Untangling the APOE4 gene, the main genetic risk factor for Alzheimer’s disease

Overview: The genetic background surrounding the APOE region may alter the APOE4 risk effects associated with Alzheimer’s disease.

Source: Boston University

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia, affecting more than 5.8 million individuals in the US. Scientists have discovered some genetic variants that increase the risk of developing Alzheimer’s disease; the most famous of these for those over 65 is the APOE ε4 allele.

Although the association between APOE4 and the increased AD risk is well established, the mechanisms responsible for the underlying risk in human brain cell types have been unclear until now.

Boston University School of Medicine (BUSM) researchers have discovered two important new aspects of the gene: 1) human genetic background inherited with APOE4 is unique to APOE4 patients and 2) the mechanistic defects due to APOE4 are unique to human cells.

“Our research showed what the APOE4 gene does and which brain cells are most affected in humans by comparing human and mouse models. These are important findings because we can find therapies if we understand how and where this risk gene destroys our brains,” said corresponding author Julia TCW, PhD, assistant professor of pharmacology and experimental therapy at BUSM.

To investigate the effects of APOE4 on brain cell types, the researchers used three models, human-induced pluripotent stem cells (hiPSCs), post-mortem human brain and experimental models. They used a population hiPSC model, comparing APOE4 (mutation) vs. APOE3 (mutation free) from AD patients and normal humans.

For the second model, they compared AD brains with a control brain with different APOE genotypes.

For the third model, they used an experimental model that transported people APOE genes. Taken together, they used genetic screening and RNA sequencing to identify human cell-type-specific defects due to: APOE4

They used a population hiPSC model, comparing APOE4 (mutation) versus APOE3 (mutation-free) of AD patients and normal humans. Image is in the public domain

“Our study supports that the genetic background around APOE region can change the APOE4 risk effects. Therefore, apart from finding drugs to reduce the APOE4 risk, modulating targets to mimic brains carrying protective genes or genetic backgrounds, may be another strategy to reduce the risk of developing AD,” adds TCW.

While this study is about APOE4 gene using samples from Alzheimer’s patients, it is also known that: APOE4 is the risk of Parkinson’s disease (PD). According to TCW, this study has implications for any disease associated with: APOE as risk, such as AD and PD, or for any disease phenotype similar to that caused by APOE4such as rare genetic diseases.

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These findings appear online in the journal Cell

Financing: Funding for this study was provided by NIH NIA K01AG062683 (J.TCW.), New York Stem Cell Foundation (NYSCF) (J.TCW.-Drunkenmiller fellowship), NIA U01AG058635 (AMG), the JPB foundation (AMG, DMH), NIA P50AG016573 (WWP), Alzheimer’s Orange County AOC-207373 (WWP), NINDS RF1NS090934 (DMH), NIA RF1AG047644 (DMH), NHLBI R01HL093324 (FRM), Cure Alzheimer’s Fund (FRM), NIA U01AG046170 (BZ), NIA RF1AG057440 ( BZ), NIA RF1AG074010 (BZ), and NIA RF1AG054014 (BZ, AMG). We thank the NYSCF, Mount Sinai Stem Cell Core, Washington University at St. Louis Knight ADRC (P30AG066444) and University of California, Irvine ADRC (P30AG066519) for providing fibroblasts and hiPSCs, Jill K. Gregory for image illustration, Melanie Oaks and Seung-Ah Chung at the UCI Genomics High-Throughput Facility for RNAseq (NCRR 1S10RR025496-01, NIH OD 1S10OD010794-01 and 1S10OD021718-01), Louisa Normington (LCN Bioinformatics) for WGCNA assistance, Santiago Sole Domenech, Ana Maria Cuervo and Aurora Scrivo for discussion of lysosome and autophagic function.

J.TCW. co-founder of Asmos Therapeutics, LLC, serves on the scientific advisory board of NeuCyte, Inc, and has consulted for FIND Genomics Inc., CareCureSystems Corporation, TheWell Biosciences Inc. and Aleta Neuroscience, LLC. AMG has consulted for Eisai, Biogen, Pfizer, AbbVie, Cognition Therapeutics, and GSK, and served on the scientific advisory board of Denali Therapeutics from 2015-2018. DMH co-founded and serves on the scientific advisory board of C2N Diagnostics, LLC (licensed anti-tau antibody to AbbVie) and the scientific advisory board of Denali, advising for Genentech and Idorsia. FRM has consulted for Denali Therapeutics in 2019. WWP is co-inventor of patent WO/2018/160496 (microglia differentiation). The authors declare no competing interests.

About this genetics research news

Author: Gina DiGravio
Source: Boston University
Contact: Gina DiGravio – Boston University
Image: The image is in the public domain

Original research: The findings appear in Cell

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