So,  as we’ve discussed over the past few days (check yesterday’s blog, if you want), the FDA approved Aduhelm, the monoclonal antibody that attaches to amyloid.  The problem is that there is no clinical data demonstrating this will help alleviate the memory loss in Alzheimer’s patients- despite the FDA approval.

Apolipoprotein E (ApoE), a lipid-binding protein,  is linked to cholesterol metabolism and Alzheimer’s disease; as a matter of fact ApoE provides the strongest genetic risk factor for Alzheimer’s.  High levels of cholesterol are also associated with Alzheimer’s incidence- but we lack the full reason for this association.

Of the alleles of ApoE, ApoE4 is the one that greatly increases the risk of late onset Alzheimer’s.  ApoE also regulates amyloid deposition. (ApoE2 and ApoE3 are also associated with Alzheimer’s, but at decreased risk from ApoE4.  [The risk decreases (4 to 3 to 2) for both factors- Alzheimer’s risk and amyloid deposition!]  This is the reason why examining which proteins control ApoE metabolism can be vital to the understanding of Alzheimer’s.

Which is why these studies from Washington University (St. Louis MO) seem so interesting to me.  Raising the amount of low-density lipoprotein receptors (LDLR) [a normal protein found in the brain] may protect against Alzheimer’s related brain damage.  (LDLR is also known to effect a reduction in the potential of developing heart disease.)  The decreased neurodegeneration and ameliorated brain injury effected by augmenting LDLR levels may be just the key we need to solve the Alzheimer’s puzzle.

The Washington University team hypothesized that increasing the levels of LDLR could decrease the levels of ApoE- which means augmented amyloid clearance from the brain, as well as decreased amyloid deposition on the neurons.  The hypothesis was tested in mice modified to manifest Alzheimer’s disease; and it proved to be  correct.  Augmenting the LDLR levels decreased the ApoE levels by 50 to 90%,  decreased amyloid aggregation, and enhanced amyloid clearance from the brain’s extracellular space.

These test results have been reported in Neuron (Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms) by senior author Dr. David Holtzman (along with Drs. Jungsu Kim,  Joseph M. Castellano, Hong Jiang, Jacob M. Basak, Maia Parsadanian, Vi Pham and Stephanie M. Mason, [all from Washington University], as well as Dr. Steven M. Paul [Eli Lilly]).

One of the problems with attempting to arrest or cure Alzheimer’s disease is that it progresses in the body for a long time before the subject manifests memory or cognitive problems (often for two decades or so). And, at that time there is significant damage to the brain. During that period, amyloid proteins accumulate (which are the compounds treated by Aduhelm).  This amyloid explosion is then followed by the Tau protein infestation that forms tangles in the brain.  (These tangles, toxic to the brain neurons, become evident right before symptoms manifest.)

It is the LDLR that improves the clearance of ApoE lipoproteins (which drives the tau- caused degeneration of the brain [by activating microglia- the sewage channel system of the brain- and in their zealous pursuit of molecular debris can damage neural tissue])  The LRLR binds to ApoE and effects its degradation.

Now, to see if these results are mimicked in humans…

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