Cognitive Variability Predicts Incident Alzheimer’s Disease and Mild Cognitive Impairment Comparable to a Cerebrospinal Fluid Biomarker

Article type: Research Article

Authors: Gleason, Carey E.^{a; b; c; *} | Norton, Derek^{c; d} | Anderson, Eric D.^e | Wahoske, Michelle^{a; c} | Washington, Danielle T.^{a; b; c} | Umucu, Emre^f | Koscik, Rebecca L.^g | Dowling, N. Maritza^h | Johnson, Sterling C.^{a; b; c; h} | Carlsson, Cynthia M.^{a; b; c; h} | Asthana, Sanjay^{a; b; c; h} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [b] Geriatric Research, Education and Clinical Center (11G), William S. Middleton Memorial Veterans Hospital, Madison, WI, USA | [c] Wisconsin Alzheimer’s Disease Research Center, Madison, WI, USA | [d] University of Wisconsin, Department of Biostatistics and Medical Informatics, Madison, WI, USA | [e] Wright State University, School of Education and Human Services, Dayton, OH, USA | [f] Department of Rehabilitation Sciences, University of Texas at El Paso, El Paso, TX, USA | [g] Wisconsin Alzheimer’s Institute, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [h] George Washington University, School of Nursing, Washington, DC, USA

Correspondence: [*] Correspondence to: Carey Gleason, PhD, MS, Associate Professor, Department of Medicine, Division of Geriatrics, School of Medicine and Public Health, University of Wisconsin, Madison; Madison VA GRECC (11G), Wm. S. Middleton Memorial VA, 2500 Overlook Terrace, Madison, WI 53705, USA. Tel.: +1 608 280 7000; E-mail: ceg@medicine.wisc.edu.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Alzheimer’s disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures. A cognitive marker, intra-individual cognitive variability (IICV) may provide an alternative or adjunct marker of disease risk for individuals unable or disinclined to undergo lumbar puncture. Objective:To contrast risk of incident AD and mild cognitive impairment (MCI) associated with IICV to risk associated with well-established biomarkers: cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau181) and amyloid-β 42 (Aβ42) peptide. Methods:Dispersion in cognitive performance, IICV, was estimated with a published algorithm, and included Trail Making Test A and B, Rey Auditory Verbal Learning Test (RAVLT), and the American National Adult Reading Test (ANART). CSF biomarkers were expressed as a ratio: p-tau181/Aβ42, wherein high values signified pathognomonic profiles. Logistic regression models included longitudinal data from 349 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who completed lumbar puncture. All subjects were cognitively healthy (n = 105) or diagnosed with MCI (n = 244) at baseline. We examined odds of conversion associated with baseline elevations in IICV and/or ratio of CSF p-tau181/Aβ42. Results:When included in models alone or in combination with CSF p-tau181/Aβ42, one standard IICV unit higher was associated with an estimated odds ratio for incident AD or MCI of 2.81 (95% CI: 1.83–4.33) in the most inclusive sample, and an odds ratio of 3.41 (95% CI: 2.03–5.73) when restricted to participants with MCI. Iterative analyses suggested that IICV independently improved model fit even when individual index components were included in comparative models. Conclusions:These analyses provide preliminary support for IICV as a marker of incident AD and MCI. This easily-disseminated, non-invasive marker compared favorably to well-established CSF biomarkers

Keywords: Alzheimer’s disease, amyloid beta-protein, biological markers, cerebrospinal fluid, cognition, cognitive dysfunction, incidence studies, mild cognitive impairment, tau protein

DOI: 10.3233/JAD-170498

Journal: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 79-89, 2018