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February 28, 2023 • 1hr 48min
#079 Blood-Brain Barrier Dysfunction in Alzheimer’s Disease and Dementia | Axel Montagne, Ph.D.
FoundMyFitness
In this episode, Dr. Rhonda Patrick interviews Dr. Axel Montagne, a professor and group leader at the Dementia Research Institute at the University of Edinburgh. Dr. Montagne's research focuses on understanding how dysfunction of the blood-brain barrier contributes to dementia and cognitive decline. This work represents an important shift in how we view dementia - not just as a disease of amyloid plaques and tau tangles, but as one with a crucial vascular component.
The blood-brain barrier is a protective border of tightly connected cells that controls what can enter the brain from the bloodstream. When this barrier becomes leaky or dysfunctional, it can allow harmful substances to enter the brain and disrupt normal function. Dr. Montagne's research suggests this vascular dysfunction occurs very early in the disease process, even before amyloid plaques form.
This new paradigm opens up exciting possibilities for earlier detection and intervention in dementia and Alzheimer's disease. It also highlights the importance of vascular health for maintaining cognitive function as we age. The discussion covers the mechanisms of blood-brain barrier dysfunction, how it can be measured, risk factors that contribute to it, and potential ways to prevent or treat it.
#079 Blood-Brain Barrier Dysfunction in Alzheimer’s Disease and Dementia | Axel Montagne, Ph.D.
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Key Takeaways
- Blood-brain barrier dysfunction is an early feature of dementia and Alzheimer's disease, occurring even before amyloid plaques form. This suggests vascular issues may be upstream of amyloid accumulation.
- Breakdown of the blood-brain barrier can be detected up to 10+ years before cognitive decline using advanced MRI techniques and plasma biomarkers. This opens up possibilities for early intervention.
- APOE4 carriers show accelerated breakdown of the blood-brain barrier, which may explain their increased dementia risk. Targeting vascular health could be especially important for this group.
- Loss of pericytes (cells that wrap around blood vessels) is a key driver of blood-brain barrier dysfunction. Preserving pericyte function is a promising therapeutic target.
- Chronic inflammation, hypertension, and other vascular risk factors contribute to blood-brain barrier breakdown over time. Managing these factors through lifestyle is crucial for prevention.
- Exercise is one of the most important ways to maintain blood-brain barrier integrity and brain vascular health as we age. It helps keep small vessels open and functioning.
- Omega-3 fatty acids may help protect blood-brain barrier function, potentially by supporting pericytes and reducing inflammation. More research is needed in this area.
- Targeting the blood-brain barrier and vascular health, in addition to amyloid, may be necessary for effective Alzheimer's treatments. Combination approaches could be most promising.
- Early and sustained hypertension appears particularly damaging to brain vascular health. Managing blood pressure starting in early adulthood is important for prevention.
- New diagnostic tools and biomarkers are being developed to detect early blood-brain barrier dysfunction, which could enable earlier intervention before cognitive symptoms appear.
Introduction
In this episode, Dr. Rhonda Patrick interviews Dr. Axel Montagne, a professor and group leader at the Dementia Research Institute at the University of Edinburgh. Dr. Montagne's research focuses on understanding how dysfunction of the blood-brain barrier contributes to dementia and cognitive decline. This work represents an important shift in how we view dementia - not just as a disease of amyloid plaques and tau tangles, but as one with a crucial vascular component.
The blood-brain barrier is a protective border of tightly connected cells that controls what can enter the brain from the bloodstream. When this barrier becomes leaky or dysfunctional, it can allow harmful substances to enter the brain and disrupt normal function. Dr. Montagne's research suggests this vascular dysfunction occurs very early in the disease process, even before amyloid plaques form.
This new paradigm opens up exciting possibilities for earlier detection and intervention in dementia and Alzheimer's disease. It also highlights the importance of vascular health for maintaining cognitive function as we age. The discussion covers the mechanisms of blood-brain barrier dysfunction, how it can be measured, risk factors that contribute to it, and potential ways to prevent or treat it.
Topics Discussed
Blood-Brain Barrier Dysfunction in Dementia (12:43)
Dr. Montagne explains that about 50% of all dementias start with breakdown of the smallest vessels in the brain. This vascular dysfunction can be detected very early, even in cognitively normal individuals:
- Using advanced MRI techniques, they can visualize leakiness of the blood-brain barrier
- Certain brain regions, like the hippocampus, show increased leakiness with normal aging
- This leakiness is accelerated in people progressing towards dementia
- New plasma and CSF biomarkers are being developed to measure blood-brain barrier integrity
Importantly, the areas showing blood-brain barrier leakage are distinct from where amyloid plaques first appear. This suggests vascular dysfunction may be an independent process occurring upstream of amyloid accumulation.
APOE4 and Blood-Brain Barrier Dysfunction (18:54)
The APOE4 gene variant is the strongest genetic risk factor for late-onset Alzheimer's disease. Dr. Montagne's research has found:
- APOE4 carriers show much more vascular problems and blood-brain barrier leakage, even when cognitively normal
- This can be detected at least 10 years before cognitive decline
- APOE4 appears to trigger a cascade in pericytes (cells that wrap around blood vessels) that leads to blood-brain barrier breakdown
This suggests vascular dysfunction could be a key mechanism by which APOE4 increases dementia risk. Targeting vascular health may be especially important for APOE4 carriers.
Role of Pericytes in Blood-Brain Barrier Function (24:19)
Dr. Montagne explains that pericytes are crucial cells for maintaining blood-brain barrier integrity:
- Pericytes wrap around the smallest blood vessels in the brain
- They help maintain the tight junctions between endothelial cells that form the blood-brain barrier
- Pericytes also help regulate blood flow in the brain's microvasculature
- Loss of pericytes is seen in normal aging (10-20% loss) but is accelerated in dementia (up to 60% loss)
Preserving pericyte function and preventing their detachment from blood vessels is a promising therapeutic target for maintaining blood-brain barrier integrity.
Inflammation and Blood-Brain Barrier Dysfunction (27:24)
Chronic low-grade inflammation appears to be a key driver of blood-brain barrier breakdown:
- As we age, endothelial cells lining blood vessels become more pro-inflammatory
- This leads to increased expression of cell adhesion molecules that recruit immune cells
- The resulting neuroinflammation can cause pericytes to detach from blood vessels
- This creates a vicious cycle of increasing inflammation and barrier dysfunction
Managing chronic inflammation through lifestyle factors like diet and exercise may help preserve blood-brain barrier function with age.
Omega-3 Fatty Acids and Blood-Brain Barrier Function (32:27)
Dr. Montagne discusses emerging research on omega-3 fatty acids and blood-brain barrier health:
- The omega-3 transporter MFSD2A is reduced in aging and Alzheimer's disease
- Areas with reduced MFSD2A correlate with areas of pericyte loss
- Omega-3s may help resolve inflammation and support pericyte function
- More research is needed, but omega-3s could be a promising preventive approach
Exercise and Blood-Brain Barrier Health (35:25)
Dr. Montagne emphasizes that exercise is crucial for maintaining blood-brain barrier integrity:
- Regular aerobic exercise keeps small blood vessels open and functioning
- Without exercise, tiny capillaries can collapse and disappear
- This leads to reduced blood flow and potential loss of neurons
- The "critical window" for exercise benefits may be ages 40-55, but it's never too late to start
"Exercise is the number one thing if you're prone to go to cognitive decline...If you want to stay healthy in terms of brain function. Yeah. No other choice." - Dr. Axel Montagne
Hypertension and Brain Vascular Health (1:25:14)
Dr. Montagne discusses how hypertension impacts brain health:
- Early-onset hypertension (30s-40s) may be more harmful than late-onset
- Chronic hypertension over many years impacts blood vessel stiffness and pericyte function
- It's associated with increased microbleeds and white matter damage
- The cumulative exposure over time seems to be most important
- Managing blood pressure early in life is crucial for prevention
Obesity and Blood-Brain Barrier Function (1:37:13)
The relationship between obesity and blood-brain barrier dysfunction appears complex:
- Obesity is associated with higher levels of inflammatory markers that can damage the barrier
- However, some research suggests blood-brain barrier leakage in certain brain regions may actually contribute to obesity
- This could create a vicious cycle where obesity and barrier dysfunction reinforce each other
New Diagnostic Tools and Biomarkers (1:41:12)
Dr. Montagne discusses emerging tools for detecting early blood-brain barrier dysfunction:
- Advanced MRI techniques can visualize barrier leakage
- New plasma biomarkers are being developed and validated
- These could enable detection of vascular issues years before cognitive symptoms
- The goal is to develop simple blood tests, similar to glucose monitoring
While still in research phases, these tools could eventually enable much earlier intervention.
Conclusion
This episode highlights an important paradigm shift in how we view dementia and Alzheimer's disease. Rather than focusing solely on amyloid plaques, we must also consider the crucial role of vascular health and blood-brain barrier integrity. This vascular dysfunction appears to occur very early in the disease process, potentially even before amyloid accumulation.
This new understanding opens up exciting possibilities for earlier detection and intervention. It also emphasizes the importance of lifestyle factors in prevention. Exercise, managing chronic inflammation and hypertension, and potentially omega-3 supplementation may all help preserve blood-brain barrier function as we age.
For treatment, targeting vascular health in addition to amyloid may be necessary for truly effective therapies. Combination approaches that address multiple aspects of the disease are likely to be most promising.
Ultimately, this research underscores that dementia is not an inevitable part of aging. There is much we can do throughout our lives to maintain cognitive health, even in the face of genetic risk factors. As new diagnostic tools and treatments emerge from this work, we may be able to dramatically reduce the burden of dementia in the coming decades.
