Associations between sex, body mass index and the individual microglial response in Alzheimer’s disease
Authors: Biechele Gloria , Rauchmann Boris-Stephan , Janowitz Daniel , Buerger Katharina , Franzmeier Nicolai , Weidinger Endy , Guersel Selim , Schuster Sebastian , Finze Anika , Harris Stefanie , Lindner Simon , Albert Nathalie L. , Wetzel Christian , Rupprecht Rainer , Rominger Axel , Palleis Carla , Katzdobler Sabrina , Burow Lena , Kurz Carolin , Zaganjori Mirlind , Trappmann Lena-Katharina , Goldhardt Oliver , Grimmer Timo , Haeckert Jan , Keeser Daniel , Stoecklein Sophia , Morenas-Rodriguez Estrella , Bartenstein Peter , Levin Johannes , Höglinger Günter U. , Simons Mikael , Perneczky Robert , Brendel Matthias 
Published: October 2023

Abstract
Background and Objectives:
18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer’s disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between β-amyloid-accumulation and microglial activation in AD.
Methods:
49 patients with AD (29 females, all Aβ-positive) and 15 Aβ-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and β-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aβ-PET on TSPO-PET was used to determine the Aβ-plaque dependent microglial response (slope) and the Aβ-plaque independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI).
Results:
In AD, females showed higher mean cortical TSPO-PET z-scores (0.91±0.49; males 0.30±0.75; p=0.002), while Aβ-PET z-scores were similar. The Aβ-plaque independent microglial response was stronger in females with AD (+0.37±0.38; males with AD -0.33±0.87; p=0.006), pronounced at the prodromal stage. Contrary, the Aβ-plaque dependent microglial response was not different between sexes. The Aβ-plaque independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r=0.757, p=0.003), but not in males. BMI and the Aβ-plaque independent microglial response were significantly associated in females (r=0.44, p=0.018) but not in males (BMI*sex interaction: F(3,52)=3.077, p=0.005).
Conclusion:
While microglia response to fibrillar Aβ is similar between sexes, women with AD show a stronger Aβ-plaque independent microglia response. This sex difference in Aβ-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aβ-plaque independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD.