease and Down's syndrome). RESULTS: Our search strategy identified 14 relevant trials (4 independent) with suitable data. Trials sponsored by pharmaceutical companies reported a larger effect of donepezil on standardised cognitive tests than trials published by independent research groups (standardised mean difference (SMD)=0.46, 95% CI 0.37 to 0.55 vs SMD=0.33, 95% CI 0.18 to 0.48, respectively). This difference remained when only data representing change up to 12 weeks from baseline were analysed (industry SMD=0.44, 95% CI 0.34 to 0.53 vs independent SMD=0.35, 95% CI 0.18 to 0.52). Analysis revealed that the effect of funding as a moderator variable of study heterogeneity was not statistically significant at either time point. CONCLUSIONS: The effect size of donepezil on cognition is larger in industry-funded than independent trials and this is not explained by the longer duration of industry-funded trials. The lack of a statistically significant moderator effect may indicate that the differences are due to chance, but may also result from lack of power.