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

## TL;DR

This study explores how amyloid-β and tau affect brain metabolism in a genetic form of Alzheimer’s, finding that distant effects may explain differences between pathology and metabolism.

## Contribution

The study reveals region-specific interactions between amyloid-β, tau, and hypometabolism in autosomal-dominant Alzheimer’s disease.

## Key findings

- Mutation carriers showed lower glucose metabolism in the precuneus and isthmus cingulate.
- Frontal tau accumulation correlated with hypometabolism independently of global tau burden.
- Memory decline was linked to hypometabolism in tau-affected regions, mediated by pathology interactions.

## 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.

Tristão-Pereira et al. investigate the local and global contributions of amyloid-β and tau to glucose metabolism in autosomal-dominant Alzheimer’s disease using PET. Their findings suggest that distant rather than local effects may explain regional discrepancies between pathology accumulation and metabolic decline, underscoring that region-specific pathology interactions contribute to memory function.

Graphical Abstract