title: Dissecting IWG-2 typical and atypical Alzheimer's disease: insights from cerebrospinal fluid analysis.
abstract: Pathobiological factors underlying phenotypic diversity in Alzheimer's disease (AD) are incompletely understood. We used an extended cerebrospinal fluid (CSF) panel to explore differences between "typical" with "atypical" AD and between amnestic, posterior cortical atrophy, logopenic aphasia and frontal variants. We included 97 subjects fulfilling International Working Group-2 research criteria for AD of whom 61 had "typical" AD and 36 "atypical" syndromes, and 30 controls. CSF biomarkers included total tau (T-tau), phosphorylated tau (P-tau), amyloid β1-42, amyloid βX-38/40/42, YKL-40, neurofilament light (NFL), and amyloid precursor proteins α and β. The typical and atypical groups were matched for age, sex, severity and rate of cognitive decline and had similar biomarker profiles, with the exception of NFL which was higher in the atypical group (p = 0.03). Sub-classifying the atypical group into its constituent clinical syndromes, posterior cortical atrophy was associated with the lowest T-tau [604.4 (436.8-675.8) pg/mL], P-tau (79.8 ± 21.8 pg/L), T-tau/Aβ1-42 ratio [2.3 (1.4-2.6)], AβX-40/X-42 ratio (22.1 ± 5.8) and rate of cognitive decline [1.9 (0.75-4.25) MMSE points/year]. Conversely, the frontal variant group had the highest levels of T-tau [1185.4 (591.7-1329.3) pg/mL], P-tau (116.4 ± 45.4 pg/L), T-tau/Aβ1-42 ratio [5.2 (3.3-6.9)] and AβX-40/X-42 ratio (27.9 ± 7.5), and rate of cognitive decline. Whilst on a group level IWG-2 "typical" and "atypical" AD share similar CSF profiles, which are very different from controls, atypical AD is a heterogeneous entity with evidence for subtle differences in amyloid processing and neurodegeneration between different clinical syndromes. These findings also have practical implications for the interpretation of clinical CSF biomarker results.
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, London, UK. r.paterson@ucl.ac.uk.
authors.forename: Ross W
authors.initials: RW
authors.lastname: Paterson
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Toombs
authors.affiliation: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK.
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Slattery
authors.affiliation: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Nicholas
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.affiliation: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK.
authors.forename: Nadia K
authors.initials: NK
authors.lastname: Magdalinou
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Warren
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Cath J
authors.initials: CJ
authors.lastname: Mummery
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.affiliation: Department of Clinical Neuroimmunology, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lunn
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Crutch
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, London, UK. j.schott@ucl.ac.uk.|Box 16 National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK. j.schott@ucl.ac.uk.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000145:classification* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D015415:Biomarkers
keywords: Alzheimer’s disease; Biomarkers; Cerebrospinal fluid; IWG-2