Dominantly Inherited Alzheimer Network (DIAN)

Dominantly Inherited Alzheimer Network (DIAN)

Overview

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

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

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:

Key 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)

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:

Research 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:

Natural 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

• 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:

Comparison 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

Biomarker 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

Annual 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

• [Is disrupted sleep a cause or consequence of neurodegeneration? Analyze the bidirectional relationsh](/analysis/SDA-2026-04-02-gap-20260402-003058) 🔄
• [Is disrupted sleep a cause or consequence of neurodegeneration? Analyze the bidirectional relationsh](/analysis/SDA-2026-04-02-gap-20260402-003115) 🔄