Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 10;103(11):e209866.
doi: 10.1212/WNL.0000000000209866. Epub 2024 Nov 4.

Lumipulse-Measured Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer Disease

Michelle Safransky  1 , Jenna R Groh  1 , Kaj Blennow  1 , Henrik Zetterberg  1 , Yorghos Tripodis  1 , Brett Martin  1 , Jason Weller  1 , Breton M Asken  1 , Gil D Rabinovici  1 , Wendy Wei Qiao Qiu  1 , Ann C McKee  1 , Thor D Stein  1 , Jesse Mez  1 , Rachel L Henson  1 , Justin Long  1 , John C Morris  1 , Richard J Perrin  1 , Suzanne E Schindler  1 , Michael L Alosco  1
Affiliations

Lumipulse-Measured Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer Disease

Michelle Safransky et al. Neurology. .

Abstract

Background and objectives: CSF biomarkers of Aβ42 and phosphorylated tau (p-tau181) are used clinically for the detection of Alzheimer disease (AD) pathology during life. CSF biomarker validation studies have largely used clinical diagnoses and/or amyloid PET imaging as the reference standard. The few existing CSF-to-autopsy studies have been restricted to late-stage AD. This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathologic changes among brain donors who had normal cognition at the time of lumbar puncture (LP).

Methods: This was a retrospective study of brain donors from the National Alzheimer's Coordinating Center who had normal cognition at the time of LP and who had measurements of CSF Aβ42 and p-tau181 performed with Lumipulse assays. All brain donors were from Washington University Knight ADRC. Staging of AD neuropathologic change (ADNC) was made based on National Institute on Aging-Alzheimer's Association criteria. For this study, participants were divided into 2 categories: "AD-" (no AD/low ADNC) and "AD+" (intermediate/high ADNC). Accuracy of each biomarker for discriminating AD status was evaluated using area under the curve (AUC) statistics generated using predicted probabilities from binary logistic regressions that controlled for age, sex, APOE ε4, and interval between LP and death.

Results: The average age at LP was 79.3 years (SD = 5.6), and the average age at death was 87.1 years (SD = 6.5). Of the 49 brain donors, 24 (49%) were male and 47 (95.9%) were White. 20 (40.8%) had autopsy-confirmed AD. The average interval from LP until death was 7.76 years (SD = 4.31). CSF p-tau181/Aβ42 was the optimal predictor of AD, having excellent discrimination accuracy (AUC = 0.97, 95% CI 0.94-1.00, p = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, p = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, p = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, p = 0.005). Effects remained after controlling for prevalent comorbid neuropathologies. CSF p-tau181/Aβ42 was strongly associated with CERAD ratings of neuritic amyloid plaque scores and Braak staging of NFTs.

Discussion: This study supports Lumipulse-measured CSF Aβ42 and p-tau181 and, particularly, the ratio of p-tau181 to Aβ42, for the early detection of AD pathophysiologic processes.

Classification of evidence: This study provides Class II evidence that Lumipulse measures of p-tau181/Aβ42 in the CSF accurately discriminated cognitively normal participants with and without Alzheimer disease neuropathologic change.

PubMed Disclaimer

Conflict of interest statement

M.J. Safransky and J.R. Groh report no disclosures relevant to this manuscript. K. Blennow reports serving as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; he has served at data monitoring committees for Julius Clinical and Novartis; he has given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. H. Zetterberg reports serving on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). Y. Tripodis, B. Martin, J. Weller, and B. Asked report no disclosures relevant to this manuscript. G.D. Rabinovici reports that he receives research support from NIA, NINDS, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, Alliance for Therapeutics in Neurodegeneration, Avid, GE Healthcare, LMI (all for New IDEAS); Genentech; is a paid consultant (SAB, last 36 months) for Alector, Eli Lilly, Merck; is a paid DSMB member for Johnson & Johnson; and he is an associate editor of JAMA Neurology. W.Q. Qiu, A.C. McKee, T.D. Stein, J. Mez, R.L. Henson, and J. Long report no disclosures relevant to this manuscript. J.C. Morris reports that he consults for Barcelonaβeta Brain Research Foundation Scientific Advisory Board and Diverse VCID Observational Study Monitoring Board; is on the advisory board for Cure Alzheimer's Fund Research Strategy Council and LEADS Advisory Board, University of Indiana. Neither J.C. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. R.J. Perrin reports that his laboratory receives cost recovery funding from Biogen for tissue procurement and processing services related to ALS clinical trials. Neither R.J. Perrin nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. S.E. Schindler reports that she has served on scientific advisory boards and consulted for Eisai. M.L. Alosco reports that he receives royalties from Oxford University Press Inc., and research support from Life Molecular Imaging Inc and Rainwater Charitable Foundation Inc. Go to Neurology.org/N for full disclosures.

References

    1. Olsson B, Lautner R, Andreasson U, et al. . CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15(7):673-684. doi:10.1016/S1474-4422(16)00070-3 - DOI - PubMed
    1. Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6(3):131-144. doi:10.1038/nrneurol.2010.4 - DOI - PubMed
    1. Counts SE, Ikonomovic MD, Mercado N, Vega IE, Mufson EJ. Biomarkers for the early detection and progression of Alzheimer's disease. Neurotherapeutics. 2017;14(1):35-53. doi:10.1007/s13311-016-0481-z - DOI - PMC - PubMed
    1. Hansson O, Seibyl J, Stomrud E, et al. . CSF biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression: a study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018;14(11):1470-1481. doi:10.1016/j.jalz.2018.01.010 - DOI - PMC - PubMed
    1. Moscoso A, Karikari TK, Grothe MJ, et al. . CSF biomarkers and plasma p-tau181 as predictors of longitudinal tau accumulation: implications for clinical trial design. Alzheimers Dement. 2022;18(12):2614-2626. doi:10.1002/alz.12570 - DOI - PubMed

Grants and funding