APOE, ABCA7, and RASGEF1C are associated with earlier onset of amyloid deposition from more than 4000 harmonized positron emission tomography images

Tonnar Castellano ¹, Ting Chen Wang ^1,2, Emma Nolan ¹

¹Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California, USA.
⁴Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, USA.
⁵Department of Population Health Sciences, University of Wisconsin, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
⁶Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁷Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
⁸Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
⁹Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁰Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹¹Department of Radiology and Imaging Sciences, Center for Neuroimaging, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
¹²Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
¹³Department of Neurology, Columbia University Medical Center, New York, New York, USA.
¹⁴Department of Neurology, The New York Presbyterian Hospital, New York, New York, USA.
¹⁵Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Medical Center, New York, New York, USA.
¹⁶The Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, USA.
¹⁷Department of Medicine, University of Wisconsin School of Medicine and Public Health, Health Sciences Learning Center, Madison, Wisconsin, USA.
¹⁸Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
¹⁹Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
²⁰Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Irving Medical Center, New York, New York, USA.
²¹Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA.
²²Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²³Department of Radiology, Mayo Clinic of Arizona, Scottsdale, Arizona, USA.

⁰Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Alzheimer's & Dementia : the Journal of the Alzheimer's Association +

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December 13, 2025

View abstract on PubMed

Summary

Researchers identified key genes, including APOE and ABCA7, influencing the age of amyloid positivity onset in Alzheimer's disease. These findings offer potential targets for early intervention strategies.

Area Of Science

Neurogenetics
Alzheimer's Disease Pathogenesis
Biomarker Discovery

Background

New methods enable estimation of amyloid positivity onset age (EAOA) using amyloid positron emission tomography (PET).
Understanding the genetic underpinnings of EAOA is crucial for identifying molecular factors involved in the earliest stages of Alzheimer's disease (AD).

Purpose Of The Study

To explore the genetics of EAOA.
To identify molecular factors influencing the earliest AD changes.
To investigate genetic associations with the age of amyloid positivity.

Main Methods

Genome-wide survival analyses of EAOA using harmonized amyloid PET data from 4216 participants.
Tissue-specific gene expression and genetic covariance analyses were performed.
Expression quantitative trait locus (eQTL) analysis for identified variants.

Main Results

Genetic variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C were significantly associated with earlier EAOA.
APOE ε4/ε4 and ε3/ε4 genotypes converted approximately 6.3 and 5 years earlier than ε3/ε3, respectively; APOE ε2 showed a protective effect.
A specific ABCA7 variant (rs4147929) associated with a 4-year earlier EAOA and reduced brain ABCA7 expression, correlating with increased amyloid pathology.

Conclusions

APOE, ABCA7, and RASGEF1C are implicated in determining the age of amyloid positivity onset.
Tissue-specific expression analyses support the genetic findings, highlighting ABCA7's role in amyloid pathology.
These genetic insights provide potential targets for interventions aimed at early stages of Alzheimer's disease.

Keywords:

ABCA7 Alzheimer's disease amyloid amyloid clearance apolipoprotein E genetics harmonization positron emission tomography