Scientists may have advanced our understanding of the brain mechanisms behind Alzheimer's disease, after uncovering a process that precedes the buildup of toxic proteins that is a hallmark of the condition.
In a mouse study, scientists at the University of Southern California (USC) in Los Angeles reveal how damage to cells called pericytes can trigger white matter disease, which is associated with dementia.
Also, the study findings suggest that these brain changes may occur as early as the age of 40.
White matter disease is characterized by the degeneration of white matter. This is the brain tissue that contains nerve fibers, the thread-like structures that carry signals from the nerve cells, or neurons, to other areas of the body.
In white matter disease, these nerve fibers become damaged, and this causes problems with memory, thinking, and balance.
According to senior study author Berislav Zlokovic, of the Keck School of Medicine at USC, white matter disease is common in older adults, and research has linked the condition to cerebral small vessel disease, which they say "contributes to almost 50 percent of dementia cases worldwide, including Alzheimer's disease."
However, the precise mechanisms by which white matter disease may lead to dementia has been unclear. But the new study from Zlokovic and colleagues sheds some light.
The researchers recently reported their findings in the journal Nature Medicine.
Pericytes and white matter health
First, the team conducted a postmortem analysis of the brains of people who had Alzheimer's disease, and they compared them with the brains of healthy adults.
The researchers found that the brains of people with Alzheimer's disease had 50 percent fewer pericytes than healthy brains, and levels of a protein called fibrinogen — a blood-circulating protein that aids wound healing — were increased by threefold in white matter regions.
By using MRI to study mouse models that were deficient in pericytes, it was found that these cells play a key role in white matter health.
When the pericyte-deficient mice were 12–16 weeks old — which is the equivalent to approximately 40 human years — their levels of fibrinogen were around 10 times higher in the corpus callosum, a brain region that plays a role in transmitting cognitive and sensory data from one side of the brain to the other.
At 36–48 weeks old — the equivalent to 70 human years — pericyte-deficient mice demonstrated a 50 percent increase in blood vessel leakage, the team reports.
"Our observations suggest that once pericytes are damaged, blood flow in the brain reduces like a drain that is slowly getting clogged," says co-first study author Angeliki Maria Nikolakopoulou, of the Zilkha Neurogenetic Institute at the Keck School of Medicine.
Uncovering 'the beginnings of dementia'
For the next part of the study, the team assessed the rodents' running speed using a wheel test. When they reached 12–16 weeks old, the pericyte-deficient mice were found to run 50 percent slower than the control mice.
"The mice deficient in pericytes function slower because there are structural changes in their white matter and a loss of connectivity among neurons," notes Zlokovic.
Confirming their theory with MRI, the researchers found that by the age of 12–16 weeks, the mice deficient in pericytes showed structural changes to white matter.
"Pericytes are compromised early on," explains co-first study author Axel Montagne, also of the Zilkha Neurogenetic Institute. "Think of it as hair clogging a drain over time. 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."
Montagne adds that this finding indicates that in humans, white matter disease could begin as early as the age of 40.
"Many scientists," notes Zlokovic, "have focused their Alzheimer's disease research on the buildup of toxic amyloid and tau proteins in the brain, but this study and others from my lab show that the problem starts earlier — with leaky blood vessels in the brain."
A new approach to preventing dementia?
When the researchers used a compound to reduce fibrinogen levels in the blood and brains of the rodents, they found that white matter volume was restored to 90 percent, while the connectivity of white matter was restored to 80 percent.
"Our study provides proof that targeting fibrinogen and limiting these protein deposits in the brain can reverse or slow white matter disease."
The researchers believe that their findings may point toward fibrinogen as a target for preventing this dementia precursor, but further studies are needed to determine the best strategy.
"We must figure out the right approach," says Zlokovic, adding, "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."