Meta-analysis of glucose metabolism across Alzheimer’s, Parkinson’s and ALS reveals distinct patterns of cortical hypometabolism versus subcortical hypermetabolism with disease-specific spatial signatures

The purpose of this meta-analysis was to determine the common signature of dysregulated brain glucose metabolism in late-onset age-associated neurodegenerative diseases (A2NDs), including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. FDG-PET studies published through July 2025 were identified from MEDLINE, Embase, PsycINFO, Scopus, and Cochrane databases. Studies comparing adults with late-onset neurodegenerative disease to healthy controls and reporting whole-brain coordinate findings were included.

Activation likelihood estimation meta-analyses were conducted using extracted coordinates of hypo- and hypermetabolism. A total of 130 studies were included, comprising 5,298 individuals with A2ND and 3,499 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A2NDs and included both hypo- and hypermetabolic patterns.

However, the spatial distribution of metabolic abnormalities differed across diseases, with each disease demonstrating distinct neuroanatomical patterns associated with disease-relevant functional systems. While hypometabolism primarily in the cortex remains a primary focus in neurodegenerative disease research due to functional relevance, hypermetabolism was also consistently identified across all three diseases, predominantly in subcortical, limbic, and cerebellar structures. This dissociation, with hypermetabolic regions localized to structures with known functional connectivity to affected cortical networks, suggests compensatory upregulation as a plausible interpretation, though alternative mechanisms, including neuroinflammation, cannot be excluded.

Collectively, the findings indicate that altered brain bioenergetics are shared across neurodegenerative diseases with unique disease-specific metabolic hypo- and hypermetabolic signatures. These findings highlight the potential importance of addressing bidirectional metabolic dysregulation alongside disease-specific pathological drivers in future prevention and treatment strategies. We acknowledge Amanda Tack for her contributions in article screening and project management.

This work was supported by NIA grants P01AG026572, R01AG063826, and T32AG061897 to RDB and the Center for Innovation in Brain Science to RDB. Center for Innovation in Brain Science, University of Arizona, 1230 N. Cherry Ave Tucson, Tucson, AZ, 85721, USA Adam C.

Raikes, Melissa Garza, Coco Tirambulo & Roberta Diaz Brinton Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA Health Sciences Library, University of Arizona, Tucson, AZ, USA Department of Neurology, College of Medicine, University of Arizona, Tucson, AZ, USA The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Below is the link to the electronic supplementary material.