Longitudinal Early-onset Alzheimer Disease Study (LEADS)

<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>
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</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

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

Data Sharing and Collaboration

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

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/)

Related Pages

• [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)

See Also

• [Alzheimer's Disease Research Centers](/institutions/)
• [AD Biomarkers](/biomarkers/)
• [Clinical Trials](/therapeutics/)
• [Genetics of Alzheimer's Disease](/genes/)

References