Blood Biomarkers Indicate That the Preclinical Stages of Alzheimer's Disease Present Overlapping Molecular Features

Overview

Journal Sci Rep

Specialty Science

Date 2020 Sep 25

PMID 32973179

Citations 20

Authors

Alfonso di Costanzo

Debora Paris

Dominique Melck

Antonella Angiolillo

Gaetano Corso

Mauro Maniscalco

Andrea Motta

Affiliations

Soon will be listed here.

Abstract

It is still debated whether non-specific preclinical symptoms of Alzheimer's disease (AD) can have diagnostic relevance. We followed the evolution from cognitively normal to AD by NMR-based metabolomics of blood sera. Multivariate statistical analysis of the NMR profiles yielded models that discriminated subjective memory decline (SMD), mild cognitive impairment (MCI) and AD. We validated a panel of six statistically significant metabolites that predicted SMD, MCI and AD in a blind cohort with sensitivity values ranging from 88 to 95% and receiver operating characteristic values from 0.88 to 0.99. However, lower values of specificity, accuracy and precision were observed for the models involving SMD and MCI, which is in line with the pathological heterogeneity indicated by clinical data. This excludes a "linear" molecular evolution of the pathology, pointing to the presence of overlapping "gray-zones" due to the reciprocal interference of the intermediate stages. Yet, the clear difference observed in the metabolic pathways of each model suggests that pathway dysregulations could be investigated for diagnostic purposes.

Citing Articles

Transcriptomic predictors of rapid progression from mild cognitive impairment to Alzheimer's disease.

Huang Y, Tsai T, Shen Z, Chan Y, Tu C, Tung C Alzheimers Res Ther. 2025; 17(1):3.

PMID: 39754267 PMC: 11697870. DOI: 10.1186/s13195-024-01651-0.

The Effect of APOE ε4 on Alzheimer's Disease Fluid Biomarkers: A Cross-Sectional Study Based on the COAST.

Zhao B, Zang P, Quan M, Wang Q, Guo D, Jia J CNS Neurosci Ther. 2025; 31(1):e70202.

PMID: 39749650 PMC: 11696244. DOI: 10.1111/cns.70202.

NMR-based metabolomics in Alzheimer's disease research: a review.

Vignoli A, Tenori L Front Mol Biosci. 2023; 10:1308500.

PMID: 38099198 PMC: 10720579. DOI: 10.3389/fmolb.2023.1308500.

Angelica polysaccharides relieve blood glucose levels in diabetic KKAy mice possibly by modulating gut microbiota: an integrated gut microbiota and metabolism analysis.

Tang X, Yang L, Miao Y, Ha W, Li Z, Mi D BMC Microbiol. 2023; 23(1):281.

PMID: 37784018 PMC: 10546737. DOI: 10.1186/s12866-023-03029-y.

Artificial intelligence for biomarker discovery in Alzheimer's disease and dementia.

Winchester L, Harshfield E, Shi L, Badhwar A, Al Khleifat A, Clarke N Alzheimers Dement. 2023; 19(12):5860-5871.

PMID: 37654029 PMC: 10840606. DOI: 10.1002/alz.13390.

References

Hye A, Lynham S, Thambisetty M, Causevic M, Campbell J, Byers H . Proteome-based plasma biomarkers for Alzheimer's disease. Brain. 2006; 129(Pt 11):3042-50. DOI: 10.1093/brain/awl279. View

Price J, McKeel Jr D, Buckles V, Roe C, Xiong C, Grundman M . Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009; 30(7):1026-36. PMC: 2737680. DOI: 10.1016/j.neurobiolaging.2009.04.002. View

Ryu J, McLarnon J . A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer's disease brain. J Cell Mol Med. 2008; 13(9A):2911-25. PMC: 4498946. DOI: 10.1111/j.1582-4934.2008.00434.x. View

Casanova R, Varma S, Simpson B, Kim M, An Y, Saldana S . Blood metabolite markers of preclinical Alzheimer's disease in two longitudinally followed cohorts of older individuals. Alzheimers Dement. 2016; 12(7):815-22. PMC: 4947451. DOI: 10.1016/j.jalz.2015.12.008. View

Snowden S, Ebshiana A, Hye A, An Y, Pletnikova O, OBrien R . Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study. PLoS Med. 2017; 14(3):e1002266. PMC: 5360226. DOI: 10.1371/journal.pmed.1002266. View

Ossenkoppele R, Zwan M, Tolboom N, van Assema D, Adriaanse S, Kloet R . Amyloid burden and metabolic function in early-onset Alzheimer's disease: parietal lobe involvement. Brain. 2012; 135(Pt 7):2115-25. DOI: 10.1093/brain/aws113. View

Ellis A, Patterson M, Dudenbostel T, Calhoun D, Gower B . Effects of 6-month supplementation with β-hydroxy-β-methylbutyrate, glutamine and arginine on vascular endothelial function of older adults. Eur J Clin Nutr. 2015; 70(2):269-73. PMC: 4740211. DOI: 10.1038/ejcn.2015.137. View

Almeida O, Almeida S . Short versions of the geriatric depression scale: a study of their validity for the diagnosis of a major depressive episode according to ICD-10 and DSM-IV. Int J Geriatr Psychiatry. 1999; 14(10):858-65. DOI: 10.1002/(sici)1099-1166(199910)14:10<858::aid-gps35>3.0.co;2-8. View

Laske C . Phase 3 trials of solanezumab and bapineuzumab for Alzheimer's disease. N Engl J Med. 2014; 370(15):1459. DOI: 10.1056/NEJMc1402193. View

10.

Mapstone M, Cheema A, Fiandaca M, Zhong X, Mhyre T, MacArthur L . Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014; 20(4):415-8. PMC: 5360460. DOI: 10.1038/nm.3466. View

11.

Wood P, Barnette B, Kaye J, Quinn J, Woltjer R . Non-targeted lipidomics of CSF and frontal cortex grey and white matter in control, mild cognitive impairment, and Alzheimer's disease subjects. Acta Neuropsychiatr. 2015; 27(5):270-8. DOI: 10.1017/neu.2015.18. View

12.

Fernandez-Blazquez M, Avila-Villanueva M, Maestu F, Medina M . Specific Features of Subjective Cognitive Decline Predict Faster Conversion to Mild Cognitive Impairment. J Alzheimers Dis. 2016; 52(1):271-81. DOI: 10.3233/JAD-150956. View

13.

Louzada P, Paula Lima A, Mendonca-Silva D, Noel F, de Mello F, Ferreira S . Taurine prevents the neurotoxicity of beta-amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alzheimer's disease and other neurological disorders. FASEB J. 2004; 18(3):511-8. DOI: 10.1096/fj.03-0739com. View

14.

Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K . Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007; 13(11):1359-62. DOI: 10.1038/nm1653. View

15.

Fiandaca M, Mapstone M, Cheema A, Federoff H . The critical need for defining preclinical biomarkers in Alzheimer's disease. Alzheimers Dement. 2014; 10(3 Suppl):S196-212. DOI: 10.1016/j.jalz.2014.04.015. View

16.

Jessen F, Amariglio R, van Boxtel M, Breteler M, Ceccaldi M, Chetelat G . A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement. 2014; 10(6):844-52. PMC: 4317324. DOI: 10.1016/j.jalz.2014.01.001. View

17.

Parnetti L, Gaiti A, Polidori M, Brunetti M, Palumbo B, Chionne F . Increased cerebrospinal fluid pyruvate levels in Alzheimer's disease. Neurosci Lett. 1995; 199(3):231-3. DOI: 10.1016/0304-3940(95)12058-c. View

18.

Ghaisas S, Maher J, Kanthasamy A . Gut microbiome in health and disease: Linking the microbiome-gut-brain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases. Pharmacol Ther. 2015; 158:52-62. PMC: 4747781. DOI: 10.1016/j.pharmthera.2015.11.012. View

19.

Gonzalez-Dominguez R, Garcia-Barrera T, Gomez-Ariza J . Combination of metabolomic and phospholipid-profiling approaches for the study of Alzheimer's disease. J Proteomics. 2014; 104:37-47. DOI: 10.1016/j.jprot.2014.01.014. View

20.

Carrasco S, Merida I . Diacylglycerol, when simplicity becomes complex. Trends Biochem Sci. 2006; 32(1):27-36. DOI: 10.1016/j.tibs.2006.11.004. View