Once Alzheimer's disease starts, how long until the first symptoms appear?

As we explained in Beating the Dementia Monster, Alzheimer's disease may begin as much as 15 years before the first symptoms appear and 20 years before actual dementia.  Now new tests are emerging that can determine that someone has developed Alzheimer's disease before there are symptoms.  So if you find someone has presymptomatic (or "prodromal") Alzheimer's disease, is it possible to predict when actual symptoms of memory loss etc. will begin to appear?  Well, apparently so, and with a good bit of accuracy.  Well, maybe not from the very beginning of the disease, but at least from when the amyloid plaques begin to form. 

We know that in Alzheimer's disease, variant forms of amyloid peptide (strings of amino acids that were supposed to be proteins but got sidetracked) and variants of tau protein appear in the brain.  There is more than one variant of each with varying levels of toxicity.  The problematic version of amyloid forms the plaques and the tau forms the tangles we discussed in Beating the Dementia Monster.  The plaques and tangles continue forming until the brain reaches a "tipping point" when there's an explosion of tau tangles throughout the brain.  

So researchers would like to measure the time from when the first plaques appear to when the first symptoms appear.  And it appears that's a fairly well defined and regular time period.  Researchers at Washington University Saint Louis measured the amount of the protein known as p-tau217 in cerebrospinal fluid and found that it rises at a pretty consistent rate among different people after passing the tipping point.  This means that if you know someone's age when they reached the tipping point, you can predict when symptoms will begin with reasonable accuracy.  The research results were presented by Dr. Suzanne Schindler at the TAU2022 virtual Global Conference this past February 22-23.

So why would we want to know this?  Primarily as an aid in clinical trials for different treatments, especially those (like aducanumab) directed at dealing with amyloid plaques.  The expectation is that a new, effective treatment for Alzheimer's disease must be active during the preclinical phase of the disease -- before the first symptoms.  Researchers measuring the effectiveness of a given treatment will want to know throughout the trial how far the disease has progressed and anticipate when symptoms will begin to present. 

So why do I care about this?  Mostly I just thought it was really interesting to learn how consistently the disease develops among different people.  However, since the symptoms manifest with varying effect in different people, I'm led to speculate that, while the underlying disease may advance similarly in different people, life style choices nevertheless influence the severity of the symptoms.  In Beating the Dementia Monster, we discussed the Nun Study.  In the Nun Study, Sister Mary lived to be over 100 years old and appeared to be cognitively healthy.  But her autopsy found that her brain had been ravaged by Alzheimer's disease.  This has been correlated with her healthy lifestyle.