{"doi":"10.1002/ana.26492","title":"Association of Presynaptic Loss with Alzheimer's Disease and Cognitive Decline","abstract":"Objective Increased presynaptic dysfunction measured by cerebrospinal fluid (CSF) growth‐associated protein‐43 (GAP43) may be observed in Alzheimer's disease (AD), but how CSF GAP43 increases relate to AD‐core pathologies, neurodegeneration, and cognitive decline in AD requires further investigation. Methods We analyzed 731 older adults with baseline β‐amyloid (Aβ) positron emission tomography (PET), CSF GAP43, CSF phosphorylated tau181 (p‐Tau 181 ), and 18 F‐fluorodeoxyglucose PET, and longitudinal residual hippocampal volume and cognitive assessments. Among them, 377 individuals had longitudinal 18 F‐fluorodeoxyglucose PET, and 326 individuals had simultaneous longitudinal CSF GAP43, Aβ PET, and CSF p‐Tau 181 data. We compared baseline and slopes of CSF GAP43 among different stages of AD, as well as their associations with Aβ PET, CSF p‐Tau 181 , residual hippocampal volume, 18 F‐fluorodeoxyglucose PET, and cognition cross‐sectionally and longitudinally. Results Regardless of Aβ positivity and clinical diagnosis, CSF p‐Tau 181 ‐positive individuals showed higher CSF GAP43 concentrations ( p < 0.001) and faster rates of CSF GAP43 increases ( p < 0.001) compared with the CSF p‐Tau 181 ‐negative individuals. Moreover, higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases were strongly related to CSF p‐Tau 181 independent of Aβ PET. They were related to more rapid hippocampal atrophy, hypometabolism, and cognitive decline ( p < 0.001), and predicted the progression from MCI to dementia (area under the curve for baseline 0.704; area under the curve for slope 0.717) over a median 4 years of follow up. Interpretation Tau aggregations rather than Aβ plaques primarily drive presynaptic dysfunction measured by CSF GAP43, which may lead to sequential neurodegeneration and cognitive impairment in AD or neurodegenerative diseases. ANN NEUROL 2022;92:1001–1015","journal":"Annals of Neurology","year":2022,"id":246089,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8973,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":881829,"name":"Yue Cai","orcid":"0000-0002-3711-5325","position":1,"is_corresponding":false},{"id":639119,"name":"Anqi Li","orcid":"0000-0002-3037-9483","position":2,"is_corresponding":false},{"id":693576,"name":"Zhen Liu","orcid":"0000-0002-5978-3412","position":3,"is_corresponding":false},{"id":881830,"name":"Shaohua Ma","orcid":"0000-0001-6649-171X","position":4,"is_corresponding":false},{"id":277015,"name":"Tengfei Guo","orcid":"0000-0003-2982-0865","position":5,"is_corresponding":false},{"id":300139,"name":"for the Alzheimer's Disease Neuroimaging Initiative","orcid":null,"position":6,"is_corresponding":false},{"id":881828,"name":"Guoyu Lan","orcid":"0000-0003-2925-1738","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T00:23:43.438539Z","pmid":"36056679","pmcid":null,"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":[]}