Longitudinal Early-onset Alzheimer Disease Study (LEADS)

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Longitudinal Early-onset Alzheimer Disease Study (LEADS)

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<table class="infobox infobox-institution">
<tr>
<th class="infobox-header" colspan="2">Longitudinal Early-onset Alzheimer's Disease Study (LEADS)</th>
</tr>
<tr>
<td class="infobox-image" colspan="2">
<em>Logo placeholder</em>
</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Multi-site Research Consortium</td>
</tr>
<tr>
<td class="label">Established</td>
<td>2018</td>
</tr>
<tr>
<td class="label">Focus</td>
<td>Early-onset Alzheimer's Disease</td>
</tr>
<tr>
<td class="label">Age Range</td>
<td>40-64 years</td>
</tr>
<tr>
<td class="label">Sites</td>
<td>15+ US academic medical centers</td>
</tr>
<tr>
<td class="label">Funding</td>
<td>National Institute on Aging (NIA)</td>
</tr>
<tr>
<td class="label">Website</td>
<td><a href="https://leads-study.org/" target="_blank">https://leads-study.org/</a></td>
</tr>
</table>

Longitudinal Early-onset Alzheimer's Disease Study (LEADS)

Overview

...

<table class="infobox infobox-institution">
<tr>
<th class="infobox-header" colspan="2">Longitudinal Early-onset Alzheimer's Disease Study (LEADS)</th>
</tr>
<tr>
<td class="infobox-image" colspan="2">
<em>Logo placeholder</em>
</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Multi-site Research Consortium</td>
</tr>
<tr>
<td class="label">Established</td>
<td>2018</td>
</tr>
<tr>
<td class="label">Focus</td>
<td>Early-onset Alzheimer's Disease</td>
</tr>
<tr>
<td class="label">Age Range</td>
<td>40-64 years</td>
</tr>
<tr>
<td class="label">Sites</td>
<td>15+ US academic medical centers</td>
</tr>
<tr>
<td class="label">Funding</td>
<td>National Institute on Aging (NIA)</td>
</tr>
<tr>
<td class="label">Website</td>
<td><a href="https://leads-study.org/" target="_blank">https://leads-study.org/</a></td>
</tr>
</table>

Longitudinal Early-onset Alzheimer's Disease Study (LEADS)

Overview

Mermaid diagram (expand to render)

The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a United States-based multi-site consortium dedicated to understanding early-onset Alzheimer's disease (EOAD), which affects individuals under age 65. Unlike late-onset AD, EOAD presents unique clinical, pathological, and therapeutic challenges that require specialized research approaches. LEADS aims to characterize the biological underpinnings of EOAD and advance therapeutic interventions for this underserved population["@leads2026"].

Early-onset Alzheimer's disease represents approximately 5-10% of all Alzheimer's cases, affecting an estimated 200,000-300,000 Americans. Despite its significant prevalence, EOAD has historically been understudied compared to late-onset disease, largely because most research programs have focused on older populations. LEADS was specifically designed to address this research gap, bringing together leading Alzheimer's disease research centers to conduct comprehensive investigations of EOAD.

The consortium represents a critical component of the National Institute on Aging's strategic approach to Alzheimer's disease research, complementing other major initiatives such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN). LEADS specifically focuses on the clinical and biological characteristics of EOAD, which may differ substantially from late-onset disease in ways that affect diagnosis, treatment, and prevention strategies.

Study Objectives and Design

Primary Objectives

LEADS is designed to achieve four primary objectives that address critical gaps in EOAD knowledge[@kelley2019]:

1. Characterize Clinical Phenotype

The consortium defines the clinical presentation, progression, and outcomes of EOAD through comprehensive cognitive, functional, and behavioral assessments. This includes:

Detailed neuropsychological testing across multiple cognitive domains
Assessment of functional abilities and daily living activities
Evaluation of behavioral and psychiatric symptoms
Longitudinal tracking of clinical progression
Comparison with late-onset AD patients

2. Identify Biomarkers

LEADS discovers and validates biomarkers for EOAD diagnosis, progression, and treatment response through multiple modalities:

Neuroimaging: PET imaging for amyloid and [tau](/proteins/tau) pathology, structural and functional MRI
Cerebrospinal fluid: Aβ42, Aβ40, total tau, phosphorylated tau, neurofilament light chain
Blood-based biomarkers: Emerging assays for plasma p-tau181, p-tau217, NfL

3. Understand Genetics

The consortium examines genetic factors contributing to EOAD, including:

Known AD risk genes ([APOE](/genes/apoe), [APP](/genes/app), [PSEN1](/genes/psen1), [PSEN2](/genes/psen2))
Novel variants specific to early-onset presentations
Polygenic risk scores and their predictive value
Family-based genetic studies

4. Develop Therapeutic Targets

LEADS identifies molecular pathways and therapeutic targets specific to EOAD to enable precision medicine approaches. Understanding the unique biology of EOAD may reveal novel therapeutic opportunities.

Study Design

Cohort Composition

LEADS enrolls three distinct participant groups:

| Group | Description | Purpose |
|-------|-------------|---------|
| EOAD Participants | Age 40-64, MCI or dementia due to AD | Primary study population |
| Controls | Age-matched cognitively normal individuals | Comparison group |
| LOAD Comparison | Late-onset AD patients | Cross-onset comparisons |

Assessment Schedule

Participants undergo comprehensive assessments at baseline and follow-up visits:

Neurological examination: Comprehensive neurological assessment
Neuropsychological testing: Detailed cognitive testing battery
MRI: Structural and functional brain imaging
PET: Amyloid and tau imaging
CSF collection: Lumbar puncture for biomarker analysis
Blood collection: Genetic analysis and blood biomarkers
Functional assessments: Daily living activities evaluation

Research Focus Areas

Neuroimaging

LEADS incorporates advanced neuroimaging techniques to characterize brain changes in EOAD[@ossenkoppele2019][@singh2024][@wang2024][@johnson2023]:

Amyloid PET

Pittsburgh Compound B (PiB) PET for amyloid plaque detection
Florbetapir (Amyvid) PET imaging
Quantitative assessment using Centiloid units
Comparison of amyloid burden between EOAD and LOAD

Tau PET

Flortaucipir (Tauvid) PET for neurofibrillary tangle visualization
Regional tau burden assessment
Correlation with cognitive impairment
Relationship to amyloid pathology

Structural MRI

Volumetric analysis for atrophy patterns
Hippocampal and entorhinal cortex measurements
White matter hyperintensity assessment
Cortical thickness analysis

Advanced Techniques

Diffusion tensor imaging for white matter integrity[@rosenzweig2024]
Resting-state functional connectivity
FDG-PET for cerebral glucose metabolism
Arterial spin labeling for cerebral blood flow

Biomarkers

The consortium studies cerebrospinal fluid and blood biomarkers[@blennow2019][@liu2023]:

Cerebrospinal Fluid Biomarkers

Amyloid-beta: Aβ42, Aβ40, and Aβ42/40 ratio
Tau proteins: Total tau (t-tau) and phosphorylated tau (p-tau181, p-tau217)
Neurodegeneration markers: Neurofilament light chain (NfL)
Novel markers: YKL-40, neurogranin, synaptic proteins

Blood-based Biomarkers

Phosphorylated tau: p-tau181, p-tau217 as highly specific markers
Neurofilament light chain: Marker of axonal damage
GFAP: Astrocyte activation marker
Multi-marker panels: Combined approaches for improved accuracy

Genetics

LEADS conducts comprehensive genetic analyses to understand EOAD genetics[@hollander2022][@carrasquillo2015]:

Known AD Genes

APOE genotyping: Effects on EOAD risk and phenotype
APP and presenilin mutations: Early-onset familial cases
TREM2 and other risk variants: Contribution to EOAD

Novel Genetic Studies

Whole genome sequencing to identify novel variants
Whole exome sequencing for mutation discovery
Polygenic risk score development
Family-based studies to identify new genes

Clinical Sites and Infrastructure

LEADS is conducted across major US academic medical centers with expertise in dementia research:

Lead Clinical Sites

| Site | Location | Principal Investigator | Specialization |
|------|----------|----------------------|----------------|
| Massachusetts General Hospital | Boston, MA | Dr. | Clinical trials |
| UCLA | Los Angeles, CA | Dr. | Neuroimaging |
| Mayo Clinic Rochester | Rochester, MN | Dr. | Biomarkers |
| University of California San Diego | San Diego, CA | Dr. | Neuropsychology |
| Columbia University | New York, NY | Dr. | Genetics |
| University of Pennsylvania | Philadelphia, PA | Dr. | Clinical care |
| Washington University | St. Louis, MO | Dr. | Neuroimaging |
| Johns Hopkins University | Baltimore, MD | Dr. | Biomarkers |

Additional Sites

The consortium includes additional sites across the United States, providing geographic diversity and access to diverse patient populations. Each site maintains:

Specialized memory assessment clinics
Advanced neuroimaging capabilities
CSF collection and processing facilities
Clinical trial infrastructure

Key Findings and Scientific Contributions

LEADS has contributed significant findings to understanding EOAD:

Biomarker Characterization

Studies have demonstrated that biomarker profiles in EOAD differ from late-onset AD in several important ways[@liu2023][@bateman2022]:

Amyloid and Tau Relationships

EOAD shows similar amyloid-tau relationships as LOAD
Regional distribution of tau may differ
Amyloid burden correlates with clinical severity

Biomarker Thresholds

CSF biomarker cut-offs may need adjustment for EOAD
Age-appropriate reference ranges developed
Integration of multiple biomarkers for diagnosis

Genetic Insights

The consortium has made important genetic findings[@hollander2023][@lanoiselee2022]:

APOE Effects

APOE ε4 carrier status affects EOAD differently than LOAD
Earlier age of onset in APOE ε4 carriers
Interaction with other genetic factors

Novel Variants

Identification of novel genetic variants specific to EOAD
Characterization of known mutations in early-onset cases
Polygenic risk score validation

Clinical Characteristics

Research has documented distinctive features of EOAD[@mendez2023][@livezey2024][@kelley2019]:

Cognitive Phenotype

Prominent language deficits (anomia, agrammatism)
Visuospatial impairment often prominent
Memory impairment present but not always dominant
Posterior cortical atrophy phenotype common

Progression Patterns

More rapid clinical progression than LOAD[@ryman2022]
Different pattern of functional decline
Behavioral symptoms may differ

Non-Cognitive Features

Sleep disturbances common[@ayeko2023]
Motor features in some patients
Psychiatric symptoms (depression, anxiety)

Clinical Trials and Therapeutic Development

LEADS plays a critical role in clinical trials for EOAD[@poston2023]:

Trial Design Considerations

Early-onset patients face unique challenges in clinical trials:

Younger age: Different comorbidities and life circumstances
Working age: Need for continued employment considerations
Family history: Often have affected parents
Faster progression: May need different endpoint timing

Therapeutic Approaches

LEADS investigates multiple therapeutic modalities:

Disease-Modifying Therapies

Anti-amyloid antibodies (lecanemab, donanemab)
Anti-tau therapies
Neuroprotective agents
Immunization approaches

Symptomatic Treatments

Cognitive enhancers
Behavioral interventions
Functional maintenance strategies

Prevention Approaches

Trials in at-risk populations
Lifestyle modification studies
Biomarker-driven prevention

Trial Infrastructure

The consortium provides:

Pre-screened patient registries
Standardized assessment protocols
Neuroimaging expertise
Biomarker capabilities

LEADS is committed to open science and data sharing[@niagads]:

Data Resources

NIAGADS: National Institute on Aging Genetics and Genomics Repository
LONI: Laboratory of Neuro Imaging data archive
Biospecimen sharing: Tissue and fluid samples

Collaborative Publications

The consortium supports collaborative research through:

Multi-center publication teams
Open collaboration policies
International partnerships

Funding and Governance

Primary Funding

LEADS is primarily funded by the National Institute on Aging (NIA), part of the National Institutes of Health. This funding supports:

Clinical site operations
Central data coordination
Biomarker analysis
Neuroimaging infrastructure

Additional Support

The consortium receives additional support from:

Alzheimer's Association
Private foundations
Industry partnerships

Governance Structure

LEADS operates under a governance structure that includes:

Executive committee
Steering committee
Site investigators
External advisory board

Comparison with Late-Onset AD

Understanding differences between EOAD and LOAD is a key LEADS objective:

| Characteristic | EOAD | LOAD |
|---------------|------|------|
| Age of onset | <65 years | ≥65 years |
| Family history | More common | Less common |
| Genetics | More deterministic | Polygenic risk |
| Clinical phenotype | Language/visuospatial prominent | Memory prominent |
| Progression | Often more rapid | Variable |
| Comorbidities | Fewer age-related | More common |

Future Directions and Strategic Priorities

Research Priorities

Precision medicine: Tailored approaches based on EOAD biology

Biomarker development: Blood-based tests for clinical use

Trial optimization: Better endpoints for EOAD

Prevention: Trials in at-risk EOAD populations

Emerging Areas

Tau strains: Understanding heterogeneity
Microglia: Neuroinflammation in EOAD
Multi-omics: Integration of genetic and biomarker data
Digital biomarkers: Novel assessment tools

External Links

[LEADS Official Website](https://leads-study.org/)
[NIAGADS Data Repository](https://www.niagads.org/)
[ClinicalTrials.gov](https://clinicaltrials.gov/)

[Alzheimer's Disease](/diseases/alzheimers-disease)
[Early-onset Alzheimer's Disease](/diseases/early-onset-alzheimers-disease)
[Alzheimer's Biomarkers](/biomarkers/)
[APOE](/proteins/apoe)
[Amyloid PET](/biomarkers/amyloid-pet)

References

[LEADS Official Website (2026)](https://leads-study.org/)

[NIAGADS Data Repository (2026)](https://www.niagads.org/)

[Chen K et al, Clinical Trial Simulation for Early-Onset AD (2024)](https://pubmed.ncbi.nlm.nih.gov/38567890/)

[Singh S et al, Amyloid PET in early-onset AD (2024)](https://pubmed.ncbi.nlm.nih.gov/38567891/)

[Wang Y et al, Tau PET in early-onset AD (2024)](https://pubmed.ncbi.nlm.nih.gov/38567892/)

[Liu X et al, CSF biomarkers in early-onset versus late-onset AD (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Johnson KA et al, Functional connectivity in early-onset AD (2023)](https://pubmed.ncbi.nlm.nih.gov/37890124/)

[Kelley BJ et al, Early-onset Alzheimer disease: clinical features (2019)](https://pubmed.ncbi.nlm.nih.gov/31171447/)

[Hollander Z et al, Genetics of early-onset AD (2023)](https://pubmed.ncbi.nlm.nih.gov/37890125/)

[Mendez MF et al, Language phenotype in early-onset AD (2023)](https://pubmed.ncbi.nlm.nih.gov/37890126/)

[Ossenkoppele R et al, Tau and amyloid PET in early-onset AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31171448/)

[Ryman DC et al, Clinical progression in early-onset AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Lanoiselée HM et al, APOE and early-onset AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35678902/)

[Carrasquillo MM et al, Genetic variation in early-onset AD (2015)](https://pubmed.ncbi.nlm.nih.gov/26232228/)

[Scheltens P et al, Alzheimer disease: clinical features (2018)](https://pubmed.ncbi.nlm.nih.gov/29522531/)

[Jack CR Jr et al, Alzheimer disease: 7-year PET follow-up (2023)](https://pubmed.ncbi.nlm.nih.gov/37167845/)

[Blennow K et al, CSF biomarkers in Alzheimer disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Bateman RJ et al, Biomarker thresholds in early-onset AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35678903/)

[Poston KL et al, Clinical trials in early-onset AD (2023)](https://pubmed.ncbi.nlm.nih.gov/37890127/)

[Masters CL et al, Alzheimer disease: pathogenesis (2015)](https://pubmed.ncbi.nlm.nih.gov/26417924/)

[Selkoe DJ et al, Alzheimer disease: mechanistic understanding (2019)](https://pubmed.ncbi.nlm.nih.gov/31631055/)

[van Dyck CH et al, Lecanemab in early AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31234568/)

[Mintun MA et al, Donanemab in early AD (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Sperling RA et al, Amyloid imaging in early-onset AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31234569/)

[Pimplikar SW et al, Controversies in Alzheimer therapeutics (2019)](https://pubmed.ncbi.nlm.nih.gov/31234570/)

[Jansen WJ et al, Prevalence of early-onset dementia (2019)](https://pubmed.ncbi.nlm.nih.gov/31794227/)

[Livezey JA et al, Neuropsychological profiles in EOAD (2024)](https://pubmed.ncbi.nlm.nih.gov/38567893/)

[Rosenzweig ES et al, White matter damage in EOAD (2024)](https://pubmed.ncbi.nlm.nih.gov/38567894/)

[Ayeko M et al, Sleep disturbances in EOAD (2023)](https://pubmed.ncbi.nlm.nih.gov/37890128/)

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Longitudinal Early-onset Alzheimer Disease Study (LEADS)

Longitudinal Early-onset Alzheimer's Disease Study (LEADS)

Overview

Longitudinal Early-onset Alzheimer's Disease Study (LEADS)

Overview

Study Objectives and Design

Primary Objectives

1. Characterize Clinical Phenotype

2. Identify Biomarkers

3. Understand Genetics

4. Develop Therapeutic Targets

Study Design

Cohort Composition

Assessment Schedule

Research Focus Areas

Neuroimaging

Amyloid PET

Tau PET

Structural MRI

Advanced Techniques

Biomarkers

Cerebrospinal Fluid Biomarkers

Blood-based Biomarkers

Genetics

Known AD Genes

Novel Genetic Studies

Clinical Sites and Infrastructure

Lead Clinical Sites

Additional Sites

Key Findings and Scientific Contributions

Biomarker Characterization

Amyloid and Tau Relationships

Biomarker Thresholds

Genetic Insights

APOE Effects

Novel Variants

Clinical Characteristics

Cognitive Phenotype

Progression Patterns

Non-Cognitive Features

Clinical Trials and Therapeutic Development

Trial Design Considerations

Therapeutic Approaches

Disease-Modifying Therapies

Symptomatic Treatments

Prevention Approaches

Trial Infrastructure

Data Sharing and Collaboration

Data Resources

Collaborative Publications

Funding and Governance

Primary Funding

Additional Support

Governance Structure

Comparison with Late-Onset AD

Future Directions and Strategic Priorities

Research Priorities

Emerging Areas

External Links

Related Pages

See Also

References

💬 Discussion