Schindler spent years trying to figure out how to use the data in amyloid PET scans to estimate the age at which symptoms would appear. The breakthrough came when she realized that amyloid accumulation has a tipping point and that each individual hits that tipping point at a different age. After this tipping point, amyloid accumulation follows a reliable trajectory.

“You may hit the tipping point when you’re 50; it may happen when you’re 80; it may never happen,” Schindler said. “But once you pass the tipping point, you’re going to accumulate high levels of amyloid that are likely to cause dementia. If we know how much amyloid someone has right now, we can calculate how long ago they hit the tipping point and estimate how much longer it will be until they are likely to develop symptoms.”


People in the study who reached the tipping point at younger ages took longer to develop cognitive symptoms than those who reached it later in life. Participants who hit the tipping point at age 50 typically took nearly 20 years to develop symptoms; those who hit it at age 80 took less than 10 years.

“When we look at the brains of relatively young people who have died with Alzheimer’s, they typically look pretty healthy, other than Alzheimer’s,” Schindler said. “But older people more frequently have damage to the brain from other causes, so their cognitive reserves are lower, and it takes less amyloid to cause impairment.”

The power of this new technique is that it requires just one brain scan, plus the person’s age. With that data, the model can estimate the time to symptom onset, plus or minus several years. In this study, the correlation between the expected age of symptom onset and the true age at diagnosis was better than 0.9 on a scale of 0 (no correlation) to 1 (perfect correlation).

After age, the genetic variant APOE4 is the strongest risk factor for Alzheimer’s dementia. People who carry one copy of the variant are two to three times more likely to develop Alzheimer’s dementia than the general population, and people who carry two copies are 10 times more likely. In this study, people with the high-risk variant hit the tipping point younger, but once that point was passed, they followed the same trajectory as everyone else.

“APOE4 seems to have a seeding effect,” Schindler said. “At very low levels, below the tipping point, you see amyloid rising in people with APOE4 while it’s not changing in people without APOE4. That means APOE4 carriers are going to hit the tipping point sooner. People with two copies of APOE4 hit the tipping point about 10 years earlier than people with no copies. But after that point, we see no difference between the APOE4 carriers and noncarriers.”

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