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. 2014 Nov;71(11):1379-85.
doi: 10.1001/jamaneurol.2014.2031.

Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals

Elizabeth C Mormino  1 , Rebecca A Betensky  2 , Trey Hedden  3 , Aaron P Schultz  4 , Rebecca E Amariglio  5 , Dorene M Rentz  5 , Keith A Johnson  6 , Reisa A Sperling  6
Affiliations

Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals

Elizabeth C Mormino et al. JAMA Neurol. 2014 Nov.

Abstract

Importance: Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes.

Objective: To determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals.

Design, setting, and participants: Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women).

Main outcomes and measures: The Aβ status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ-/ND-), stage 1 (Aβ(+)/ND-), stage 2 (Aβ(+)/ND(+)), and suspected non-Alzheimer disease pathology (Aβ-/ND(+)). Cognition was assessed with a composite of neuropsychological tests administered annually.

Results: The Aβ(+) CN individuals were more likely to be classified as ND+: 59.6% of Aβ(+) CN individuals were ND(+), whereas 31.9% of Aβ- CN individuals were ND(+) (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04).

Conclusions and relevance: The co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mormino reported receiving funding by grants F32AG044054 and P01 AG036694 from the National Institutes of Health. Dr Betensky reported receiving funding by grants R01 CA075971, R03 CA165070, UL 1RR025758, P50 NS051343, P50 NS051343, P30 CA006516, P50 AG005134, P01 AG036694, R01 NS070834, R01 NS070834, and R01 AG026484 from the National Institutes of Health. Dr Hedden reported receiving funding by grants K01 AG040197, P01 AG036694, and R01 AG034556 from the National Institutes of Health. Dr Schultz reported serving as a paid consultant on an advisory board for Janssen Pharmaceuticals Inc. Dr Amariglio reported receiving funding by grant NIRG-12-243012 from the Alzheimer’s Association and by grants P01AG036694 and RO1-AG027435 from the National Institutes of Health. Dr Rentz reported receiving research support by grants P01 AG036694, R01 MH090291, U01 AG024904, R01 AG027435, R01 AG037497, and P50 AG005134 from the National Institutes of Health and by grant IIRG-08-90934 from the Alzheimer’s Association. Dr Johnson reported serving as paid consultant for Bayer, Bristol-Myers Squibb, GE Healthcare, Genzyme, Janssen Alzheimer’s Immunotherapy, and Siemens Medical Solutions. He reported serving as a site coinvestigator for Bristol-Myers Squibb, Janssen Immunotherapy, Lilly/Avid, Navidea, and Pfizer. He reported speaking at symposia sponsored by Janssen Alzheimer’s Immunotherapy and Pfizer. He reported receiving funding by grants R01EB014894, R21 AG038994, R01 AG026484, R01 AG034556, P50 AG00513421, U19 AG10483, P01 AG036694, R13 AG042201174210, R01 AG027435, and R01 AG037497 from the National Institutes of Health and by grant ZEN-10-174210 from the Alzheimer’s Association. Dr Sperling reported serving as a paid consultant for Bristol-Myers Squibb, Eisai, Janssen Alzheimer Immunotherapy, Merck, Pfizer, and Roche and reported serving as an unpaid consultant to Avid and Eli Lilly. She reported serving as a site coinvestigator for Avid, Bristol-Myers Squibb, Janssen Alzheimer Immunotherapy, and Pfizer clinical trials. She reported speaking at symposia sponsored by Eli Lilly, Janssen Alzheimer Immunotherapy, and Pfizer. She reported that these relationships are not related to the content in the present article. She reported receiving research support by grants U01 AG032438, U01 AG024904, R01 AG037497, R01 AG034556, K24 AG035007, P50 AG005134, U19 AG010483, R01 AG027435, and P01 AG036694 from the National Institutes of Health and by grant ZEN-10-174210 from the Alzheimer’s Association.

Figures

Figure
Figure. Cognitive Decline Across Preclinical Stages
Beta estimates from a linear mixed model examining decline across preclinical stages are plotted. Practice effects are observed in stage 0 and are diminished in stage 1 and suspected non–Alzheimer disease pathology (SNAP), whereas decline is observed in stage 2. Plotted lines extend to the maximum follow-up period of 3 years, while the median follow-up period across all participants was 2.09 years. Although there is a lower estimated baseline value in the SNAP group than in the other groups, this effect did not reach statistical significance (P = .44 for SNAP vs stage 0, P = .63 for SNAP vs stage 1, and P = .55 for SNAP vs stage 2). Stage 2 showed significantly greater decline over time than all other groups (P = .001 for all).
See this image and copyright information in PMC

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References

    1. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280–292. - PMC - PubMed
    1. Mormino EC, Kluth JT, Madison CM, et al. Alzheimer’s Disease Neuroimaging Initiative. Episodic memory loss is related to hippocampal-mediated β-amyloid deposition in elderly subjects. Brain. 2009;132(pt 5):1310–1323. - PMC - PubMed
    1. Jack CR, Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207–216. - PMC - PubMed
    1. Jack CR, Jr, Wiste HJ, Weigand SD, et al. Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity. Neurology. 2013;81(20):1732–1740. - PMC - PubMed
    1. Knopman DS, Jack CR, Jr, Wiste HJ, et al. Brain injury biomarkers are not dependent on β-amyloid in normal elderly. Ann Neurol. 2013;73(4):472–480. - PMC - PubMed

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