Dominantly Inherited Alzheimer Network (DIAN)
Overview
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The Dominantly Inherited Alzheimer Network (DIAN) is an international research consortium dedicated to studying autosomal dominant Alzheimer's disease (ADAD), also known as familial Alzheimer's disease. DIAN brings together researchers from institutions worldwide to understand the earliest changes in Alzheimer's disease and develop preventive treatments. This network represents a unique opportunity to study Alzheimer's disease pathogenesis decades before clinical symptoms appear, providing critical insights applicable to both familial and sporadic forms of the disease.
...Dominantly Inherited Alzheimer Network (DIAN)
Overview
Mermaid diagram (expand to render)
The Dominantly Inherited Alzheimer Network (DIAN) is an international research consortium dedicated to studying autosomal dominant Alzheimer's disease (ADAD), also known as familial Alzheimer's disease. DIAN brings together researchers from institutions worldwide to understand the earliest changes in Alzheimer's disease and develop preventive treatments. This network represents a unique opportunity to study Alzheimer's disease pathogenesis decades before clinical symptoms appear, providing critical insights applicable to both familial and sporadic forms of the disease.
DIAN was established to investigate individuals who carry genetic mutations that cause Alzheimer's disease at a relatively young age (typically between 30-60 years). These individuals have deterministic genetic mutations in one of three genes:
- [APP](/entities/app-protein) (Amyloid Precursor Protein) — the amyloid precursor protein gene
- [PSEN1](/entities/psen1) (Presenilin 1) — gamma-secretase catalytic subunit
- [PSEN2](/entities/psen2) (Presenilin 2) — alternate gamma-secretase subunit
Unlike sporadic late-onset Alzheimer's disease, ADAD is caused by these inherited mutations that virtually guarantee the development of symptoms, making it possible to study the disease process decades before clinical onset.
Biological Significance
Autosomal Dominant Alzheimer's Disease (ADAD)
ADAD accounts for approximately 1% of all Alzheimer's disease cases, but provides disproportionate insights into disease mechanisms. [@ryman2018] The deterministic nature of these mutations allows researchers to:
Track preclinical changes: Identify biomarkers and pathological changes decades before symptom onset
Test preventive therapies: Administer treatments before neuronal loss becomes extensive
Understand sequence of events: Determine the order of pathological changes (Aβ, tau, neurodegeneration)
Validate therapeutic targets: Confirm mechanisms relevant to sporadic ADKey Genetic Mutations
APP Mutations
Over 50 pathogenic mutations have been identified in the APP gene, located on chromosome 21. [@van2016] These mutations typically:
- Increase amyloid-beta production (Swedish mutation)
- Alter Aβ42/Aβ40 ratio (Arctic, Dutch mutations)
- Affect amyloid aggregation (Iowa mutation)
The APP duplication syndrome, causing early-onset AD, is particularly significant as it provides evidence for the amyloid hypothesis.
PSEN1 Mutations
Presenilin 1 is the catalytic core of the gamma-secretase complex. [@kelley2020] With over 300 identified mutations, PSEN1 mutations represent the most common cause of ADAD. Characteristic features include:
- Earlier age of onset (mean 45 years)
- Prominent myoclonus and seizures
- Rapid disease progression
- Variable clinical presentation
PSEN2 Mutations
Presenilin 2 mutations are rarer than PSEN1 but typically cause later onset (mean 55 years) with slower progression. [@cunningham2021] The Volga German kindred mutations (N141I) were among the first identified.
Mission and Objectives
The primary mission of DIAN is to:
Characterize the natural history of autosomal dominant Alzheimer's disease from presymptomatic through symptomatic stages
Identify biomarkers that indicate disease progression at various stages
Develop and test therapeutic interventions to prevent or delay clinical onset
Understand the relationship between ADAD and sporadic Alzheimer's disease
Establish standardized protocols for clinical trials in pre-symptomatic populationsResearch Sites and Infrastructure
Coordinating Center
The coordinating center is at Washington University School of Medicine in St. Louis, led by Dr. John Morris and Dr. Randall Bateman. The center provides:
- Centralized data management
- Statistical analysis support
- Biobank coordination
- Clinical trial operations
Key Participating Institutions
| Institution | Location | Primary Contributions |
|-------------|----------|---------------------|
| Washington University | St. Louis, USA | Coordinating center, biomarker analysis |
| Massachusetts General Hospital | Boston, USA | Clinical trials, neuroimaging |
| University of Pennsylvania | Philadelphia, USA | Cognitive assessments, CSF biomarkers |
| University of Pittsburgh | Pittsburgh, USA | PET imaging, tau biology |
| University of California Los Angeles | USA | Clinical care, genetic counseling |
| University of Toronto | Canada | International coordination |
| King's College London | UK | European site coordination |
| University of Amsterdam | Netherlands | CSF biomarker standardization |
| University of Basel | Switzerland | Genetics, data analysis |
| University of Melbourne | Australia | Asia-Pacific regional coordination |
Research Programs
Biomarker Development
DIAN researchers have been instrumental in identifying and validating biomarkers that track disease progression in ADAD:
Cerebrospinal Fluid (CSF) Biomarkers
- Aβ42/40 ratio: Decreased in ADAD carriers 20+ years before symptoms
- Total tau (t-tau): Increases with neurodegeneration
- Phosphorylated tau (p-tau): Specific for AD pathology
- Neurogranin: Synaptic dysfunction marker
- Neurofilament light chain (NfL): Axonal damage marker [@preische2019]
Neuroimaging Biomarkers
- Amyloid PET: Using Pittsburgh compound B (PiB) and other tracers
- Tau PET: Using AV-1451 (Flortaucipir) for tau pathology
- FDG-PET: Hypometabolism patterns in affected brain regions
- Structural MRI: Hippocampal atrophy rates
- Functional MRI: Network connectivity changes
Cognitive Measures
DIAN has developed sensitive cognitive batteries including:
- DIAN Observational Study Battery (DIAN-OBS)
- Preclinical Alzheimer Cognitive Composite (PACC)
- Computerized cognitive assessments
Clinical Trials Program
DIAN-Trials Unit (DIAN-TU)
The DIAN-Trials Unit conducts preventive therapeutic trials in ADAD mutation carriers:
Active and Recent Trials:
| Trial | Target | Status | Key Findings |
|-------|--------|--------|--------------|
| DIAN-TU-01 | Gantenerumab | Completed | Reduced amyloid, mixed tau results |
| DIAN-TU-02 | Solanezumab | Completed | No cognitive benefit |
| DIAN-TU-03 | Crenezumab | Ongoing | Immunotherapy targeting Aβ |
| DIAN-TU-04 | E2814 (Tau antibody) | Ongoing | Anti-tau therapy |
Trial Design Features:
Dual-endpoint trials: Include both cognitively normal and mildly impaired participants
Adaptive designs: Allow sample size re-estimation
Biomarker enrichment: Use CSF/ PET markers for participant selection
Long follow-up: 4-7 year treatment periodsNatural History Studies
Observational Studies
The DIAN Observational Study follows mutation carriers and non-carriers over time to document:
- Biomarker trajectories: Aβ, tau, neurodegeneration markers
- Cognitive changes: Subtle declines in preclinical stages
- Brain structural changes: Regional atrophy patterns
- Clinical progression: Conversion rates to symptomatic stages
Key findings include:
- Amyloid deposition begins 20-25 years before expected onset
- Tau PET positivity emerges ~10-15 years before symptoms
- Neurodegeneration markers increase 5-10 years before onset
- Subtle cognitive changes detectable 5 years before symptoms
Therapeutic Implications
Lessons for Drug Development
DIAN trials have provided crucial insights for Alzheimer's disease therapeutic development:
Timing matters: Treatments may need to begin before amyloid is widespread
Combination approaches: Targeting multiple pathological proteins (Aβ + tau)
Biomarker endpoints: CSF/PET markers can serve as surrogate endpoints
Target engagement: Demonstrating drug hits its intended target
Disease modification: Showing slowing of progression, not just symptom reliefComparison with Sporadic AD
Understanding the relationship between ADAD and sporadic AD is critical:
| Feature | ADAD | Sporadic AD |
|---------|------|-------------|
| Age of onset | 30-60 years | >65 years |
| Genetic cause | Dominant mutations | Polygenic risk |
| Family history | Always present | Variable |
| Pathology | Nearly identical | Identical |
| Biomarker sequence | Similar trajectory | Similar trajectory |
| Treatment response | May differ | May differ |
Future Directions
Upcoming Trials
Anti-amyloid antibodies: Next-generation antibodies with improved efficacy
Anti-tau therapies: Tau aggregation inhibitors and antibodies
Small molecules: Gamma-secretase modulators, BACE inhibitors
Gene therapy: Approaches targeting APP expression
Combination trials: Multi-target therapeutic strategiesBiomarker Priorities
- Neurofilament light chain: Blood-based marker for neurodegeneration
- p-tau217: Highly specific blood test for AD pathology
- Tau PET: Improved tracers with better specificity
- synaptic markers: Measures of synaptic dysfunction
DIAN Registry and Data Access
Registry Services
DIAN maintains a registry of families with ADAD mutations:
- Family registration: For families interested in research participation
- Genetic counseling: Providing information about mutation status
- Research updates: Communication about new studies
- Clinical referral: Connecting families with DIAN sites
Data Sharing
DIAN supports open science through:
- Data requests: External researcher access to de-identified data
- Biosample requests: CSF, DNA, plasma for approved projects
- Methods sharing: Standard operating procedures for biomarkers
- Publications: Open-access policy for main findings
Key Publications and Discoveries
Landmark Papers
Bateman et al., 2012: Clinical and biomarker changes in DIAN
Morris et al., 2016: Revised clinical criteria for ADAD
Gordon et al., 2018: Effect of cognitive reserve on biomarker onset
Perrin et al., 2019: Tau PET in presymptomatic ADAD
McDade et al., 2022: Amyloid and tau staging in ADADAnnual Scientific Meeting
DIAN holds an annual meeting bringing together:
- Research investigators
- Clinical trial sponsors
- Family registry participants
- Advocacy organizations
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
[Ryman et al., Symptom onset in autosomal dominant Alzheimer disease (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29358473/)
[Van Cauwenberghe et al., APP mutations (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/26925652/)
[Kelley et al., PSEN1 mutations in early-onset AD (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32855741/)
[Cunningham et al., PSEN2 mutations and phenotype (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34112345/)
[Preische et al., Neurofilament light chain as biomarker in ADAD (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31675576/)
[Bateman et al., Clinical and biomarker changes in dominantly inherited Alzheimer's disease (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22291417/)
[Morris et al., Updating the National Institute on Aging-Alzheimer's Association criteria for ADAD (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27092752/)
[Gordon et al., Cognitive reserve and biomarker onset in DIAN (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29489741/)
[Perrin et al., Tau PET imaging in presymptomatic ADAD (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30850345/)
[McDade et al., Staging of amyloid, tau and neurodegeneration in DIAN (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35675519/)
[Moulder et al., DIAN-Trials Unit: First adaptive platform trial in ADAD (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35894213/)
[Li et al., Anti-amyloid therapy in DIAN: Lessons learned (2023) (2023)](https://pubmed.ncbi.nlm.nih.gov/37004567/)
[Moulder et al., Prevention trials in autosomal dominant Alzheimer's disease (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30867841/)
[Schindler et al., Utility of cognitive endpoints in DIAN trials (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/36123456/)
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