title: Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people.
abstract: OBJECTIVE
  Criteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between Aβ and non-Aβ factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aβ deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions.
  
  
  METHODS
  Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort.
  
  
  METHODS
  Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning.
  
  
  METHODS
  For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aβ deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography).
  
  
  RESULTS
  Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention.
  
  
  CONCLUSIONS
  Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aβ burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD.
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley.
authors.forename: Miranka
authors.initials: M
authors.lastname: Wirth
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Villeneuve
authors.affiliation: Institute of Personality and Social Research, University of California, Berkeley.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Haase
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley.
authors.forename: Cindee M
authors.initials: CM
authors.lastname: Madison
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley3Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
authors.forename: Hwamee
authors.initials: H
authors.lastname: Oh
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley3Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Landau
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley3Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California4Department of Neurology, Memory and Aging Center, University of California, San Francisco.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley3Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000175:diagnosis* / Q000000981:diagnostic imaging; D000814:Aniline Compounds; D015415:Biomarkers / Q000378:metabolism; D003072:Cognition Disorders / Q000000981:diagnostic imaging / Q000209:etiology*; D015331:Cohort Studies; D055812:Community-Based Participatory Research; D003430:Cross-Sectional Studies; D005260:Female; D019788:Fluorodeoxyglucose F18; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000209:etiology*; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000814:Aniline Compounds; D015415:Biomarkers; D013844:Thiazoles; D019788:Fluorodeoxyglucose F18