The Most Significant Genetic Risk Factor for Alzheimer’s Disease Has Been Untangled

https://scitechdaily.com ^ | JULY 20, 2022 | By BOSTON UNIVERSITY SCHOOL OF MEDICINE

[Red Badger]

Alzheimer’s disease is a brain disorder that gradually impairs thinking and memory abilities as well as the capacity to do even the most basic activities.

The researchers believe that new treatments and medications for the condition might result from the findings More than 5.8 million people in the United States are affected by Alzheimer’s disease (AD), the most prevalent form of dementia. AD is a progressive neurodegenerative disorder. Scientists have identified a few gene variants that raise the risk of Alzheimer’s; the APOE 4 allele is the most well-known of them for individuals over the age of 65. Although there is a well-established link between APOE4 and an elevated risk of AD, the mechanisms behind the risk in human brain cell types have remained a mystery.

Two crucial new characteristics of the gene have been identified by researchers at the Boston University School of Medicine: 1) the APOE4-related mechanistic defects are unique to human cells and 2) the human genetic background inherited by APOE4 patients is distinct from other populations. Their findings were recently published in the journal Cell.

“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, Ph.D., assistant professor of pharmacology & experimental therapeutics at Boston University School of Medicine.

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 the APOE4 gene using Alzheimer’s patient samples, it is also known that APOE4 increases the risk for Parkinson’s disease (PD). According to TCW, this study has implications for any disease associated with APOE as risks such as AD and PD, or for any disease phenotype found similar to the one caused by APOE4, such as rare genetic diseases.

The study was funded by the 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.

Reference: “Cholesterol and matrisome pathways dysregulated in astrocytes and microglia” by Julia TCW, Lu Qian, Nina H. Pipalia, Michael J. Chao, Shuang A. Liang, Yang Shi, Bharat R. Jain, Sarah E. Bertelsen, Manav Kapoor, Edoardo Marcora, Elizabeth Sikora, Elizabeth J. Andrews, Alessandra C. Martini, Celeste M. Karch, Elizabeth Head, David M. Holtzman, Bin Zhang, Minghui Wang, Frederick R. Maxfield, Wayne W. Poon and Alison M. Goate, 23 June 2022, Cell.

DOI: 10.1016/j.cell.2022.05.017

[Guenevere]

G

[George from New England]

Ok, good read.

But no solutions offered.

I really don’t trust any internet outfit claims on this. They will be all over the place.

[Magnum44]

Well, we certainly should have learned alot about alzheimers since Biden occupied the White House...

[NTHockey]

English, please.

[RummyChick]

if you have your dna you can try to go through your SNPs with this

https://www.snpedia.com/index.php/APOE

[Red Badger]

If you possess a certain gene, APOE4, and it becomes defective, you are at risk for Alzheimers................

[AppyPappy]

I’ve noticed Dementia seems to be more prevalent with people who live alone or spend most of their time involving push technology like television. Early treatment and therapy seems to work at holding it off but everyone I know just ignored the symptoms.

One of the first things you lose is analytical skills. You can ask a patient what time it is and they can’t tell you even in a room full of clocks.

[bert]

I think the conclusion developed from the study NCRR 1S10RR025496-01might be faulty and not really problematic nor germane to the primary arguments developed.

[Red Badger]

I won’t argue with that conclusion.........................

[nagant]

https://medicalxpress.com/news/2016-08-scientists-reveal-people-apoe4-gene.html

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.....To find the protein responsible for degrading ApoE4, Saghatelian and research associate Qian Chu, first author of the new paper, screened tissues for potential suspects and homed in on one enzyme called high-temperature requirement serine peptidase A1 (HtrA1).

When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells—and more of the breakdown products of the protein.

“There’s been an idea tossed around that ApoE4 breakdown products could be toxic,” said Saghatelian. “Now, knowing the enzyme that breaks it down, we have a way to actually test this idea.”

But it’s not just a lack of full-length ApoE or an increase in its fragments that may be causing Alzheimer’s in people with ApoE4. Saghatelian and Chu also found that ApoE4—because it binds so well to HtrA1—keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer’s.....
~~~~~~~~~~~~~~~~~~

[nikos1121]

I was expecting some reference for testing...

[Bob434]

Sure woul,d be nice if they could find something to reverse it. Lots of folks in our town have gotten it and they just fade out of view (though their relatives suffer tremendously caring for them), slowly degetiorating- such a terrible way to go.

[Red Badger]

Yes, and that’s why it’s also called “The Long Goodbye”....................

[Dave Wright]

This is actually the hypothesis behind the Avanex Life Sciences Anavex2-73 clinical trial that is ongoing. Their drug is designed to scavange the peroxynitrite biproducts caused by the breakdown of the ApoE4 generated protein. It appears to have been successful in pre-clinical and mouse model studies but they won’t be announcing results until later this year.

https://clinicaltrials.gov/ct2/show/NCT03790709

[LilFarmer]

My FIL is stage 7c now, at home with us on hospice. He is unrecognizable from the man he used to be - quiet, thoughtful, good-natured, intelligent (engineer). It is very hard to see him like this - agitated, angry, confused, immobile, incontinent, and incapable of even holding a spoon. It’s a very isolating experience too because DH’s siblings have pretty much abandoned us to his care except to call and check in. We haven’t had respite in 5 years except a few months in memory care. Sigh. Long goodbye indeed.

[Red Badger]

Same thing happened to my grandfather, back in the 60’s.................

[TiGuy22]

So Tucker Carlson speaks extremely confidently of late about Biden being drugged up. I think most think that, but to speak of it on the air, as he does, suggests he has inside source in the know... what are they likely juicing diapers up with?

[Bob434]

We know all too well. Dreadful condition

[Taxman]

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