Biomarker-guided clustering of Alzheimer's disease clinical syndromes

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)

doi:10.1016/j.neurobiolaging.2019.08.032

Biomarker-guided clustering of Alzheimer's disease clinical syndromes

Neurobiol Aging. 2019 Nov:83:42-53. doi: 10.1016/j.neurobiolaging.2019.08.032. Epub 2019 Sep 10.

Authors

Nicola Toschi¹, Simone Lista², Filippo Baldacci³, Enrica Cavedo⁴, Henrik Zetterberg⁵, Kaj Blennow⁶, Ingo Kilimann⁷, Stefan J Teipel⁷, Antonio Melo Dos Santos², Stéphane Epelbaum², Foudil Lamari⁸, Remy Genthon⁹, Marie-Odile Habert¹⁰, Bruno Dubois², Roberto Floris¹¹, Francesco Garaci¹², Andrea Vergallo², Harald Hampel¹³; INSIGHT-preAD study group; Alzheimer Precision Medicine Initiative (APMI)

Affiliations

¹ Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy; Department of Radiology, "Athinoula A. Martinos" Center for Biomedical Imaging, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
² Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Brain & Spine Institute (ICM), INSERM U 1127, Paris, France; Department of Neurology, Institute of Memory and Alzheimer's Disease (IM2A), Pitié-Salpêtrière Hospital, Paris, France.
³ Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Brain & Spine Institute (ICM), INSERM U 1127, Paris, France; Department of Neurology, Institute of Memory and Alzheimer's Disease (IM2A), Pitié-Salpêtrière Hospital, Paris, France; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁴ Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Brain & Spine Institute (ICM), INSERM U 1127, Paris, France; Department of Neurology, Institute of Memory and Alzheimer's Disease (IM2A), Pitié-Salpêtrière Hospital, Paris, France; Qynapse, Paris, France.
⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute, London, UK.
⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁷ Department of Psychosomatic Medicine, University of Rostock & DZNE Rostock, Rostock, Germany.
⁸ AP-HP, UF Biochimie des Maladies Neuro-métaboliques, Service de Biochimie Métabolique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
⁹ Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Department of Neurology, Institute of Memory and Alzheimer's Disease (IM2A), Pitié-Salpêtrière Hospital, Paris, France.
¹⁰ Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; Centre pour l'Acquisition et le Traitement des Images, France; Département de Médecine Nucléaire, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
¹¹ Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
¹² Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy; Casa di Cura "San Raffaele Cassino", Cassino, Italy.
¹³ Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Eisai Inc., Neurology Business Group, Woodcliff Lake, NJ, USA. Electronic address: harald.hampel@med.uni-muenchen.de.

PMID: 31585366
DOI: 10.1016/j.neurobiolaging.2019.08.032

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 (Aβ_1-42, 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.

Keywords: Alzheimer's disease; Biomarker-guided categorization; Clustering; Pathophysiology; Precision medicine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / cerebrospinal fluid*
Alzheimer Disease / diagnosis
Amyloid beta-Peptides / cerebrospinal fluid
Biomarkers / cerebrospinal fluid*
Cognitive Dysfunction / cerebrospinal fluid*
Cognitive Dysfunction / diagnosis
Female
Humans
Male
Middle Aged
Peptide Fragments / cerebrospinal fluid
Risk Factors
tau Proteins / cerebrospinal fluid*

Substances

Amyloid beta-Peptides
Biomarkers
Peptide Fragments
tau Proteins