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Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
Literature Information
| DOI | 10.1056/NEJMoa1202753 |
|---|---|
| PMID | 22784036 |
| Journal | The New England journal of medicine |
| Impact Factor | 78.5 |
| JCR Quartile | Q1 |
| Publication Year | 2012 |
| Times Cited | 1917 |
| Keywords | Alzheimer's disease, biomarkers, pathological changes, cognitive impairment, brain imaging |
| Literature Type | Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't |
| ISSN | 0028-4793 |
| Pages | 795-804 |
| Issue | 367(9) |
| Authors | Randall J Bateman, Chengjie Xiong, Tammie L S Benzinger, Anne M Fagan, Alison Goate, Nick C Fox, Daniel S Marcus, Nigel J Cairns, Xianyun Xie, Tyler M Blazey, David M Holtzman, Anna Santacruz, Virginia Buckles, Angela Oliver, Krista Moulder, Paul S Aisen, Bernardino Ghetti, William E Klunk, Eric McDade, Ralph N Martins, Colin L Masters, Richard Mayeux, John M Ringman, Martin N Rossor, Peter R Schofield, Reisa A Sperling, Stephen Salloway, John C Morris |
TL;DR
This study investigated the sequence and timing of pathological changes in autosomal dominant Alzheimer's disease, revealing that amyloid-beta levels decline 25 years before expected symptom onset, with subsequent changes in tau protein, brain atrophy, and cognitive impairment occurring in a predictable order. These findings enhance our understanding of the disease's progression, although further longitudinal research is needed to validate these results in sporadic Alzheimer's cases.
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Alzheimer's disease · biomarkers · pathological changes · cognitive impairment · brain imaging
Abstract
BACKGROUND The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.
METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.
RESULTS Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
CONCLUSIONS We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).
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Primary Questions Addressed
- How do the identified biomarkers in dominantly inherited Alzheimer's disease compare to those found in sporadic cases?
- What are the implications of early biomarker changes for potential therapeutic interventions in at-risk populations?
- How might genetic factors influence the variability of clinical and biomarker changes in individuals with dominantly inherited Alzheimer's disease?
- What role do lifestyle factors play in modulating the progression of pathophysiological changes in Alzheimer's disease?
- How can longitudinal studies enhance our understanding of the timeline of Alzheimer's disease development in familial cases?
Key Findings
Background and Objective
Alzheimer's disease (AD) pathophysiology is complex and poorly understood due to its long development period. This study aims to elucidate the sequence and magnitude of pathological changes leading to symptomatic Alzheimer's disease, specifically in cases of autosomal dominant Alzheimer's disease, which has a predictable age of onset.
Main Methods/Materials/Experimental Design
This prospective, longitudinal study involved 128 participants who underwent comprehensive assessments, including clinical evaluations, cognitive testing, brain imaging, and analyses of cerebrospinal fluid (CSF) and blood samples.
Key methodological steps included:
- Baseline Assessments: Participants underwent clinical and cognitive assessments.
- Data Collection: Brain imaging and CSF/blood tests were conducted.
- Age Calculations: Estimated years from expected symptom onset were calculated using the participant's age at assessment and the parent's age at symptom onset.
- Cross-Sectional Analysis: Baseline data were analyzed to determine the timing and magnitude of pathophysiological changes relative to the estimated years from expected symptom onset.
The following flowchart summarizes the methodological approach:
Key Results and Findings
The study identified a sequence of pathological changes occurring at different time points relative to the expected onset of symptoms:
- 25 years before: Decline in CSF amyloid-beta (Aβ)(42) concentrations.
- 15 years before: Detection of Aβ deposition via PET imaging and increased CSF tau protein concentrations, along with brain atrophy.
- 10 years before: Observations of cerebral hypometabolism and impaired episodic memory.
- 5 years before: Global cognitive impairment as measured by the Mini-Mental State Examination and Clinical Dementia Rating scale.
- 3 years after: Patients met diagnostic criteria for dementia.
| Time Before Symptom Onset | Pathological Change |
|---|---|
| 25 years | Decline in CSF Aβ(42) |
| 15 years | Aβ deposition detected, increased tau protein, brain atrophy |
| 10 years | Cerebral hypometabolism, impaired episodic memory |
| 5 years | Global cognitive impairment |
| 3 years after | Diagnostic criteria for dementia met |
Main Conclusions/Significance/Innovation
The study concludes that autosomal dominant Alzheimer's disease is associated with a clear sequence of pathophysiological changes over decades, encompassing biochemical markers, brain amyloid deposition, and cognitive decline. This research enhances understanding of the disease's progression and emphasizes the importance of early detection and potential interventions. However, the findings are preliminary and require validation through longitudinal studies.
Limitations and Future Directions
- Limitations: The study's findings may not be generalizable to sporadic Alzheimer's disease patients. Additionally, the sample size may limit the robustness of the conclusions.
- Future Directions: Further longitudinal studies are necessary to confirm these results and explore interventions that could mitigate the identified pathophysiological changes. Investigating the applicability of these findings to sporadic Alzheimer's disease could also provide valuable insights into the disease's overall pathology.
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Literatures Citing This Work
- The genetics and neuropathology of neurodegenerative disorders: perspectives and implications for research and clinical practice. - Vivianna M Van Deerlin - Acta neuropathologica (2012)
- Lifelong management of amyloid-beta metabolism to prevent Alzheimer's disease. - Sam Gandy - The New England journal of medicine (2012)
- Tracking the insidious course of Alzheimer's disease. - Nature medicine (2012)
- Alzheimer disease: from inherited to sporadic AD-crossing the biomarker bridge. - Harald Hampel;Simone Lista - Nature reviews. Neurology (2012)
- Therapeutic strategies for tau mediated neurodegeneration. - Yasumasa Yoshiyama;Virginia M Y Lee;John Q Trojanowski - Journal of neurology, neurosurgery, and psychiatry (2013)
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- Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study. - Eric M Reiman;Yakeel T Quiroz;Adam S Fleisher;Kewei Chen;Carlos Velez-Pardo;Marlene Jimenez-Del-Rio;Anne M Fagan;Aarti R Shah;Sergio Alvarez;Andrés Arbelaez;Margarita Giraldo;Natalia Acosta-Baena;Reisa A Sperling;Brad Dickerson;Chantal E Stern;Victoria Tirado;Claudia Munoz;Rebecca A Reiman;Matthew J Huentelman;Gene E Alexander;Jessica B S Langbaum;Kenneth S Kosik;Pierre N Tariot;Francisco Lopera - The Lancet. Neurology (2012)
- Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional study. - Adam S Fleisher;Kewei Chen;Yakeel T Quiroz;Laura J Jakimovich;Madelyn Gutierrez Gomez;Carolyn M Langois;Jessica B S Langbaum;Napatkamon Ayutyanont;Auttawut Roontiva;Pradeep Thiyyagura;Wendy Lee;Hua Mo;Liliana Lopez;Sonia Moreno;Natalia Acosta-Baena;Margarita Giraldo;Gloria Garcia;Rebecca A Reiman;Matthew J Huentelman;Kenneth S Kosik;Pierre N Tariot;Francisco Lopera;Eric M Reiman - The Lancet. Neurology (2012)
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... (1907 more literatures)
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