Dylan Reil

All Publications

• Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk. Annals of neurology Peña-Tauber, A., Hernández Arriaza, R., Reil, D., Muntaner, M., Park, J., Grenier-Boley, B., Hulsman, M., Amouyel, P., Bellenguez, C., Charbonnier, C., Deleuze, J. F., Dols-Icardo, O., Hardy, J., Holstege, H., Nicolas, G., Mead, S., Wagner, M., Ramirez, A., Sims, R., van Swieten, J., Willams, J., Lambert, J. C., Khosla, C., Le Guen, Y., Greicius, M. D. 2026

  Abstract

  ATP-binding cassette transporter A1 (ABCA1) has been associated with Alzheimer's disease (AD), but the mechanisms by which it impacts disease risk are unknown. ABCA1 is known to bind apolipoprotein E (ApoE) and catalyze apolipoprotein lipidation. We explored whether genetic variants altering ABCA1 function interact with APOE isoforms to modify AD risk.Using data from the Alzheimer's Disease Sequencing Project (ADSP), UK Biobank, and the Alzheimer Disease European Sequencing consortium, we assessed the impact of ABCA1 variants on AD risk in APOE subgroups and tested for statistical interactions with APOE ε2 and ε4 in an all-APOE cohort. We first examined damaging nonsynonymous ABCA1 variants previously associated with AD. We then constructed a measure of predicted ABCA1 activity based on HDL-associated variants and tested its association with AD risk. Finally, we explored potential pathogenic mechanisms of missense variants of interest.Damaging nonsynonymous ABCA1 variants had differential AD risk effects between APOE genotype groups and exhibited interaction effects with APOE ε2 and ε4. Predicted ABCA1 activity based on HDL-associated variants was associated with reduced AD risk and interacted with APOE ε4. Replication analyses suggested similar differences in effect size of ABCA1 variants between APOE groups and had concordant effect directions, although not statistically significant, in the APOE interaction model. ABCA1 missense variants N1800H and E1172D were strongly associated with plasma HDL and interacted with APOE in AD risk. In cell-based assays, ABCA1-N1800H showed plasma membrane localization defects potentially driven by misfolding.Genetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026.

  View details for DOI 10.1002/ana.78303

  View details for PubMedID 42548036

• ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer's Disease Pathogenesis. Biochemistry Hernandez Arriaza, R., Reil, D., Fatuzzo, N., Fu, M., Dai, Y., Fernandez Martinez, D., Jiang, H., Holtzman, D. M., Greicius, M. D., Khosla, C. 2025

  Abstract

  The brain is the most cholesterol-rich organ in the body, and ApoE is the main lipid carrier protein in the brain. Although very little, if any, ApoE exists in its apoprotein form in physiological fluids, recombinant ApoE is typically prepared in a lipid-free state to study its physiological functions. We describe a lipid nanoparticle (LNP) form of ApoE as a primary extracellular product of the eukaryotic protein export system. Whereas the apoprotein is the dominant secreted product when the APOE gene is overexpressed in mammalian cells, an LNP form of ApoE is also observed. The LNP form is, however, the major secreted product from unmodified CCF-STTG1 astrocytoma cells. The C-terminal domain of ApoE plays a key role in LNP biosynthesis as the ApoE3 W210* truncation mutant is secreted without lipidation. Secreted ApoE LNPs are markedly better substrates than the apoprotein itself for further growth via the action of ATP-dependent lipid pumps. Compared to ApoE3 or the Alzheimer's disease-protective ApoE2 variant, the recovered yield of the LNP form of the disease-predisposing ApoE4 variant is higher. Intriguingly, the LNP yield of the rare disease-protective R251G variant of ApoE4 is comparable to that of ApoE3 and ApoE2. Analogous to the well-documented intracellular biosynthesis of ApoB-containing LNPs, the biogenesis and pathophysiological relevance of the LNP form of ApoE warrant further investigation.

  View details for DOI 10.1021/acs.biochem.5c00503

  View details for PubMedID 41134549