title: Subtle Cognitive Decline and Biomarker Staging in Preclinical Alzheimer's Disease.
abstract: The NIA-AA criteria for "preclinical" Alzheimer's disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and "subtle cognitive decline," which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define "subtle cognitive decline" using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.
authors.affiliation: Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Edmonds
authors.affiliation: Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA.|Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Delano-Wood
authors.affiliation: Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA.|Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.|Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Galasko
authors.affiliation: Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Salmon
authors.affiliation: Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA.|Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Bondi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000175:diagnosis* / Q000523:psychology; D000686:Amyloidosis / Q000150:complications; D015415:Biomarkers; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration; D059906:Neuroimaging; D009483:Neuropsychological Tests; D062706:Prodromal Symptoms; D011569:Psychiatric Status Rating Scales
chemical_list: D015415:Biomarkers
keywords: Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s disease; amyloid; biomarkers; cerebrospinal fluid; dementia; neurodegeneration; neuropsychology; preclinical Alzheimer’s disease; subtle cognitive decline