Sex and gender considerations in Alzheimer’s disease: The Women’s Brain Project contribution

The global population is expected to have about 131.5 million people living with Alzheimer’s disease (AD) and other dementias by 2050, posing a severe health crisis. Dementia is a progressive neurodegenerative condition that gradually impairs physical and cognitive functions. Dementia has a variety of causes, symptoms, and heterogeneity concerning the influence of sex on prevalence, risk factors, and outcomes. The proportion of male-to-female prevalence varies based on the type of dementia. Despite some types of dementia being more common in men, women have a greater lifetime risk of developing dementia. AD is the most common form of dementia in which approximately two-thirds of the affected persons are women. Profound sex and gender differences in physiology and pharmacokinetic and pharmacodynamic interactions have increasingly been identified. As a result, new approaches to dementia diagnosis, care, and patient journeys should be considered. In the heart of a rapidly aging worldwide population, the Women’s Brain Project (WBP) was born from the necessity to address the sex and gender gap in AD. WBP is now a well-established international non-profit organization with a global multidisciplinary team of experts studying sex and gender determinants in the brain and mental health. WBP works with different stakeholders worldwide to help change perceptions and reduce sex biases in clinical and preclinical research and policy frameworks. With its strong female leadership, WBP is an example of the importance of female professionals’ work in the field of dementia research. WBP-led peer-reviewed papers, articles, books, lectures, and various initiatives in the policy and advocacy space have profoundly impacted the community and driven global discussion. WBP is now in the initial phases of establishing the world’s first Sex and Gender Precision Medicine Institute. This review highlights the contributions of the WBP team to the field of AD. This review aims to increase awareness of potentially important aspects of basic science, clinical outcomes, digital health, policy framework and provide the research community with potential challenges and research suggestions to leverage sex and gender differences. Finally, at the end of the review, we briefly touch upon our progress and contribution toward sex and gender inclusion beyond Alzheimer’s disease

Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare

Precision Medicine implies a deep understanding of inter-individual differences in health and disease that are due to genetic and environmental factors. To acquire such understanding there is a need for the implementation of different types of technologies based on artificial intelligence (AI) that enable the identification of biomedically relevant patterns, facilitating progress towards individually tailored preventative and therapeutic interventions. Despite the significant scientific advances achieved so far, most of the currently used biomedical AI technologies do not account for bias detection. Furthermore, the design of the majority of algorithms ignore the sex and gender dimension and its contribution to health and disease differences among individuals. Failure in accounting for these differences will generate sub-optimal results and produce mistakes as well as discriminatory outcomes. In this review we examine the current sex and gender gaps in a subset of biomedical technologies used in relation to Precision Medicine. In addition, we provide recommendations to optimize their utilization to improve the global health and disease landscape and decrease inequalities.This work is written on behalf of the Women’s Brain Project (WBP) (www.womensbrainproject.com/), an international organization advocating for women’s brain and mental health through scientific research, debate and public engagement. The authors would like to gratefully acknowledge Maria Teresa Ferretti and Nicoletta Iacobacci (WBP) for the scientific advice and insightful discussions; Roberto Confalonieri (Alpha Health) for reviewing the manuscript; the Bioinfo4Women programme of Barcelona Supercomputing Center (BSC) for the support. This work has been supported by the Spanish Government (SEV 2015–0493) and grant PT17/0009/0001, of the Acción Estratégica en Salud 2013–2016 of the Programa Estatal de Investigación Orientada a los Retos de la Sociedad, funded by the Instituto de Salud Carlos III (ISCIII) and European Regional Development Fund (ERDF). EG has received funding from the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement No 116030 (TransQST), which is supported by the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA).Peer ReviewedPostprint (published version

Magnetic Resonance Imaging in Studying Schizophrenia, Negative Symptoms, and the Glutamate System

Schizophrenia is characterized by positive, negative and cognitive symptoms. While positive symptoms occur periodically during psychotic exacerbations, negative and cognitive symptoms often emerge before the first psychotic episode and persist with low functional outcome and poor prognosis. This review article outlines the importance of modern functional magnetic resonance imaging (fMRI) techniques for developing a stratified therapy of schizophrenic disorders. Functional neuroimaging evidence on the neural correlates of positive and particularly negative symptoms and cognitive deficits in schizophrenic disorders is briefly reviewed. Acute dysregulation of dopaminergic neurotransmission is crucially involved in the occurrence of psychotic symptoms. However, increasing evidence also implicates glutamatergic pathomechanisms, in particular N-methyl-D-aspartate (NMDA) receptor dysfunction in the pathogenesis of schizophrenia and in the appearance of negative symptoms and cognitive dysfunctions. In line with this notion, several gene variants affecting the NMDA receptor’s pathway have been reported to increase susceptibility for schizophrenia, and have been investigated using the imaging genetics approach. In recent years, several attempts have been made to develop medications modulating the glutamatergic pathway with modest evidences for efficacy. The most successful approaches were those that aimed at influencing this pathway using compounds that enhance NMDA receptor function. The selective glycine reuptake inhibitor Bitopertin has been shown to improve NMDA receptor hypofunction by increasing glycine concentrations in the synaptic cleft. Further research is required to test whether pharmacological agents with effects on the glutamatergic system can help to improve the treatment of negative symptoms in schizophrenic disorders

Acute effects of muscarinic M1 receptor modulation on AβPP metabolism and amyloid-β levels in vivo: a microdialysis study

Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-β (Aβ) production by shifting endoproteolytic amyloid-β protein precursor (AβPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aβ production in awake and freely moving AβPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aβ concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aβ levels while treatment with the M1 antagonist dicyclomine increased ISF Aβ levels reaching significance within 120 minutes of treatment. The reduction in Aβ levels was associated with PKCα and ERK activation resulting in increased levels of the α-secretase ADAM17 and a shift in AβPP processing toward the non-amyloidogenic processing pathway. In contrast, treatment with the M1 receptor antagonist dicyclomine caused a decrease in levels of phosphorylated ERK that was independent of PKCα, and led to an elevation of β-secretase levels associated with increased amyloidogenic AβPP processing. The results of this study demonstrate rapid effects of in vivo M1 receptor modulation on the ISF pool of Aβ and suggest that intracerebral microdialysis with retrodialysis is a useful technical approach for monitoring acute treatment effects of muscarinic receptor modulators on AβPP/Aβ metabolism

Artificial Intelligence–Aided Precision Medicine for COVID-19: Strategic Areas of Research and Development

Artificial intelligence (AI) technologies can play a key role in preventing, detecting, and monitoring epidemics. In this paper, we provide an overview of the recently published literature on the COVID-19 pandemic in four strategic areas: (1) triage, diagnosis, and risk prediction; (2) drug repurposing and development; (3) pharmacogenomics and vaccines; and (4) mining of the medical literature. We highlight how AI-powered health care can enable public health systems to efficiently handle future outbreaks and improve patient outcomes.We are deeply thankful to the Women’s Brain Project (WBP) (www.womensbrainproject.com), an international organization advocating for women’s brain and mental health through scientific research, debate, and public engagement. The authors would like to thank Maria Teresa Ferretti and Shahnaz Radjy for the helpful comments. DC, AM, and AV have received funding from the European Commission’s Horizon 2020 Program H2020-SC1-DTH-2018-1, “iPC-individualizedPaediatricCure” (ref. 826121), and H2020-ICT-2018-2, “INFORE-Interactive Extreme-Scale Analytics and Forecasting” (ref. 825070).Peer ReviewedPostprint (published version

Simulating SARS-CoV-2 epidemics by region-specific variables and modeling contact tracing app containment

Targeted contact-tracing through mobile phone apps has been proposed as an instrument to help contain the spread of COVID-19 and manage the lifting of nation-wide lock-downs currently in place in USA and Europe. However, there is an ongoing debate on its potential efficacy, especially in light of region-specific demographics. We built an expanded SIR model of COVID-19 epidemics that accounts for region-specific population densities, and we used it to test the impact of a contact-tracing app in a number of scenarios. Using demographic and mobility data from Italy and Spain, we used the model to simulate scenarios that vary in baseline contact rates, population densities, and fraction of app users in the population. Our results show that, in support of efficient isolation of symptomatic cases, app-mediated contact-tracing can successfully mitigate the epidemic even with a relatively small fraction of users, and even suppress altogether with a larger fraction of users. However, when regional differences in population density are taken into consideration, the epidemic can be significantly harder to contain in higher density areas, highlighting potential limitations of this intervention in specific contexts. This work corroborates previous results in favor of app-mediated contact-tracing as mitigation measure for COVID-19, and draws attention on the importance of region-specific demographic and mobility factors to achieve maximum efficacy in containment policies.This material is based upon work supported by the European Commission’s Horizon 2020 Program, H2020-ICT-12-2018-2020, “INFORE - Interactive Extreme-Scale Analytics and Forecasting” (ref. 825070). The authors would like to acknowledge the Spanish Ministry of Transport, Mobility and Urban Agenda for assistance and support with mobility data.Peer ReviewedPostprint (published version

Regulatory and Health Technology Assessment Considerations for Disease-Modifying Drugs in Alzheimer's Disease

Although there are a growing number of well-reported, late-stage clinical trial failures in Alzheimer's disease, the introduction of a disease-modifying therapy within the next 5 years may be anticipated. These treatments are likely to target Alzheimer's disease in the earlier disease stages, unlike drugs that are currently available that treat symptoms of moderate-to-severe dementia. Therefore, there is a need to establish a consensus on regulatory and health technology assessment requirements for Alzheimer's disease, as a new drug will need to undergo regulatory and health technology assessments before it becomes available to patients. This article reports the discussions and activities of the regulatory and health technology assessment expert advisory group of the 2-year ROADMAP (real-world outcomes across the Alzheimer's disease spectrum: a multimodal data access platform) project. The expert advisory group discussions identified a lack of consensus on validated outcomes in the earliest Alzheimer's disease stages, the need for filling gaps between outcomes used across clinical trials and real-world settings, and the role that real-world evidence might have in characterising the impact of a possible disease-modifying therapy on caregivers, resource use and long-term outcomes