Are We Diagnosing Dementia All Wrong? Part 2

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Hello everybody. Welcome to another brand new episode of The Truth, Lies Alzheimer's Show. I'm Lisa Skinner, your host. Now, today's episode is a continuation of the last episode, and the name of it is Are we diagnosing dementia all wrong? This is part 2. To recap, in part 1, I shared with everybody a very famous and very important study called the Nun Study and what those results and findings showed our scientists that, to me, have been baffling for a couple of decades. What really causes Alzheimer's disease? There was a contradiction about that in the findings. So I discussed that Nun study so you'd have a really comprehensive understanding of the results of that study, which are actually really important. So as we fast forward to today's episode, I did a lot of research. To find out if the information that was revealed in the Nun Study is still consistent with the research today. So that's where we are starting off. So what questions are researchers today still trying to answer? Well, when and why Does amyloid start to build up in different people? Which forms of amyloid are most harmful and how do they actually interact with tau? Why tau spreads in some people but not others and how to stop it? What is the best combination of therapies and the best time to start them? How can we predict who will progress and who might stay stable longer? What's the bottom line for the public? Alzheimer's is driven by multiple brain changes with plaques and tangles playing central roles, but we now know they're not acting alone. So early detection and multi-pronged treatment approaches do hold promise, especially if they're started before significant brain damage occurs. So result of the Nun Study sparked all these other questions, and they've been questions that have been in my mind for— since I learned about the Nun Study. I don't think that we know everything, but we know more than we did. What are the main things scientists find in Alzheimer's brains? Well, they find amyloid plaques, which are sticky clumps of a protein fragment called amyloid that build up outside brain cells. They also find tau tangles, which are twisted threads of another protein called tau that build up inside the brain cells. So together with nerve damage and brain cell death, these changes lead to what we see: memory loss and cognitive decline. So the $64 bazillion question here is still, do plaques and tangles cause Alzheimer's? And the answer is, it is still very complicated. Because in some people, especially those with genetic forms of the disease, amyloid plaques do seem to kick off the whole process. In most people who get Alzheimer's disease later in life, plaques are a risk indicator and may help start the process, but they still don't explain everything. Now, the tau tangles tend to be more closely linked to how bad the symptoms are or get. And many researchers now think that Alzheimer's is not caused by one thing alone, primarily plaques and tangles. It actually— the new theory is that it is a mix of several factors working together amyloid buildup, tau problems, inflammation in the brain, blood vessel health, aging, and other accompanying health conditions. What did the latest research say about the role of plaques? This is what I found: that plaques often appear before symptoms and raise the risk of developing dementia. Some studies showed that the tiny soluble forms of amyloid, not the big plaque clumps, may be especially harmful to brain connections and thinking skills in older people. A lot of people have plaques but don't have dementia yet. This is what they found in the autopsies of the nuns who participated in than unsteady, which means that plaques aren't the whole story. And what about those tau tangles? Well, they line up with how severe memory and thinking problems are, more than the plaques do, especially as the disease progresses. The tau seems to spread through the brain in a way that follows connected brain networks. Which does help explain why certain areas get hit in a predictable pattern. Researchers are testing these therapies that target tau to see if they can slow down or stop the spread of the damage. So what does this mean for diagnosis and treatment now? Biomarkers. Which are tests that measure substances in the spinal fluid or blood, and the brain scans that look for plaques and tangles, are now helping doctors identify the disease earlier and more— give them more understanding of how it is progressing. Treatments that remove or neutralize amyloid have shown mixed results. They may actually help some people if started very early, but they have not shown that they do much for people, for everyone. Treatments targeting tau inflammation and blood, brain blood vessels are being studied, often in combination with anti-amyloid approaches. So the big idea now is to Start treatment early and use a multi-pronged approach tailored to a person's biology and risk factors like genetics and other health issues that they also may have along with dementia. What is the bottom line for the public? That Alzheimer's is driven by multiple changes in the brain, with amyloid plaques and tau tangles playing a central role, but they're not the exclusive role as once believed. Early detection using biomarkers and imaging is improving, and that may lead to better, earlier treatments. The future of therapy likely lies in addressing several disease processes at once and starting treatment sooner rather than later. So, could plaques and tangles actually be part of the brain's defense mechanism? This is a new theory now that's being studied and explored. This idea has a name. It's actually called a protective response or compensatory hypothesis. It's a real thing. It suggests that some brain changes seen in Alzheimer's might arise, at least in part, as the brain's attempt to cope with injury, stress, or other problems. So in this view, what we measure as plaques and tangles could actually reflect the brain trying to isolate contain and/or stabilize damaged components rather than actually being the initial cause of the disease. Well, this is still a topic of active research and debate, and most scientists see a nuanced picture, which is that certain pathological features may be harmful while others could be secondary responses to other underlying problems. Now, this makes total sense, and I really think this needs to be determined before we move on to what is really the best treatment for Alzheimer's disease. So how does this idea fit with current evidence? It fits because plaques, or amyloid, and tangles, or tau, are consistently found in Alzheimer's disease brains, but their roles may differ by disease stage and by each individual person. The early idea was that amyloid buildup starts a cascade that leads to tau tangles and neurodegeneration. That's not the case anymore. The protective angle Well, in some contexts, amyloid or tau might form as a response to another insult like mitochondrial dysfunction or vascular problems in an attempt to protect neurons from further damage. For example, the plaques might actually sequester toxic fragments, and tangles might wall off damaged tau to prevent it from spreading. But the most, the strongest evidence still supports a multifactorial model that amyloid may act as an upstream trigger in many people, especially with genetic predispositions, and that tau pathology tends to correlate more closely with cognitive decline decline and neuronal loss as the disease progresses. As far as inflammation, blood vessel health, and metabolic factors, well, they believe now that these things also play a major role. The protective hypothesis does not yet explain all of these observations. For instance, in most cases, Removing the amyloid later in the disease provides limited or no cognitive benefits, suggesting that once neurons are lost, simply clearing the plaques may not reverse the damage. Some robust data do show that certain brain responses to stress can become maladaptive over timing, contributing to a cycle. Of injury. If plaques or tangles are partly protective in some contexts, completely eliminating them without understanding the timing and context could prove to be less effective or even harmful in certain patients. And this has implications for timing of treatment. Therapies might need to target upstream causes like the inflammation, vascular health, and/or metabolic factors before the plaques and tangles become dominant. Or a combination of approaches like addressing multiple pathways, which include amyloid, tau, inflammation, and blood flow., which may be more effective than targeting one single feature. Taking into consideration biomarker interpretations. In other words, finding plaques or tangles doesn't necessarily or automatically tell us whether they're causing harm or reflecting a protective attempt. Additional biomarkers in clinical context are extremely important. In this scenario. So what are researchers doing now? They are currently studying how brain cells respond to stress and injury, including how immune cells or microglia and blood vessels interact with amyloid and tau, using animal and cellular models to test whether plaque or tau formation can actually be a protective response to specific insults and under what conditions it might become maladaptive. They're designing clinical trials that consider multiple targets and early intervention rather than focusing on a single pathology in isolation. They're now exploring why some people with high amyloid or tau burden do remain cognitively intact for a long time or for the rest of their life, which might hint at compensatory mechanisms are at work. So the quick take for our viewers here is that plaques and tangles are still believed to be central features of Alzheimer's, but that their roles are likely much more complex than we originally thought. And may include both harmful and potentially protective aspects depending on the context. The leading view today is that Alzheimer's arises from a mix of factors: the amyloid, the tau, inflammation, vascular health, aging, and other health conditions that are interacting with one another over time. Understanding when and why plaques or tangles form and how the brain tries to cope could help us immensely design better, earlier, and more personalized treatments. So it's a step in the right direction from what we knew just 20 years ago. Now, quick summary. Some researchers wonder if amyloid plaques and tau tangles might partially reflect the brain's attempt to cope with injury or stress. And in this view, these changes could be protective responses in certain contexts, or the downstream results of other problems like inflammation or vascular issues are at hand as well. Now, most evidence now supports a multifactorial model where plaques and tangles can be harmful, but they might also arise as part of the brain's attempt to shield its neurons. And the timing matters. Early intervention targeting multiple pathways, not just plaques and tangles, may turn out to be most effective. So here's what we know. Amyloid plaques and tau tangles are still considered key brain changes in Alzheimer's disease, and that the tau tends to track with symptoms more closely than the plaques do. And then, of course, the protective hypothesis, the idea that plaques and tangles could be the brain's attempt to contain damage. Not cause damage. Examples of that: sequestration of toxic fragments, walling off damaged material to slow spread. And why does this even matter for treatment? Because if the plaques and tangles can turn out to be protective in some contexts, we will need careful timing and multi-target approaches for treatment. Treatments may work best when started early and address inflammation, address blood flow, and address metabolism in addition to amyloid plaques and tau tangles. How are researchers moving forward with this? They're studying brain stress responses, the microglia, the blood vessels, They're testing multi-target therapies in early disease stages. So at the end of the day, the bottom line is what we know today, and the evidence supports it, is that Alzheimer's is likely a mix of harmful and potentially protective brain processes, and they vary by person and by stage. So early personalized multi-prong strategies will hold the most promise. Now, now I'm going to kind of dive into Lewy body dementia and how it differs from the research done on Alzheimer's disease. And This is information that I found by Dr. Greenland, who is the founder of the AI Growth Clinic Systems for Private Clinics. He is a physician in London and he's top 1% health and wellness on LinkedIn. And this is very, very current information. It was published May 24th of '26. So for those of you who are not familiar with the term Lewy body dementia, um, or why it even matters to know about it, I'm gonna give you a quick explanation. Lewy body dementia is actually one of the most common causes of dementia worldwide, affecting an estimated 1 to 1.4 million Americans alone. We've recently heard about it. As, as recently as a week ago when Ted Turner passed away and it was found that he had Lewy body dementia. Most people have never heard of it. It's caused by abnormal deposits of a protein, which is very different than the plaques and tangles that we find with Alzheimer's disease. And these deposits in Lewy body dementia are a protein called alpha-synuclein, which forms clumps that they are called Lewy bodies inside brain cells. And this is again very different from the amyloid beta that is found with Alzheimer's disease. These alpha-synuclein deposits disrupt how our brain processes movement, mood, sleep, behavior, and thinking. The clinical picture is distinctive once you know, once clinicians know what to look for, which are fluctuating cognition. Patients can be sharp one hour and completely confused the next. They experience visual hallucinations, often early in the illness. Their REM sleep behavior is disrupted where patients act out their dreams, sometimes years before the cognitive symptoms appear. And they also will tend to display Parkinsonian features like stiffness, slowness, or tremors that are, you know, very indicative of Parkinson's disease. They may experience autonomic dysfunction, including blood pressure drops, constipation, and bladder problems. And despite all this, it's still routinely mistaken for Alzheimer's disease, Parkinson's disease, or a psychiatric illness. And that mistake matters because some of the standard antipsychotic drugs used to manage hallucinations can actually be catastrophic in persons living with Lewy body dementia. The trouble is that postmortem studies keep showing us something very inconvenient. Lewy body pathology often sits alongside Alzheimer's pathology in the same brain. So we call that mixed dementia, where they have more than one brain disease. Developing at the same time. And that is not as uncommon as a lot of us might think. Diagnostic accuracy during life remains imperfect, just like Alzheimer's disease. Many patients labeled with one disease actually have features of two or three simultaneously. And we've been arguing about which protein matters most. When the real story is that several proteins, several systems, and several insults are usually at play in the same person. The plot twist that nobody saw coming. And here's where it generally gets interesting. For years, the proteins that define Alzheimer's, the amyloid beta and Lewy body disease, α-nuclein were treated as junk, toxic waste, things to clear out. But now that view is shifting. Amyloid beta behaves like an antimicrobial peptide in experimental work, trapping bacteria, fungi, and herpes viruses in neural models. Alpha-synuclein can restrict viral infection in the brain and shows antibacterial and antifungal activity in lab studies. In other words, these proteins may have started life as part of the brain's immune defense. We talked about that in part 1, and this is not proof by any stretch of the imagination that dementia is an infection. This evidence is experimental. The human data is messier, and herpes virus links in particular do remain contested. But the bigger picture is hard to ignore. Host defense, inflammation, and protein misfolding are entangled in ways that the old textbooks never captured. A protein recruited to protect the brain can become the thing that also destroys it. Imagine that! Especially when the signal becomes chronic, when clearance fails, and when the host is metabolically and immunologically vulnerable. So why the downstream picture matters more. Because once these proteins misfold, what happens next looks oddly familiar across diagnoses. Both proteins activate the same inflammatory machinery in microglia known as the NLRP3 inflammasome. Both are linked to mitochondrial dysfunction. Both disease families show significant cholinergic deficits, which is why drugs like donanemab and lecanemab can ease symptoms without changing the underlying disease. If the upstream triggers differ but the downstream damage rhymes, then a single target, single disease mindset starts to look outdated. What does this mean for clinicians and families? These practical shifts in their view: one is to spot Lewy body disease much earlier than we do. Watch for fluctuating cognition, visual hallucinations, dream enactment behavior, autonomic symptoms, and Parkinsonian features alongside cognitive change. Now, these cues are often still missed, often for years. Therefore, early recognition does matter because antipsychotics can be dangerous in this population, and because families can then better plan when they know what they're dealing with. Number 2 is stop treating the diagnostic label as the whole story. Roughly half of dementia risk is potentially modifiable. The Lancet Commission has just increased their statistic from 40% to 45%. And they keep reminding us of the list. Vascular risk and hypertension. Play a role. Hearing and vision loss play a role. Physical inactivity plays a role as a risk factor. Depression and social isolation, diabetes and obesity, smoking and excess alcohol, poor sleep. These are all risk factors that are manageable. So the next decade, of dementia care belongs to the clinicians who can hold two things at once. The biology is moving from symptom-based guesswork toward protein-based diagnosis, with new tests for alpha-synuclein finally sharpening what was previously a clinical coin toss. The patient is never just a textbook diagnosis. They're a mixed pathology. They're a multi-system that's complex. They're individual human beings who deserve an approach that reflects that. And one of the comments to this article was given by Dr. G, who is a psychiatrist and functional medicine doctor. And he said, and I'm going to leave you with this, we have spent years studying amyloid and tau as the enemy. But if they started as a host defense mechanism, the real question now shifts. Not why they are there, but why did the system stop coping? That's a very, very different clinical problem. I love that comment. So that wraps this episode up for The Truth, Lies Alzheimer's Show. I'm Lisa Skinner, your host. I hope you have found episodes 1 and 2 of Are We Diagnosing Dementia All Wrong? as fascinating as I find it, and that there definitely is hope on the horizon that we are making positive strides to understanding these brain diseases more than we ever have, and that there's hope to finding at least a treatment, if not a cure. So I'll be back next week with another episode of The Truth, Lies Alzheimer's Show. And in the meantime, I hope you all have a wonderful rest of your week. And as always, try to be happy and stay healthy, and I'll be back next week with another episode for you. Bye for now.

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