Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design

Alzheimers Dement. 2023 Jan;19(1):318-332. doi: 10.1002/alz.12814. Epub 2022 Oct 14.


Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

Keywords: Lewy body dementia; MRI neurodegeneration; PET; cerebrospinal fluid; clinical trials; dementia; dementia with Lewy bodies; parkinsonism; α-synuclein.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / pathology
  • Biomarkers
  • Clinical Trials as Topic
  • Cross-Sectional Studies
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Lewy Body Disease* / complications
  • Lewy Body Disease* / pathology
  • Parkinsonian Disorders / etiology
  • REM Sleep Behavior Disorder / etiology


  • Biomarkers
  • TARDBP protein, human
  • DNA-Binding Proteins