Journal
JAMA NEUROLOGY
Volume 73, Issue 10, Pages 1192-1200Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jamaneurol.2016.2642
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Funding
- NIH [P01 AG026276, P01 AG003991, P50 AG005681]
- Washington University Institute of Clinical and Translational Sciences from the National Center for Advancing Translational Sciences [UL1 TR000448]
- NIH (services of the Neuroimaging Informatics and Analysis Center) [5P30NS048056]
- Barnes-Jewish Hospital Foundation
- Charles F. and Joanne Knight Alzheimer's Research Initiative
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IMPORTANCE Preclinical Alzheimer disease (AD) can be staged using a 2-factor model denoting the presence or absence of beta-amyloid (A beta+/-) and neurodegeneration (ND+/-). The association of these stages with longitudinal biomarker outcomes is unknown. OBJECTIVE To examine whether longitudinal A beta accumulation and hippocampal atrophy differ based on initial preclinical staging. DESIGN, SETTING, AND PARTICIPANTS This longitudinal population-based cohort study used data collected at the Knight Alzheimer Disease Research Center, Washington University, St Louis, Missouri, from December 1, 2006, to June 31, 2015. Cognitively normal older adults (n = 174) were recruited from the longitudinal Adult Children Study and Healthy Aging and Senile Dementia Study at the Knight Alzheimer Disease Research Center. At baseline, all participants had magnetic resonance imaging (MRI) scans, positron emission tomography (PET) scans with carbon 11-labeled Pittsburgh Compound B (PiB), and cerebrospinal fluid assays of tau and phosphorylated tau (ptau) acquired within 12 months. Using the baseline biomarkers, individuals were classified into preclinical stage 0 (A beta-/ND-), 1 (A beta+/ND-), or 2+ (A beta+/ND+) or suspected non-AD pathophysiology (SNAP; A beta-/ND+). MAIN OUTCOMES AND MEASURES Subsequent longitudinal accumulation of A beta assessed with PiB PET and loss of hippocampal volume assessed with MRI in each group. RESULTS Among the 174 participants (81 men [46.6%]; 93 women [53.4%]; mean [SD] age, 65.7 [8.9] years), a proportion (14%-17%) of individuals with neurodegeneration alone (SNAP) later demonstrated A beta+. The rates of A beta accumulation and loss of hippocampal volume in individuals with SNAP were indistinguishable from those without any pathologic features at baseline (for A beta accumulation: when hippocampal volume was used to define ND, t = 0.00 [P > .99]; when tau and ptau were used to define ND, t = -0.02 [P = .98]; for loss of hippocampal volume: when hippocampal volume was used to define ND, t = -1.34 [P = .18]; when tau and ptau were used to define ND, t = 0.84[P = .40]). Later preclinical stages (stages 1 and 2+) had elevated A beta accumulation. Using hippocampal volume to define ND, individuals with stage 1 had accelerated A beta accumulation relative to stage 0 (t = 11.06; P < .001), stage 2+ (t = 2.10; P = .04), and SNAP (t = 9.32; P < .001), and those with stage 2+ had accelerated A beta accumulation relative to stage 0 (t = 4.38; P < .001) and SNAP (t = 4.08; P < .001). When ND was defined using tau and ptau, individuals with stage 2+ had accelerated A beta accumulation relative to stage 0 (t = 4.96) and SNAP (t = 4.06), and those with stage 1 had accelerated A beta accumulation relative to stage 0 (t = 8.44) and SNAP (t = 6.61) (P < .001 for all comparisons). When ND was defined using cerebrospinal fluid biomarkers, individuals with stage 2+ had accelerated hippocampal atrophy relative to stage 0 (t = -3.41; P < .001), stage 1 (t = -2.48; P = .03), and SNAP (t = -2.26; P = .03). CONCLUSIONS AND RELEVANCE More advanced preclinical stages of AD have greater longitudinal A beta accumulation. SNAP appears most likely to capture inherent individual variability in brain structure or to represent comorbid pathologic features rather than early emerging AD. Low hippocampal volumes or elevated levels of tau or ptau in isolation may not accurately represent ongoing neurodegenerative processes.
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