Contribution of local amyloid-β and tau burden to hypometabolism in autosomal-dominant Alzheimer's disease

Abstract

Glucose hypometabolism is observed in early Alzheimer's disease. However, there are regional discrepancies in hypometabolism and Alzheimer's pathological markers. We examined the local and global contributions of amyloid-β and tau pathology to glucose metabolism and their interplay in memory decline in Presenilin-1 E280A mutation carriers and non-carriers from the largest autosomal-dominant Alzheimer's disease kindred. This cross-sectional study included 43 mutation carriers (6 cognitively impaired) and 39 non-carriers from the Colombia-Boston Biomarker Study. Glucose metabolism was assessed with [18F]fluorodeoxyglucose PET, and memory performance with the Consortium to Establish a Registry for Alzheimer's Disease word list learning. A subgroup of 22 carriers and 26 non-carriers additionally had measures of amyloid-β and tau using 11C-Pittsburgh compound B and 18F-flortaucipir PET, respectively. First, we compared regional glucose metabolism between groups using the Wilcoxon rank-sum test. Then, we studied regional glucose metabolism associations with age, co-localized amyloid-β and tau pathology, and memory using Spearman correlation. Local specificity was assessed by partial correlations controlling for global amyloid-β and tau burden. Finally, we studied whether the link between Alzheimer's pathology and memory was mediated by regional glucose hypometabolism. Mutation carriers exhibited lower glucose metabolism in the precuneus and isthmus cingulate compared to non-carriers. Hypometabolism correlated locally with greater tau accumulation in the medial temporal lobe, inferior temporal gyrus and prefrontal cortex, and with greater amyloid-β accumulation in the inferior temporal gyrus in carriers. These associations were no longer significant when controlled for global pathology, except for the frontal tau-hypometabolism correlation, which was independent of global tau burden, suggesting local specificity. Additionally, lower memory performance in carriers was associated with hypometabolism in regions typically affected by tau. The mediation analysis revealed a region-specific interplay in pathology, with the associations of amyloid-β and tau pathology with memory decline being mediated by hypometabolism in the inferior temporal. Our findings highlight the metabolic vulnerability of the precuneus in early stages, supporting a common pathophysiology between autosomal-dominant and sporadic Alzheimer's disease. The lack of local correlations between amyloid-β, tau and hypometabolism suggests that distant effects may explain the regional discrepancies between pathology accumulation and metabolic alterations. This study describes a model where pathology advances and interacts in a region-specific manner to impact clinical outcomes, underscoring the importance of regional [18F]fluorodeoxyglucose PET as an independent predictor of cognitive decline. Overall, our findings improve understanding of the spatial progression of pathology, which could have important implications in disease management.

Keywords: FDG–PET; autosomal-dominant Alzheimer’s disease; cerebral hypometabolism; cognition; imaging biomarkers.

Graphical Abstract

Figure 1

Regional glucose metabolism differences between PSEN1 mutation carriers and non-carriers. Ordered effect sizes of the differences in regional FDG SUVR between groups calculated as the rank-biserial correlation r of the Wilcoxon rank-sum test (dots, n = 82) (A). Whiskers represent upper and lower bounds of bootstrap-derived 95% confidence intervals. Negative effect sizes indicate lower FDG SUVR in PSEN1 mutation carriers compared to non-carriers. Brain projections highlight the regions with statistically significant differences between groups (P < 0.05), with light colours representing larger effect sizes. Regions highlighted within the forest plot represent models that survived Bonferroni correction for multiple comparisons. Scatter plots showing the associations between age and FDG SUVR in the precuneus (B) and isthmus cingulate (C) for PSEN1 mutation carriers (n = 43) and non-carriers (n = 39), using Spearman correlation ρ. Data points represent subjects; colour lines represent estimated regression slopes; and shadows represent 95% confidence intervals. *: p_adj < 0.05. FDG, [18F]fluorodeoxyglucose; SUVR, standardized uptake value ratio; Banks Sup Temp Sulcus, banks of the superior temporal sulcus; Ventral DC, ventral diencephalon.

Figure 2

Regional association between glucose metabolism and Aβ and tau pathology in PSEN1 mutation carriers. Ordered correlation coefficients ρ of the regional associations of FDG SUVR with FTP SUVR (A) and PiB DVR (D) in PSEN1 mutation carriers (dots, n = 22) calculated from Spearman correlation. Whiskers represent upper and lower bounds of bootstrap-derived 95% confidence intervals. Brain projections highlight the regions with statistically significant correlations, with light colours representing larger effect sizes for negative correlations. Regions highlighted within the forest plot represent models that survived Bonferroni correction for multiple comparisons. Scatter plots showing the associations of FDG SUVR with FTP SUVR in the caudal middle frontal (B) and inferior temporal (C) and with PiB DVR in the inferior temporal (E) and inferior parietal (F) in PSEN1 mutation carriers (n = 22) and non-carriers (n = 26), using Spearman correlation ρ. Data points represent subjects; colour lines represent estimated regression slopes; and shadows represent 95% confidence intervals. *: p_adj < 0.05, **: p_adj < 0.01, ***: p_adj < 0.001. DVR, distribution value ratio; FDG, [18F]fluorodeoxyglucose; FTP, [18F]flortaucipir; PiB, [11C]Pittsburgh compound B; SUVR, standardized uptake value ratio; Banks Sup Temp Sulcus, banks of the superior temporal sulcus; ventral DC, Ventral diencephalon; CMF, caudal middle frontal.

Figure 3

Association between regional glucose metabolism and memory performance in PSEN1 mutation carriers. Ordered correlation coefficients ρ of the associations of regional FDG SUVR with CERAD word list learning (memory performance, (A) in PSEN1 mutation carriers (dots, n = 43) calculated from Spearman correlation. Whiskers represent upper and lower bounds of bootstrap-derived 95% confidence intervals. Brain projections highlight the regions with statistically significant correlations, with light colours representing larger effect sizes for positive correlations. Regions highlighted within the forest plot represent models that survived Bonferroni correction for multiple comparisons. Scatter plots showing the associations of CERAD word list learning in the hippocampus (B) and inferior temporal (C) for PSEN1 mutation carriers (n = 43) and non-carriers (n = 39), using Spearman correlation ρ. Data points represent subjects; colour lines represent estimated regression slopes; and shadows represent 95% confidence intervals. *: p_adj < 0.05, **: p_adj < 0.01. CERAD, Consortium to Establish a Registry for Alzheimer’s disease; FDG, [18F]fluorodeoxyglucose; SUVR , standardized uptake value ratio; Banks Sup Temp Sulcus, banks of the superior temporal sulcus; ventral DC, ventral diencephalon.

Figure 4

Mediator role of glucose metabolism on the memory correlates of Aβ and tau pathology. Associations of PiB DVR and FTP SUVR with memory performance (CERAD’s word list learning) mediated by FDG SUVR in the precuneus (A), caudal middle frontal (B), inferior temporal (C) and hippocampus (D) in the imaging sub-sample (n = 48). Mediation was performed with bootstrapping. Arrows indicate the effect of the exposure on the outcome. Solid/dashed lines represent statistically significant/non-significant associations (P < 0.05). The total and direct effects are the effects of the exposure on the outcome before and after accounting for the mediator, respectively; the indirect effect is the contribution of the mediator on the total effect; and the proportion mediated is the indirect effect over the total effect. Results are represented as standardized regression coefficients. *: P < 0.05, **: P < 0.01, ***: P < 0.001. DVR, distribution value ratio; FDG, [18F]fluorodeoxyglucose; FTP, [18F]flortaucipir; PiB, [11C]Pittsburgh compound B; SUVR, standardized uptake value ratio.