Microglial sex dimorphism poses greater vulnerability to Alzheimer's disease in females: A cross‐species study: Neuroimaging / multi‐modal comparisons. (7th December 2020)

• Record Type: Journal Article
• Authors: Kang, Min Su; Ottoy, Julie; Aliaga, Arturo Aliaga; Mathotaarachchi, Sulantha; Savard, Mélissa; Chamoun, Mira; Stevenson, Jenna; Rahmouni, Nesrine; Thomas, Emilie; Benedet, Andréa Lessa; Tissot, Cécile; Therriault, Joseph; Lussier, Firoza Z; Wang, Yi‐Ting; Arias, Jaime Fernandez; Massarweh, Gassan; Soucy, Jean‐Paul; Gauthier, Serge; Rosa‐Neto, Pedro; Terada, Tatsuhiro
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.046730
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Understanding sex dimorphism in neurodevelopment and neurodegeneration is imperative for therapeutic strategy, clinical trial enrichment, and personalized medicine. However, the cellular underpinning of sex dimorphism in Alzheimer's disease (AD) pathophysiology is still poorly understood. Here, we aimed to investigate the effect of sex on microglial activation and its effect on cognition using the major targets of AD clinical trials – amyloid ([ 18 F]AZD4694), tau ([ 18 F]MK6240), and neuroinflammation ([ 11 C]PBR28) – through a multimodal PET study in humans and rats. Method: A total of 108 participants (70 CN, 25 MCI, and 13 AD; 36 M, 72 F) with a high‐affinity binder for TSPO from the TRIAD cohort underwent 3 PET scans and MMSE for cognitive assessment. Static [ 18 F]AZD4694, [ 18 F]MK6240, and [ 11 C]PBR28 SUVR images were generated. All PET images were normalized to the ADNI template, used cerebellar grey as a reference region. Furthermore, 29 rats (8 WT, 21 Tg; 13 M, 16 F) underwent a 60‐min dynamic [ 18 F]AZD4694 and [ 11 C]PBR28 PET scans. All PET images were normalized to the average template. [ 18 F]AZD4694 and [ 11 C]PBR28 BPND were quantified based on SRTM method using Pons and midbrain as a reference region, respectively. The sex effect on neuroinflammation is evaluated based on a linear regression model in humans and rats. Consequently, sex dimorphism induced neuroinflammation effect on cognition was assessed using MMSE. All the models were corrected for age, APOE, education, amyloid and tau status. Result: In this study, females showed greater [ 11 C]PBR28 binding in basal temporal regions in humans and parietotemporal cortex, hippocampus, and basal forebrain in rats. Consequently, greater neuroinflammation in females showed negative effects on MMSE but not in males, p = 0.033. Conclusion: This study demonstrated the greater microglia activation in females compared to males. Considering the difference in the microglia reaction to amyloidosis in rodents compared to humans, the increased microglial activation effect on cognition was only assessed in humans. Here, microglial sex dimorphism showed deleterious effects on cognition only in females. This study highlights the difference in microglial reactivity leading to greater vulnerability to cognitive decline in females. As such, it is imperative to explore a sex‐specific therapeutic strategy for AD clinical trial.