We've mentioned before that the Alzheimer's Association is the third leading funder of Alzheimer's disease research in the world. The United States government is first, but who's in between? Answer: The government of China. So we should expect to see some good quality research findings coming from China.
Yesterday, my doorbell rang, and it was my neighbor. Stu is a retired physician who has helped me a lot in the past with this project. He came over bringing an article from the February 22 issue of the New England Journal of Medicine (NEJM), "Biomarker Changes during 20 Years Preceding Alzheimer's Disease." The article published some research from China that was consistent with something we said in Beating the Dementia Monster: Alzheimer's disease begins as much as 15 years before the first symptoms of cognitive impairment and 20 years before actual dementia.
Since 2011, the medical community has been defining dementia as the point in the advancement of a neurodegenerative disease when someone can no longer completely care for themselves. (This definition was intended to clear up confusion on how to understand the disease, but some in the medical community have been slow to get on board.) So someone may have experienced cognitive impairment for five years, but they could still function independently. Then they reach the point when they can no longer manage their finances. They have crossed over into dementia.
The Chinese study confirms the existing timeline. However, it refines it and adds more certainty to our understanding by working with a large population and collecting the results of an array of biomarkers. Currently, a diagnosis of Alzheimer's disease requires both evidence of cognitive impairment and biomarker evidence.
The biomarker evidence used to diagnose me in 2015 was my MRI, notably by measuring changes in the volumes of my hippocampus and ventricles. But that was then. This is now. PET scans, spinal tap analyses, and now blood tests provide different ways of understanding what's going on in the brain as the disease begins, and as it advances.
What was helpful about the study was that it took a cohort of about 32,000 people and observed them for 20 years, while testing them every few years using an array of diagnostic tools. All were initially found to show no evidence of cognitive deficit, but some developed Alzheimer's disease during the 20 year study period. The number actually used at the end of the study was 1,789, since many had dropped out or were untraceable for various reasons. At the end, the researchers identified 648 individuals who had developed Alzheimer's disease and matched them up, person by person, with a control population that did not. Matching was with others in the study with similar sex, age, and education level.
Interesting to me was their ranking of how early different biomarkers would anticipate a medical diagnosis, indicating the sensitivity of the test. Least sensitive was cognitive testing, which means that all of the biomarkers have some level of predictive power for future cognitive impairment. But the least sensitive biomarker was hippocampal volume ... how I was diagnosed. They concluded it would anticipate a straightforward Alzheimer's disease diagnosis by only eight years. This was how I was diagnosed, but I was already impaired.
Next was "neurofilament light chain" (from spinal tap cerebrospinal fluid (CSF)) that anticipated a diagnosis by an average of nine years, total tau protein in CSF - 10 years, and some specific tau protein measurements that would anticipate a diagnosis by 14 and 18 years. (Since the disease is detectable at an average of 18 years, we can infer that some would actually be detectable at 20 years -- if you use the right test.)
Based on my read of the report of my own spinal tap, I believe that I actually received this most sensitive of these analyses. The conclusion of those who read and interpreted my results was that the results could be Alzheimer's disease, but they were ambiguous.
There were a couple of qualifiers in the report. One was that the population of subjects was entirely Han Chinese. We know that studies of diverse populations for Alzheimer's disease have produced diverse results. Whether due to genetic differences or lifestyle differences, Alzheimer's disease affects different ethnic groups differently.
Another qualifier was that they excluded people with a family history of Alzheimer's disease and those carrying genes associated with developing the disease. This means they excluded persons with young onset disease, because it is so strongly associated with three specific genes. It also excluded those carrying the APOe4 gene, which is the one 23andMe and other genetic services test for. So they excluded certain types of Alzheimer's disease.
On the other hand, they primarily included only people like me, people for whom no cause other than lifestyle could be correlated as causing the disease. Presumably, they also excluded people who developed the disease because of lifestyle factors that they shared with others in their families. (In Beating the Dementia Monster, we discussed how the appearance of multiple cases of Alzheimer's disease in one family may result from shared habits more than shared genetics.)
We define Alzheimer's disease as a neurodegenerative disease characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain. A big question: when we see plaques and tangles in the brain, is it always the same disease? Is the disease arising in the presence of a variant of the gene for the amyloid precursor protein the same as the disease that arises in the presence of the APOe4 gene? Is that the same disease I have (and, presumably, the Chinese subjects) where there is no apparent genetic factor? We don't really know. In fact, the more we learn about this disease, the more we find out that we don't know.
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