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Related Experiment Video

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Absolute Winding Number Differentiates Mouse Spatial Navigation Strategies With Genetic Risk for Alzheimer's Disease.

Alexandra Badea1,2,3,4, Didong Li5,6, Andrei R Niculescu1

  • 1Department of Radiology, Duke University, Durham, NC, United States.

Frontiers in Neuroscience
|July 5, 2022
PubMed
Summary
This summary is machine-generated.

New spatial navigation metrics reveal distinct Alzheimer's disease (AD) risk patterns. The absolute winding number metric identified unique search strategies in APOE3 mice and highlighted APOE4 female vulnerability, suggesting potential early AD biomarkers.

Keywords:
APOEAlzheimer’s diseaseMRIbrainconnectivitymemorymouse

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Area of Science:

  • Neuroscience
  • Genetics
  • Cognitive Science

Background:

  • Spatial navigation deficits are early indicators of cognitive decline in Alzheimer's disease (AD).
  • APOE gene alleles (APOE2, APOE3, APOE4) influence AD risk, with APOE4 being the major genetic risk factor.
  • Understanding genotype-specific navigation strategies can reveal preclinical AD biomarkers.

Purpose of the Study:

  • To introduce and validate a novel metric, the absolute winding number, for analyzing spatial search strategies in mouse models.
  • To investigate how different humanized APOE genotypes (APOE2, APOE3, APOE4) affect spatial memory and navigation.
  • To explore sex-specific differences in navigation strategies related to AD risk.

Main Methods:

  • Utilized mouse models with humanized APOE alleles (APOE2, APOE3, APOE4).
  • Assessed spatial memory and navigation using the Morris water maze task.
  • Introduced and applied the absolute winding number metric to quantify swim path shapes and search strategies.
  • Analyzed brain network reliance (hippocampal and caudate putamen circuits) and white matter connections.

Main Results:

  • The absolute winding number metric effectively differentiated spatial search strategies, with APOE3 carriers exhibiting straighter paths than APOE2 and APOE4 carriers.
  • APOE4 female mice showed increased vulnerability, indicating sex-specific effects on navigation.
  • Genotype-dependent differences in reliance on hippocampal and caudate putamen circuits were observed, suggesting altered brain network involvement.
  • These differences were more pronounced in females, highlighting sex-specific neural circuit engagement.

Conclusions:

  • The absolute winding number is a robust metric for characterizing spatial navigation strategies and identifying subtle cognitive differences.
  • Spatial navigation strategies and brain network engagement vary significantly across APOE genotypes, particularly in females.
  • This network-based approach, moving beyond a hippocampal-centric view, offers new avenues for identifying individuals at risk for AD before clinical manifestation.
  • Novel biomarkers based on spatial navigation could enhance early detection and intervention opportunities for prodromal Alzheimer's disease.