Alzheimer’s breakthrough: Blood treatment stops disease

Alzheimer’s disease could be cured by developing drugs that target a protein found in blood, a new study reveals. 

A technique that reduces levels of a blood protein called fibrinogen that is toxic to the brain protected mice from Alzheimer’s in a new study from the University of Southern California. 

Fibrinogen is necessary to blood clotting, but sometimes it leaks into the brain through weak blood vessels and the blood-brain barrier, causing toxic build-up and contributing to the white matter degeneration that precedes dementia.

Reducing fibrinogen in middle-aged mice restored their white matter, but because we need the protein for blood clotting, the study’s findings suggest that strengthening the blood-brain barrier in humans could have promising effects.    

The breakthrough opens the door to a more effective way of combating dementia – when patients are as young as 40 – two or three decades before memory loss starts.

Amyloid-beta protein deposits and plaques occur after exposure to too much of any of a number of kinds of protein – including fibrinogen – and are thought to be one of the primary causes of Alzheimer’s. 

Trials of medications that target beta-amyloid and tau proteins that clog the brains of Alzheimer’s patients have been largely disappointing, however.

They have mainly failed because the blood-brain barrier that protects that acts as an extra defense mechanism to protect the brain from any pathogens that might get into the body also blocks the protein-busting drugs from reaching their target.    

But the latest findings, published in Nature Medicine, suggest strengthening this ‘wall’ could be key – by stopping fibrinogen entering the brain.

When the team used an enzyme that reduced the chemical in the blood and brains of mice their volume of white matter returned to 90 percent of normal state.

Connections between the brain cells also improved dramatically – back to 80 percent productivity.

Dr Berislav Zlokovic, chair in Alzheimer’s Disease Research at the Keck School of Medicine at Southern California University, said: ‘Our study provides proof targeting fibrinogen and limiting these protein deposits in the brain can reverse or slow white matter disease.

‘Perhaps focusing on strengthening the blood-brain barrier integrity may be an answer because you can’t eliminate fibrinogen from blood in humans.

‘This protein is necessary in the blood. It just happens to be toxic to the brain.’

His study sheds fresh light on how a breakdown in the brain’s vascular system predates the accumulation of toxic plaques of amyloid and tangles of tau in the brains of Alzheimer’s sufferers.

The research suggests an earlier target for preventing dementia. It’s believed all drugs have failed so far because they are given too late once the illness has taken hold.

Almost 50 percent of all forms of dementia begin with the breakdown of the smallest blood vessels in the brain and their protective ‘gatekeeper cells’, said the researchers.

Senior author Dr Zlokovic said: ‘Many scientists have focused their Alzheimer’s disease research on the build-up of toxic amyloid and tau proteins in the brain.

‘But this study and others from my lab show the problem starts earlier – with leaky blood vessels in the brain.

‘The collapse of pericytes – gatekeeper cells that surround the brain’s smallest blood vessels – reduces myelin and white matter structure in the brain.

‘Vascular dysfunctions – including blood flow reduction and blood-brain barrier breakdown – kick off white matter disease.’

This is the wearing away of myelin – a fatty sheath that allows neurons to transfer messages within the brain network.

In an animal, model researchers found that brain deterioration associated with dementia may begin as early 40 in humans.

For over 25 years scientists have known white matter disease impedes a person’s ability to learn or remember new things, slows thinking and causes people to fall more often due to balance issues.

They identified a link between crippled small blood vessels in the brain and white matter disease but didn’t know what started that process – until now.

The study explains the ‘pericyte’ gatekeeper cells play a critical role in white matter health and disease via fibrinogen.

When these are compromised, an unhealthy amount of fibrinogen slinks into the brain and causes white matter and brain structures – including nerve fibers and cells that produce protective myelin – to die.

First author Dr Axel Montagne said the protein enters the brain through a leaky blood-brain barrier.

He said: ‘We demonstrated controlling fibrinogen levels can, in a mouse model, reverse or slow white matter disease – the harbinger to dementia.’

Dementia affects 50 million people worldwide and costs the US an estimated $157 to $2015 billion annually. 

The study found about 50 percent fewer gatekeeper cells and three times more fibrinogen proteins in watershed white matter areas in postmortem brains of people who had Alzheimer’s when they die compared to healthy brains..

Using MRI (magnetic resonance imaging) brain scans, they noticed 50 percent increased vessel leakage in mice that were 36 to 48 weeks old – roughly equivalent to 70 year-old humans. 

The scientists also found reduced cerebral blood flow and increased accumulation of fibrinogen in the brains of mice deficient in gatekeeper cells.

At only 12 to 16 weeks old the mice had 10 times more fibrinogen in the corpus callosum compared to the control group.

This is the brain’s central transit terminal that routes motor, sensory and cognitive information to their final destinations. 

Co-first author Dr Angeliki Maria Nikolakopoulou said: ‘Our observations suggest once pericytes are damaged blood flow in the brain reduces like a drain that is slowly getting clogged.’

Theoretically that means white matter disease in humans could begin when they are just 40 years old, said Dr Montagne. 

‘Once the drain is clogged cracks begin forming in the ‘pipes’ or brain’s blood vessels. White matter frays and brain connections are disrupted. That’s the beginnings of dementia.’