{"doi":"10.1093/brain/awad398","title":"Insulin-like growth factor binding protein-2 in at-risk adults and autopsy-confirmed Alzheimer brains","abstract":"Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signalling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein in the CSF, IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed during up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the Quebec Founder Population (QFP) cohort, a unique population isolated from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 [CSF Aβ(+)/t-tau(+)]. In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (hazard ratio = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049); however, IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2 in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion.","journal":"Brain","year":2023,"id":335730,"datarank":1.8441937988883121,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":1.3875154332297988,"self_endowment_contribution":0.4566783656585135,"citer_contribution":1.3875154332297988,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":16,"citers_with_citation_signal":11,"citers_with_endowment":11,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1065662,"name":"Anne Labonté","orcid":"0000-0001-8076-7540","position":1,"is_corresponding":false},{"id":1065663,"name":"Cynthia Picard","orcid":"0000-0003-1107-6839","position":2,"is_corresponding":false},{"id":27601,"name":"Henrik Zetterberg","orcid":"0000-0003-3930-4354","position":3,"is_corresponding":false},{"id":27600,"name":"Kaj Blennow","orcid":"0000-0002-1890-4193","position":4,"is_corresponding":false},{"id":585722,"name":"Ann Brinkmalm","orcid":"0000-0002-7396-3233","position":5,"is_corresponding":false},{"id":351879,"name":"Sylvia Villeneuve","orcid":"0000-0003-2338-0467","position":6,"is_corresponding":false},{"id":276910,"name":"Judes Poirier","orcid":"0000-0002-8018-4545","position":7,"is_corresponding":false},{"id":243718,"name":"for the Alzheimer’s Disease Neuroimaging Initiative","orcid":null,"position":8,"is_corresponding":false},{"id":1031430,"name":"Michael W Weiner","orcid":null,"position":9,"is_corresponding":false},{"id":229340,"name":"Paul Aisen","orcid":null,"position":10,"is_corresponding":false},{"id":27599,"name":"Ronald C. 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