(Reposting since nobody noticed the first time.)

This is big!

Amyloid beta has long been implicated in Alzheimer's. Now they've found a mechanism to generate it in the liver, cause it to reach the brain (crossing the barrier), and trigger the disease. It's a very plausible mechanism that worked end-to-end and seems to fit all of the observational evidence we've gathered.

Pretty spectacular. Could be a smoking gun, here.

The paper: Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype

https://journals.plos.org/plosbiology/article?id=10.1371/jou...

Abstract:

> Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

The abstract spells it all out.

We knew amyloid beta was highly associated with Alz. We've been studying this for decades.

They noticed amyloid beta was found in lipoprotein complexes (fat+protein), then modified the liver to produce it. The protein leaks out and causes neurodegeneration.

> Insight into how blood Aβ increases risk for AD comes from findings that in humans, greater than 90% of blood Aβ1–40 and 97% of the particularly pro-amyloidogenic Aβ1–42 is associated with plasma lipoproteins [3], principally the triglyceride-rich lipoproteins (TRLs) of hepatically derived very low-density lipoproteins (VLDLs) and of postprandial chylomicrons [4,5]. Direct evidence of a peripheral TRL-Aβ/vascular risk pathway for AD comes from studies in preclinical models, which show that cerebral capillary amyloid-angiopathy, a common early neurovascular pathology of AD, may be a consequence of parenchymal extravasation of TRL-Aβ.

This implicates fatty acids originating from the liver migrating (extravasation). And they just experimentally reproduced this!

Some quotes from the linked article:

> “This study,” he added, “shows that exaggerated abundance in blood of potentially toxic fat-protein complexes can damage microscopic brain blood vessels called capillaries and, thereafter, leak into the brain, causing inflammation and brain cell death.”

Wow.

Maybe we have it now!

> “[Changes] in dietary behaviors and certain medications could potentially reduce blood concentration of these toxic fat-protein complexes, [subsequently] reducing the risk for Alzheimer’s or [slowing] down the disease progression,” he concluded.

This would suggest that diet plays a huge role in disease development.

This is incredible.