Multiple Etiology Dementias: Facilitate basic and clinical research

AD-Related Dementias Focus

Advance basic research on the common and interacting risk factors and mechanisms of multiple etiology cognitive impairment and dementia in diverse populations.

2027 PAS-17-028: Common Mechanisms and Interactions Among Neurodegenerative Diseases (R01) PAR-18-661: Pathway and Target Identification for Alzheimer's Disease Related Dementias (ADRDs) RFA-NS-19-026: Clinical and Biological Measures of TBI-related dementia including Chronic Traumatic Encephalopathy (CTE) (R01) RFA-NS-19-030: Neuropathological Assessment of TBI-related Neurodegeneration and Neurocognitive Decline - Center Without Walls (NATBI CWOW) (U54) PAR-19-167: Development and Validation of Advanced Mammalian Models for Alzheimer's Disease-Related Dementias (ADRD) (R61/R33) RFA-NS-19-027: Human Three-Dimensional Cell Model Systems for Alzheimer's Disease-Related Dementias (ADRDs) (UG3/UH3) RFA-NS-20-005: Mechanistic Basis of TDP-43-Dependent Pathobiology in Common Dementias (R01) RFA-NS-21-006: Mechanisms of Pathological Spread of Abnormal Proteins in LBD and FTD (R01 Clinical Trial Not Allowed) NOT-NS-21-040: Administrative Supplements for Collaborative Activities to Promote Sleep/Circadian Research in ADRD PAR-22-023: Multi-Disciplinary Collaborations to Understand Mechanisms of Systemic Immune Signaling and Inflammation in ADRD and its Progression (R01 Clinical Trial Not Allowed) PAR-22-029: Longitudinal Single Cell Characterization of ADRD Postmortem Tissue (R01 Clinical Trial Not Allowed) PAR-22-037: Role of Astrocytes in Degeneration of the Neurovascular Unit in AD/ADRDs (R01 Clinical Trial Not Allowed) PAR-22-048: Clinical Relevance of the Linkage between Environmental Toxicant Exposures and Alzheimer’s Disease and Related Dementias (R01 Clinical Trial Not Allowed) https://grants.nih.gov/grants/guide/pa-files/par-22-059.html PAR-22-211: Impact of the Microbiome-Gut-Brain Axis on Alzheimer's Disease and Alzheimer's Disease-Related Dementias (R01 Clinical Trial Not Allowed) PAR-22-235: Blood Brain Barrier Response to Antibodies Targeting Beta-Amyloid (R01 - Clinical Trial Not Allowed) PAR23-023: Cellular and Molecular Mechanisms of Prion-Like Aggregate Seeding, Propagation, and Neurotoxicity in AD/ADRD (R01 Clinical Trial Not Allowed) PAR-23-140: Blood Brain Barrier Response to Antibodies Targeting Beta-Amyloid (R01 - Clinical Trial Not Allowed) (Reissue of PAR-22-235) PAR-23-211: Mechanistic Investigations into ADRD Multiple Etiology Dementias (R01 - Clinical Trial Not Allowed) RFA-NS-24-009: Optimization of Genome Editing Therapeutics for Alzheimer's Disease-Related Dementias (ADRD) (U01 - Clinical Trials Not Allowed) (Reissue of RFA-NS-23-017) PAR-24-147: Mechanistic Investigations into ADRD Multiple Etiology Dementias (R01 - Clinical Trial Not Allowed) RFA-NS-25-014: Mechanisms of Cognitive Fluctuations in ADRD Populations (R01 - Clinical Trial Optional) 2.L In Progress Promote basic and clinical research in multi-etiology dementia. DN 2016 ADRD Summit: Multiple Etiology Dementias (MED) Focus Area 2: Basic and Clinical Research in Interactions between Dementia Pathophysiologies, Recommendation 5 (PDF, 901K) 2022 ADRD Summit: Multiple Etiology Dementias (MED) Milestone 4, Priority 2 News: Gene expression signatures of Alzheimer’s disease News: Pathogenic tau and cognitive impairment are precipitated by a high-salt diet News: Gene variant may help protect against Alzheimer's disease News: Unique case of disease resistance reveals possible Alzheimer's treatment Potential contributor to sex differences in Alzheimer’s risk Press Release: Salty immune cells surrounding the brain linked to hypertension-induced dementia Highlight: Neurodegeneration in a genetic form of Alzheimer’s disease is independent of beta-amyloid Highlight: The Long Life Family Study (LLFS): Whole genome sequence of long-lived families identifies MTUS gene as a novel candidate for late onset AD Research on Disease Mechanisms Pathway and Target Identification for Alzheimer's Disease Related Dementias (ADRDs) Clinical and Biological Measures of TBI-related dementia including Chronic Traumatic Encephalopathy (CTE) (R01) Neuropathological Assessment of TBI-related Neurodegeneration and Neurocognitive Decline - Center Without Walls (NATBI CWOW) (U54) Development and Validation of Advanced Mammalian Models for Alzheimer's Disease-Related Dementias (ADRD) (R61/R33) Human Three-Dimensional Cell Model Systems for Alzheimer's Disease-Related Dementias (ADRDs) (UG3/UH3) Center Without Walls for Imaging Proteinopathies with PET (CW2IP2) Select projects funded in FY21 Select projects funded in FY22 Alzheimer’s Disease Research Centers Mind Your Risks

  • At least three new mechanistic projects on interacting molecular pathways and risk factors that either accelerate or protect against cognitive decline and dementia in general and diverse US populations.

Summary of Key Accomplishments

NIH issued several funding opportunities to explore common and interacting mechanisms of AD/ADRD, understand the impact of the microbiome on AD/ADRD, elucidate mechanisms of how co-pathologies affect disease processes and accelerate disease progression, investigate the role of environmental stress on health inequities in AD/ADRD, and identify new potential clinical targets that can detect characteristics of Alzheimer’s vs. Alzheimer’s related dementias as compared to healthy individuals. As one example, NINDS funds the “Center Without Walls for Imaging Proteinopathies with PET,” which is using novel, sophisticated technology to visualize and differentiate several different AD- and ADRD brain changes. Researchers are also working to determine the impact of air pollution exposure on cognition and neuropathology in models of AD. Additionally, NIH-funded researchers have been investigating resilience mechanisms and how they influence immune responses and alter AD/ADRD neuropathology.

NIH-funded researchers are also studying the mechanisms underlying sex differences in AD/ADRD risk. Recently, NIH-funded scientists studying how and why buildup of an abnormal form of a protein called tau occurs at higher levels in women over time than in males identified a possible new therapeutic target called USP11. The protein USP11 is a regulator of tau levels in cells, and the gene for this protein is located on the X-chromosome, thus linking it to female biology. Scientists found that high USP11 levels were more strongly associated with tau tangles in samples taken from female brains than from male brains. These findings show how USP11 can affect the development of Alzheimer’s disease differently in men and women and may contribute to cognitive impairment with a greater effect in women than men.

The key accomplishments summary is current as of June 2024.