Alzheimer's Subtypes Differentiated by How and Why Amyloid-β Accumulates

The authors of this open access commentary paint a picture of Alzheimer's disease as a condition that starts in a variety of different ways, all of which lead to amyloid-β accumulation, and this is then the common gateway to pathology and dementia. Once an individual begins to accumulate raised levels of amyloid-β, then the characteristic degeneration of Alzheimer's proceeds from there. This is a slow burn over years or decades in which the biochemistry of the brain becomes ever more aberrant, culminating in the development of tau aggregates, inflammation, dementia, and cell death.

The question has always been why only a fraction of people with any given risk factor go on to develop raised amyloid-β levels and full blown Alzheimer's disease. A variety of explanations are presently in various stages of construction and proof, most of which propose a way in which elevated amyloid-β levels might arise in only a portion of the population. Examples include persistent viral infection and differences in the drainage of cerebrospinal fluid through the cribriform plate.

Postmortem data clearly shows that Alzheimer's disease (AD) pathology rarely occurs in isolation. Most AD patients harbor more than one pathology in the brain, with cerebrovascular disease being the most common coexisting pathology. Furthermore, the frequency of both cerebrovascular and Alzheimer's disease increases with age. However, in what way cerebrovascular disease and AD pathology act in synergy leading to downstream neurodegeneration and dementia is still unknown.

Cerebral amyloid angiopathy (CAA), a form of cerebrovascular disease resulting from amyloid deposition in vessel walls, may be the link between these two frequently coexisting pathologies. It is interesting that anti-amyloid therapy has been reported to increase the incidence of microbleeds, potentially due to removal of amyloid through vessel walls. The big question is whether CAA is just a passenger on the AD train. How does CAA interact with amyloid and tau pathology? For instance, does CAA come in early on in disease pathogenesis by affecting the spread of neurofibrillary tangles across the brain? Or is CAA an event occurring in later stages, acting downstream to amyloid and tau pathology thus mostly contributing to neurodegeneration and brain atrophy? All these questions remain largely unanswered.

We recently conducted a comprehensive characterization of these AD subtypes in terms of cerebrovascular disease. We concluded that CAA seems to make a stronger contribution to hippocampal-sparing and minimal atrophy AD, whereas hypertensive arteriopathy, another form of cerebrovascular disease, may make a stronger contribution to typical and limbic-predominant AD. Evidence suggests that neurodegeneration can be expressed differently across different AD subtypes. Future research will also have to answer why amyloid pathology starts, what is triggering the cascade, and whether this differs in the different subtypes. Current data shows that dementia in AD is a downstream event that can be reached along different pathways. These different pathways may necessitate their own specific therapeutic strategies.



This is another way of saying that there are no diseases of aging but only a single disease called aging, with many contributing causes, and that the only way to cure it is to address all those causes in parallel. So to prevent/cure dementia you need to fix A-beta, tau, hypertension, etc. Trying to address them one at a time is like trying to tie a knot with one hand at a time.

Posted by: Antonio at November 21st, 2018 6:17 AM

Amyloidosis is one of the most common causes of death of centenarians. with age it clogs the blood vessels and results in cardiovascular failure. Perhaps AD is just another form of amyloidosis, but of the brain instead of the vascular system. I'm also thinking that fibrosis that occurs in many organs of the body such as the lungs, heart, liver, and kidney in the elderly is a related disease, and perhaps similar cures are required to fix these fibroid diseases. For example, overexpression of FOXO3 is known to reduce fibrosis formation in lung fibrosis disease. And now, it has been suggested that FOXO1/3 overexpression has the potential to reduce all or most forms of fibrosis in the lungs, cardiac system, kidney, and liver (Ref. Zhenlong, et al, Jan. 2018.

Posted by: Biotechy Marcks at November 21st, 2018 9:58 AM

This is mostly my own speculation on amyloidosis and fibrosis diseases. Amyloid is produced by the platelets in the blood vessels and how much you produce may determine your risk of amyloidosis, AD, or both in old age. Amyloid may contribute to clogging of the blood vessels and may be exported to the brain, where in a 2 step process it forms amyloid beta, implicated in AD. Humans only need a platelet count of 100K for clotting purposes, yet many people have a platelet count of 300-500K. My platelet count is about 110K and I have no adverse clotting or bleeding problems, but I have some gene mutation that naturally lower my platelet count. If we could genetically reduce platelet counts with CRISPR technology, perhaps we could reduce amyloidosis and AD risk. With regards fibrosis diseases, perhaps we could over express FOXO1/3 by use of drugs or natural supplements such as resveratrol and pterostilbene. Another aspect that may help is having the longevity SNP alleles of FOXO1/3. I, for example am homozygous for the longevity alleles of at least 13 FOXO3. Again, with genetic use of CRISPR, possibly in the future, the longevity SNP alleles could be transplanted to people who do not have them.

Posted by: Biotechy Marcks at November 26th, 2018 11:33 AM
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