Fight Aging!

Alzheimer's disease might be considered as the consequence of the related, interacting buildup of two primary forms of metabolic waste in the brain, tau and amyloid-β. Either, independently, can cause neurodegeneration, but they have a complicated relationship with one another in which the presence of both makes the pathology worse. Which comes first? There is evidence to suggest that amyloid aggregation leads to tau aggregation, and there is also evidence for things to be the other way around, such as that presented in the research materials here.

Both of these options could be the case, in that either tau or amyloid-β produces disruption that can accelerate aggregation of the other. Or it may be that a third mechanism, such as loss of effective drainage of cerebrospinal fluid, causes aggregation of both, and interactions between the two are less important to the amount present and more important to the damage done. Alzheimer's is a very complex area of study. Until therapies start to make some inroads into improving the condition, thereby quantifying some of the mechanisms and their effects, it is likely that greater understanding of the details of the progression of the condition, and the degree to which different aspects contribute to cognitive decline, will be slow to arrive.

In the commonly held definition of Alzheimer's disease, one type of amyloid-beta (Aβ42) starts to form clumps between nerve cells, injuring them. Worsening injury is then marked by the release and toxic buildup of a second protein called tau. Together, changes in Aβ42 and tau levels represent the standard international measure of a patient's risk for future cognitive decline. A new study found that the build-up in the brain of amyloid beta cannot be the sole trigger of subsequent nerve damage because many relatively younger people who develop disease later do not show signs of the buildup. "Once you stop assuming that the starting point of Alzheimer disease is marked by the buildup of Aβ42 in brain cells, a different picture emerges. By recognizing an earlier disease phase, we may be able to start treating earlier and in tailored ways based on a better understanding of disease biology."

For many years, neuroscientists have sought to predict AD risk by tracking protein levels in the cerebrospinal fluid (CSF) that fills the spaces around brain tissue, and which can be sampled by lumbar puncture as part of a spinal tap. In 1999, researchers started collecting clinical and CSF protein level data from healthy normal subjects every two years. Combining this database with two others, the current study is the largest of its kind to date, including roughly 700 patients. The study found that the best predictor of future AD risk was not, as currently thought, decreased CSF Aβ42 levels with elevated tau. Elevated CSF Aβ42 levels were also found to confer future AD risk.

The results add to the evidence that an increase in CSF tau over a lifetime may be the more relevant, early feature of AD than a drop in CSF Aβ42 (taken as evidence of a buildup in brain cells). While the actual mechanism behind Alzheimer's disease and the trajectory of Aβ42 and tau levels remains obscure, the results provide evidence in support of the "clearance theory." It holds that the pumping of the heart, along with constriction of blood vessels, pushes cerebrospinal fluid through the spaces between brain cells, clearing potentially toxic proteins into the bloodstream. Mid-life cardiovascular changes that bring on heart failure and hypertension may lessen the CSF flow needed to clear tau, and perhaps disease-causing proteins yet to be identified.

Aside from Aβ42 which is readily deposited into the brain, the team found that CSF levels of two other common forms of amyloid beta that are less able to build up, Aβ38 and Aβ40, increase in proportion to rising tau throughout the normal older adult lifespan, even after CSF Aβ42 starts to decrease. This is further evidence of a decline in clearance with age. "Future CSF studies need to follow normal subjects, starting at age 40, for decades to get an unbiased look at the trajectory of CSF proteins and the likelihood of developing cognitive impairment decades later."

Link: https://www.eurekalert.org/pub_releases/2018-02/nlh-rab020618.php