Associations between sex, body mass index and the individual microglial response in Alzheimer's disease

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. On the 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.

Keywords: Amyloid; Microglia; Sex differences; TSPO; Tau.

Fig. 1

[¹⁸F]GE-180 TSPO-PET binding in predefined target regions. A Group levels of [¹⁸F]GE-180 TSPO-PET z-scores (cerebellum scaled standardized uptake value ratio, SUV_R) between sexes in AD patients and cognitively normal controls, presented as axial overlays upon a standard magnetic resonance imaging template. B TSPO-PET z-scores in the comparison of AD diagnosis group vs. cognitively normal males and females for frontal, temporal, parietal and posterior cingulate cortex/ precuneus (PCC²). Anatomic regions are shown upon an axial MRI atlas. C TSPO-PET z-scores in the comparison of AD diagnosis group vs. cognitively normal males and females for Braak-stage I–VI regions. Anatomic regions are shown upon an axial MRI atlas. D Axial images show group levels of [¹⁸F]flutemetamol Aβ-PET (cerebellum scaled standardized uptake value ratio, SUV_R) in AD and cognitively normal controls in comparison between sexes, projected upon a standard MRI anatomic template. AD female n = 29, AD male n = 20, CN female n = 8, CN male n = 7

Fig. 2

Impact of individual Aβ-plaque-independent and associated microglial response. A Cerebellum corrected standardized uptake value ratios (SUV_R) were calculated for 210 cortical regions for TSPO-, Aβ- and Tau-PET. Per AD patient and brain region, the averaged regional increase (z-score) was calculated versus cognitively normal controls and plotted as a function of both tracers as shown. A two-dimensional microglia response index per patient was calculated, defined by the individual intercept and slope. B Comparison of Aβ-plaque-independent TSPO-PET (intercept) between female and male AD patients and cognitively normal controls and C prodromal AD and AD dementia (ADD). D Comparison of Aβ-plaque associated TSPO-PET (slope) between female and male AD patients and cognitively normal controls and E prodromal AD and ADD. P-values of the group comparisons derive from an ANCOVA with age, BMI and TSPO gene SNP as covariates, including FDR correction for multiple comparisons

Fig. 3

[¹⁸F]PI-2620 tau-PET binding in predefined target regions. A Group level binding intensity of [¹⁸F]PI-2620 tau-PET (cerebellum scaled standardized uptake value ratio, SUV_R) for female and male AD patients and mixed sex cognitively normal individuals (CN), presented as axial overlays on a standard magnetic resonance imaging template. B Correlation of tau-PET z-scores for Braak-stage regions I–VI with the Aβ-plaque-independent microglial response (intercept) for females and males with AD. Anatomic regions are shown on an axial MRI atlas. AD female n = 14, AD male n = 10, CN mixed sex n = 5

Fig. 4

Associations of obesity with the indices of microglial response. A Correlation between the body mass index (BMI) and the Aβ-plaque-independent TSPO-PET signal (intercept) for females and males with AD. B Correlation between the BMI and the Aβ-plaque associated TSPO-PET signal (slope) for females and males with AD. C Voxel-wise association of BMI and TSPO-PET values as shown by surface projections for female and male AD patients after controlling for age and TSPO gene SNP using statistical parametric mapping (SPM, V12; significance threshold: topological FDR p < 0.05; cluster threshold: 50 voxels). AD female n = 29, AD male n = 20