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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.
Literature Information
| DOI | 10.1016/j.jalz.2011.03.003 |
|---|---|
| PMID | 21514248 |
| Journal | Alzheimer's & dementia : the journal of the Alzheimer's Association |
| Impact Factor | 11.1 |
| JCR Quartile | Q1 |
| Publication Year | 2011 |
| Times Cited | 3449 |
| Keywords | Alzheimer's disease, preclinical stage, biomarkers, cognitive impairment, intervention |
| Literature Type | Consensus Development Conference, NIH, Journal Article, Research Support, Non-U.S. Gov't |
| ISSN | 1552-5260 |
| Pages | 280-92 |
| Issue | 7(3) |
| Authors | Reisa A Sperling, Paul S Aisen, Laurel A Beckett, David A Bennett, Suzanne Craft, Anne M Fagan, Takeshi Iwatsubo, Clifford R Jack, Jeffrey Kaye, Thomas J Montine, Denise C Park, Eric M Reiman, Christopher C Rowe, Eric Siemers, Yaakov Stern, Kristine Yaffe, Maria C Carrillo, Bill Thies, Marcelle Morrison-Bogorad, Molly V Wagster, Creighton H Phelps |
TL;DR
This study emphasizes the importance of the preclinical phase of Alzheimer's disease (AD) as a critical window for therapeutic intervention, proposing a conceptual framework and operational criteria to identify factors predicting the progression from normal cognition to mild cognitive impairment and AD dementia. By synthesizing biomarker and epidemiological evidence, the recommendations aim to enhance research on preclinical AD, ultimately facilitating earlier interventions that could be more effective in modifying the disease.
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Alzheimer's disease · preclinical stage · biomarkers · cognitive impairment · intervention
Abstract
The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
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Primary Questions Addressed
- What specific biomarkers are being recommended for identifying the preclinical stages of Alzheimer's disease?
- How do the proposed recommendations aim to enhance the understanding of the transition from normal cognition to mild cognitive impairment?
- What are the implications of the findings from the National Institute on Aging-Alzheimer's Association workgroups for future clinical trials?
- In what ways could the operational research criteria proposed impact the development of disease-modifying therapies for Alzheimer's?
- What challenges might researchers face in implementing the recommendations for studying preclinical Alzheimer's disease?
Key Findings
Research Background and Objectives
Alzheimer’s disease (AD) is characterized by a prolonged preclinical phase where pathophysiological changes occur years before clinical symptoms manifest. This research aims to define the preclinical stages of AD, identify biomarkers that predict progression from normal cognition to mild cognitive impairment (MCI) and AD dementia, and establish a framework for future research.
Main Methods/Materials/Experimental Design
The study involved a comprehensive review of existing biomarker, epidemiological, and neuropsychological evidence related to AD. The National Institute on Aging and Alzheimer’s Association convened a workgroup to develop operational research criteria for preclinical AD. The focus was on identifying the biomarkers indicative of early AD pathology and their correlation with cognitive decline.
Key Results and Findings
Biomarkers: The study identified several biomarkers linked to AD pathology, including:
- Amyloid-beta accumulation (detected via CSF and PET imaging)
- Neurodegeneration markers (tau levels, brain atrophy via MRI)
- Synaptic dysfunction (FDG-PET hypometabolism)
Cognitive Decline: Subtle cognitive changes can be detected years before MCI, and certain individuals show early biomarkers without ever developing clinical symptoms.
Preclinical Staging: The workgroup proposed a three-stage model for preclinical AD:
- Stage 1: Asymptomatic cerebral amyloidosis (evidence of amyloid accumulation).
- Stage 2: Amyloid positivity with evidence of neurodegeneration (tau elevation, brain atrophy).
- Stage 3: Amyloid positivity, neurodegeneration, and subtle cognitive decline.
Main Conclusions/Significance/Innovativeness
The study emphasizes the importance of early detection of AD pathology to facilitate timely intervention. By establishing a framework for the preclinical stages of AD, it aims to advance research into effective therapeutic strategies that could modify the disease process before significant cognitive decline occurs. The proposed criteria can standardize research methodologies and improve the understanding of AD's progression.
Research Limitations and Future Directions
- Limitations: The proposed research criteria are not yet clinically applicable and are primarily intended for research purposes. The link between biomarkers and clinical symptoms requires further validation.
- Future Directions: Additional longitudinal studies are needed to confirm the predictive value of identified biomarkers and to explore new biomarkers that could enhance early detection of AD. Research should also focus on developing effective interventions for individuals in the preclinical stage.
Summary Table of Preclinical AD Stages
| Stage | Description | Biomarker Evidence |
|---|---|---|
| 1 | Asymptomatic cerebral amyloidosis | Amyloid accumulation (CSF/PET) |
| 2 | Amyloid positivity + early neurodegeneration | Elevated tau, FDG-PET hypometabolism, MRI atrophy |
| 3 | Amyloid positivity + neurodegeneration + subtle cognitive decline | Cognitive changes from baseline |
References
- Depressive symptoms and cognitive decline in late life: a prospective epidemiological study. - Mary Ganguli;Yangchun Du;Hiroko H Dodge;Graham G Ratcliff;Chung-Chou H Chang - Archives of general psychiatry (2006)
- Frequent amyloid deposition without significant cognitive impairment among the elderly. - Howard Jay Aizenstein;Robert D Nebes;Judith A Saxton;Julie C Price;Chester A Mathis;Nicholas D Tsopelas;Scott K Ziolko;Jeffrey A James;Beth E Snitz;Patricia R Houck;Wenzhu Bi;Ann D Cohen;Brian J Lopresti;Steven T DeKosky;Edythe M Halligan;William E Klunk - Archives of neurology (2008)
- Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. - Christopher C Rowe;Kathryn A Ellis;Miroslava Rimajova;Pierrick Bourgeat;Kerryn E Pike;Gareth Jones;Jurgen Fripp;Henri Tochon-Danguy;Laurence Morandeau;Graeme O'Keefe;Roger Price;Parnesh Raniga;Peter Robins;Oscar Acosta;Nat Lenzo;Cassandra Szoeke;Olivier Salvado;Richard Head;Ralph Martins;Colin L Masters;David Ames;Victor L Villemagne - Neurobiology of aging (2010)
- Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. - Leslie M Shaw;Hugo Vanderstichele;Malgorzata Knapik-Czajka;Christopher M Clark;Paul S Aisen;Ronald C Petersen;Kaj Blennow;Holly Soares;Adam Simon;Piotr Lewczuk;Robert Dean;Eric Siemers;William Potter;Virginia M-Y Lee;John Q Trojanowski; - Annals of neurology (2009)
- Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB. - S M Resnick;J Sojkova;Y Zhou;Y An;W Ye;D P Holt;R F Dannals;C A Mathis;W E Klunk;L Ferrucci;M A Kraut;D F Wong - Neurology (2010)
- Selective disruption of the cerebral neocortex in Alzheimer's disease. - Rahul S Desikan;Mert R Sabuncu;Nicholas J Schmansky;Martin Reuter;Howard J Cabral;Christopher P Hess;Michael W Weiner;Alessandro Biffi;Christopher D Anderson;Jonathan Rosand;David H Salat;Thomas L Kemper;Anders M Dale;Reisa A Sperling;Bruce Fischl; - PloS one (2010)
- Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. - Anne M Fagan;Catherine M Roe;Chengjie Xiong;Mark A Mintun;John C Morris;David M Holtzman - Archives of neurology (2007)
- Serial MRI and CSF biomarkers in normal aging, MCI, and AD. - P Vemuri;H J Wiste;S D Weigand;D S Knopman;J Q Trojanowski;L M Shaw;M A Bernstein;P S Aisen;M Weiner;R C Petersen;C R Jack; - Neurology (2010)
- Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer's disease. - V L Villemagne;K E Pike;D Darby;P Maruff;G Savage;S Ng;U Ackermann;T F Cowie;J Currie;S G Chan;G Jones;H Tochon-Danguy;G O'Keefe;C L Masters;C C Rowe - Neuropsychologia (2008)
- Predictors of maintaining cognitive function in older adults: the Health ABC study. - K Yaffe;A J Fiocco;K Lindquist;E Vittinghoff;E M Simonsick;A B Newman;S Satterfield;C Rosano;S M Rubin;H N Ayonayon;T B Harris; - Neurology (2009)
Literatures Citing This Work
- Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. - B C Dickerson;T R Stoub;R C Shah;R A Sperling;R J Killiany;M S Albert;B T Hyman;D Blacker;L Detoledo-Morrell - Neurology (2011)
- The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. - Marilyn S Albert;Steven T DeKosky;Dennis Dickson;Bruno Dubois;Howard H Feldman;Nick C Fox;Anthony Gamst;David M Holtzman;William J Jagust;Ronald C Petersen;Peter J Snyder;Maria C Carrillo;Bill Thies;Creighton H Phelps - Alzheimer's & dementia : the journal of the Alzheimer's Association (2011)
- The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. - Guy M McKhann;David S Knopman;Howard Chertkow;Bradley T Hyman;Clifford R Jack;Claudia H Kawas;William E Klunk;Walter J Koroshetz;Jennifer J Manly;Richard Mayeux;Richard C Mohs;John C Morris;Martin N Rossor;Philip Scheltens;Maria C Carrillo;Bill Thies;Sandra Weintraub;Creighton H Phelps - Alzheimer's & dementia : the journal of the Alzheimer's Association (2011)
- Face-name associative memory performance is related to amyloid burden in normal elderly. - Dorene M Rentz;Rebecca E Amariglio;J Alex Becker;Meghan Frey;Lauren E Olson;Katherine Frishe;Jeremy Carmasin;Jacqueline E Maye;Keith A Johnson;Reisa A Sperling - Neuropsychologia (2011)
- Neuroimaging markers for the prediction and early diagnosis of Alzheimer's disease dementia. - Michael Ewers;Reisa A Sperling;William E Klunk;Michael W Weiner;Harald Hampel - Trends in neurosciences (2011)
- Progress in Alzheimer's disease. - Daniela Galimberti;Elio Scarpini - Journal of neurology (2012)
- Role of cerebrospinal fluid and plasma biomarkers in the diagnosis of neurodegenerative disorders and mild cognitive impairment. - Luis F Gonzalez-Cuyar;Joshua A Sonnen;Kathleen S Montine;C Dirk Keene;Thomas J Montine - Current neurology and neuroscience reports (2011)
- Perspective: prevention is better than cure. - Sam Gandy - Nature (2011)
- Perspective: in search of biomarkers. - Neil S Buckholtz - Nature (2011)
- Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease. - Clifford R Jack;Frederik Barkhof;Matt A Bernstein;Marc Cantillon;Patricia E Cole;Charles Decarli;Bruno Dubois;Simon Duchesne;Nick C Fox;Giovanni B Frisoni;Harald Hampel;Derek L G Hill;Keith Johnson;Jean-François Mangin;Philip Scheltens;Adam J Schwarz;Reisa Sperling;Joyce Suhy;Paul M Thompson;Michael Weiner;Norman L Foster - Alzheimer's & dementia : the journal of the Alzheimer's Association (2011)
... (3439 more literatures)
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