AD Related Dementias Focus Epidemiology/Population Studies Health Equity: Identify risk factors across diverse populations (Milestone 1.I) Assess epidemiology and mechanistic pathways of disparities in health burden of AD/ADRD. Health Equity: Monitor trends of different ADRDs in diverse populations (Milestone 1.J) Develop a system to monitor the magnitude and trends in health disparities in incidence of AD/ADRD. LBD: Characterize LBD brain pathology (Milestone 1.K) Characterize nervous system changes in LBD cohorts that have come to autopsy to identify disease-specific underlying mechanisms to guide biomarker and therapeutic approaches. LBD: Understand LBD genetic, epigenetic, and environmental influences (Milestone 1.L) Identify novel common and rare genetic variants, epigenetic changes, and environmental influences that impact the risk for and clinical features of LBD. FTD Studies: Understand the natural history of FTD (Milestone 1.M) Understand phenotypic heterogeneity and natural history in FTD. TBI in AD/ADRD: Encourage research collaborations (Milestone 1.N) Encourage crosstalk and interdisciplinary collaboration between TBI and dementia researchers. TBI in AD/ADRD: Develop infrastructure for risk factor identification (Milestone 1.O) Establish infrastructure to study TBI as a risk factor for AD/ADRD. Disease Mechanisms Multiple Etiology Dementias: Facilitate basic and clinical research (Milestone 2.L) Promote basic and clinical research in multi-etiology dementia. LBD: Understand Lewy body spreading and interactions with other AD/ADRD-related pathologies (Milestone 2.M) Develop LBD animal, cellular, and in vitro models that recapitulate key features, including clinical pathophysiologic heterogeneity to identify mechanistic candidates for interventions. FTD Basic Mechanisms: Determine role of tau and multiple pathologies (Milestone 2.N) Clarify the mechanism of tau pathogenesis and associated neurodegeneration. FTD Basic Mechanisms: Understand role of genetic mutations (Milestone 2.O) Determine the molecular basis for C9ORF72 expansion-and GRN mutation-related neurodegeneration. FTD Basic Mechanisms: Characterize TDP-43 and FUS roles in FTD (Milestone 2.P) Determine the mechanism of TDP-43 and FUS pathogenesis and toxicity. VCID Basic Research: Role of the neurovascular unit (Milestone 2.Q) Encourage basic science research that investigates the impact of aging, AD pathology, and genes on peri- and para-vascular clearance mechanisms, the NVU, and cerebrovascular function. VCID Basic Research: Understand cerebrovascular and cardiovascular risk factors for dementia (Milestone 2.R) Encourage basic science research that investigates the impact of cerebrovascular risk factors/genes and atherosclerosis on AD-related neurodegeneration. VCID Clinical Research: Determine interrelationship between VCID and AD biomarkers in humans (Milestone 2.S) Determine interrelationships among aging, cerebrovascular disease and risk factors, resilience factors, genetic variants, amyloid, tau, and neurodegeneration. LBD: Effects on non-motor brain areas and cognition (Milestone 2.T) Understanding the molecular, cellular and α-synuclein in the context of non-motor brain areas. TDP-43 in AD/ADRD: Determine molecular mechanisms of TDP-43-related disease (Milestone 2.U) Determine underlying pathobiologic and molecular mechanisms of cellular TDP-43 displacement, post-translational modifications such as phosphorylation, and pathology in pre-symptomatic and manifest common dementias. TDP-43 in AD/ADRD: Determine why TDP-43 brain pathology cccurs in both cognitively normal and cognitively impaired individuals (Milestone 2.V) Examine the pathologic phenotype(s) of TDP-43 pathology in asymptomatic persons and those with common dementias. TBI in AD/ADRD: Basic and clinical research (Milestone 2.W) Promote basic and clinical research examining the development and progression of TBI AD/ADRD neuropathologies and associated clinical symptoms. Diagnosis, Assessment, and Disease Monitoring Health Equity: Develop early cognitive assessment tools for diverse populations (Milestone 11.H) Improve tools for assessment of risks, preclinical characteristics, and costs among health disparities populations by leveraging existing data/cohorts, designing targeted studies, and using psychometric analyses. Health Equity: Disseminate culturally validated cognitive assessment tools (Milestone 11.I) Increase utilization of culturally- and linguistically-appropriate assessment tools within ongoing and newly generated studies of AD/ADRD and vascular health intervention trials. Workforce: Train AD/ADRD research and clinical health professionals (Milestone 11.J) Increase training of health professionals to meet the demand for cognitive impairment and dementia diagnosis, care, and need for human-based research. TBI in AD/ADRD: Diagnosis and clinical measurement of progressive neurodegeneration (Milestone 11.K) Characterize the clinical phenotype of progressive dementia associated with TBI Multiple Etiology Dementia: Implement interventions for reversible causes (Milestone 11.L) Intervention studies to investigate reversible causes of dementia. LBD: Develop biomarkers to detect disease prior to symptom onset (Milestone 9.J) Longitudinal antemortem LBD characterization Multiple Etiology Dementias: Support research on early detection of cognitive impairment/dementia in everyday settings (Milestone 9.K) Detect cognitive impairment when a patient or relative voices a concern to health care providers. Multiple Etiology Dementias: Develop differential AD/ADRD diagnosis (Milestone 9.L) Improving differential diagnosis of symptomatic cognitive impairment. Multiple Etiology Dementias: Establish pre-symptomatic diagnostics and biomarkers (Milestone 9.M) Develop diagnostics/biomarkers in asymptomatic individuals. Multiple Etiology Dementias: Determine impact of cognitive screening in midlife (Milestone 9.N) Determining the value of screening for clinically relevant cognitive impairment in the absence of a cognitive complaint. LBD: Develop neuroimaging markers of disease progression (Milestone 9.O) Neuroimaging characterization of LBD LBD: Biomarker development (Milestone 9.P) LBD biomarker development FTD: Biomarker development (Milestone 9.Q) Develop FTD biomarkers for diagnosis and disease progression. VCID: Develop and validate VCID biomarkers (Milestone 9.R) Develop and validate longitudinally tracked noninvasive markers of key vascular processes related to cognitive and neurologic impairment. FTD: Clinical trials (Milestone 9.S) Develop novel blood/CSF biomarkers or PET ligands for FTLD-tau, -TDP or -FUS during life TDP-43 in AD/ADRD: Establish biomarkers and dementia risk profiles (Milestone 9.T) Biomarker and risk profiles for TDP-43 Translational and Clinical Research Interventions – Non-Pharmacological VCID Clinical Trials: Interventions to reduce vascular risk factors (Milestone 8.E) Test for efficacy across the spectrum of VCID severity Translational and Clinical Research Interventions – Pharmacological LBD: Clinical trials (Milestone 5.D) Prepare for and initiate clinical trials that aim to alleviate or slow the course of LBD symptoms, and delay or prevent the onset of disease. FTD: Genetics and epigenetics (Milestone 6.I) Expand efforts to genotype patients with FTD and identify new genes and their functional relationship to FTLD pathogenesis. Translational Research and Clinical Interventions – Trial Innovation Health Equity: Optimize vascular health trial design for diverse populations (Milestone 10.G) Enrich the design of trials of vascular health interventions to improve their application to AD/ADRD among aging diverse populations. Health Equity: Design culturally tailored interventions (Milestone 10.H) Implement culturally tailored multimodal intervention trials and drug therapy trials reduce AD/ADRD burden Health Equity: Inclusion and retention of underrepresented populations in clinical research (Milestone 12.K) Develop novel and identify existing community engagement and outreach methods to facilitate engagement, understanding and partnership with health disparities populations. Dementia Care and Impact of Disease Multiple Etiology Dementia: Implementation research for dementia care (Milestone 13.L) Conducting implementation research on proven dementia care programs Health Equity: Research on disparities in health care access (Milestone 13.M) Increase policy-relevant research on disparities in access to care Research Resources Community Engagement: Facilitate NIH-NGO interactions on ADRD (Milestone 14.K) Establish effective communication between NIH and NGOs AD/ADRD Nomenclature: Research, clinical practice, and stakeholder working groups (Milestone 14.L) Organize a working group of stakeholders, including health disparities communities, to develop more consistent nomenclature in dementia research and care. Health Equity: Health disparities task force (Milestone 14.M) Generate an AD/ADRD health disparities task force AD/ADRD Nomenclature: Standardized research, clinical practice, and stakeholder nomenclature (Milestone 14.N) Integrate and refine recommendations from working groups into standardized, acceptable and accurate nomenclature that works across the spectrum of stakeholders. FTD Clinical Research: International trial network (Milestone 4.P) Create an international FTD clinical trial network. FTD Basic Research: Establish new animal and cellular models (Milestone 4.Q) Develop better FTLD in vivo and cell-based model systems. VCID Research: Establish new experimental models and imaging methods (Milestone 4.R) Develop models that: reproduce small vessel disease; are relevant to VCID and AD; address white and grey matter VCID; or include genetic and acquired VCID. Verify models, including via imaging. Health Equity: Facilitate health disparities research training (Milestone 4.S) Improve and increase training, including for individuals who are members of under-represented populations, and of different career levels of scholars who conduct health disparities research in AD/ADRD. VCID: Conduct basic research informed by findings from human studies (Milestone 4.T) Use data and other resources from large-scale clinical research and trials to test hypothesized mechanisms of human VCID in basic science models. VCID: Conduct clinical research informed by basic research findings (Milestone 4.U) Incorporate VCID findings from basic science into the design of clinical research and trials targeting VCID-relevant cognitive impairment and dementia. TDP-43 in AD/ADRD: Develop animal models (Milestone 4.V) Build new animal models to advance knowledge about TDP-43 pathology in common dementias, capitalizing on lessons learned from animal models in FTLD/ALS, AD and other diseases.