Contributions of a high-fat diet to Alzheimer's disease-related decline: A longitudinal behavioural and structural neuroimaging study in mouse models

Neuroimage Clin. 2019;21:101606. doi: 10.1016/j.nicl.2018.11.016. Epub 2018 Nov 20.


Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported that obesity accelerates AD-related pathophysiology and memory impairment in mouse models of AD. However, the nature of the brain structure-behaviour relationship mediating this acceleration remains unclear. In this manuscript we evaluated the impact of adolescent obesity on the brain morphology of the triple transgenic mouse model of AD (3xTg) and a non-transgenic control model of the same background strain (B6129s) using longitudinally acquired structural magnetic resonance imaging (MRI). At 8 weeks of age, animals were placed on a high-fat diet (HFD) or an ingredient-equivalent control diet (CD). Structural images were acquired at 8, 16, and 24 weeks. At 25 weeks, animals underwent the novel object recognition (NOR) task and the Morris water maze (MWM) to assess short-term non-associative memory and spatial memory, respectively. All analyses were carried out across four groups: B6129s-CD and -HFD and 3xTg-CD and -HFD. Neuroanatomical changes in MRI-derived brain morphology were assessed using volumetric and deformation-based analyses. HFD-induced obesity during adolescence exacerbated brain volume alterations by adult life in the 3xTg mouse model in comparison to control-fed mice and mediated volumetric alterations of select brain regions, such as the hippocampus. Further, HFD-induced obesity aggravated memory in all mice, lowering certain memory measures of B6129s control mice to the level of 3xTg mice maintained on a CD. Moreover, decline in the volumetric trajectories of hippocampal regions for all mice were associated with the degree of spatial memory impairments on the MWM. Our results suggest that obesity may interact with the brain changes associated with AD-related pathology in the 3xTg mouse model to aggravate brain atrophy and memory impairments and similarly impair brain structural integrity and memory capacity of non-transgenic mice. Further insight into this process may have significant implications in the development of lifestyle interventions for treatment of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / chemically induced
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Behavior, Animal / physiology*
  • Brain / pathology
  • Cognitive Dysfunction / pathology
  • Cognitive Dysfunction / physiopathology*
  • Diet, High-Fat*
  • Disease Models, Animal
  • Female
  • Magnetic Resonance Imaging / methods
  • Male
  • Memory Disorders / physiopathology
  • Memory, Short-Term / physiology
  • Mice
  • Neuroimaging*
  • Spatial Memory / physiology
  • tau Proteins / metabolism


  • Amyloid beta-Protein Precursor
  • tau Proteins