Premium
Orderings of biomarker changes for Alzheimer disease in cognitively normal individuals from 18 to 101 years of age
Author(s) -
Xiong Chengjie,
Luo Jingqin,
Masters Colin L,
Johnson Sterling C.,
Albert Marilyn S.,
McDade Eric,
Fagan Anne M.,
Benzinger Tammie L.S.,
Hassenstab Jason,
Cruchaga Carlos,
Bateman Randall J.,
Morris John C.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043187
Subject(s) - biomarker , pittsburgh compound b , dementia , cognitive decline , oncology , medicine , positron emission tomography , magnetic resonance imaging , standardized uptake value , alzheimer's disease , neuroimaging , senile plaques , psychology , disease , pathology , gerontology , neuroscience , nuclear medicine , radiology , chemistry , biochemistry
Background The temporal orderings of pathologic biomarker changes during preclinical AD have been hypothesized graphically, incorporated into diagnostic criteria of preclinical AD, and further extended to the A/T/N framework. These hypotheses, however, remain to be rigorously and statistically tested. Methods Biomarker and cognitive data were harmonized across eight ongoing longitudinal studies: 1) Washington University (WU) Adult Children Study; 2) Johns Hopkins University Biomarkers for Older Controls at Risk for Dementia Study; 3) Wisconsin Registry for Alzheimer's Prevention; 4) Australian Imaging, Biomarkers and Lifestyle Study; 5) WU Dominantly Inherited Alzheimer Network; 6) WU Healthy Aging and Senile Dementia study; 7) WU Knight Alzheimer Disease Research Center (ADRC); and 8) Wisconsin ADRC. Cerebrospinal fluid (CSF) analytes, molecular imaging of cerebral fibrillar β‐amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound‐B (PIB), magnetic resonance imaging (MRI)‐based brain structures, and clinical/cognitive outcomes for 3284 cognitively normal individuals aged 18 to 101 years, were analyzed. The age at which each marker exhibited an accelerated change (called the change‐point) was estimated by piecewise regression models, and compared across the markers by bootstrapping. Results Accelerated changes in CSF Aβ1‐42 (Aβ42) occurred at 48.28 years of age, followed by PET 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 about 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‐point for CSF Aβ42, albeit not significantly different from that for PIB SUVR, occurred significantly earlier than that for CSF Tau and 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 These findings support the hypothesized early changes in amyloid in preclinical AD, and further suggest that changes in neuronal injury and neurodegeneration markers occur close in time to each other and to cognitive decline. These results have important implications for the design and analysis of future prevention trials in AD.