Biomarker-guided clustering of Alzheimer's disease clinical syndromes.

Abstract

Alzheimer's disease (AD) neuropathology is extremely heterogeneous, and the evolution from preclinical to mild cognitive impairment until dementia is driven by interacting genetic/biological mechanisms not fully captured by current clinical/research criteria. We characterized the heterogeneous "construct" of AD through a cerebrospinal fluid biomarker-guided stratification approach. We analyzed 5 validated pathophysiological cerebrospinal fluid biomarkers (Aβ1-42, t-tau, p-tau181, NFL, YKL-40) in 113 participants (healthy controls [N = 20], subjective memory complainers [N = 36], mild cognitive impairment [N = 20], and AD dementia [N = 37], age: 66.7 ± 10.4, 70.4 ± 7.7, 71.7 ± 8.4, 76.2 ± 3.5 years [mean ± SD], respectively) using Density-Based Spatial Clustering of Applications with Noise, which does not require a priori determination of the number of clusters. We found 5 distinct clusters (sizes: N = 38, 16, 24, 14, and 21) whose composition was independent of phenotypical groups. Two clusters showed biomarker profiles linked to neurodegenerative processes not associated with classical AD-related pathophysiology. One cluster was characterized by the neuroinflammation biomarker YKL-40. Combining nonlinear data aggregation with informative biomarkers can generate novel patient strata which are representative of cellular/molecular pathophysiology and may aid in predicting disease evolution and mechanistic drug response.

• Authors: Nicola Toschi, Simone Lista, Filippo Baldacci, Enrica Cavedo, Henrik Zetterberg, Kaj Blennow, Ingo Kilimann, Stefan J Teipel, Antonio Melo Dos Santos, Stéphane Epelbaum, Foudil Lamari, Remy Genthon, Marie-Odile Habert, Bruno Dubois, Roberto Floris, Francesco Garaci, Andrea Vergallo, Harald Hampel, INSIGHT-preAD study group, Alzheimer Precision Medicine Initiative (APMI)
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 83 Pg. 42-53 (11 2019) ISSN: 1558-1497 [Electronic] United States
• PMID: 31585366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Biomarkers
• Peptide Fragments
• tau Proteins

Topics

• Aged
• Alzheimer Disease (cerebrospinal fluid, diagnosis)
• Amyloid beta-Peptides (cerebrospinal fluid)
• Biomarkers (cerebrospinal fluid)
• Cognitive Dysfunction (cerebrospinal fluid, diagnosis)
• Female
• Humans
• Male
• Middle Aged
• Peptide Fragments (cerebrospinal fluid)
• Risk Factors
• tau Proteins (cerebrospinal fluid)