Axel Montagne, PhD, on Solving Alzheimer’s and Dementia with Blood-​​Brain Barrier Repair

Exercise and Brain Health

• Exercise is crucial for maintaining brain health 
  • Tiny blood vessels in the brain can collapse without regular exercise
  • This can lead to loss of neurons and accelerated cognitive decline
• Exercise also benefits heart health and eye vision

Dementia as a Vascular Disease

• Vascular dysfunction is an early component in various forms of dementia
• Research shows that vascular problems can be detected early on in Alzheimer’s disease
• Understanding the role of vascular dysfunction in dementia is a growing area of research

Leaky Blood Brain Barrier and Dementia

• Leaky blood brain barrier can be detected in cognitively normal individuals using MRI and biomarkers
• This leakage is not directly related to amyloid plaques and tau tangles
• Two schools of thought: amyloid plaques cause vascular dysfunction or vascular dysfunction promotes amyloid plaque formation

Early Diagnostics and Potential Interventions

• Early diagnostics can detect vascular problems in cognitively normal individuals up to 10 years before cognitive decline
• This provides a window for potential interventions to protect blood vessels and maintain brain health

• Research is ongoing to develop therapeutics targeting different cell types in the neurovascular unit, such as pericytes, which help maintain the integrity of the blood brain barrier
  Blood Vessels and Alzheimer’s Disease

• Blood vessels in the brain play a crucial role in maintaining integrity and avoiding leakages

• Researchers are exploring gene therapy, stem cell therapy, and other interventions to fix blood vessels
• Clinical trials are needed to determine the effectiveness of these interventions
• Potential treatments may not cure Alzheimer’s disease, but could postpone symptoms for several years

Role of Pericytes and Endothelial Cells

• Pericytes are sensitive and vulnerable cells that wrap around the smallest blood vessels in the brain
• They help maintain the blood-​​brain barrier and regulate blood flow by constricting and dilating vessels
• Pericytes can detach and die with normal aging, leading to a 10–20% loss of these cells
• Endothelial cells can become inflamed as we age, leading to increased detachment of pericytes

Inflammation and Blood Vessels

• Inflammation is a central factor in both normal aging and neurodegenerative diseases
• Increased inflammation in blood vessels can cause pericytes to detach and die
• Chronic inflammation can lead to a leaky blood-​​brain barrier and reduced blood flow
• Therapeutic targeting of inflammation in blood vessels could potentially improve vascular function

Omega‑3 and Blood-​​Brain Barrier Function

• Omega‑3 fatty acids play a role in regulating blood-​​brain barrier function through the MFSD2A transporter
• Omega‑3 metabolites are involved in resolving inflammation
• Studies suggest a link between reduced MFSD2A levels, pericyte loss, and dementia

• Omega‑3 status may have clinical relevance in regulating dementia-​​associated blood-​​brain barrier leakiness
  Small Vessel Disease and Alzheimer’s Disease

• Small vessel disease (SVD) is a common form of dementia, separate from Alzheimer’s disease (AD)

• SVD and AD share some common features in brain imaging, such as microbleeds and white matter hyperintensities
• SVD is characterized by endothelial dysfunction, inflammation of the vasculature, and pericyte dysfunction
• Exercise is crucial for maintaining brain health and preventing the decline of cognitive functions
• Genetic forms of small vessel disease, such as CADASIL and CARASIL, involve pericytes and vascular muscle cells, leading to rapid cognitive decline
• It is common for individuals to have multiple forms of dementia simultaneously, making research more complicated

Importance of Exercise for Brain Health

• Aerobic exercise helps maintain the tiny blood vessels in the brain
• Lack of exercise can lead to the constriction and collapse of these vessels, resulting in neuron loss
• Exercise is essential for maintaining cognitive functions, especially for those with genetic risk factors for cognitive decline

Overlap between Small Vessel Disease and Alzheimer’s Disease

• Some individuals with small vessel disease may also develop Alzheimer’s disease or other forms of dementia

• It is difficult to determine the exact ratio of individuals with both conditions due to the complexity of dementia and the presence of multiple neurological comorbidities
  Blood Brain Barrier and Glucose Metabolism

• Blood brain barrier is important for glucose transport

• Reduced brain glucose metabolism can be measured decades before Alzheimer’s or dementia symptoms occur
• Type 3 diabetes: term used to describe the connection between glucose metabolism and Alzheimer’s disease
• Glut1: main transporter of glucose at the blood brain barrier 
  • Found to be reduced in Alzheimer’s disease
  • Less Glut1 means less glucose can penetrate the brain
• FDG-​​PET: a technique used to measure glucose metabolism in the brain 
  • Controversial and not fully understood
  • Could be a marker of neuronal activity or vascular problems

Omega‑3 Deficiency and Glut1 Transporters

• Omega‑3 deficiency can cause a reduction in Glut1 transporters in the brain
• Omega‑3 deficiency also breaks down the blood brain barrier
• Chicken and egg question: is reduced glucose getting into the brain affecting the blood brain barrier, or is the blood brain barrier affecting glucose transporters, or both?

Fibrinogen and Blood Brain Barrier Breakdown

• Fibrinogen: a protein involved in blood coagulation and inflammation
• Found in the brain when the blood brain barrier is “leaky”
• Toxic to neurons and oligodendrocytes (cells that make up myelin and maintain white matter)
• Fibrinogen may play a role in the formation of white matter disease, which is a common feature of Alzheimer’s and small vessel disease

• Reducing fibrinogen levels in animal models has shown to partially restore vascular functions and blood flow, as well as the integrity of the blood brain barrier
  Targeting Toxins in Blood to Protect the Brain

• Leaky blood-​​brain barrier can lead to damage in the brain

• Fibrinogen can activate microglia cells through CD11B receptor 
  • Overreaction and inflammation in the brain can be detrimental to surrounding cells
• Katerina Cassidlu at Gladstone University developed an antibody to block interaction between fibrinogen and microglia 
  • Aim to prevent overactivation of microglia cells and inflammation

Omega‑3 and Air Pollution

• Air pollution can cause an increase in fibrinogen levels
• High amounts of omega‑3 can blunt the increase in fibrinogen in plasma 
  • May help prevent white matter dysfunction caused by fibrinogen entering the brain
• Omega‑3 plays a role in vascular function and may be more important in people at risk for Alzheimer’s

Environmental Factors and Alzheimer’s

• Living in a big city increases the chances of developing dementia
• Studies have shown that exposure to air pollution can lead to blood-​​brain barrier breakdown and pericyte degeneration
• Possible mechanisms include particles penetrating the brain through the olfactory area or particles in the bloodstream activating endothelium

APOE4 and Blood-​​Brain Barrier Breakdown

• APOE4 is a major genetic risk factor for late-​​onset Alzheimer’s disease
• APOE4 carriers have a higher risk of blood-​​brain barrier leakage in the medial temporal lobe
• APOE4 affects the blood-​​brain barrier through a cascade involving cyclophilin A and matrix metalloproteinase‑9 (MMP‑9)
  • MMP‑9 disrupts tight junctions between endothelial cells and degrades the basement membrane, leading to blood-​​brain barrier breakdown
• MMP‑9 is a marker for blood-​​brain barrier leakage, with levels correlating with breakdown after a stroke

Blocking Cyclophilin A to Restore Vascular Function

• Targeting cyclophilin A in APOE4 mice to see if blocking it can restore vascular function and improve neural function and cognition

• Humanized APOE4 mice were used to study the effects of blocking cyclophilin A on blood-​​brain barrier function and cognition
  Blood Brain Barrier and Vascular Function

• Mice with reduced blood flow in the brain, leaky blood brain barrier, and cognitive problems

  • Treated with Debut 25, an inhibitor of cyclophena, for one month
  • Partially and significantly restored vascular function
  • Less neuronal damage and cognitive problems

Cyclophena and Safety

• Debut 25 used in clinical trials for hepatitis C and COVID-19 
  • Some trials stopped due to cardiac issues in a participant
  • Safety and effectiveness still uncertain
  • Targeting MMP Nine or other targets might be a better approach

Glymphatic System and Blood Brain Barrier

• Dysfunction in blood brain barrier can impair glymphatic system 
  • Affects clearance of toxins, including amyloid plaques
  • Vascular function and blood brain barrier integrity are upstream of amyloid accumulation

Amyloid-​​targeting Drugs

• Lacanimab targets soluble form of amyloid 
  • Some positive results, but not a complete solution
  • Combination of treatments, including improving blood vessels, might be more effective

Hypertension and Brain Health

• Hypertension can impact brain health and increase dementia risk 
  • Early hypertension may be more harmful than later in life
  • Affects stiffness of blood vessels and pericyte function
  • Associated with microbleedings in basal ganglia and blood brain barrier leakage
  • Antihypertensive drugs can have a positive impact on cognition

Small Vessel Disease

• Not solely caused by hypertension

  • Many patients with small vessel disease do not have hypertension
  • More complex relationship between hypertension and small vessel disease
    Effects of Hypertension and Other Factors on Blood-​​Brain Barrier

• Hypertension and dementia

  • Duration and chronic hypertension are critical factors
  • Hypertension can damage arterial stiffness and blood-​​brain barrier over time
• Exercise
  • Critical window for exercise to improve vascular function: 40–55 years old
  • Exercise improves blood pressure, arterial function, and reduces dementia risk
• Alcohol
  • Chronic alcohol consumption can lead to leaky blood-​​brain barrier
  • Moderate alcohol consumption’s effects are controversial
  • Red wine contains flavonoids, which may have positive effects on brain function and vascular properties
• Obesity
  • Obesity can lead to higher levels of pro-​​inflammatory markers, affecting blood-​​brain barrier function
  • Blood-​​brain barrier leakage may also trigger obesity
• Homocysteine
  • High homocysteine is associated with brain dysfunction and dementia
  • Treatment with B6, B12, and folate can improve cognition and blood-​​brain barrier markers

Biomarkers and Future Research

• New techniques for measuring vascular biomarkers 
  • Electrochemiluminescence platforms (e.g., mesoscale Discovery, Simoa)
  • High-​​throughput, small fluid sample analysis
• Current biomarkers are in the research phase, not yet available for clinical use

• Future goal: diagnose Alzheimer’s and other conditions with a drop of blood
  Soluble Platelet Derived Growth Factor Receptor One (sPDGFR1)

• Ongoing clinical trials in the US

  • Hundreds of patients participated, aiming for thousands
  • Requires validation step with a larger cohort
• Potential availability in months or a couple of years

Biomarkers of Dementia and Alzheimer’s

• Researchers working on identifying new biomarkers and treatments
• Focus on vascular biomarkers and preventative measures
• Understanding dementia and Alzheimer’s in a different way

Axel Montagne

• Twitter handle: @axel_montagne
• Lab website: Montagnelab​.com
• Research focuses on the role of vascular function in cognitive function, preventing neurodegenerative diseases, and healthy brain aging