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Alzheimer's Pathology: An Integrated View
by Jeffrey Morby, Cure Alzheimer’s Fund chairman and co-founder
As a result of Cure Alzheimer’s Fund research, an integrated view of the causes of Alzheimer’s pathology has emerged. That view begins with a concept of what makes up a healthy brain. Abeta, we now know, performs a number of useful functions within the brain. In a healthy brain, moderate amounts of Abeta will be produced and cleared from time to time. Clearance is provided by several proteins, the most important of which are the APOE proteins (of which there are three variants). Hence, the healthy brain maintains a proper equilibrium between the production of Abeta and its clearance—a healthy hemostasis.
In an unhealthy brain, that proper equilibrium is not maintained, and the brain ends up with too much Abeta—allowing Alzheimer’s pathology to begin. Too much Abeta in the brain can result from a number of causes, including defective genes. Some genes produce too much Abeta; other genes hinder Abeta clearance from the brain. Some brains are hit by both problems at the same time—over-production and inadequate clearance. This often leads to Alzheimer’s disease.
Based on recent evidence, we now believe one of the main functions of Abeta, in its role as part of the innate immune system, is to attack pathogens. In a healthy brain, when invading pathogens are detected, new Abeta is produced to attack and destroy them. Once the pathogens are eliminated, excess Abeta is cleared from the brain, and equilibrium is restored. In the unhealthy brain, too much Abeta may be produced, or it may not be sufficiently cleared, or both. The excess Abeta will then amalgamate into amyloid plaques, which causes inflammation and damages neural cells (and further provokes the creation of more Abeta). Concussions, stroke and other injuries also will provoke the creation of additional Abeta, and may initiate a chain of events leading to Alzheimer’s disease.
Tau is the next piece in the integrated portrait of Alzheimer’s. Too much Abeta apparently initiates the creation of Tau “tangles,” which destroy nerve cells, provoke the creation of more Abeta and inflammation in a vicious feedback loop, and proliferate to other parts of the brain. The processes involved in Tau proliferation are not yet well understood.
To summarize, Alzheimer’s pathology requires three elements:
• Too much Abeta, due to excessive generation and/or inadequate clearance;
• Tau tangles, sparked by the overabundance of Abeta leading to neurodegeneration; and
• Inflammation, provoked by too much Abeta and by Tau tangle-induced neurodegeneration, which subsequently produces more Abeta and Tau tangles. One leads to the next and eventually, a vicious cycle begins.
Cure Alzheimer’s Fund is tackling all of the above elements.