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AD-Related Dementias Focus
LBD Pathogenesis and Mechanisms of Toxicity: Identify mechanisms of selective vulnerability, disease heterogeneity, disease spread/propagation, and interaction with other age-related pathologies as therapeutic targets.
2027 RFA-NS-18-024: Lewy Body Dementia Center Without Walls (CWOW) (U54) RFA-NS-19-013: Lewy Body Dementia Center Without Walls (CWOW) (U54) RFA-NS-19-027: Human Three-Dimensional Cell Model Systems for Alzheimer's Disease-Related Dementias (ADRDs) (UG3/UH3) PAR-19-167: Development and Validation of Advanced Mammalian Models for Alzheimer's Disease-Related Dementias (ADRD) (R61/R33) RFA-NS-21-006: Mechanisms of Pathological Spread of Abnormal Proteins in LBD and FTD (R01 Clinical Trial Not Allowed) RFA-NS-21-007: Mechanisms of Selective Vulnerability in LBD and FTD (R01 Clinical Trial Not Allowed) PAR-23-211: Mechanistic Investigations into ADRD Multiple Etiology Dementias (R01 - Clinical Trial Not Allowed) PAR-23-154: Development and Validation of Models for Alzheimer’s Disease-Related Dementias (ADRD) (R61/R33 - Clinical Trial Not Allowed) 2.M Achieved Develop LBD animal, cellular, and in vitro models that recapitulate key features, including clinical pathophysiologic heterogeneity to identify mechanistic candidates for interventions. DN 2016 ADRD Summit: Lewy Body Dementias (LBD) Focus Area 4: Model Disease Processes to Develop Potential Symptomatic and Disease Modifying Therapies, Recommendation 7 Highlight: A common marker of neurological diseases may play role in healthy brains Workshop: Dementia with Lewy Bodies: Filling the Gaps in Translational and Clinical Research Research on Disease Mechanisms Lewy Body Dementia Center Without Walls (CWOW) (U54) Human Three-Dimensional Cell Model Systems for Alzheimer's Disease-Related Dementias (ADRDs) (UG3/UH3) Development and Validation of Advanced Mammalian Models for Alzheimer's Disease-Related Dementias (ADRD) (R61/R33) Select projects funded in FY21 Select projects funded in FY22
- At least one new project investigating α-synuclein spreading and α-synuclein interactions with other dementia-associated pathologies and how these interactions increase (or decrease) risk of symptomatic disease.
- At least two studies to understand why some brain cells are vulnerable to pathological alpha-synuclein accumulation while others are resistant.
Summary of Key Accomplishments
NINDS currently supports a Center Without Walls with four separate projects that are devoted to understanding how misfolded alpha-synuclein (αSyn) protein seen in the brain cells of people with Lewy body dementia interacts with other AD/ADRD-related misfolded proteins, like beta-amyloid and tau, to initiate or accelerate brain disease in LBD. NINDS has also funded several awards in response to a funding opportunity to encourage research on how alpha-synuclein spreads and why certain brain regions and cell types are more vulnerable to abnormal aSyn accumulation than others, respectively.
While these awards are ongoing, they have already yielded important findings. For example, researchers found that αSyn accumulation was increased in people living with LBD or Alzheimer’s who were also carriers of the ApoE4 gene, and that this effect occurred regardless of how much beta amyloid or tau was also present. Another study showed that abnormal aSyn can be transferred between individual brain cells, and that the shapes that buildups of αSyn assumed in the nucleus of the cell predicted how quickly the cell would die. Other NIH-funded researchers showed that αSyn-related pathology in a specific brain region called the amygdala was structurally unique and associated with worse disease progression in people with LBD than in people with AD. These and other studies are advancing our understanding of how aSyn spreads, how it interacts with other abnormal proteins, and how certain brain regions might be affected by it.
The key accomplishments summary is current as of June 2024.