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Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease. ​

Literature Information ​

DOI10.1186/alzrt59
PMID21211070
JournalAlzheimer's research & therapy
Impact Factor7.6
JCR QuartileQ1
Publication Year2011
Times Cited292
KeywordsAutosomal Dominant, Alzheimer's Disease, Clinical Trials, Amyloid Hypothesis
Literature TypeJournal Article
Pages1
Issue3(1)
AuthorsRandall J Bateman, Paul S Aisen, Bart De Strooper, Nick C Fox, Cynthia A Lemere, John M Ringman, Stephen Salloway, Reisa A Sperling, Manfred Windisch, Chengjie Xiong

TL;DR ​

This review explores the clinical and biological aspects of autosomal-dominant Alzheimer's disease, emphasizing its similarities and differences with sporadic cases, while also discussing recent developments such as the Dominantly Inherited Alzheimer Network and its clinical trial initiatives. The findings highlight the potential of targeted trials to validate the amyloid hypothesis, optimize treatment timing, and advance preventive strategies for Alzheimer's disease.

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Autosomal Dominant · Alzheimer's Disease · Clinical Trials · Amyloid Hypothesis

Abstract ​

Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including the international Dominantly Inherited Alzheimer Network and this network's initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimer's disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimer's disease prevention.

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Primary Questions Addressed ​

  1. What are the key differences in the pathophysiology between autosomal-dominant Alzheimer's disease and sporadic Alzheimer's disease?
  2. How might findings from the Dominantly Inherited Alzheimer Network influence future treatment strategies for Alzheimer's disease?
  3. What role do genetic factors play in the progression and treatment response of autosomal-dominant Alzheimer's disease compared to sporadic cases?
  4. How can early intervention in autosomal-dominant Alzheimer's disease inform preventive measures for the broader Alzheimer's disease population?
  5. What specific biomarkers are being investigated in clinical trials for autosomal-dominant Alzheimer's disease, and how do they relate to treatment outcomes?

Key Findings ​

Research Background and Purpose ​

Autosomal-dominant Alzheimer's disease (ADAD) is a rare but critical area of study that has provided significant insights into the pathophysiology of Alzheimer's disease (AD). This review by Bateman et al. aims to summarize current knowledge regarding ADAD, its similarities and differences with sporadic Alzheimer's disease (SAD), and propose strategies for the prevention of Alzheimer's disease through early intervention and clinical trials.

Main Methods/Materials/Experimental Design ​

The review encompasses a comprehensive analysis of various studies related to ADAD, including clinical, pathological, imaging, biochemical, and molecular research. Key methodologies include:

  1. Genetic Analysis: Identification of mutations in APP, PSEN1, and PSEN2 genes linked to ADAD.
  2. Neuroimaging: Utilization of MRI and PET scans to observe structural and functional brain changes in ADAD carriers.
  3. Biomarker Studies: Evaluation of cerebrospinal fluid (CSF) and blood biomarkers associated with AD, such as Aβ42 and tau levels.
  4. Clinical Trials: Discussion of ongoing and proposed clinical trials aimed at testing disease-modifying therapies in presymptomatic individuals.

The following flowchart outlines the technical route of the research:

Mermaid diagram

Key Results and Findings ​

  • Clinical Presentation: ADAD typically presents with an earlier onset (30-50 years) compared to SAD, which usually occurs after age 60. Symptoms often include memory impairment and cognitive decline.
  • Neuropathology: Similar to SAD, ADAD is characterized by neuronal loss, neurofibrillary tangles, and amyloid plaques. However, specific mutation types can lead to distinctive pathological features.
  • Biomarkers: CSF Aβ42 levels are significantly reduced in ADAD, paralleling findings in SAD, while tau and phospho-tau levels are increased, indicating similar disease mechanisms.
  • Neuroimaging: Presymptomatic changes in brain structure and function, such as hippocampal atrophy and glucose hypometabolism, have been documented in mutation carriers.

Main Conclusions/Significance/Innovation ​

The review highlights the importance of studying ADAD as a model for understanding the broader mechanisms of Alzheimer's disease. It emphasizes the potential for early intervention in at-risk individuals, which could lead to the development of preventive strategies and therapeutic interventions. The establishment of the Dominantly Inherited Alzheimer Network (DIAN) is a significant step towards coordinating research efforts and clinical trials targeting ADAD.

Research Limitations and Future Directions ​

  • Limitations: The rarity of ADAD cases poses challenges for recruitment in clinical trials, and the genetic testing uptake among at-risk individuals remains low.
  • Future Directions: The authors advocate for larger, multi-center studies and the development of more targeted therapeutic interventions. Continued exploration of biomarkers and their relationship to clinical outcomes is essential for improving the efficacy of future trials.

In conclusion, this review serves as a call to action for the scientific community to prioritize ADAD research, which holds promise for advancing our understanding and treatment of Alzheimer's disease.

References ​

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  2. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. - A Goate;M C Chartier-Harlin;M Mullan;J Brown;F Crawford;L Fidani;L Giuffra;A Haynes;N Irving;L James - Nature (1991)
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Literatures Citing This Work ​

  1. Alzheimer's disease: the challenge of the second century. - David M Holtzman;John C Morris;Alison M Goate - Science translational medicine (2011)
  2. Should persons with autosomal dominant AD be included in clinical trials? - Joshua D Grill;John M Ringman - Alzheimer's research & therapy (2011)
  3. Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease. - Marcus O W Grimm;Sven Grösgen;Tatjana L Rothhaar;Verena K Burg;Benjamin Hundsdörfer;Viola J Haupenthal;Petra Friess;Ulrike Müller;Klaus Fassbender;Matthias Riemenschneider;Heike S Grimm;Tobias Hartmann - International journal of Alzheimer's disease (2011)
  4. Cerebral microbleeds in familial Alzheimer's disease. - Natalie S Ryan;António J Bastos-Leite;Jonathan D Rohrer;David J Werring;Nick C Fox;Martin N Rossor;Jonathan M Schott - Brain : a journal of neurology (2012)
  5. Defining and describing the pre-dementia stages of familial Alzheimer's disease. - Natalie S Ryan;Martin N Rossor - Alzheimer's research & therapy (2011)
  6. Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. - Eric M Reiman;Jessica B S Langbaum;Adam S Fleisher;Richard J Caselli;Kewei Chen;Napatkamon Ayutyanont;Yakeel T Quiroz;Kenneth S Kosik;Francisco Lopera;Pierre N Tariot - Journal of Alzheimer's disease : JAD (2011)
  7. Alzheimer's disease clinical trials: changing the paradigm. - Jeffrey L Cummings - Current psychiatry reports (2011)
  8. PET amyloid-beta imaging in preclinical Alzheimer's disease. - Andrei G Vlassenko;Tammie L S Benzinger;John C Morris - Biochimica et biophysica acta (2012)
  9. Testing the right target and right drug at the right stage. - Reisa A Sperling;Clifford R Jack;Paul S Aisen - Science translational medicine (2011)
  10. Brain imaging in the study of Alzheimer's disease. - Eric M Reiman;William J Jagust - NeuroImage (2012)

... (282 more literatures)

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