Genes help explain why Alzheimer’s drugs have been so unsuccessful

  • A gene present in 75% of the human population may be a key reason why a class of drugs for Alzheimer’s disease seem promising in animal studies but fail in human studies.
  • Cell study finds APOE4 protein is slightly misshapen, causing it to break down into disease-causing fragments. But APOE4 doesn't affect amyloid-beta in mice.

Data from a ten-year study involving 345 Alzheimer's patients has found that cholinesterase inhibitors work better with those who don't have the gene CHRFAM7A. The gene is a fusion between a gene that codes for an Alpha 7 receptor for acetylcholine, and a kinase, a type of enzyme. It is not present in the animals genetically engineered to provide Alzheimer's models, but is present in 75% of humans.

Three of the four available Alzheimer’s drugs work by stimulating all receptors that respond to acetylcholine. More specific drugs for Alpha 7 have been in development for over 10 years but have yet to be successful.

The Alpha 7 receptor is one of the receptors binding amyloid beta.

More research is needed to confirm these preliminary findings.

https://www.eurekalert.org/pub_releases/2019-07/uab-sfc071719.php

https://www.futurity.org/alzheimers-disease-drugs-chrfam7a-2108902/

Scientists fix APOE4 gene in human brain cells

Research using human brain cells has found that the APOE4 protein is slightly misshapen and can’t function properly. It breaks down into disease-causing fragments, resulting in a number of problems, including the accumulation of the protein tau and of amyloid peptides.

The presence of APOE4 does not change the production of amyloid beta in mouse neurons, so this is a crucial species difference which shows why our animal models are of limited value.

Further research confirmed that it was specifically the presence of APOE4, and not the absence of the more common allele, APOE3, that promotes Alzheimer’s.

The human APOE4 neurons were treated with compounds developed to change the structure of the apoE4 protein so it resembles the APOE3 protein. This treatment eliminated the signs of Alzheimer's disease, restored normal function to the cells, and improved cell survival.

https://www.eurekalert.org/pub_releases/2018-04/gi-sfg040818.php

Reference: 

The first study was presented at the annual Alzheimer's Association International Conference (AAIC) in Los Angeles, July 2019.

[4416] Wang, C., Najm R., Xu Q., Jeong D-eun., Walker D., Balestra M. E., et al.
(2018).  Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector.
Nature Medicine. 24(5), 647 - 657.

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