Abstract
The APOE Ɛ4 genotype is the most prevalent genetic risk for Alzheimer's disease (AD). Women carriers of Ɛ4 have higher risk for an early onset of AD than men. Human imaging studies suggest apolipoprotein Ɛ4 may affect brain structures associated with cognitive decline in AD many years before disease onset. It was hypothesized that female APOE Ɛ4 carriers would present with decreased cognitive function and neuroradiological evidence of early changes in brain structure and function as compared to male carriers.Six-month old wild-type (WT) and human APOE Ɛ4 knock-in (TGRA8960), male and female Sprague Dawley rats were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas.Quantitative volumetric analysis revealed areas involved in memory and arousal were significantly different between Ɛ4 and wild-type (WT) females, with few differences between male genotypes. Diffusion weighted imaging showed few differences between WT and Ɛ4 females, while male genotypes showed significant different measures in fractional anisotropy and apparent diffusion coefficient. Resting state functional connectivity showed Ɛ4 females had greater connectivity between areas involved in cognition, emotion, and arousal compared to WT females, with male Ɛ4 showing few differences from controls. Interestingly, male Ɛ4 showed increased anxiety and decreased performance in spatial and episodic memory tasks compared to WT males, with female genotypes showing little difference across behavioral tests.The sex differences in behavior and diffusion weighted imaging suggest male carriers of the Ɛ4 allele may be more vulnerable to cognitive and emotional complications compared to female carriers early in life. Conversely, the data may also suggest that female carriers are more resilient to cognitive/emotional problems at this stage of life perhaps due to altered brain volumes and enhanced connectivity.
Highlights
Apolipoprotein E (ApoE) is found throughout the body, and is known for its role in regulating protein metabolism and lipid transport between cells [1]
There were very few brain areas that differed in volume between the male genotypes (See Supplementary Fig. 1) Comparisons between WT females vs WT males and Ɛ4 females and Ɛ4 males were few in number (See Supplementary Figs. 1 & 2)
Female Ɛ4 had larger brain volumes in reticular activating system (RAS), brainstem, and cerebellum than WT females, while there were no significant differences in brain volumes between male genotypes
Summary
Apolipoprotein E (ApoE) is found throughout the body, and is known for its role in regulating protein metabolism and lipid transport between cells [1]. The Ɛ4 allele is: i) more often found in women with AD than men [6], ii) is associated with an earlier age of familial AD onset [7], and iii) presents an overall greater risk for developing AD [8]. These combined associated factors indicate that sex differences influence the pathogenesis and progression of AD, related studies investigating early cognitive decline in Ɛ4 carriers have yielded contradicting findings. It was hypothesized that female APOE Ɛ4 carriers would present with decreased cognitive function and neuroradiological evidence of early changes in brain structure and function as compared to male carriers
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