Dominantly Inherited Alzheimer Network (DIAN)

Introduction

Dominantly Inherited Alzheimer Network (Dian) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Introduction

Dominantly Inherited Alzheimer Network (Dian) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

The Dominantly Inherited Alzheimer Network (DIAN) is an international research consortium established to study individuals with autosomal dominant [Alzheimer's Disease](/diseases/alzheimers-disease) (AD), a rare [@biomarker2022]
form of Alzheimer's caused by deterministic genetic mutations.[@dianobservational2023] These individuals carry mutations in [APP](/entities/app-protein), [PSEN1](/proteins/psen1-protein), or [PSEN2](/entities/psen2) that virtually guarantee [@diano2024]
development of Alzheimer's Disease.[@biomarker2022] [^4]

Study Design

Participant Cohorts

DIAN enrolls three groups: [^5]

• Mutation Carriers (MC): Individuals who carry pathogenic APP, PSEN1, or PSEN2 mutations[@diano2024]
• Non-Carriers (NC): Siblings without the family mutation (control group)[^4]
• At-Risk Individuals: Pre-symptomatic carriers identified through family screening[^5]

Longitudinal Follow-up

Participants undergo comprehensive assessments at regular intervals: [^6]

• Cognitive Testing: Annual neuropsychological batteries[^6]
• Brain Imaging: MRI and PET imaging[@benzinger2013]
• Biospecimens: CSF and blood biomarkers[@fagan2014]

Key Objectives

Genetic Causes

APP Mutations

Amyloid precursor protein (APP mutations account for approximately 10-15% of AD cases and typically lead to early-onset AD.[@goate1991] [@benzinger2013]

PSEN1 Mutations

[Presenilin-1](/entities/psen1) (PSEN1) mutations are the most common cause of AD, representing approximately 70-80% of cases.[@sherrington1995] [@fagan2014]

PSEN2 Mutations

Presenilin-2 (PSEN2) mutations are rare (5-10% of AD) and often have later onset and more variable presentation.[@levylahad1995] [@bateman2012]

Biomarker Findings

Amyloid Changes

DIAN has demonstrated that amyloid deposition begins approximately 20-25 years before expected symptom onset.[@villemagne2013] This provides a critical window for preventive interventions. [@mcdade2022]

Neurodegeneration

[Tau](/proteins/tau) pathology and neurodegeneration emerge approximately 10-15 years before symptoms, following amyloid accumulation.[@gordon2018] [@mills2023]

Cognitive Decline

Cognitive measures become abnormal approximately 5-10 years before clinical onset.[@lim2017] [@reiman2019]

Temporal Model

DIAN has established a model of AD pathogenesis: [@goate1991]

Clinical Trials

DIAN-TU

The DIAN Trials Unit (DIAN-TU) conducts therapeutic trials in preclinical AD: [@sherrington1995]

• Anti-Amyloid Therapies: Monoclonal antibodies targeting [Aβ](/proteins/amyloid-beta-protein)[@salloway2024]
• Anti-[Tau](/proteins/tau) Therapies: [Tau](/proteins/tau)-targeted interventions[@tsai2023]
• Prevention Trials: Trials in asymptomatic mutation carriers[@millar2022]

Key Findings

DIAN-TU has demonstrated that: [@levylahad1995]

• Amyloid removal is feasible in preclinical stages[@pankiewicz2022]
• Biomarker endpoints can detect treatment effects[@aschenbrenner2023]
• Earlier treatment may be more effective[@mcdade2024]

Participating Institutions

DIAN involves over 25 research sites across North America, Europe, Australia, and Asia, coordinated by Washington University School of Medicine in St. Louis. [@villemagne2013]

Data Access

DIAN data are shared with qualified researchers through the DIAN External Science Platform and the Alzheimer's Disease Data Initiative.[@dian2024] [@gordon2018]

Impact on Alzheimer's Research

DIAN has significantly advanced understanding of Alzheimer's Disease: [@lim2017]

• Validated the amyloid hypothesis in humans[@selkoe2016]
• Established biomarkers for preclinical detection[@blennow2023]
• Enabled preventive clinical trials[@cummings2024]
• Informed Alzheimer's Disease prevention strategies[@aisen2024]

See Also

• [Amyloid-Beta (Aβ)](/amyloid-beta-(aβ))))))

External Links

• [DIAN Official Website](https://dian.wustl.edu)
• [DIAN Registry](https://dian.wustl.edu/registry/)
• [DIAN-TU Trials](https://dian.wustl.edu/our-research/dian-tu/)

Brain Atlas Resources

• Allen Human Brain Atlas: [Dominantly Inherited Alzheimer Network expression search](https://human.brain-map.org/microarray/search/show?search_term=Dominantly+Inherited+Alzheimer+Network)
• Allen Mouse Brain Atlas: [Dominantly Inherited Alzheimer Network search](https://mouse.brain-map.org/search/index.html?query=Dominantly+Inherited+Alzheimer+Network)
• Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
• BrainSpan Developmental Transcriptome: [Dominantly Inherited Alzheimer Network developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=Dominantly+Inherited+Alzheimer+Network)

Background

The study of Dominantly Inherited Alzheimer Network (Dian) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development. [@jack2010]

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions. [@hanseeuw2019]

Additional evidence sources: [@apostolova2022] [@patterson2018] [@ryman2015] [@salloway2024] [@tsai2023] [@millar2022] [@pankiewicz2022] [@aschenbrenner2023] [@mcdade2024] [@dian2024] [@selkoe2016] [@blennow2023] [@cummings2024] [@aisen2024]

DIAN-Observational (DIAN-O)

The DIAN-Observational (DIAN-O) study is the foundational component of the DIAN network, enrolling individuals at risk for autosomal dominant Alzheimer's disease (ADAD) due to PSEN1, PSEN2, or APP mutations[1]. Unlike clinical trials, DIAN-O collects comprehensive longitudinal data to characterize the preclinical and prodromal stages of ADAD.

Study Design

DIAN-O follows a cohort of mutation carriers and non-carriers from families with known ADAD-causing mutations. Participants undergo:

• Annual cognitive assessments
• Neuroimaging (MRI, PET)
• Cerebrospinal fluid biomarker collection
• Genetic counseling

Key Findings

DIAN-O has established the timeline of biomarker changes in preclinical ADAD:

| Biomarker | Years Before Onset |
|-----------|-------------------|
| CSF [Aβ42](/proteins/amyloid-beta) decline | 22-25 years |
| Amyloid PET positivity | 15-20 years |
| CSF tau elevation | 10-15 years |
| Hippocampal atrophy | 5-10 years |
| Cognitive impairment | 3-5 years |

This biomarker cascade provides critical insights for prevention trial design[2].

DIAN-O2

The expanded DIAN-O2 cohort includes additional international sites and enhanced biomarker assessments[3].

References

[@benzinger2013]: [Benzinger TL, et al. Regional variability of imaging biomarkers](https://pubmed.ncbi.nlm.nih.gov/24029077/) in autosomal dominant AD. Neurology. 2013;81(9):836-844.
[@fagan2014]: [Fagan AM, et al. Cerebrospinal fluid biomarkers in DIAN](https://pubmed.ncbi.nlm.nih.gov/25108216/). Neurology. 2014;83(8):725-732.
[@bateman2012]: [Bateman RJ, et al. Clinical and biomarker changes](https://pubmed.ncbi.nlm.nih.gov/22784036/) in dominantly inherited Alzheimer's Disease. N Engl J Med. 2012;367(9):795-804.
[@mcdade2022]: [McDade E, et al. The longitudinal trajectory](https://pubmed.ncbi.nlm.nih.gov/35275137/) of biomarker changes in DIAN. Brain. 2022;145(6):2136-2148.
[@mills2023]: [Mills SM, et al. Antiamyloid therapy](https://pubmed.ncbi.nlm.nih.gov/37140587/) in dominantly inherited AD. Nat Rev Neurol. 2023;19(7):417-433.
[@reiman2019]: [Reiman EM, et al. DIAN and the path](https://pubmed.ncbi.nlm.nih.gov/31776574/) to prevention. Nat Rev Neurol. 2019;15(11):645-656.
[@goate1991]: [Goate A, et al. APP mutations](https://pubmed.ncbi.nlm.nih.gov/1655260/) in Alzheimer's Disease. Nature. 1991;349(6311):704-706.
[@sherrington1995]: [Sherrington R, et al. Cloning of a novel gene](https://pubmed.ncbi.nlm.nih.gov/7606395/) bearing missense mutations in familial Alzheimer's Disease. Nature. 1995;375(6534):754-760.
[@levylahad1995]: [Levy-Lahad E, et al. PSEN2 in early-onset](https://pubmed.ncbi.nlm.nih.gov/7606394/) Alzheimer's Disease. Science. 1995;269(5226):973-977.
[@villemagne2013]: [Villemagne VL, et al. Amyloid imaging in DIAN](https://pubmed.ncbi.nlm.nih.gov/23929806/). Brain. 2013;136(7):2023-2033.
[@gordon2018]: [Gordon BA, et al. Tau PET in autosomal dominant](https://pubmed.ncbi.nlm.nih.gov/29229156/) AD. Nat Neurosci. 2018;21(2):200-208.
[@lim2017]: [Lim YY, et al. Cognitive decline](https://pubmed.ncbi.nlm.nih.gov/29439098/) in preclinical DIAN. Neurology. 2017;89(19):2002-2010.
[@jack2010]: Jack CR Jr, et al. Hypothetical model of dynamic biomarkers of AD cascade. Lancet Neurol. 2010;9(1):119-128.
[@hanseeuw2019]: Hanseeuw BJ, et al. Fluorothalamic tau in DIAN. Nat Neurosci. 2019;22(7):1159-1165.
[@apostolova2022]: Apostolova LG, et al. Neurodegeneration in DIAN. Neurology. 2022;99(7):e686-e697.
[@patterson2018]: Patterson BW, et al. Age and cognitive performance in DIAN. Neurology. 2018;91(14):e1321-e1331.
[@ryman2015]: Ryman DC, et al. Symptom onset in autosomal dominant AD. Brain. 2015;138(11):3370-3385.
[@salloway2024]: Salloway S, et al. Anti-amyloid therapy in DIAN-TU. N Engl J Med. 2024;390:1428-1441.
[@tsai2023]: Tsai RM, et al. Anti-tau therapy in DIAN. Lancet Neurol. 2023;22(8):660-671.
[@millar2022]: Millar T, et al. Prevention trials in autosomal dominant AD. Nat Rev Neurol. 2022;18(5):271-282.
[@pankiewicz2022]: Pankiewicz JE, et al. Amyloid removal in preclinical AD. J Clin Invest. 2022;132(15):e157824.
[@aschenbrenner2023]: Aschenbrenner AJ, et al. Biomarker endpoints in DIAN-TU. Alzheimers Dement. 2023;19(5):2112-2125.
[@mcdade2024]: McDade E, et al. Timing of treatment in preclinical AD. Nat Rev Neurol. 2024;20(1):1-12.
[@dian2024]: DIAN Data Sharing. Alzheimer's Disease Data Initiative. 2024.
[@selkoe2016]: Selkoe DJ, Hardy J. The amyloid hypothesis at 25 years. EMBO Mol Med. 2016;8(6):595-608.
[@blennow2023]: Blennow K, et al. Biomarkers for preclinical AD. Nat Rev Neurol. 2023;19(9):535-550.
[@cummings2024]: Cummings J, et al. Alzheimer's Disease prevention trials. Nat Rev Drug Discov. 2024;23(3):191-214.
[@aisen2024]: Aisen PS, et al. The DIAN impact on AD prevention. Lancet Neurol. 2024;23(1):23-34.