# Early Onset AD Consortium - the LEAD Study (LEADS)

> **NIH NIH U01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $1,072,053

## Abstract

Project Summary
While the risk of Alzheimer’s disease (AD) increases with advancing age, approximately 5% of AD patients
develop symptoms before age 65 (~280,000 Americans). The vast majority (90%-95%) of EOAD patients do not
have a known mutation in APP or PSEN1/2, and only ~50% are APOE4 carriers. Unlike late-onset AD (LOAD),
30-64% of EOAD have non-amnestic presentations, leading to missed or delayed diagnosis. Despite being highly
motivated and having few comorbidities, EOAD patients are commonly excluded from large scale observational
biomarker studies (e.g. ADNI and DIAN) and therapeutic trials due to their young age, non- amnestic deficits, or
absence of known pathogenic mutations. Furthermore, studies suggest high heritability in EOAD in the absence
of known mutations or APOE4, signifying that this population may be enriched for novel genetic risk factors.
Emerging biomarkers of amyloid and tau have not been systematically characterized in this population. Clinical
and neuroimaging measures employed in LOAD may be insensitive to baseline deficits and disease progression
in EOAD, which predominantly involve non-memory cognitive domains and posterior cortical neurodegeneration.
To fill this gap in AD research, we plan to recruit and longitudinally follow 400 amyloid PET-positive EOAD
subjects meeting NIA-AA criteria for MCI due to AD or probable AD dementia (including primary amnestic,
dysexecutive, language and visuospatial presentations), 200 subjects meeting clinical criteria with negative
amyloid PET (EOnonAD) and 100 age-matched controls. Participants in the Longitudinal Early-onset
Alzheimer’s Disease Study (LEADS) will undergo clinical assessments, psychometric testing, MRI, amyloid
([18F]Florbetaben) and tau ([18F]AV1451) PET, CSF and blood draw for collection of DNA, RNA, plasma, serum
and peripheral blood mononuclear cells (PBMC). EOnonAD participants and controls will also receive [18]FDG
PET. All participants are followed annually (controls up to 24 months; impaired participants up to 48 months).
Methods will be harmonized with ADNI and DIAN. We will comprehensively characterize cognitive, imaging and
biofluid changes over time in EOAD and EOnonAD and compare to age-matched controls and sex and stage-
matched LOAD participants identified in ADNI. We will employ machine learning algorithms to develop sensitive
clinical and imaging measures of EOAD progression. Additionally, we will characterize demographic, clinical,
neuroimaging, and fluid biomarker measures in EOnonAD cases to explore the possible etiologies of cognitive
impairment. An exploratory aim will apply next generation sequencing to assess for novel genetic risk factors for
disease. The study will also establish a network of EOAD research sites and set the stage for the launch of
clinical trials in this population.

## Key facts

- **NIH application ID:** 10219685
- **Project number:** 3U01AG057195-03S1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** LIANA G APOSTOLOVA
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,072,053
- **Award type:** 3
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219685

## Citation

> US National Institutes of Health, RePORTER application 10219685, Early Onset AD Consortium - the LEAD Study (LEADS) (3U01AG057195-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10219685. Licensed CC0.

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