We've said before that there seems to be more than one variation of the disease we call Alzheimer's. Alzheimer's itself is characterized by the amyloid plaques around brain cells and tangles of collapsed microtubules inside dead cells. We discussed in Beating the Dementia Monster how amyloid plaques and defective proteins in microtubules apparently kill brain cells. In the form of the disease we call "young onset" or "familial" Alzheimer's disease, we see certain specific genes in play, and the symptoms appear when someone is in their 40s or 50s. This differs from the form of the disease we call "old onset" or "sporadic" Alzheimer's, where symptoms don't generally appear before the age of 65. Sporadic Alzheimer's (like mine) seems to be less influenced by genetic factors and more by lifestyle and environmental factors. And genetic influence appears to be from different genes than those involved with young onset Alzheimer's, perhaps more than 30 different ones.
By the way, many researchers and doctors try to avoid the term "early onset Alzheimer's," because it confuses the age of the person with the stage of the disease. Is it early in the persons life (like with young onset disease), or is it an early stage of the sporadic form of the disease but occurring when the person is, say, 80?
So we see here two varieties of Alzheimer's disease. But can the disease be divided more finely? Or is it possible that we really have more than one disease that we're dealing with? In my opinion, we don't understand the disease well enough to say if there is more than one disease, but there is new evidence that we can discern at least five subtypes. That's important, because it may be that experimental therapies that seemed to fail only failed because they were tried on one or two specific subtypes of the disease -- without realizing the therapy might be more suitable for another subtype. Also, the varieties may progress differently, confusing expectations and treatments.
Research on different subtypes was published in the journal Nature Aging, "Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles." Researchers, primarily from the Alzheimer's disease research center in Amsterdam, studied the cerebrospinal fluid of 609 people, examining the proteins they found. Some study participants had normal cognition and no evidence of disease (the control group), while others had been diagnosed with varying stages of the disease. Based on this evidence, the researchers believe they discerned five different subtypes of the disease.
One thing that struck me right off the bat about these varieties was that subjects with one subtype went from the onset of dementia to death in an average of 5.6 years, while another subtype had an average survival time of 8.9 years. That's a distinction. Alzheimer's disease is the third leading cause of death in my state of Washington, and the sixth leading cause of death in the United States. And, as we said in Beating the Dementia Monster, when I was 66, a researcher told me I was on track to be dead by the time I was 75. That made sense, because at the time I was still in the mild cognitive impairment stage and so was still a few years out from actual dementia. He also indicated that if I would just keep up my recent lifestyle changes, I could extend that 85. And that seems to be what is happening, since I am now 75. And I'm not dead.
But what are these five subtypes? Well, if you're not a doctor or physiologist, they can be a bit hard to understand. Or maybe a lot hard to understand, so we won't try to break them all down here.
But one subtype significantly weakens the blood-brain barrier (BBB), allowing trash to enter the brain from the blood. As we discussed in Beating the Dementia Monster and in other posts on this blog, the BBB prevents larger molecules (including pathogens) from passing from blood into the brain. This isolates the brain from the body's general immune system, so the brain must have its own immune system. This system uses cells we call microglia. Apparently, with this subtype, the BBB is weakened, and a variety of unwanted proteins enter the brain and begin to cause damage.
In Beating the Dementia Monster, we said that problems with microglia could play a central role in the development of the disease. Well, in another of these subtypes, the ability of microglia to protect the brain is impaired. One thing the microglia are supposed to do is glom onto amyloid plaques and stop them from damaging cells. But, in the variety here, the microglia are weakened, and their protective function is seriously reduced.
As we always hear, the authors of the study say more research is required. And it's clear that a better understanding of these subtypes is important. That will better inform research into treatments, since one treatment might better address subtype A than subtype B. Also, some trials may have mistakenly found a treatment ineffective simply because it was tested on the wrong subtype.
I have always believed that there were more varieties of Alzheimer's disease than we recognized. This research confirms my suspicions.
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