Alzheimer’s disease is the most common form of dementia. For many years, researchers believed that its main cause was a buildup of toxic proteins. But recent findings suggest that the problem may have another origin, specifically in the bloodstream.Contrary to a commonly held belief, dementia isn’t just about memory. Imagine the brain as a car. To run properly, this complex system depends, among other things, on an engine (our neurons, the central component) and a set of pipes (our cerebral vascular system) to deliver fuel (oxygen and nutrients) to the engine.This article is part of our ongoing series The Grey Revolution. The Conversation Canada and La Conversation are exploring the impact of the aging boomer generation on Canadian society, including housing, working, culture, nutrition, travelling and health care. The series explores the upheavals already underway and those looming ahead.As we age, this machinery wears out. If the pipes become damaged, rust sets in. If the engine breaks down, it affects the vehicle’s performance and inevitably leads to premature failure. In the case of Alzheimer’s disease, the “rust” is characterized by the accumulation of two toxic proteins: amyloid plaques and tau fibres, which bring about a decline in cognitive abilities, including memory.However, several observations call into question the role of these proteins. It becomes essential to identify the cause of this “rust” and understand its origin.The amyloid hypothesisFor many years, pharmaceutical research on Alzheimer’s disease has focused on the amyloid hypothesis, which is one form of “rust.” According to this hypothesis, the accumulation of Beta-amyloid proteins in the brain, in the form of plaques, is believed to be the primary cause of dementia.Beta-amyloid protein is cleared naturally by the blood and lymphatic systems, or is eliminated within the brain by protective cells (microglia and astrocytes) and enzymes. A malfunction in these cleanup mechanisms, combined with the production of Beta-amyloid, leads to the accumulation of Beta-amyloid proteins and the formation of plaques. Prolonged exposure to this protein over decades is thought to damage neurons and cause memory loss.However, two major discoveries have challenged this hypothesis:The presence of plaques in healthy people: Significant accumulations of plaques have been discovered in individuals with no cognitive impairment. It is also important to understand that amyloid is a protein that can be produced naturally in response to a viral infection or inflammation.The limitations of new treatments: Recently, drugs like lecanemab and aducanumab have been developed to directly break down these plaques. However, even though amyloid is almost completely eliminated, cognitive decline continues at a similar rate as with older treatments, which have the advantage of being less expensive and better tolerated.These findings suggest a new idea: amyloid plaques may not be the source of the problem, but rather the consequence of an underlying abnormality.But then, where does this initial inflammation — which causes the accumulation of proteins — come from?To return to our metaphor, relentlessly scrubbing rust off a car does not solve the problem that causes it. Since the damage is already done, the vehicle’s lifespan is permanently altered. Consequently, the focus must be on prevention and the early detection of the first signs of wear and tear.This is where biomarkers come into play — biological indicators that help identify the disease before symptoms appear, in the hope of tracing the problem back to its true source.The importance of the blood systemIn this context, the cerebral vascular system has come under the microscope of scientists. Consistent with our metaphor, if the pipes that carry fuel are damaged, the engine’s performance drops and the machinery eventually fails.Similarly, the brain’s proper operation depends on the vascular system, which supplies neurons with oxygen and nutrients. A new hypothesis has emerged over the past decade: certain conditions, such as vascular diseases, hypertension, or type 2 diabetes, damage blood vessels and create areas of inflammation. In addition to restricting blood flow to the brain, inflammation is thought to cause the accumulation of Beta-amyloid, ultimately leading to the death of neurons.Many important findings support this hypothesis. Today, vascular abnormalities — such as changes in blood flow dynamics (that is, a decrease in blood flow and blood volume), as well as the presence of hemorrhages — are recognized as early signs of Alzheimer’s disease.Furthermore, one of the most comprehensive reviews of the literature on dementia recently found that certain risk factors could account for up to 45 per cent of dementia cases. Looking at the figure above, we see that a significant proportion of these risks is directly linked to our vascular health. Among these are high levels of LDL cholesterol, physical inactivity, type 2 diabetes, smoking, high blood pressure, excessive alcohol consumption and obesity.Together, these factors carry significant weight and contribute substantially to the risk of developing a form of dementia. Addressing these factors provides concrete avenues for action to prevent or treat these conditions throughout life, thereby reducing the burden on our brains.All these findings point to a crucial role of the vascular system in the development of Alzheimer’s disease. The current challenge? To precisely characterize the vascular system at an early stage — even decades before diagnosis — to identify the changes that lead to the disease. In fact, while the relationship between the vascular system and dementia is beginning to be studied in greater depth, there is a significant lack of precise data on the subject.Toward a comprehensive approach beyond amyloidFortunately, research is increasingly examining non-amyloid factors that may be responsible for the disease. Among other things, the tau protein appears to play an important role. But other mechanisms are also attracting interest from the scientific community: the role of the immune system, mitochondrial dysfunction and communication problems between neurons. Today, more and more scientists are even proposing a multi-factorial approach in which the various aspects of the disease interact with one another rather than acting in isolation.The emergence of new vascular biomarkers supports the idea that damage to the brain’s blood-brain barrier is linked to Alzheimer’s disease. For example, the discovery that certain cells from the blood system infiltrate the central nervous system — a sign that our “plumbing” is leaking — is correlated with cognitive decline and the presence of amyloid plaques.Furthermore, with improvements in imaging techniques and the advent of artificial intelligence in biomedical research, we can assess the brain’s health much faster and with greater sensitivity than was previously possible.We are gradually getting closer to finding a way to defeat this disease.While we wait for the development of these new therapeutic approaches, the best way to protect your brain is to focus on what you can control. In other words, keep your “car” in good working order by staying active, both physically and socially, throughout your life.Rémi Lamontagne-Caron has received funding from the CIHR.