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Pathologies Underlying Longitudinal Cognitive Decline in the Oldest Old

Nguyen, Madeline T., MD, MS*; Mattek, Nora, MPH*; Woltjer, Randy, MD, PhD*; Howieson, Diane, PhD*; Silbert, Lisa, MD*,†; Hofer, Scott, PhD*,‡; Kaye, Jeffrey, MD*,†; Dodge, Hiroko, PhD*,§; Erten-Lyons, Deniz, MD*,†

Alzheimer Disease & Associated Disorders: October-December 2018 - Volume 32 - Issue 4 - p 265–269
doi: 10.1097/WAD.0000000000000265
Original Articles

Background: Understanding contributions of different brain pathologies to domain-specific cognitive trajectories in the oldest old is crucial to guide future intervention studies.

Methods: Two-hundred-twenty Oregon Alzheimer’s Disease Center research participants who were cognitively intact at entry were followed on average for 7.3 years with annual neuropsychological testing until death (mean age, 93.7 y) and autopsy. Mixed effects models examined the relationship between trajectories in memory, verbal fluency, and mini-mental state examination (MMSE) and pathology (neurofibrillary tangles, neuritic plaques, gross infarcts, hippocampal sclerosis, Lewy bodies, APOE genotype, age at death, and years of education). The association between the MMSE trajectory and pathologic variables were examined using a Poisson model with MMSE errors as outcomes given the nonlinear distribution of MMSE scores.

Results: Memory trajectory was associated with the APOε4 allele (P=0.006). Verbal fluency trajectory was associated with gross infarcts (P=0.008). MMSE trajectory was associated with high Braak scores (P=0.03), gross infarcts (P<0.0001), hippocampal sclerosis (P=0.003), moderate neuritic plaques (P=0.04), and the APOε4 allele (P=0.02).

Conclusions: The association between trajectory of decline in global cognitive scores and multiple brain pathologies highlights the importance of accounting for comorbid pathologies in therapeutic trials aimed at one specific pathology in the oldest old. Only the APOε4 allele showed an association with memory decline, despite accounting for Alzheimer’s disease pathology, suggesting that APOE may be involved in mechanisms beyond amyloid metabolism in its role in memory. Further studies are needed to examine the role of APOE in brain aging.

*Oregon Health & Science University

Portland VA Health Care System, Portland, OR

University of Victoria, Victoria, BC, Canada

§University of Michigan, Ann Arbor, MI

Supported in part by grants from the National Institute on Aging, National Institutes of Health: P30 AG08017 and P01 AG043362.

M.T.N.: is the primary author on this manuscript. She was involved in the design and conceptualization of the study, and drafted the manuscript. N.M.: was involved in the design and conceptualization of the study, drafting the manuscript, and statistical analysis. R.W.: contributed to data analysis and made substantive contributions in revising the manuscript for intellectual content. D.H.: participated in initial design and conceptualization of the study and made substantive contributions to revising the manuscript for intellectual content. L.S.: made substantive contributions in revising the manuscript for intellectual content. S.H.: contributed to the design and conceptualization, and made substantive contributions in revising the manuscript for intellectual content. J.K.: made substantive contribution in revising the manuscript for intellectual content. H.D.: contributed to the design and conceptualization, and made substantive contributions in data analysis and in revising the manuscript for intellectual content, and performed the statistical analyses. D.E.-L.: led the design and conceptualization of the study, performed some of the data analysis, and made substantive contributions to data analysis and revising the manuscript for intellectual content.

L.S. receives research support from the NIH (R01 AG036772, P30 AG008017, P50 NS062684). She also receives reimbursement through Medicare or commercial insurance plans for providing clinical assessment and care for patients and for intraoperative neurophysiological monitoring, and is salaried to see patients at the Portland VA Medical Center. S.H. receives research support from the NIH (P01 AG043362). J.K. receives research support from the NIH (P30 AG008017, R01 AG024059, P30 AG024978, P01 AG043362, U01 AG010483); directs a center that receives research support from the NIH, CDC, Nestle Institute of Health Sciences, Roche, Lundbeck, Merck, and Eisai; is compensated for serving on Data Safety Monitoring Committees for Eli Lilly and Suven; receives reimbursement through Medicare or commercial insurance plans for providing clinical assessment and care for patients; and serves on the editorial advisory board of the journal, Alzheimer’s & Dementia. H.D. receives research support from the NIH (R01 AG033581, R01AG051628, R01AG056102, P30 AG008017, P30AG024978, U2CAG054397, R01AG043398, and U01NS100611). She serves as a senior associate editor for Alzheimer’s & Dementia and a statistical editor for International Psychogeriatrics. D.E.-L. receives reimbursement through Medicare or commercial insurance plans for providing clinical assessment and care for patients and is salaried to see patients at the Portland VA Medical Center. Within the past year, she has served as coinvestigator on a research project funded by Glaxo-Smith Kline and serving consultant to Acadia Pharmaceuticals Inc. The remaining authors declare no conflicts of interest.

Reprint: Deniz Erten-Lyons, MD, Department of Neurology, Layton Aging and Alzheimer’s Disease Center, Oregon Health & Science University, CR-131, 3181 S.W., Sam Jackson Park Road, Portland, OR 97239 (e-mail: ertenlyo@ohsu.edu).

Received August 30, 2017

Accepted July 2, 2018

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