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Articles
February 13, 2015

Differences in Alzheimer disease clinical trial outcomes based on age of the participants

March 17, 2015 issue
84 (11) 1121-1127

Abstract

Objective:

We tested the a priori hypothesis that older participants differ in rates of decline on cognitive outcomes compared with younger participants, and examined the potential effect of age distributions on individual clinical trial outcomes.

Methods:

From a meta-database of 18 studies from the Alzheimer's Disease Cooperative Study and the Alzheimer's Disease Neuroimaging Initiative, we included a cohort of 2,793 participants for whom there were baseline demographic data and at least one postbaseline cognitive assessment on the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-cog), Clinical Dementia Rating–Sum of Boxes (CDR-SB), or Mini-Mental State Examination (MMSE). We used mixed-effects models (random coefficient models) to estimate change on the outcomes across 7 age groups ranging from younger than 61 years to older than 85 years after adjusting for education.

Results:

Significant worsening occurred in all age groups on all outcomes over time. The 4 older groups, aged 71 years and older, showed slower rates of decline on the ADAS-cog than the younger groups (p = 0.001). The older groups scored 2–3, 2–5, and 4–6 points better than the younger groups at 12, 18, and 24 months, respectively. There were similar differences across age groups for the MMSE, but not for the CDR-SB.

Conclusions:

The differences in change on the ADAS-cog between older and younger participants are substantially greater than differences expected between experimental drugs and placebo in current trials or differences between marketed cholinesterase inhibitors and placebo. The clinical interpretation of change on the ADAS-cog or MMSE differs depending on age. Until predictors of decline are better understood, considering effects of age on rates of change is particularly important regarding clinical practice and outcomes of trials.

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Supplementary Material

File (figures-tables.pdf)
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Information & Authors

Information

Published In

Neurology®
Volume 84Number 11March 17, 2015
Pages: 1121-1127
PubMed: 25681452

Publication History

Received: August 3, 2014
Accepted: November 10, 2014
Published online: February 13, 2015
Published in print: March 17, 2015

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Disclosure

L. Schneider reports being an editor on the Cochrane Collaboration Dementia and Cognitive Improvement Group, which oversees systematic reviews of drugs for cognitive impairment and dementia; receiving a grant from the Alzheimer's Association for a registry for dementia and cognitive impairment trials; within the past 3 years receiving grant or research support from NIA, Baxter, Eli Lilly, Forum, Genentech, Lundbeck, Merck, Novartis, Pfizer, and TauRx; and having served as a consultant for or receiving consulting fees from AC Immune, Allon, AstraZeneca, Avraham Pharmaceutical, Ltd., Baxter, Biogen Idec, CereSpir, Cytox, Elan, Eli Lilly, Forum, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Merck, Pfizer, Roche, Servier, Takeda, Toyama, and Zinfandel. R. Kennedy reports receiving grant support from NIA, National Institute of Neurological Disorders and Stroke, NHLBI, NIDDK, and the Department of Education. G. Wang reports receiving grant support from NIA. G. Cutter reports receiving grant or research support from Participation of Data and Safety Monitoring Committees; all of the following organizations are focused on medical research: Apotek, Biogen Idec, Cleveland Clinic, GlaxoSmithKline Pharmaceuticals, Gilead Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Neuren, Revalesio, Sanofi-Aventis, Teva, Vivus, NHLBI (Bone Marrow Transplant Protocol Review Committee), National Institute of Neurological Disorders and Stroke, NMSS, and NICHD (OPRU oversight committee). Consulting, speaking fees, and advisory boards: Alexion, Allozyne, Bayer, Celgene, Coronado Biosciences, Consortium of MS Centers (grant), DioGenix, Klein Buendel Incorporated, MedImmune, Novartis, Nuron Biotech, Receptos, Spinifex Pharmaceuticals, and Teva Pharmaceuticals. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc., a private consulting company located in Birmingham, AL. Go to Neurology.org for full disclosures.

Study Funding

Supported by NIH R01 AG037561.

Authors

Affiliations & Disclosures

Lon S. Schneider, MD
From the Departments of Psychiatry and Neurology (L.S.S.), Keck School of Medicine of USC, Los Angeles, CA; Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine (R.E.K.), and Department of Biostatistics (G.W., G.R.C.), University of Alabama at Birmingham.
Disclosure
Scientific Advisory Boards:
1.
AC Immune, Biogen Idec, Cerespir, Cytos, Merck, Novartis, Roche, Takeda, Toyama
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Editor, Alzheimer & Dementia: Translational Research and Clinical Interventions, Senior Associate Editor, Alzheimer and Dementia, Associate Editor, Current Alzheimer's Research, Section Editor, BMC Psychiatry, Cochrane Collaboration:
Patents:
1.
NONE
Publishing Royalties:
1.
Evidence-based Dementia Practice, Blackwell
Employment, Commercial Entity:
1.
University of Southern California
Consultancies:
1.
During last two years: Abbvie, AC Immune, Avraham Pharmaceutical Ltd, Baxter, Biogen Idec, Cerespir, Cytox, GliaCure, Johnson & Johnson, Lundbeck, Medavante, Merck, Novartis, Roche, Servier, Takeda, Targacept, Toyama, Zinfandel
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Clinical trials research support past two years: Alzheimer's Disease Cooperative Study, Baxter, Eli Lilly, Forum, Genentech, Lundbeck, Merck, Novartis, Pfizer, TauRx
Research Support, Government Entities:
1.
U01 AG024904, ADNI, P50 AG05142, R01 AG033288, R01 AG037561, R01 AG031348,RF1 AG041705, California 09-11413
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Alzheimer's Association
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Richard E. Kennedy, MD, PhD
From the Departments of Psychiatry and Neurology (L.S.S.), Keck School of Medicine of USC, Los Angeles, CA; Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine (R.E.K.), and Department of Biostatistics (G.W., G.R.C.), University of Alabama at Birmingham.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NIH/NIA 1 R01 AG 037561 (PI: Schneider), role: co- investigator, 2011-present NIH/NIA 5 R01 AG015062 (PI:Allman/Brown), role: co-investigator, 2011- present NIH/NIA 5 P30 AG031054 (PI:Allman/Burgio), role: investigator, 2014- present Department of Education/NIDRR H133A070039 (PI:Novack), role: investigator, 2012-present
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Guoqiao Wang, MS
From the Departments of Psychiatry and Neurology (L.S.S.), Keck School of Medicine of USC, Los Angeles, CA; Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine (R.E.K.), and Department of Biostatistics (G.W., G.R.C.), University of Alabama at Birmingham.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NIH/NIA, R01 AG037561(Schneider),statistician, 04/01/2011 ? 03/31/2014,
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Gary R. Cutter, PhD
From the Departments of Psychiatry and Neurology (L.S.S.), Keck School of Medicine of USC, Los Angeles, CA; Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine (R.E.K.), and Department of Biostatistics (G.W., G.R.C.), University of Alabama at Birmingham.
Disclosure
Scientific Advisory Boards:
1.
Participation of Data and Safety Monitoring Committees: Apotek; Biogen-Idec; Cleveland Clinic; Glaxo Smith Klein Pharmaceuticals; Gilead Pharmaceuticals; Modigenetech/Prolor; Merck/Ono Pharmaceuticals; Merck; Neuren; PCT Bio; Revalesio; Sanofi-Aventis; Teva; Vivus; NHLBI (Protocol Review Committee); NINDS; NMSS; NICHD (OPRU oversight committee);
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Consortium of MS Centers, speaker honoraria; (2) Genzyme - consulting fees (3) Teva, Speaker honoraria (4) Icahn School of Medicine - grand rounds honoraria
Editorial Boards:
1.
(1) Multiple Sclerosis, Editorial Board, 2010-present (2) JASN, 2013- present, statistical consulting reviewer
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Consulting, Speaking fees & Advisory Boards: Alexion; Allozyne; Bayer; Celgene; Coronado Biosciences; Consortium of MS Centers (grant); Diogenix; Immunotherapeutics Klein-Buendel Incorporated; Medimmune; Merck Novartis; Nuron Biotech; Opexa Receptos; Spiniflex Pharmaceuticals; Teva pharmaceuticals
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
(1) NINDS Grant with Multiple Sclerosis as the patient population (2) NARCOMS MS Patient Registry
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
No direct grants, but work on studies funded to the Consortium of MS Centers subcontracted for analysis of NARCOMS Registry.
Research Support, Government Entities:
1.
ACTIVE U01 NS 042685 (Cutter) 09/23/2005 ? 08/31/2015 1.5 calendar NIH/NINDS $ 744,084 current year direct Thymectomy Plus Prednisone vs. Prednisone Alone in NonThymomatous Myasthenia Gravis This multinational clinical trial aims to assess the utility of thymectomy in treating nonthymomatous Myasthenia Gravis patients comparing surgery plus medications versus medications alone. P30-AI 027767 (Saag, M.) 06/01/2014 ? 05/31/2019 1.2 calendar NIH/NIAID $ 3,214,372 current year direct UAB Center for Aids Research This CFAR is organized as a partnership between the University of Alabama at Birmingham and the Southern Research Institute. The primary purpose of this partnership is to generate interdisciplinary AIDS research efforts. This Center is responsible for planning, evaluating, managing and documenting a broad array of research activities within two institutions. Particular emphasis is placed upon linking clinical and basic science studies through the use of shared facilities and to translate as quickly as possible fundamental knowledge about AIDS and its related disorders into clinical treatment and prevention programs. U01-HL 119242 (Cutter) 09/01/2014 ? 05/31/2020 1.2 calendar NIH/NHLBI $426,203 current year direct Chronic Hypertension and Pregnancy (CHAP): Data Coordinating Center We propose a large pragmatic multi-center randomized trial of pregnant women with mild chronic hypertension to evaluate the benefits and harms of antihypertensive therapy to a goal <140/90 mmHg (as recommended for the general population in the US) compared with ACOG's current policy of expectant management of mild chronic hypertension in pregnancy. The trial will be conducted in 12 experienced research-oriented Ob/Gyn departments (including 25 clinical sites) in the United States. The monitoring plan will include a pre-specified option to increase the planned sample size of 4700 women after interim evaluation by an independent Data Safety and Monitoring Board. R01 HD 064729 (Tita) 04/01/2010 ? 07/31/2015 0.6 calendar NIH/NICHD $ NCE Caesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) Trial A multicenter randomized trial to determine the efficacy and safety of a modified (extended-spectrum) antibiotic prophylaxis strategy at cesarean delivery to reduce surgical site infections. R01 AG 021927 (Marson) 07/01/2010 ? 06/30/2015 0.12 calendar NIH/NIA $ 393,971 current year direct Functional Change in Mild Cognitive Impairment (COINS) This R01 project investigates longitudinal change in higher order functional abilities in patients with MCI, and develops predictor models for clinical progression and conversion from MCI to dementia. No number assigned (Cutter) 01/01/2004 ? 12/31/2014 0.05 calendar Consortium of MS Centers (CMSC) $ 600,000 North American Research Consortium on Multiple Sclerosis (NARCOMS) The goals of this project are to facilitate a confidential way for patients to supply valuable information to researchers about their course of disease that may lead to more effective treatments and care for people living with MS, while reducing the time and cost of conducting studies; provide a worldwide research resource for people living with multiple sclerosis so they can provide information about themselves and their course of disease; and develop new collaborations between researchers, patients, and healthcare providers. UAB provides programming and analytic support for the NARCOMS registry. W81XWH-12-1-0155 (Korf) 05/15/2012 ? 05/14/2017 1.8 calendar U.S. Department of Defense $1,621,899 current year direct NEUTOFIBOMATOSIS CLINICAL CONSORTIUM AWARD This is a cooperative study group that is focusing on multiple trials in NF. The role of the operations center is both as the data center and the overall coordinating of the study group. U01NS45719 (Lublin) 06/01/2004 ? 11/30/2014 2.4 calendar NIH/NINDS $ NCE CombiRx Statistical and Data Management Center A Phase III, multi-center, double-blind, randomized study comparing the combined use of Interferon Beta-1a and Glatiramer Acetate to either agent alone in patients with relapsing remitting multiple sclerosis. The Department of Biostatistics at UAB is the Statistical and Data Management Center for the trial. 140305 (Greenberg) 09/01/2013 ? 08/31/2016 1.2 calendar Patient Centered Outcomes Research Institute $24,771 current year direct Collaborative Assessment of Pediatric Transverse Myelitis: Understand, Reveal, Educate (CAPTURE) Study U34 AR062891 (K. Saag) 04/15/2013 ? 03/31/2015 .36 calendar NIH/NIAMS $ 225,953 current year direct Effectiveness of DiscontinuinG BisphosphonatEs Study (EDGE) Planning grant for a Pragmatic Clinical Trial (PCT), ?Effectiveness of DiscontinuinG bisphosphonatEs (EDGE) Study?, a ?real world? effectiveness trial of an initially estimated 4,100 patients randomized to continuation or discontinuation of prior alendronate therapy. P30DK079337 (Agarwal) 09/20/13 ? 07/31/18 .3 calendar NIH/NIDDK $976,357 current year direct UAB/UCSD O?Brien Core Center for Acute Kidney Injury Research In summary, these cores and the outstanding cohort of investigators assembled for this center will provide unique expertise that is critical for innovative and productive research in AKI. With its Extended Research Base that includes both clinical and basic investigators, this O'Brien center will accelerate the translation of new investigative insights towards novel therapies for patients with AKI. R01AI101138 (Shimamura) 08/08/13 ? 07/31/18 .24 calendar NIH/NIAID $250,000 current year direct Innate Immunity and Viral Renal Allograft Injury Kidney transplantation improves longevity and quality of life for patients with renal failure, but late allograft loss limits the long-term success of transplantation as a therapy. Human cytomegalovirus (HCMV) infection is associated epidemiologically with inferior transplant outcomes, but the pathogenesis remains cryptic. Natural killer (NK) cells are activated during graft rejection and with HCMV infection in renal transplant patients. A murine renal transplant model recapitulates this finding of NK cell induction by murine CMV (MCMV) infection during rejection. This model will be used to define mechanisms of MCMV induced NK activation in renal transplants, followed by extension of the mechanistic intragraft analyses from the animal model to examine NK activation in clinical renal transplant biopsies. NK activation in biopsies will be correlated with peripheral blood NK activation, HCMV infection, and outcome in renal transplant patients, linking the intragraft events in human and animal studies to clinical CMV infection and peripheral blood NK markers in a transplant population. Understanding the pathogenesis of CMV associated allograft injury in both the animal model and transplant patients will contribute toward development of strategies to improve kidney transplant survival for HCMV infected patients. RSTFD0000541263 (Cutter) 09/01/13 ? 08/31/17 .18 calendar Children?s Hospital (Boston) $60,314 current year direct Early Biomarkers of Autism Spectrum Disorders in Infants with Tuberous Sclerosis
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) Consortium of MS Centers (2) Myasthenia Gravis Foundation of America, grant for MG Registry
Stock/stock Options/board of Directors Compensation:
1.
Pythagoras, Inc. Sub S Corporation - President.
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence to Dr. Schneider: [email protected]
Presented, in part, at Alzheimer's Association International Conference, Copenhagen, Denmark, July 15, 2014.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Author Contributions

Lon S. Schneider, MD: drafting/revising the manuscript for content, including medical writing for content, study concept or design, analysis, and interpretation of data. Richard E. Kennedy, MD, PhD: revising the manuscript for content, including medical writing for content, study concept and design, analysis, and interpretation of data. Guoqiao Wang, MS: revising the manuscript for content, analysis, and interpretation of data. Gary R. Cutter, PhD: revising the manuscript for content, study concept and design, analysis, and interpretation of data.

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