(T1030-05-28) Sex Difference of Glucose Transport in an Alzheimer’s disease Transgenic Mouse Model

Purpose: Brain energy metabolism underlies complex mechanisms that can be altered during aging and under neurodegenerative conditions. Position emission tomography/computed tomography with [¹⁸F] fluorodeoxyglucose (¹⁸FDG-PET/CT) as a tracer to evaluate brain glucose uptake is widely used to detect regional hypometabolism in Alzheimer’s disease (AD) patients. Recently, large population studies have shown that women are at a greater risk of developing AD and show faster cognitive decline after diagnosis than men. Despite the close association of brain hypometabolism with AD progression, sex-related differences in glucose transport in AD brain and the underlying pathophysiological mechanisms have not yet been fully understood. The current study is aimed at elucidating sex differences in glucose transport in an AD transgenic mouse model (APP/PS1).

Methods: To estimate the ¹⁸FDG transport kinetics, non-transgenic or APP/PS1 transgenic mice that over express toxic amyloid beta petides (Aß) in the brain were bolus injected with 500 µCi of ¹⁸FDG into the femoral vein. Subsequently, the animals were scanned by dynamic PET/CT imaging to monitor the brain accumulation of ¹⁸FDG from 0 to 30 minutes. Plasma was simultaneously sampled periodically from the femoral artery between 0-30 minutes. Further, the brain influx clearance (Ki) and distribution volume of ¹⁸FDG were estimated by using Gjedde-Patlak Graphical analysis and Logan plot, respectively.  To identify molecular pathways driving sex-dependent vulnerability to aberrant glucose transport into the brain, RNA-Seq data (prefrontal cortex) of AD and non-cognitively impaired (NCI) individuals from the Rush Religious Orders Study and Memory and Aging Project (ROSMAP) was obtained. Pathway scores were calculated at an individual sample level by gene set variation analysis (GSVA) using R-package. The Limma analysis of the GSVA scores was then conducted to evaluate sex difference within the AD and healthy controls.

Results: The blood-to-brain influx rate (Ki) of ¹⁸FDG between the male and female non- transgenic as well as APP/PS1 transgenic mice showed statistically significant differences (two-way ANOVA analysis). In female mice, the Ki of ¹⁸FDG was significantly increased in APP/PS1 transgenic mice compared to  non-transgenic mice, while no changes were observed within male mice. Moreover, both transgenic and non-transgenic mice showed a significantly higher Ki of ¹⁸FDG in female mice compared to male mice. Similarly, distribution volume of 18FDG between the male and female was found to be significantly different within APP/PS1 transgenic mice but not different within non- transgenic mice. In female APP/PS1 transgenic mice, the distribution volume of 18FDG was significantly higher compared to male APP/PS1 transgenic mice. Moreover, growth factor signaling, and inflammatory pathways are differentially expressed in male versus female AD patients. Specifically, growth factor signaling pathways are activated in males, and inflammatory pathways are activated in female patients (FDR < 0.05). However, no sex-related difference was found in non-cognitively impaired (NCI) subjects.

Conclusion: Consequently, selectivity of BBB glucose transport regulated by these pathways are changed differently in females compared to their male counterparts. The rise in ¹⁸FDG uptake in female mice may reflect inflammation activation, which further cause higher risk of AD.

Gene expression differences between male and female (A) AD patients and (B) non-cognitively impaired (NCI) individuals.



Inflammatory pathways (A) and insulin pathways (B) are respectively activated in AD females (A.F) and AD males (A.M). No significant difference was observed between NCI males (N.M) and females (N.F.). (C) Summary of fold changes on gene pathway in A.M. compared to A.F.



Sex-dependent changes in the brain 18FDG uptake. (A) The Patlak plot of 18FDG comparing sex differences in non-transgenic (NC) and APP/PS1 transgenic (C) mice. (B) The brain influx clearance (Ki, mL/min) were estimated by the slope obtained from Patlak plot (mean ± S.D.). (C) Logan plot of 18FDG comparing sex differences in non-transgenic (NC) and APP/PS1 transgenic (C) mice. (D) The distribution volume (mL) of 18FDG were estimated by the slope obtained from Logan plot (mean ± S.D.)