Rhonda Patrick interview: rethinking Alzheimers with Alex Montagne, Ph.D
Dr Montagne's provides a critical lens through which to view the contributions of vascular dysfunction as a crucial common thread
We've just released a new video featuring Alex Montagne, Ph.D., a chancellor's fellow and group leader at the UK Dementia Research Institute at the University of Edinburgh Centre for Clinical Brain Sciences. His research focuses on understanding critical components of the blood-brain barrier that become dysfunctional preceding dementia and in the earliest stages of age-related cognitive decline.
Also available on Apple Podcasts and Spotify.
Dr. Montagne's work provides a critical lens through which to view the contributions of vascular dysfunction (or, conversely, vascular health – if we choose to preserve it) as a crucial common thread in dementia and neurodegeneration.
In this episode, Dr. Axel Montagne and I cover the breadth of cutting-edge science on the relationship between blood-brain barrier leaks and dementia, such as...
00:03:23 - What dementias have in common
00:04:22 - The importance of preserving small blood vessels (in the brain)
00:05:17 - Changes in the blood-brain barrier in aging that cause "leaking"
00:06:50 - Predicting cognitive decline early with biomarkers – an opportunity for intervention?
00:08:11 - Why targeting amyloid isn’t enough
00:10:34 - The impact of the APOE4 genotype on brain vasculature
00:15:58 - The cause of white matter damage in the brain
00:25:26 - Why the loss of omega-3 transport affects pericytes
00:27:04 - The role of exercise in prevention of blood-brain barrier dysfunction
00:27:25 - Why high heart rates during exercise preserve brain function
00:28:28 - The role of exercise in preserving vision health
00:31:56 - Why leaky vessels damage myelin and the brain
00:37:10 - Can you have more than one type of dementia?
00:39:34 - Does the breakdown of the blood-brain barrier cause “type 3 diabetes"?
00:45:43 - Why omega-3 may prevent detachment of pericytes
01:06:14 - Why a hepatitis drug restored cognition in APOE4 mice
01:11:19 - Why blood-brain barrier disruption results in the accumulation of amyloid-beta
01:16:54 - Why lifetime hypertension increases dementia risk
01:28:53 - Effects of obesity on blood-brain barrier leakage
"What we know for sure is [there are] early vascular problems...and
we need to fix them to avoid dementia."
- Dr. Axel Montagne
A common thread in cognitive decline and various forms of dementia?
We tend to think of cognitive decline and dementia in terms of the amyloid-beta plaques and tau tangles characteristic of Alzheimer's disease or perhaps the altered glucose metabolism – sometimes called "type 3 diabetes" – that drives insulin resistance in the brain and subsequent cognitive decline. But what if we could instead find an underlying and unifying pathology involved in most dementias?
This makes sense, really, especially when we consider that Alzheimer's disease, cerebral small vessel disease, and vascular dementia – the three most common forms of dementia – can present simultaneously, compounding the associated cognitive losses.
Breakdown of the blood-brain barrier
Roughly three decades ago, researchers observed an interesting phenomenon in the post-mortem brain tissue of some people with Alzheimer's disease: a propensity for vascular dysfunction – a broad term that describes the loss of normal endothelial tone and permeability. Scientists now know that roughly half of all forms of dementias start with the breakdown of the smallest vessels in the brain and subsequent leakiness of the blood-brain barrier.
Consequently, the health of the blood vessels that comprise the blood-brain barrier may be one of the earliest and most critical pathological features of Alzheimer's disease and other dementias.
Blood-brain barrier leakage affects brain regions involved in learning and memory
The loss of blood-brain barrier integrity is a feature of normal aging and typically begins in the hippocampus – the area of the brain where the consolidation of short-term memories to long-term memories occurs, as well as learning and spatial navigation.
In the research setting, the presence of blood-brain barrier dysfunction (along with various blood and cerebrospinal biomarkers) can predict future cognitive decline. Interestingly, leaky vessels aren't always co-located with amyloid-beta and tau protein accumulation, suggesting that these pathological events may be independent pathways for the development of dementia and that a "cocktail approach" of simultaneously addressing a leaky barrier and amyloid-beta might be helpful.
Genetic risk factors for Alzheimer's disease
A variant of the APOE gene called APOE4 is the primary genetic risk factor for late-onset Alzheimer's disease, increasing a person's risk by as much as 15-fold. APOE4 carriers often have higher blood levels of various contributors to the process of blood-brain barrier breakdown. As a result, they also exhibit poor amyloid-beta clearance.
Pericyte losses promote neurodegeneration and blood-brain barrier leakiness
A critical player in the pathophysiology of blood-brain barrier dysfunction is the detachment and loss of pericytes. These specialized endothelial cells cover as much as 80 percent of the capillaries' surface area in the human brain's cortex and hippocampus. There they wrap around the smallest vessels that make up the blood-brain barrier and regulate blood flow, provide structural support, and transport various molecules across the barrier.
However, aging contributes to neuroinflammation, causing endothelial cells to adopt a pro-inflammatory phenotype, ultimately driving the detachment of pericytes and contributing to the breakdown of the blood-brain barrier and the pathophysiology of various dementias, including Alzheimer's disease. In fact, the detachment of pericytes enables the physical entry of immune cells into the brain.
Preventing toxic proteins originating in blood from entering the brain
As the blood-brain barrier breaks down, various immune cells, inflammatory cytokines, toxic proteins, and red blood cells gain access to the brain. These blood-borne components, which include plasminogen, prothrombin, auto-antibodies, fibrinogen, and others, are neurotoxic. They should not be in the brain.
For example, fibrinogen, a protein involved in clotting, activates the microglia, the brain’s resident immune cells. The microglia switch from protecting the blood-brain barrier to attacking it, promoting a vicious cycle of blood-brain barrier dysfunction and neurotoxicity. Chronic activation of microglia causes neuroinflammation and increases dementia risk.
Strategies for preventing dementia
Therapeutic strategies for targeting the neurovascular unit of the blood-brain barrier are on the horizon, but there are things we can do now to support vascular health and help maintain the integrity of the blood-brain barrier, such as consuming marine-derived omega-3 fatty acids, maintaining healthy blood pressure, and engaging in aerobic exercise (especially vigorous exercise).
A good rule of thumb for determining whether you're engaging in vigorous-intensity exercise: It should be challenging to maintain a conversation, make you sweat, and, ideally, elevate your heart rate to 80 percent of your estimated maximum.
Want extra resources?
We've talked a lot about blood-brain barrier health in our previous FoundMyFitness content. Here are some articles, episodes, and clips that expand on the content presented in this interview that we think you'll enjoy:
FoundMyFitness Topic Pages
Episodes
Dr. Dale Bredesen on Preventing and Reversing Alzheimer's Disease
Intestinal Permeability: the Bacterial link to Aging, Brain Barrier Dysfunction & Metabolic Disorder
Clips
Omega-3 phospholipid DHA and supplementation | Rhonda Patrick
Lifestyle factors that affect Alzheimer’s risk for APOE4 carriers | Peter Attia
