title: Brain structure and function as mediators of the effects of amyloid on memory.
abstract: OBJECTIVE
  The objective of this study was to test whether effects of β-amyloid (Aβ) pathology on episodic memory were mediated by metabolism and gray matter volume in the early stages of Alzheimer disease.
  
  
  METHODS
  This was a prospective cohort study. We measured baseline Aβ (using florbetapir-PET), brain function (using fluorodeoxyglucose-PET), and brain structure (using MRI). A mediation analysis was performed to test whether statistical effects of Aβ positivity on cross-sectional and longitudinal episodic memory were mediated by hypometabolism or regional gray matter volume in cognitively healthy controls (CN, n = 280) and mild cognitive impairment (MCI, n = 463).
  
  
  RESULTS
  Lower memory scores were associated with Aβ positivity (CN, mildly; MCI, strongly), smaller gray matter volumes (CN, few regions, including hippocampus; MCI, widespread), and hypometabolism. Smaller volumes and hypometabolism mediated effects of Aβ in MCI but not in CN. The strongest individual regions mediated up to approximately 25%. A combination of brain structure and function mediated up to approximately 40%. In several regions, gray matter atrophy and hypometabolism predicted episodic memory without being associated (at p < 0.05) with Aβ positivity.
  
  
  CONCLUSIONS
  Changes in brain structure and function appear to be, in part, downstream events from Aβ pathology, ultimately resulting in episodic memory deficits. However, Aβ pathology is also strongly related to memory deficits through mechanisms that are not quantified by these imaging measurements, and episodic memory decline is partly caused by Alzheimer disease-like brain changes independently of Aβ pathology.
authors: From the Department of Veterans Affairs Medical Center (N.M., P.S.I., S.M., M.W.), Center for Imaging of Neurodegenerative Diseases, San Francisco, CA; Clinical Neurochemistry Laboratory (N.M.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Radiology and Biomedical Imaging (N.M., P.S.I., M.W.), University of California, San Francisco; Alzheimer's Disease Cooperative Study (P.S.A.), Department of Neurosciences, University of California, San Diego, La Jolla; Helen Wills Neuroscience Institute and School of Public Health (W.J.), University of California, Berkeley; and Department of Psychiatry (S.M.), University of California, San Francisco. niklas.mattsson@neuro.gu.se.
authors: Niklas
authors: N
authors: Mattsson
authors: From the Department of Veterans Affairs Medical Center (N.M., P.S.I., S.M., M.W.), Center for Imaging of Neurodegenerative Diseases, San Francisco, CA; Clinical Neurochemistry Laboratory (N.M.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Radiology and Biomedical Imaging (N.M., P.S.I., M.W.), University of California, San Francisco; Alzheimer's Disease Cooperative Study (P.S.A.), Department of Neurosciences, University of California, San Diego, La Jolla; Helen Wills Neuroscience Institute and School of Public Health (W.J.), University of California, Berkeley; and Department of Psychiatry (S.M.), University of California, San Francisco.
authors: Philip S
authors: PS
authors: Insel
authors: From the Department of Veterans Affairs Medical Center (N.M., P.S.I., S.M., M.W.), Center for Imaging of Neurodegenerative Diseases, San Francisco, CA; Clinical Neurochemistry Laboratory (N.M.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Radiology and Biomedical Imaging (N.M., P.S.I., M.W.), University of California, San Francisco; Alzheimer's Disease Cooperative Study (P.S.A.), Department of Neurosciences, University of California, San Diego, La Jolla; Helen Wills Neuroscience Institute and School of Public Health (W.J.), University of California, Berkeley; and Department of Psychiatry (S.M.), University of California, San Francisco.
authors: Paul S
authors: PS
authors: Aisen
authors: From the Department of Veterans Affairs Medical Center (N.M., P.S.I., S.M., M.W.), Center for Imaging of Neurodegenerative Diseases, San Francisco, CA; Clinical Neurochemistry Laboratory (N.M.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Radiology and Biomedical Imaging (N.M., P.S.I., M.W.), University of California, San Francisco; Alzheimer's Disease Cooperative Study (P.S.A.), Department of Neurosciences, University of California, San Diego, La Jolla; Helen Wills Neuroscience Institute and School of Public Health (W.J.), University of California, Berkeley; and Department of Psychiatry (S.M.), University of California, San Francisco.
authors: William
authors: W
authors: Jagust
authors: From the Department of Veterans Affairs Medical Center (N.M., P.S.I., S.M., M.W.), Center for Imaging of Neurodegenerative Diseases, San Francisco, CA; Clinical Neurochemistry Laboratory (N.M.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Radiology and Biomedical Imaging (N.M., P.S.I., M.W.), University of California, San Francisco; Alzheimer's Disease Cooperative Study (P.S.A.), Department of Neurosciences, University of California, San Diego, La Jolla; Helen Wills Neuroscience Institute and School of Public Health (W.J.), University of California, Berkeley; and Department of Psychiatry (S.M.), University of California, San Francisco.
authors: Scott
authors: S
authors: Mackin
authors: From the Department of Veterans Affairs Medical Center (N.M., P.S.I., S.M., M.W.), Center for Imaging of Neurodegenerative Diseases, San Francisco, CA; Clinical Neurochemistry Laboratory (N.M.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Radiology and Biomedical Imaging (N.M., P.S.I., M.W.), University of California, San Francisco; Alzheimer's Disease Cooperative Study (P.S.A.), Department of Neurosciences, University of California, San Diego, La Jolla; Helen Wills Neuroscience Institute and School of Public Health (W.J.), University of California, Berkeley; and Department of Psychiatry (S.M.), University of California, San Francisco.
authors: Michael
authors: M
authors: Weiner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging* / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D061212:Memory, Episodic; D008875:Middle Aged; D011446:Prospective Studies; D011877:Radionuclide Imaging
chemical_list: D016229:Amyloid beta-Peptides