Untangling the APOE4 Gene, the Most Significant Genetic Risk Factor for Alzheimer’s Disease

The genetic background around APOE region can modify the Alzheimer’s disease-associated APOE4 risk effects

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 U.S. Scientists have discovered some genetic variants that increase the risk for developing Alzheimer’s; the most well-known of these for people over the age of 65 is the APOE ε4 allele.

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

Researchers from Boston University School of Medicine (BUSM) have discovered two important novel 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 study demonstrated what the APOE4 gene does and which brain cells get affected the most in humans by comparing human and mouse models. These are important findings as we can find therapeutics if we understand how and where this risk gene is destroying our brain,” says corresponding author Julia TCW, PhD, assistant professor of pharmacology & experimental therapeutics 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 brains and experimental models. They used a population hiPSC model, comparing APOE4 (mutation) vs. APOE3 (mutation-free) of AD patients and normal people.

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

For the third model, they used an experimental model carrying human APOE genes. With all, they used genetic screening and RNA sequencing to identify human cell-type specific defects due to APOE4.

“Our study supports that the genetic background around APOE region can modify 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 can be another strategy to reduce the risk of developing AD,” adds TCW.

While this study is about APOE4 gene using Alzheimer’s patient samples, it is also known that APOE4 is risk for 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 found similar to the one caused by APOE4, such as rare genetic diseases.

These findings appear online in the journal Cell.

Funding: Funding for this study was provided by NIH NIA K01AG062683 (J.TCW.), New York Stem Cell Foundation (NYSCF) (J.TCW.-Drunkenmiller fellowship), NIA U01AG058635 (A.M.G), the JPB foundation (A.M.G., D.M.H.), NIA P50AG016573 (W.W.P.), Alzheimer’s Orange County AOC-207373 (W.W.P.), NINDS RF1NS090934 (D.M.H.), NIA RF1AG047644 (D.M.H.), NHLBI R01HL093324 (F.R.M.), Cure Alzheimer’s Fund (F.R.M.), NIA U01AG046170 (B.Z.), NIA RF1AG057440 (B.Z.), NIA RF1AG074010 (B.Z.), and NIA RF1AG054014 (B.Z., A.M.G.). We thank the NYSCF, Mount Sinai Stem Cell Core, Washington University in 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 lysosome and autophagic function discussion.

J.TCW. co-founded 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. A.M.G. has consulted for Eisai, Biogen, Pfizer, AbbVie, Cognition Therapeutics and GSK, and served on the scientific advisory board at Denali Therapeutics from 2015-2018. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics, LLC (licensed anti-tau antibody to AbbVie) and the scientific advisory board of Denali and consults for Genentech and Idorsia. F.R.M. has consulted for Denali Therapeutics in 2019. W.W.P. is a co-inventor of patent WO/2018/160496 (microglia differentiation). The authors declare no competing interests.