APOE genotype vs Local ancestry: what contributes the most to Alzheimer’s disease risk?
Sofia Moura, Katrina Celis, Maria Muniz, Farid Rajabli, Joe Rivero, Kara L. Hamilton‐Nelson, Patrice Whitehead, Marla Gearing, David A. A Bennett, Margaret E Flanagan, Sandra Weintraub, Changiz Geula, William K. Scott, Theresa Schuck, Fulai Jin, Derek M. Dykxhoorn, Margaret A. Pericak‐Vance, Anthony J. Griswold, Juan I. Young, Jeffery M. Vance- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
The APOEε4 confers the highest genetic risk factor for Alzheimer’s disease (AD). Specifically, Non‐Hispanic Whites (NHW) are more susceptible to developing AD than African American (AA) individuals (OR∼15 vs 8, respectively). Local ancestry (LA) surrounding the APOE region has been implicated in this risk difference, with APOEε4 carriers of European LA (ELA) having increased chromatin accessibility and higher APOEε4 expression than individuals of African LA (ALA). In contrast, carriers of APOEε3, the most common allele, are not predisposed to AD. We here sought to investigate whether this differential accessibility and gene expression are solely due to APOE LA or whether the APOE genotype also contributes to the different disease risk.
Method
We screened 94 brains from individuals self‐identified as either AA or NHW of which we identified a total of 22 AD autopsy samples (18 with ELA and 4 with ALA) by GSA, all homozygous for LA and APOEε3. We performed single nuclei ATAC‐seq and single nuclei RNA sequencing (snRNA‐seq) using frozen frontal cortex using the 10x Genomics.
Result
To date, we have performed snRNA‐seq in a total of 16,099 nuclei for four brains (2 ELA and 2 ALA). We identified 27 distinct cell clusters at a resolution of 0.6. The proportion of cells per cluster between ELA and ALA samples was similar for all clusters, except for 8 clusters (primarily neurons) which had a greater than 2‐fold difference in ELA. Preliminary results show that APOEε3 carriers with ELA have a significantly higher APOE expression in astrocytes (cluster 11) than those of ALA similar to previous reports in APOEε4 carriers (Griswold, A. et al, (2021)). Interestingly, we also observed an increase in APOE expression in ALA for one oligodendrocyte cluster and four neuronal clusters (inhibitory and excitatory neurons) independent of those mentioned above.
Conclusion
We report novel insights on the effect of APOE LA and genotype and its contributions to Alzheimer’s disease risk. Specifically, as APOEε3 allele expression follows a similar pattern of overexpression in ELA vs ALA as observed for APOEε4 carriers, our data support that LA and not allele status contribute to the differential APOE expression observed among different ancestral populations.