Sequence of Alzheimer disease biomarker changes in cognitively normal adults: A cross-sectional study

Jingqin Luo; Folasade Agboola; Elizabeth Grant; Colin L Masters; Marilyn S Albert; Sterling C Johnson; Eric M McDade; Jonathan Vöglein; Anne M Fagan; Tammie Benzinger; Parinaz Massoumzadeh; Jason Hassenstab; Randall J Bateman; John C Morris; Richard J Perrin; Jasmeer Chhatwal; Mathias Jucker; Bernardino Ghetti; Carlos Cruchaga; Neill R Graff-Radford; Peter R Schofield; Hiroshi Mori; Chengjie Xiong

doi:10.1212/WNL.0000000000010747

Sequence of Alzheimer disease biomarker changes in cognitively normal adults: A cross-sectional study

Neurology. 2020 Dec 8;95(23):e3104-e3116. doi: 10.1212/WNL.0000000000010747. Epub 2020 Sep 1.

Authors

Jingqin Luo¹, Folasade Agboola¹, Elizabeth Grant¹, Colin L Masters¹, Marilyn S Albert¹, Sterling C Johnson¹, Eric M McDade¹, Jonathan Vöglein¹, Anne M Fagan¹, Tammie Benzinger¹, Parinaz Massoumzadeh¹, Jason Hassenstab¹, Randall J Bateman¹, John C Morris¹, Richard J Perrin¹, Jasmeer Chhatwal¹, Mathias Jucker¹, Bernardino Ghetti¹, Carlos Cruchaga¹, Neill R Graff-Radford¹, Peter R Schofield¹, Hiroshi Mori¹, Chengjie Xiong²

Affiliations

¹ From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., F.A., E.G., C.X.), Knight Alzheimer Disease Research Center (F.A., E.G., A.M.F., T.B., P.M., J.H., R.J.B., J.C.M., R.J.P., C.X.), Department of Neurology (E.M.M., A.M.F., J.H., R.J.B., J.C.M., R.J.P.), Department of Radiology (T.B., P.M.), Department of Pathology (J.C.M., R.J.P.), Department of Immunology (J.C.M., R.J.P.), and Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; The Florey Institute (C.L.M.), University of Melbourne, Australia; Department of Neurology (M.S.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Wisconsin Alzheimer's Institute and Alzheimer's Disease Research Center (S.C.J.), University of Wisconsin-Madison School of Medicine and Public Health; Geriatric Research Education and Clinical Center (S.C.J.), William S. Middleton Veterans Memorial Hospital, Madison, WI; German Center for Neurodegenerative Diseases (J.V.); Department of Neurology (J.V.), Ludwig-Maximilians-Universität München, Munich, Germany; Department of Neurology (J.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen; German Center for Neurodegenerative Diseases (M.J.), Tübingen, Germany; Department of Pathology and Laboratory Medicine (B.G.), Indiana University, Indianapolis; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Neuroscience Research Australia (P.R.S.), Randwick; School of Medical Sciences (P.R.S.), University of New South Wales, Sydney, Australia; and Department of Clinical Neuroscience (H.M.), Osaka City University Medical School, Abenoku, Osaka, Japan.
² From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., F.A., E.G., C.X.), Knight Alzheimer Disease Research Center (F.A., E.G., A.M.F., T.B., P.M., J.H., R.J.B., J.C.M., R.J.P., C.X.), Department of Neurology (E.M.M., A.M.F., J.H., R.J.B., J.C.M., R.J.P.), Department of Radiology (T.B., P.M.), Department of Pathology (J.C.M., R.J.P.), Department of Immunology (J.C.M., R.J.P.), and Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; The Florey Institute (C.L.M.), University of Melbourne, Australia; Department of Neurology (M.S.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Wisconsin Alzheimer's Institute and Alzheimer's Disease Research Center (S.C.J.), University of Wisconsin-Madison School of Medicine and Public Health; Geriatric Research Education and Clinical Center (S.C.J.), William S. Middleton Veterans Memorial Hospital, Madison, WI; German Center for Neurodegenerative Diseases (J.V.); Department of Neurology (J.V.), Ludwig-Maximilians-Universität München, Munich, Germany; Department of Neurology (J.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen; German Center for Neurodegenerative Diseases (M.J.), Tübingen, Germany; Department of Pathology and Laboratory Medicine (B.G.), Indiana University, Indianapolis; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Neuroscience Research Australia (P.R.S.), Randwick; School of Medical Sciences (P.R.S.), University of New South Wales, Sydney, Australia; and Department of Clinical Neuroscience (H.M.), Osaka City University Medical School, Abenoku, Osaka, Japan. [email protected].

Abstract

Objective: To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals.

Methods: Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [¹¹C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers.

Results: Accelerated changes in CSF Aβ_1-42 (Aβ₄₂) occurred at 48.28 years of age and in Aβ₄₂/Aβ₄₀ ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ₄₂ and Aβ₄₂/Aβ₄₀ ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other.

Conclusions: Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Age Factors
Aged
Aged, 80 and over
Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Alzheimer Disease* / physiopathology
Amyloid beta-Peptides / cerebrospinal fluid
Amyloid beta-Peptides / metabolism*
Aniline Compounds
Biomarkers / metabolism
Cerebral Cortex* / diagnostic imaging
Cerebral Cortex* / pathology
Cognitive Dysfunction* / diagnostic imaging
Cognitive Dysfunction* / metabolism
Cognitive Dysfunction* / pathology
Cognitive Dysfunction* / physiopathology
Cross-Sectional Studies
Female
Hippocampus / diagnostic imaging
Hippocampus / pathology
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Peptide Fragments / cerebrospinal fluid
Positron-Emission Tomography
Prodromal Symptoms
Thiazoles
Young Adult
tau Proteins / cerebrospinal fluid*

Substances

2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
Amyloid beta-Peptides
Aniline Compounds
Biomarkers
MAPT protein, human
Peptide Fragments
Thiazoles
amyloid beta-protein (1-40)
amyloid beta-protein (1-42)
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding