Phthalate and phthalate replacement concentrations in relationship to adiposity in a multi-racial cohort of children.

BACKGROUND/OBJECTIVE: Phthalates and phthalate replacements are used in multiple everyday products, making many of them bioavailable to children. Experimental studies suggest that phthalates and their replacements may be obesogenic, however, epidemiologic studies remain inconsistent. Therefore, our objective was to examine the association between phthalates, phthalate replacements and childhood adiposity/obesity markers in children. SUBJECTS/METHODS: A cross-sectional study was conducted in 630 racial/ethnically diverse children ages 4-8 years. Urinary oxidative metabolites of DINCH and DEHTP, three low molecular weight (LMW) phthalates, and eleven high molecular weight (HMW) phthalates were measured. Weight, height, waist circumference and % body fat were measured. Composite molar sum groups (nmol/ml) were natural log-transformed. Linear regression models adjusted for urine specific gravity, sex, age, race-ethnicity, birthweight, breastfeeding, reported activity level, mother's education and pre-pregnancy BMI. RESULTS: All children had LMW and HMW phthalate metabolites and 88% had DINCH levels above the limit of detection. One unit higher in the log of DINCH was associated with 0.106 units lower BMI z-score [ß = -0.106 (95% CI: -0.181, -0.031)], 0.119 units lower waist circumference z-score [ß = -0.119 (95% CI: -0.189, -0.050)], and 0.012 units lower percent body fat [ß = -0.012 (95% CI: -0.019, -0.005)]. LMW and HMW group values were not associated with adiposity/obesity. CONCLUSIONS: We report an inverse association between child urinary DINCH levels, a non-phthalate plasticizer that has replaced DEHP in several applications, and BMI z-score, waist circumference z-score and % body fat in children. Few prior studies of phthalates and their replacements in children have been conducted in diverse populations. Moreover, DINCH has not received a great deal of attention or regulation, but it is a common exposure. In summary, understanding the ubiquitous nature of these chemical exposures and ultimately their sources will contribute to our understanding of their relationship with obesity.

Weight Gain of Infants with Robin Sequence Treated Nonsurgically Using the Stanford Orthodontic Airway Plate (SOAP): 1-Year Follow-Up.

OBJECTIVE: To identify weight gain trends of infants with Robin sequence (RS) treated by the Stanford Orthodontic Airway Plate treatment (SOAP). DESIGN: Retrospective longitudinal cohort study. SETTING: Single tertiary referral hospital. PATIENTS: Eleven infants with RS treated with SOAP. INTERVENTIONS: Nonsurgical SOAP. MAIN OUTCOME MEASURES: Body weight, Weight-for-age (WFA) Z-scores, and WFA percentiles at birth (T0), SOAP delivery (T1), SOAP graduation (T2), and 12-months old (T3). RESULTS: Between T0 and T1, the weight increased but the WFA percentile decreased from 36.5% to 15.1%, and the Z-score worsened from -0.43 to -1.44. From T1 to T2, the percentile improved to 22.55% and the Z-score to -0.94. From T2 to T3, the percentile and the Z-scores further improved to 36.59% and -0.48, respectively. CONCLUSIONS: SOAP provided infants experiencing severe respiratory distress and oral feeding difficulty with an opportunity to gain weight commensurate with the WHO healthy norms without surgical intervention.

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

2,4-di-tert-butylphenol exposure impairs osteogenic differentiation.

2,4-di-tert-butylphenol (2,4-DTBP) is a synthetic antioxidant used in polyethylene crosspolymer (PEX) water distribution pipes and food-related plastics. 2,4-DTBP can leach from plastic materials and has been found in breast milk, cord blood, and placental tissue, giving rise to the concern that this compound may interfere with fetal development. The objective of this study is to assess the impacts of 2,4-DTBP on cellular differentiation. Human induced pluripotent stem (HiPS) cells were differentiated into osteoblasts or myoblasts over 40 days, and analyzed for markers of somite, dermomyotome, sclerotome, myoblast, and osteoblast development. When cultured as stem cells, 2,4-DTBP did not alter cell viability and expression of markers (NANOG, OCT4). However, upon differentiation into somite-like cells, 2,4-DTBP had reduced levels of MEOX1 and TBX6 transcripts, while NANOG and OCT4 were in turn upregulated in a dose-dependent manner. At the sclerotome-like stage, PAX9 mRNA decreased by 2-fold in the 0.5 µM and 1.0 µM 2,4-DTBP exposure groups. After 40 days of differentiation into an osteoblast-like lineage, exposure to 2,4-DTBP significantly reduced expression of the osteogenesis transcripts RUNX2 and OSX in a dose-dependent manner. Further, Alizarin Red staining of calcium deposits was decreased in the 0.5 µM and 1.0 µM treatment groups. In contrast, myogenesis was not affected by 2,4-DTBP exposure. Interestingly, KEAP1 expression was significantly increased in the sclerotomal-like cells, but decreased in the dermomytomal-like cells, which may suggest a mechanism of action. Overall, this study shows that 2,4-DTBP can delay key processes during sclerotome and osteoblast development, leading to a potential for bone developmental issues in exposed individuals.

Blood Pressure Goals: Is Cerebral Saturation the New Mean Arterial Pressure?

OBJECTIVE: The objective of this article was to correlate hypotension and cerebral saturation from near-infrared spectroscopy (cNIRS) in neonates on dopamine. STUDY DESIGN: Retrospective review of neonates receiving dopamine between August 2018 and 2019 was performed. Hypotension thresholds included mean arterial pressure (MAP) of postmenstrual age (PMA) ± 5 and 30 mm Hg and gestational age (GA) ± 5 mm Hg. Time below threshold MAP was compared with time with cerebral hypoxia (cNIRS <55%). RESULTS: Hypotension occurred 6 to 33% of the time on dopamine in 59 cases. Hypotension did not correlate with abnormal cNIRS overall, within PMA subgroups or by outcomes. Hypotensive periods with MAP < GA had fewer corresponding percent time with abnormal cNIRS events (3.7 ± 1.3%) compared with MAP < PMA (11.9 ± 4.9%, p < 0.003) or 30 mm Hg thresholds (12.2 ± 4.7%, p < 0.0001). In most premature infants, mean cNIRS values during hypotension were still within normal range (57 ± 6%). CONCLUSION: cNIRS may be a more clinically relevant measure than MAP for the assessment of neonatal hypotension. KEY POINTS: · Hypotension occurred 6 to 33% of the time on dopamine in 59 cases.. · Hypotension did not correlate with abnormal cNIRS overall, within PMA subgroups or by outcomes.. · MAP. · We found no cNIRS difference between IVH grades, mortality, average Hct, lactates, or urine output.. · cNIRS may be a more clinically relevant measure than MAP for the assessment of neonatal hypotension..

Alzheimer's disease research progress in Australia: The Alzheimer's Association International Conference Satellite Symposium in Sydney.

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.

Arsenic exposure in drinking water reduces Lgr5 and secretory cell marker gene expression in mouse intestines.

Arsenic is a global health concern that causes toxicity through ingestion of contaminated water and food. In vitro studies suggest that arsenic reduces stem and progenitor cell differentiation. Thus, this study determined if arsenic disrupted intestinal stem cell (ISC) differentiation, thereby altering the number, location, and/or function of intestinal epithelial cells. Adult male C57BL/6 mice were exposed to 0 or 100 ppb sodium arsenite (AsIII) through drinking water for 5 weeks. Duodenal sections were collected to assess changes in morphology, proliferation, and cell types. qPCR analysis revealed a 40% reduction in Lgr5 transcripts, an ISC marker, in the arsenic-exposed mice, although there were no changes in the protein expression of Olfm4. Secretory cell-specific transcript markers of Paneth (Defa1), Goblet (Tff3), and secretory transit amplifying (Math1) cells were reduced by 51%, 44%, and 30% respectively, in the arsenic-exposed mice, indicating significant impacts on the Wnt-dependent differentiation pathway. Further, protein levels of phosphorylated ß-catenin were reduced in the arsenic-exposed mice, which increased the expression of Wnt-dependent transcripts CD44 and c-myc. PCA analysis, followed by MANOVA and regression analyses, revealed significant changes and correlations between Lgr5 and the transit amplifying (TA) cell markers Math1 and Hes1, which are in the secretory cell pathway. Similar comparisons between Math1 and Defa1 show that terminal differentiation into Paneth cells is also reduced in the arsenic-exposed mice. The data suggests that ISCs are not lost following arsenic exposure, but rather, specific Wnt-dependent progenitor cell formation and terminal differentiation in the small intestine is reduced.

Long-term arsenic exposure impairs differentiation in mouse embryonal stem cells.

Arsenic is a contaminant found in many foods and drinking water. Exposure to arsenic during development can cause improper neuronal progenitor cell development, differentiation, and function, while in vitro studies have determined that acute arsenic exposure to stem and progenitor cells reduced their ability to differentiate. In the current study, P19 mouse embryonal stem cells were exposed continuously to 0.1-µM (7.5 ppb) arsenic for 32 weeks. A cell lineage array examining messenger RNA (mRNA) changes after 8 and 32 weeks of exposure showed that genes involved in pluripotency were increased, whereas those involved in differentiation were reduced. Therefore, temporal changes of select pluripotency and neuronal differentiation markers throughout the 32-week chronic arsenic exposure were investigated. Sox2 and Oct4 mRNA expression were increased by 1.9- to 2.5-fold in the arsenic-exposed cells, beginning at Week 12. Sox2 protein expression was similarly increased starting at Week 16 and remained elevated by 1.5-fold to sixfold. One target of Sox2 is N-cadherin, whose expression is a hallmark of epithelial-mesenchymal transitions (EMTs). Exposure to arsenic significantly increased N-cadherin protein levels beginning at Week 20, concurrent with increased grouping of N-cadherin positive cells at the perimeter of the embryoid body. Expression of Zeb1, which helps increase the expression of Sox2, was also increased started at Week 16. In contrast, Gdf3 mRNA expression was reduced by 3.4- to 7.2-fold beginning at Week 16, and expression of its target protein, phospho-Smad2/3, was also reduced. These results suggest that chronic, low-level arsenic exposure may delay neuronal differentiation and maintain pluripotency.

Retinal imaging in Alzheimer's and neurodegenerative diseases.

In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.

Criteria for Psychosis in Major and Mild Neurocognitive Disorders: International Psychogeriatric Association (IPA) Consensus Clinical and Research Definition.

Psychosis is common among individuals with neurocognitive disorders, is difficult to manage, and causes considerable burden and stress to patients and caregivers. Developing effective treatments is a substantial unmet medical need but research has been slowed by the need for updated consensus diagnostic criteria. To address this need, the International Psychogeriatrics Association initiated a process to develop criteria for clinical use, research, and treatment development efforts. The process included clinical, regulatory, and industry stakeholders as well as input from a global network of experts in geriatric psychiatry responding to two surveys (N = 336). Results from the consensus process confirmed that clinicians wanted elaboration of aspects of the definition proposed by Jeste and Finkel in 2000 to ensure that the criteria are applied appropriately. Based on discussions, the survey, and emerging research, criteria were revised to apply to psychosis occurring with all major and mild neurocognitive disorders. Other important changes include providing examples of hallucinations and delusions and clarifying time course, impact, and exclusionary criteria. This definition of psychosis in major and mild neurocognitive disorders can be used to advance many types of research including development of much needed pharmacologic and nonpharmacologic interventions for psychosis in patients with neurocognitive disorders.

Further understanding the connection between Alzheimer's disease and Down syndrome.

Improved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). In March 2019, the Alzheimer's Association, Global Down Syndrome Foundation and the LuMind IDSC Foundation partnered to convene a workshop to explore the state of the research on the intersection of AD and DS research; to identify research gaps and unmet needs; and to consider how best to advance the field. This article provides a summary of discussions, including noting areas of emerging science and discovery, considerations for future studies, and identifying open gaps in our understanding for future focus.

Embryonic arsenic exposure reduces intestinal cell proliferation and alters hepatic IGF mRNA expression in killifish (Fundulus heteroclitus).

Arsenic (As) is a toxicant found in food and water throughout the world, and studies suggested that exposure early in life reduces growth. Thus, the goal of this study was to examine mechanisms by which As impacted organismal growth. Killifish (Fundulus heteroclitus) were exposed to 0, 10, 50, or 200 ppb As as embryos and, after hatching, were reared in clean water for up to 40 weeks. Metabolism studies revealed that killifish biotransform As such that monomethylated and dimethylated arsenicals account for 15-17% and 45-61%, respectively, of the total metal. Growth, as measured by condition factor (CF), was significantly and dose-dependently reduced at 8 weeks of age but was similar to controls by 40 weeks. To determine mechanisms underlying the observed initial decrease, intestinal proliferation and morphology were examined. Arsenic-exposed fish exhibited significant 1.3- to 1.5-fold reduction in intestinal villus height and 1.4- to 1.6-fold decrease in proliferating cell nuclear antigen (PCNA+) intestinal cells at all weeks examined. In addition, there were significant correlations between CF, PCNA+ cells, and intestinal villus height. Upon examining whether fish might compensate for the intestinal changes, it was found that hepatic mRNA expression of insulin-like growth factor 1 (IGF-1) and its binding protein (IGFBP-1) were dose-dependently increased. These results indicate that embryonic exposure initially diminished growth, and while intestinal cell proliferation remained reduced, fish appear to compensate by enhancing transcript levels of hepatic IGF-1 and IGFBP-1.

Long-Range Modulation of PAG1 Expression by 8q21 Allergy Risk Variants.

The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. The aim of this study was to identify the target gene(s) and the functional variant(s) underlying the association between rs7009110 on chromosome 8q21 and allergies. Eight genes are located within 1 Mb of rs7009110. Multivariate association analysis of publicly available exon expression levels from lymphoblastoid cell lines (LCLs) identified a significant association between rs7009110 and the expression of a single gene, PAG1 (p = 0.0017), 732 kb away. Analysis of histone modifications and DNase I hypersensitive sites in LCLs identified four putative regulatory elements (PREs) in the region. Chromosome conformation capture confirmed that two PREs interacted with the PAG1 promoter, one in allele-specific fashion. To determine whether these PREs were functional, LCLs were transfected with PAG1 promoter-driven luciferase reporter constructs. PRE3 acted as a transcriptional enhancer for PAG1 exclusively when it carried the rs2370615:C allergy predisposing allele, a variant in complete linkage disequilibrium with rs7009110. As such, rs2370615, which overlaps RelA transcription factor (TF) binding in LCLs and was found to disrupt Foxo3a binding to PRE3, represents the putative functional variant in this locus. Our studies suggest that the risk-associated allele of rs2370615 predisposes to allergic disease by increasing PAG1 expression, which might promote B cell activation and have a pro-inflammatory effect. Inhibition of PAG1 expression or function might have therapeutic potential for allergic diseases.

Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling.

BACKGROUND: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. OBJECTIVE: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. METHODS: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. RESULTS: We tested the association between asthma and 17,190 genes that were found to have cis- and/or trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, LIMS1, TINF2, and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13, and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs. CONCLUSION: We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.

Military-related risk factors for dementia.

INTRODUCTION: In recent years, there has been growing discussion to better understand the pathophysiological mechanisms of traumatic brain injury and post-traumatic stress disorder and how they may be linked to an increased risk of neurodegenerative diseases including Alzheimer's disease in veterans. METHODS: Building on that discussion, and subsequent to a special issue of Alzheimer's & Dementia published in June 2014, which focused on military risk factors, the Alzheimer's Association convened a continued discussion of the scientific community on December 1, 2016. RESULTS: During this meeting, participants presented and evaluated progress made since 2012 and identified outstanding knowledge gaps regarding factors that may impact veterans' risk for later life dementia. DISCUSSION: The following is a summary of the invited presentations and moderated discussions of both the review of scientific understanding and identification of gaps to inform further investigations.

The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease: Perspectives from the Research Roundtable.

The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the "A, T, N System" (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.

Allergen-induced IL-6 trans-signaling activates γδ T cells to promote type 2 and type 17 airway inflammation.

BACKGROUND: A variant in the IL-6 receptor (IL-6R) gene increases asthma risk and is predicted to decrease IL-6 classic signaling and increase IL-6 trans-signaling. This suggests that inhibition of IL-6 trans-signaling, but not classic signaling, might suppress allergic airway inflammation. OBJECTIVES: We sought to determine whether IL-6 signaling contributes to (1) acute experimental asthma induced by clinically relevant allergens and (2) variation in asthma clinical phenotypes in asthmatic patients. METHODS: Mice were sensitized to house dust mite (HDM) or cockroach at day 0, treated with IL-6R inhibitors at day 13, and challenged with the same allergen at days 14 to 17. End points were measured 3 hours after the final challenge. IL-6 and soluble IL-6 receptor (sIL-6R) expression in induced sputum of asthmatic patients was correlated with asthma clinical phenotypes. RESULTS: Both HDM and cockroach induced a type 2/type 17 cytokine profile and mixed granulocytic inflammation in the airways. Both allergens increased IL-6 expression in the airways, but only cockroach induced sIL-6R expression. Therefore HDM challenge promoted IL-6 classic signaling but not trans-signaling; in this model treatment with anti-IL-6R did not suppress airway inflammation. In contrast, cockroach-induced inflammation involved activation of IL-6 trans-signaling and production of IL-17A by γδ T cells. Anti-IL-6R, selective blockade of sIL-6R, or γδ T-cell deficiency significantly attenuated cockroach-induced inflammation. Asthmatic patients with high airway IL-6 and sIL-6R levels were enriched for the neutrophilic and mixed granulocytic subtypes. CONCLUSION: Experimental asthma associated with both high IL-6 and high sIL-6R levels in the airways is attenuated by treatment with IL-6R inhibitors.

Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders.

Tau: From research to clinical development.

Alzheimer's Association Research Roundtable Fall 2015-Tau: From research to clinical development. Tau pathology is recognized as the key driver of disease progression in Alzheimer's and other neurodegenerative diseases. Although this makes tau an attractive target for the development of novel diagnostic and therapeutic strategies, the mechanisms underlying the onset and progression of tau-related neurotoxicity remain elusive. Recent strides in the development of sophisticated preclinical models and the emergence of tau PET imaging and fluid biomarkers provide new opportunities to increase our understanding of tau biology, overcome translational challenges, and accelerate the advancement of tau therapeutics from bench to bedside. With this in mind, the Alzheimer's Association convened a Research Roundtable in October 2015, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of tau pathogenic pathways and review the evolution of tau therapeutics and biomarkers currently in development. The meeting provided a forum to share experience and expertise with the common goal of advancing the discovery and development of new treatment strategies and expediting the design and implementation of efficient clinical trials.

Sex biology contributions to vulnerability to Alzheimer's disease: A think tank convened by the Women's Alzheimer's Research Initiative.

More than 5 million Americans are living with Alzheimer's disease (AD) today, and nearly two-thirds of Americans with AD are women. This sex difference may be due to the higher longevity women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimer's Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex- and gender-related disparities of risk for AD.