Understanding Amyloid in Alzheimer's Disease vs. Systemic Amyloidosis

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• Alzheimer's vs Amyloidosis Key Differences
• Importance of Precise Diagnosis
• Amyloid's Role in Alzheimer's Pathogenesis
• Novel SAP-Targeting Treatment Approach
• Upcoming Clinical Trial for Alzheimer's
• Full Transcript

Alzheimer's vs Amyloidosis Key Differences

Alzheimer's disease and systemic amyloidosis are fundamentally different conditions. Dr. Mark Pepys, MD, emphasizes that Alzheimer's involves microscopic amyloid plaques within the brain substance itself. The total amyloid burden in an Alzheimer's brain is minuscule, measuring only around 100 milligrams. In stark contrast, systemic amyloidosis involves massive amyloid deposits in organs like the liver, which can accumulate up to 5 kilograms.

The location and nature of the deposits also differ critically. In Alzheimer's, amyloid exists as tiny extracellular plaques alongside intracellular neurofibrillary tangles. Systemic amyloidosis deposits occur in organ tissues and blood vessel walls but not within the brain parenchyma. Dr. Anton Titov, MD, and Dr. Mark Pepys, MD, discuss why these distinctions matter profoundly for accurate diagnosis and appropriate treatment strategies.

Importance of Precise Diagnosis

Correct disease nomenclature is vital for effective patient care. Dr. Mark Pepys, MD, warns against the dangerous conflation of terms like "amyloidosis" across different diseases. Calling Alzheimer's, Parkinson's, or Huntington's disease "amyloidosis" creates clinical confusion because each condition has distinct pathophysiology and requires completely different treatments.

This precision is especially critical in systemic amyloidosis. Mistaking hereditary amyloidosis for AL amyloidosis could lead to administering toxic cytotoxic chemotherapy to patients who don't need it. Dr. Mark Pepys, MD, stresses that molecular-level diagnosis is essential. Treatment decisions must be based on precise identification of the amyloid protein type and its underlying cause.

Amyloid's Role in Alzheimer's Pathogenesis

The relationship between amyloid deposits and neurodegeneration in Alzheimer's remains incompletely understood. Dr. Mark Pepys, MD, notes that while amyloid beta plaques are a pathological hallmark of Alzheimer's, their causative role in neuron death is not proven. The presence of amyloid is correlated with Alzheimer's disease but may not directly cause the cognitive decline and dementia symptoms.

Genetic evidence suggests the amyloid pathway is involved in disease pathogenesis. Mutations in the amyloid precursor protein or processing enzymes cause hereditary early-onset Alzheimer's by increasing amyloid beta production. However, the exact mechanism of neuronal death remains unknown. Similar uncertainty exists about amyloid deposits in type 2 diabetes pancreas, which might be byproducts rather than causes of disease.

Novel SAP-Targeting Treatment Approach

Dr. Mark Pepys, MD, has developed a novel therapeutic approach targeting Serum Amyloid P component (SAP). This normal blood protein binds to all amyloid deposits, including those in Alzheimer's brains. His medication completely removes SAP from the blood and consequently from the brain and cerebrospinal fluid.

Research reveals two compelling mechanisms for this approach. First, removing SAP from amyloid deposits may help clear these pathological structures from the brain. Second, emerging evidence shows SAP is directly toxic to cerebral neurons, causing cell death through apoptosis. A preliminary study in five Alzheimer's patients confirmed the medication effectively removes SAP from cerebrospinal fluid. Animal models demonstrate it removes SAP from brain amyloid deposits.

Upcoming Clinical Trial for Alzheimer's

A major clinical trial will test this SAP-targeting therapy for Alzheimer's disease. Funded by the UK's National Institute for Health Research, the study will enroll 100 Alzheimer's patients in a placebo-controlled, double-blind trial lasting three years. This research aims to determine whether removing SAP can impact disease progression and various clinical measures.

Dr. Mark Pepys, MD, explains that while previous antibody approaches targeting amyloid beta have largely failed, his method takes a different approach. By targeting SAP instead of amyloid directly, the treatment may overcome previous limitations. If successful, this therapy could potentially arrest Alzheimer's progression at early stages, providing significant benefit even if it cannot reverse existing neuronal damage.

Full Transcript

Dr. Anton Titov, MD: How do Alzheimer’s disease and amyloidosis differ? What do they have in common?

Dr. Mark Pepys, MD: Alzheimer's disease is a very different disease from systemic amyloidosis. In Alzheimer's disease, there are amyloid deposits in the brain substance. This you never get with systemic amyloidosis. You can have amyloid in systemic amyloidosis in the membranes that surround the brain. Amyloid is deposited in the blood vessels that supply the brain, but you don't actually have it within the brain substance.

In Alzheimer's disease, there are amyloid deposits in the brain substance, but they are microscopically small. The total amount of amyloid in the brain in Alzheimer's disease is in milligrams. It is a small number of milligrams, maybe 100 milligrams. It is absolutely tiny!

In clinically manifesting people with Alzheimer's disease, there is a small amount of amyloid only. It is a very, very small amount of amyloid in Alzheimer's disease. There are tiny microscopic plaques. They are called little amyloid deposits.

The neuropathologists call them plaques. There are other abnormal protein structures. These are called neurofibrillary tangles. They are not actually bona fide amyloid, but they are very similar in terms of the method that proteins are folded, and so on. These are the neuropathological hallmarks of Alzheimer’s disease, but they are very, very small in amount.

In the liver of someone with systemic amyloidosis, you might have 5 kilograms of amyloid. It is a completely different situation.

5 kilograms vs. several milligrams? Yes. I don't call Alzheimer's disease "amyloidosis". It is very important in medicine to name the disease correctly.

Because the neuroscientists and a lot of the biochemists and biophysicists work in this area, but they are not clinical physicians. They use words in a very loose way. This is quite a controversial area. You may be a clinical doctor looking after patients. What you call things really matters.

You use a specific word; this is one diagnosis and has one treatment. Then you use that same word for somebody else who has got a different disease. That requires completely different treatment. It is a disaster!

Unfortunately, there is a fashion nowadays. This is probably impossible to overcome. This influence from the basic scientists has strayed into the clinical world to some extent. And people call Alzheimer's disease, Parkinson's disease, Huntington's disease. They call those diseases “amyloidosis", because they all share at the molecular level certain similarity.

There is a particular method of abnormal structures of proteins, but they are not amyloidosis. In Huntington's disease, the abnormal stuff is in the nucleus of the cell. In Parkinson's disease, amyloid is in the cytoplasm of the cell. In Alzheimer's disease, amyloid is outside the cells.

This is well understood. It is like amyloidosis is elsewhere. But all these diseases are completely different. They are more different than trying to do a long jump on Earth, a long jump on the Moon, and a long jump on Mars. Those are different for obvious reasons: no atmosphere, different gravity.

But the environment inside the nucleus, in the cytoplasm, and outside the cell is totally different. It is very important not to conflate these things. Conflation in this method is very dangerous.

Even within systemic amyloidosis, you can make a mistake. You make a diagnosis of AL amyloidosis in a patient. The treatment then is cytotoxic chemotherapy. This can kill the patient easily. Chemotherapy for AL amyloidosis does kill patients, because it is very toxic.

Other patients with amyloidosis could have a gene mutation. They do not require cytotoxic chemotherapy. To make this mistake is a disaster.

Dr. Anton Titov, MD: As clinicians, we are very sensitive to using words properly. That is very important. It underscores the point having a correct general diagnosis, "amyloidosis", "cancer of this organ", is not enough. There has to be a precise and complete diagnosis. Diagnosis has to be precise at the molecular level.

Dr. Mark Pepys, MD: Absolutely! Because it makes a huge difference in treatment! It absolutely does! The problem is that now people have gone to the molecular level. They say all of these diseases are characterized by misfolded proteins. Misfolded proteins aggregate in a particular way.

Sure enough, those things are there. But we don't know, in the case of Alzheimer's disease in particular, whether the amyloid plaques have got anything to do with neurodegeneration.

Dr. Anton Titov, MD: What makes you demented in Alzheimer's disease? What makes you lose your cognitive function? It is death of nerve cells, death of cells in the brain. We don't know, nobody knows for sure, what causes those nerve cells to die. The fact that the amyloid is there is an interesting pathological association. It is correlated with the disease. It doesn't mean it causes the disease.

Dr. Mark Pepys, MD: We know that the protein that forms the amyloid fibrils in Alzheimer’s disease is called Amyloid beta. It comes from a precursor protein that is on the surface of nerve cells. Precursor protein gets cleaved. This little fragment comes out. It aggregates up and makes amyloid deposits.

We know that that pathway from the so-called amyloid precursor protein to the A beta makes amyloid fibrils. We know that Amyloid beta is closely related to the pathogenesis of the Alzheimer's disease. Because there are some rare families who have mutations in that protein. There are other people who have mutations in the enzymes that process that protein.

If you have any of these mutations, this increases the production of the A beta fragment. These patients get hereditary early-onset Alzheimer's disease. Clearly that pathway is important. But exactly what kills the nerve cells is still not known.

So I don't at the moment consider either Alzheimer's disease or another disease to be the result of amyloid deposition. Type 2 diabetes is another disease where there is always amyloid deposited in the pancreas. Pancreas is a target organ of Type 2 diabetes.

We don't know whether these local amyloid deposits actually cause the disease or not. Amyloid deposits are very small in size and amount. They might just be byproducts, side effects, or something like that. We don't know.

Dr. Anton Titov, MD: That is the first thing to say about it. Let’s return to my proposals for treatment of Alzheimer's disease.

Dr. Mark Pepys, MD: Initially I wanted the body to remove the amyloid deposits in the brain in Alzheimer's disease. You can do that by removing the SAP from the brain. You can use our small molecule medication. I still think that is a very good idea. We are about to start a clinical trial to test exactly that therapy in Alzheimer's disease.

That was the original rationale. You may find a treatment that makes the amyloid disappear from the brain in people with Alzheimer's disease. Alzheimer's disease stops progressing. Or patients miraculously get better. That is very unlikely once you have lost brain cells. You can't really replace dead neurons.

You could at least arrest the progression at an early stage of Alzheimer's disease. Then it would have a dramatic impact on the clinical picture of the Alzheimer's disease. A treatment that removed amyloid would be a good thing to prove a "yes" or "no" hypothesis. Whether the amyloid deposits themselves do the harm in Alzheimer's disease.

But so far nobody's got such a treatment of Alzheimer's disease.

Dr. Anton Titov, MD: There have been various attempts to use antibodies against A beta. Antibodies could do in the brain what I have successfully done with systemic amyloidosis in other organs. Billions of dollars have been spent in clinical trials of Alzheimer's disease.

Dr. Mark Pepys, MD: They have not yet had any success. There are some possibly promising results most recently. Sometimes you take patients with mild Alzheimer's disease who are treated early on. Then it looks promising. Maybe there is a signal that patients could be improving with the appropriate antibody administration. But it is a long way from being proven.

Most of these treatments of Alzheimer's disease have failed due to lack of efficacy or due to toxicity. My treatment method of Alzheimer's disease is different.

I have got a medication that removes SAP completely. It removes SAP protein more or less completely from the blood. SAP is made only in the liver. There is SAP in the brain. It is normally present at a very low concentration. One thousandth of the concentration that it is in the blood circulation.

But removing all the SAP from the blood results in removal of it all from the brain. We have done a preliminary study on 5 patients with Alzheimer's disease. They had our medication for three months. It completely removed all the SAP from the cerebrospinal fluid. CSF bathes the brain.

Recently we performed animal experiments. We have a model of Alzheimer's disease with amyloid in the brain. We show that our medication removes all the SAP from those amyloid deposits in the brain. There is very strong evidence that the medication will be effective in doing biochemically what we want it to do.

Our medication removes the SAP from the amyloid deposits in the brain. That is one avenue to make a medication to treat Alzheimer's disease. That is now an old idea for me. I have had that idea for 20 years. Now we are on the verge of testing it.

But meanwhile several other laboratories have shown that human SAP is actually toxic for cerebral neurons.

Dr. Anton Titov, MD: Sometimes you grow cerebral neurons in a tissue culture. You expose neurons to human SAP. Then neurons die. When I originally saw these research articles about Alzheimer's disease, they looked very interesting. When I read the papers, I was less convinced.

Dr. Mark Pepys, MD: I wasn't convinced about purity of the protein they were using. They were using commercially bought proteins. This might or might not be authentic, not pure. Who knows how to treat Alzheimer's disease. So I was rather skeptical about them.

Logically, why would the normal blood protein kill your brain cells? It seems a bit strange! But the fact is this. We can repeat these observations. They are robustly reproducible. Human SAP is bad for cerebral neurons. Neurons die in Alzheimer's disease.

SAP protein binds to neurons, it gets inside the cells, it gets into the nucleus of the cells. The cells then die by a process called apoptosis. We don't know the precise molecular mechanisms yet. But it is a reproducible observation using highly purified pharmaceutical-grade SAP. This we uniquely have in our laboratory.

This is now a compelling second justification for our medication treatment to remove that protein from the blood and from the brain. My current hypothesis is that SAP contributes to formation and persistence of the amyloid plaques in Alzheimer's disease. SAP is also bad for the brain.

In Alzheimer's disease, you have these plaques of amyloid and the neurofibrillary tangles. All of this is coated with SAP. There is an abnormally increased amount of SAP in the brain in patients with Alzheimer's disease. SAP is bad for the brain. Let's get rid of it!

That is the rationale of our clinical trial. This is now funded by the National Institute for Health Research in the UK. We will study 100 patients with Alzheimer's disease in a placebo-controlled double-blind clinical trial. This will take three years. We will see whether it has any impact on everything that can possibly be measured in Alzheimer's disease. This is what we are doing.