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New' genetic Alzheimer's disease may impact 6.7 million Americans

An incredible new study has upended our understanding of genetic Alzheimer's disease, finding that nearly everyone carrying two copies of a culprit gene had distinct biological markers of the degenerative condition by the age of 65. This means the APOE4 gene may no longer merely a risk factor but the driver behind a new stand-alone genetic Alzheimer's disease type that could impact up to 10 million Americans and more than 200 million people worldwide.
https://newatlas.com/medical/genetic-alzheimers-apoe4

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APOEs are involved in the transference of cholesterol to cells. APOE4 has a very low level of transference compared to other APOEs leading to high levels of free floating LDL (bad) cholesterol. That free floating cholesterol accumulates into lipid rafts which are implicated in tau and amyloid plaque accumulations, lowered synaptic plasticity, arterial cholesterol accumulation and increased inflammation. It also impairs the clearance of dead cells by macrophages.

Is CCR5 implicated in any of this? Of course it is.

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CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice.

The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.
https://pubmed.ncbi.nlm.nih.gov/36878326/

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My personal thesis - APOE4 seems to be more highly expressed by anti-inflammatory macrophages. We know leronlimab increases M1 macrophages (inflammatory) and decreases M2 macrophages (anti-inflammatory)*. With decreased M2 macrophages you would see less APOE4 expressed. It would also explain why leronlimab lowers LDL (bad) cholesterol and increases HDL (good) cholesterol in the bloodstream.

Every time something like this pops up it makes me sad that those wielding the power to do something about it remain wilfully ignorant. If I can figure it out those with more knowledge then I should be able too. I am just thankful to the doctors and scientists that do realize what leronlimab can do and are doing the studies that will hopefully bring it to the wider masses.

* It's important to remember that even though leronlimab increases inflammatory macrophages it blocks the over-activity of those macrophages by blocking the chemokines that control those macrophages. It does so only on CCR5 allowing normal activity on other CCR receptors.