eprintid: 10110561 rev_number: 49 eprint_status: archive userid: 608 dir: disk0/10/11/05/61 datestamp: 2020-09-23 10:03:57 lastmod: 2022-08-17 15:04:54 status_changed: 2021-04-27 10:33:00 type: article metadata_visibility: show creators_name: Keshavan, A creators_name: Pannee, J creators_name: Karikari, T creators_name: Lantero Rodriguez, J creators_name: Ashton, NJ creators_name: Nicholas, JM creators_name: Cash, D creators_name: Coath, W creators_name: Lane, CA creators_name: Parker, TD creators_name: Lu, K creators_name: Buchanan, SM creators_name: Keuss, SE creators_name: James, SN creators_name: Murray Smith, H creators_name: Wong, A creators_name: Barnes, A creators_name: Dickson, JC creators_name: Heslegrave, A creators_name: Portelius, E creators_name: Richards, M creators_name: Fox, N creators_name: Zetterberg, H creators_name: Blennow, K creators_name: Schott, J title: Population-based blood screening for pre-clinical Alzheimer's disease in a British birth cohort at age 70 ispublished: pub subjects: UCH divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 divisions: C10 divisions: D17 divisions: D14 divisions: GA3 divisions: G17 keywords: Alzheimer’s disease, amyloid imaging, dementia, beta-amyloid, tau, epidemiology note: © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. abstract: Alzheimer’s disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques—liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181—to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden’s index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628–0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548–0.691) and phospho-tau181 (0.707; 0.646–0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770–0.864 and amyloid-β composite: 0.820; 0.775–0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10–50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence. date: 2021-02 date_type: published publisher: Oxford University Press (OUP) official_url: http://dx.doi.org/10.1093/brain/awaa403 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1814915 doi: 10.1093/brain/awaa403 lyricists_name: Buchanan, Sarah lyricists_name: Cash, David lyricists_name: Coath, William lyricists_name: Dickson, John lyricists_name: Fox, Nicholas lyricists_name: Heslegrave, Amanda lyricists_name: James, Sarah lyricists_name: Keshavan, Ashvini lyricists_name: Keuss, Sarah lyricists_name: Lu, Kirsty lyricists_name: Parker, Thomas lyricists_name: Richards, Marcus lyricists_name: Schott, Jonathan lyricists_name: Wong, Andrew lyricists_name: Zetterberg, Henrik lyricists_id: SMBUC64 lyricists_id: DMCAS28 lyricists_id: WOCOA32 lyricists_id: JCDIC92 lyricists_id: NCIFO25 lyricists_id: AJHES09 lyricists_id: SNJAM11 lyricists_id: AKESH31 lyricists_id: SEKEU60 lyricists_id: KMACP41 lyricists_id: TPARK85 lyricists_id: MRICH78 lyricists_id: JMSCH12 lyricists_id: AWKWO84 lyricists_id: HZETT94 actors_name: Allington-Smith, Dominic actors_id: DAALL44 actors_role: owner full_text_status: public publication: Brain volume: 144 number: 2 pagerange: 434-449 citation: Keshavan, A; Pannee, J; Karikari, T; Lantero Rodriguez, J; Ashton, NJ; Nicholas, JM; Cash, D; ... Schott, J; + view all <#> Keshavan, A; Pannee, J; Karikari, T; Lantero Rodriguez, J; Ashton, NJ; Nicholas, JM; Cash, D; Coath, W; Lane, CA; Parker, TD; Lu, K; Buchanan, SM; Keuss, SE; James, SN; Murray Smith, H; Wong, A; Barnes, A; Dickson, JC; Heslegrave, A; Portelius, E; Richards, M; Fox, N; Zetterberg, H; Blennow, K; Schott, J; - view fewer <#> (2021) Population-based blood screening for pre-clinical Alzheimer's disease in a British birth cohort at age 70. Brain , 144 (2) pp. 434-449. 10.1093/brain/awaa403 <https://doi.org/10.1093/brain%2Fawaa403>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10110561/9/Population-based%20blood%20screening%20for%20preclinical%20Alzheimers%20disease%20in%20a%20British%20birth%20cohort%20at%20age%2070.pdf