Yann Le Guen (United States of America)
Stanford University
Neurology and Neurological Sciences
Dr. Le Guen graduated in 2015 with Distinction from both Telecom Paris and the Imperial College London, respectively with an MSc in Computer Science and an MSc in Biomedical Bioenginerring. Then, he pursued a PhD thesis in imaging genetics at Neurospin (Paris-Saclay University) analyzing MR images and genomics data to decipher the genetic causes underlying the well-characterized brain asymmetries which support human language processing. He received his PhD in 2018 at the University Paris-Saclay and joined the Greicius lab where he is working to improve our understanding of the genetic causes of neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease. While at Stanford University, he was awarded a highly selective European fellowship (Marie Skłodowska-Curie Actions, 2019 call), which he activated in 2021. Under this fellowship, he will work two additional years at Stanford University followed by one year at the Brain and Spine Institute in Paris (ICM, Sorbonne University). The project is entitled “A multimodal approach to accelerate drug discovery and development in Alzheimer’s disease”.

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APOE MISSENSE VARIANT R145C IS ASSOCIATED WITH INCREASED ALZHEIMER’S DISEASE RISK IN AFRICAN ANCESTRY INDIVIDUALS WITH THE APOE Ε3/Ε4 GENOTYPE

Session Name
0850 - APOE MECHANISMS AND TREATMENT STRATEGIES 2 (ID 136)
Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
05:30 PM - 05:45 PM
Presenter

Abstract

Aims

The APOE gene has two common missense variants that greatly impact the risk of late-onset Alzheimer's disease (AD). Here we examined the risk of a third APOE missense variant, R145C, that is rare in European-Americans but common in African-Americans and always in phase with APOE-ε3 (Table 1).

Methods

We included 11,790 individuals of African ancestry (Table 2). The discovery sample was composed of next generation sequencing data (2,888 cases and 4,957 controls), and the replication was composed of imputed data (1,201 cases and 2,744 controls). In primary analyses, the AD risk associated with R145C was estimated using a linear-mixed-model regression on case-control diagnosis. In secondary analyses, we estimated the influence of R145C on age-at-onset using linear-mixed-model regression, and risk of conversion to AD using competing risk regression.

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Results

In ε3/ε4-stratified meta-analyses (Table 3), R145C carriers had a nearly three-fold increased risk compared to non-carriers (OR=2.75 [1.84; 4.11]; P=8.3x10-7) and had a reported AD age-at-onset nearly 6 years younger (β=-5.72 [7.87; 3.56]; P=2.0x10-7). Competing risk regression showed that the cumulative incidence of AD grows faster with age in R145C carriers compared to non-carriers (HR=2.42 [1.81; 3.25]; P=3.7x10-9; Figure 1).

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Conclusions

The R145C variant is a potent risk factor for AD among African ancestry individuals with the ε3/ε4 genotype. Our findings should enhance AD risk prediction in African ancestry individuals and help elucidate the mechanisms linking the apoE protein to AD pathogenesis. The findings add to the growing body of evidence demonstrating the importance of including ancestrally-diverse populations in genetic studies.

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