(Reposting again since it wasn't noticed ~1.5 months ago.)

This paper looks really good.

Amyloid beta has long been implicated in Alzheimer's. Now they've found a way to trigger the disease by generating amyloid in the liver and shown that it can reach the brain (by crossing the blood brain barrier). This setup was shown to 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.

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.

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

The researchers noticed amyloid beta was found in lipoprotein complexes (fat+protein), then experimentally modified the liver to produce it. The protein leaks out of the liver 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.”

> “[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 liver health and diet can play a factor in disease development.

Of course there's the chance that this is just a really good "biologically plausible" mechanism that looks good on paper, but might not naturally occur outside of this experimental setup. There will need to be much more research to either prove or rule this out.

This looks exciting though.