{"doi":"10.1002/alz.14571","title":"Influence of alpha‐synuclein on glucose metabolism in Alzheimer's disease continuum: Analyses of α‐synuclein seed amplification assay and FDG‐PET","abstract":"INTRODUCTION: We investigated the association between alpha-synuclein (α-syn) pathology and brain glucose metabolism across the cognitive spectrum of Alzheimer's disease (AD) co-pathologies. METHODS: Fluorodeoxyglucose positron emission tomography (FDG-PET) data from 829 Alzheimer's Disease Neuroimaging Initiative participants (648 cognitively impaired [CI], 181 unimpaired [CU]) were compared between α-syn seed amplification assay (SAA) positive and negative groups. Interactions with cerebrospinal fluid (CSF) AD biomarkers were examined. RESULTS: SAA+ was associated with widespread hypometabolism among CI individuals, particularly in posterior cortical regions, independent of CSF amyloid and tau levels in the occipital lobes. Regional hypometabolism mediated the effect of α-syn SAA on disease severity in CI individuals, independent of CSF amyloid and tau levels. There were no influences of SAA on FDG-PET in CU individuals. DISCUSSION: This study supports a model in which α-syn aggregation influences metabolic dysfunction, which then influences clinical disease severity, independent of AD. SAA+ could help optimize participant selection and outcome measures for clinical trials in AD. HIGHLIGHTS: α-synuclein seed amplification positivity (SAA+) was associated with hypometabolism in cognitively impaired individuals. Hypometabolism mediated the influence of α-synuclein on disease severity. Occipital hypometabolism in SAA+ was independent of cerebrospinal fluid levels of Alzheimer's disease pathology. These findings can optimize future clinical trials targeting α-synuclein pathology.","journal":"Alzheimer s & Dementia","year":2025,"id":514171,"datarank":0.33699495997636864,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.00741127337593566,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.00741127337593566,"corpus_percentile":48.38709677419355,"corpus_rank":6673,"citation_count":8,"citer_count":5,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.6419,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":259155,"name":"Scott A. Przybelski","orcid":"0009-0009-3437-3773","position":1,"is_corresponding":false},{"id":272791,"name":"Heather J. Wiste","orcid":null,"position":2,"is_corresponding":false},{"id":567109,"name":"Angela J. Fought","orcid":"0000-0002-7486-8596","position":3,"is_corresponding":false},{"id":264830,"name":"Christopher G. Schwarz","orcid":"0000-0002-1466-8357","position":4,"is_corresponding":false},{"id":226057,"name":"Matthew L. Senjem","orcid":"0000-0001-9308-9275","position":5,"is_corresponding":false},{"id":49956,"name":"Clifford R. Jack","orcid":"0000-0001-7916-622X","position":6,"is_corresponding":false},{"id":259159,"name":"Val J. Lowe","orcid":"0000-0002-5612-1667","position":7,"is_corresponding":false},{"id":27599,"name":"Ronald C. Petersen","orcid":"0000-0002-8178-6601","position":8,"is_corresponding":false},{"id":108587,"name":"Bradley F. Boeve","orcid":"0000-0002-4153-8187","position":9,"is_corresponding":false},{"id":108591,"name":"John T. O’Brien","orcid":"0000-0002-0837-5080","position":10,"is_corresponding":false},{"id":108589,"name":"Kejal Kantarci","orcid":"0000-0002-8001-2081","position":11,"is_corresponding":false},{"id":300139,"name":"for the Alzheimer's Disease Neuroimaging Initiative","orcid":null,"position":12,"is_corresponding":false},{"id":495913,"name":"Elijah Mak","orcid":"0000-0002-6437-8024","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:48:23.284782Z","pmid":"39935389","pmcid":"PMC11815207","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}