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

Abstract

Introduction: New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. Methods: Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA. Results: Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA. Discussion: APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD. Highlights: Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses.