New hypothesis argues leaky blood-brain barrier triggers Alzheimer's

This is a big idea that is also testable.  We needed to have a better explanation for this problerm.  We have been floundering around forever.

We need to address the Blood Brain Barrier or BBB and its overall health.

Earliest work identified lipid problems as part of the syndrome ,so we may well be onto something.

New hypothesis argues leaky blood-brain barrier triggers Alzheimer's

By Rich Haridy

April 10, 2022

https://newatlas.com/science/new-hypothesis-alzheimers-disease-blood-brain-barrier-lipid-invasion

A new hypothesis proposes fatty molecules in the blood stream invade the brain through a leaky blood 

A new article in the Journal of Alzheimer's Disease Reports has proposed a novel hypothesis for the cause of Alzheimer’s disease. The article argues Alzheimer’s is caused by a damaged blood-brain barrier allowing fatty molecules known as lipids to invade the brain and trigger a cascade of events that result in neurodegeneration and cognitive decline.

There are currently more than six million Americans living with Alzheimer’s and that number is expected to double by 2060. Despite decades of work and billions of dollars researchers have been unable to crack the mystery of this pervasive neurodegenerative disease.

At the beginning of the 20th century a German researcher by the name of Alois Alzheimer first reported a case of distinctive dementia in a 50-year-old woman. Over the course of the century the disease became known as Alzheimer’s disease and its pathology was robustly characterized.

Since the 1990s the dominant hypothesis to explain the cause of Alzheimer’s disease (AD) focused on a pair of proteins known as amyloid and tau. The abnormal accumulation of these proteins in the brain is one of the clearest pathological signs of Alzheimer’s and most research has centered on finding a pharmaceutical way to stop, or reverse, the toxic build up of these proteins in a human brain.

Frustratingly, literally every human clinical trial testing a novel anti-amyloid or anti-tau drug has failed and some researchers have begun to question the entire foundations of modern Alzheimer’s science. A variety of alternative hypotheses have recently been floated to explain the cause of Alzheimer’s, from it being triggered by viral infections to the suggestion it is actually an autoimmune disease.

Jonathan Rudge, a researcher from the University of Reading, has attempted to tie several strands of recent Alzheimer’s science into a new overriding hypothesis to explain the cause of this still-unexplained disease. His hypothesis is dubbed the Lipid Invasion Model, and it all begins with a disruption to the blood-brain barrier, an almost impenetrable membrane that stops harmful particles from entering the brain.

“… a healthy blood brain barrier is incredibly important to how our brains function effectively,” said Rudge. “If the barrier gets damaged, as is the case with people who develop Alzheimer's, external lipids like cholesterol and fatty acids get a chance to pass through."

The idea that the cause of Alzheimer’s could come from outside the brain is not new. Some researchers have previously floated the hypothesis that the toxic neuron-damaging amyloid proteins actually originate in the liver and travel up to the brain through a leaky blood-brain barrier. Rudge’s new hypothesis instead looks to a different collection of molecules as the cause of Alzheimer’s.

“Lipids are a class of biomolecules that do not dissolve (or not easily) in water,” Rudge states in the new article. “They include fatty acids, glycerolipids, glycerophospholipids, and sphingolipids, as well as cholesterol and other sterols.”

The idea is that a failing blood-brain barrier allows excess levels of these lipids into the brain and this invasion triggers a cascade of damaging events leading to what we recognize as Alzheimer’s disease. Rudge argues this mechanism explains some of the anomalies in Alzheimer’s science, such as the small volume of patients who can display major cognitive signs of Alzheimer’s without any corresponding amyloid pathology.

"These external lipids are managed differently to those typically found within the brain,” said Rudge. “My theory proposes that these invading lipids are resulting in brain damage, like brain shrinkage, and development of amyloid plaques and 'tau tangles', which causes the behaviors characteristic of Alzheimer's, such as memory loss, sleep disorders and paranoia."

Backing up the new hypothesis Rudge goes all the way back to Alois Alzheimer’s original case study from 1907. In describing this first case of disease, Alzheimer frequently wrote of finding “lipid aggregations” as often as he found amyloid plaques or tau accumulations, known as neurofibrillary tangles (NFTs).

“In describing the first diagnosed case of AD, Alzheimer makes frequent reference to 'adipose saccules', 'lipoid granules', and similar lipid-based aggregations within both glial and neuronal cells, as well as to amyloid plaques, NFTs, and general brain degeneration,” Rudge explained in the new article. “It is clear from Alzheimer’s writings that he regarded 'this degree of lipid degeneration', as he described it, to be as much a hallmark of the disease we now call AD as the associated plaques and NFTs.”

More modern research also backs up Rudge’s Lipid Invasion Model. Just last year, for example, a team from the University of New South Wales found a particular lipid profile in blood samples could be used to accurately diagnose Alzheimer’s disease. Another study from a team at the University of Southern California in 2018 found a leaky blood-brain barrier can be used as a diagnostic tool to identify the earliest stages of several neurodegenerative diseases, including Alzheimer’s.

Rudge’s conclusion is that early-stage treatment, or even prevention of the disease in the first place, should focus on protecting the blood-brain barrier (BBB). He also suggests that once cognitive decline is clearly apparent it may be too late to prevent further deterioration but developing treatments to reduce this “external lipid invasion” could help treat the disease in later stages.

“A clear conclusion to be drawn from the model is that the primary focus in prevention and early treatment of AD should be on protecting, and if possible, repairing the BBB,” concluded Rudge. “Diagnosing BBB disruption at the earliest stage is critical to fighting AD, certainly in the case of LOAD [late-onset Alzheimer’s disease], since relying on other signs, in the form of mild cognitive impairment, plaques, or NFTs, is quite likely, in most cases, to result in treatment starting too late to prevent further serious cognitive decline.”

The new study was published in the Journal of Alzheimer's Disease Reports.

Source: University of Reading