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However, there are regional discrepancies in hypometabolism and Alzheimer\u2019s pathological markers. We examined the local and global contributions of amyloid-\u03b2 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\u2019s 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\u2019s Disease word list learning. A subgroup of 22 carriers and 26 non-carriers additionally had measures of amyloid-\u03b2 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-\u03b2 and tau pathology, and memory using Spearman correlation. Local specificity was assessed by partial correlations controlling for global amyloid-\u03b2 and tau burden. Finally, we studied whether the link between Alzheimer\u2019s 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-\u03b2 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-\u03b2 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\u2019s disease. The lack of local correlations between amyloid-\u03b2, 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.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf508","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T12:29:53Z","timestamp":1767011393000},"source":"Crossref","is-referenced-by-count":5,"title":["Contribution of local amyloid-\u03b2 and tau burden to hypometabolism in autosomal-dominant Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"8","author":[{"given":"Catarina","family":"Trist\u00e3o-Pereira","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School , Boston, MA 02114 ,","place":["USA"]},{"name":"Department of Psychological and Brain Sciences, Boston University , Boston, MA 02215 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