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:
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.
ADAD accounts for approximately 1% of all Alzheimer's disease cases, but provides disproportionate insights into disease mechanisms. [1] The deterministic nature of these mutations allows researchers to:
Over 50 pathogenic mutations have been identified in the APP gene, located on chromosome 21. [2] These mutations typically:
The APP duplication syndrome, causing early-onset AD, is particularly significant as it provides evidence for the amyloid hypothesis.
Presenilin 1 is the catalytic core of the gamma-secretase complex. [3] With over 300 identified mutations, PSEN1 mutations represent the most common cause of ADAD. Characteristic features include:
Presenilin 2 mutations are rarer than PSEN1 but typically cause later onset (mean 55 years) with slower progression. [4] The Volga German kindred mutations (N141I) were among the first identified.
The primary mission of DIAN is to:
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:
| 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 |
DIAN researchers have been instrumental in identifying and validating biomarkers that track disease progression in ADAD:
DIAN has developed sensitive cognitive batteries including:
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:
The DIAN Observational Study follows mutation carriers and non-carriers over time to document:
Key findings include:
DIAN trials have provided crucial insights for Alzheimer's disease therapeutic development:
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 |
DIAN maintains a registry of families with ADAD mutations:
DIAN supports open science through:
DIAN holds an annual meeting bringing together:
Ryman et al. Symptom onset in autosomal dominant Alzheimer disease (2018). 2018. ↩︎
Van Cauwenberghe et al. APP mutations (2016). 2016. ↩︎
Kelley et al. PSEN1 mutations in early-onset AD (2020). 2020. ↩︎
Cunningham et al. PSEN2 mutations and phenotype (2021). 2021. ↩︎
Preische et al. Neurofilament light chain as biomarker in ADAD (2019). 2019. ↩︎