title: Certified normal: Alzheimer's disease biomarkers and normative estimates of cognitive functioning.
abstract: Normative samples drawn from older populations may unintentionally include individuals with preclinical Alzheimer's disease (AD) pathology, resulting in reduced means, increased variability, and overestimation of age effects on cognitive performance. A total of 264 cognitively normal (Clinical Dementia Rating = 0) older adults were classified as biomarker negative ("Robust Normal," n = 177) or biomarker positive ("Preclinical Alzheimer's Disease" [PCAD], n = 87) based on amyloid imaging, cerebrospinal fluid biomarkers, and hippocampal volumes. PCAD participants performed worse than robust normals on nearly all cognitive measures. Removing PCAD participants from the normative sample yielded higher means and less variability on episodic memory, visuospatial ability, and executive functioning measures. These results were more pronounced in participants aged 75 years and older. Notably, removing PCAD participants from the sample significantly reduced age effects across all cognitive domains. Applying norms from the robust normal sample to a separate cohort did not improve Clinical Dementia Rating classification when using standard deviation cutoff scores. Overall, removing individuals with biomarker evidence of preclinical AD improves normative sample quality and substantially reduces age effects on cognitive performance but provides no substantive benefit for diagnostic classifications.
authors.affiliation: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Psychological & Brian Sciences, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: hassenstabj@wustl.edu.
authors.forename: Jason
authors.initials: J
authors.lastname: Hassenstab
authors.affiliation: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Chasse
authors.affiliation: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Psychology, University of Missouri-St. Louis, St. Louis, MO, USA.
authors.forename: Perri
authors.initials: P
authors.lastname: Grabow
authors.affiliation: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurological Surgery, University of Missouri-St. Louis, St. Louis, MO, USA.
authors.forename: Tammie L S
authors.initials: TL
authors.lastname: Benzinger
authors.affiliation: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Chengjie
authors.initials: C
authors.lastname: Xiong
authors.affiliation: Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Jasielec
authors.affiliation: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Grant
authors.affiliation: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Department of Physical Therapy, Washington University School of Medicine, St. Louis, MO, USA; Department of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
mesh_terms: D000368:Aged; D000375:Aging / Q000473:pathology / Q000523:psychology; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000473:pathology / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003071:Cognition; D015331:Cohort Studies; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D059906:Neuroimaging; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer's disease; Biomarkers; Cognition; Memory; Normative data; Preclinical disease