Predicting the Onset of Alzheimer Disease Symptoms

March 2022

Previous studies of in vitro and in vivo aggregation of β-amyloid have suggested that there is a tipping point above which aggregates become nuclei for further aggregation, which proceeds at a constant and predictable rate after the tipping point.

In the new study, the researchers wanted to see whether the tipping point in amyloid accumulation could predict the time to clinically evident symptoms of dementia in patients with sporadic Alzheimer disease.

Participants had >1 amyloid positron emission tomography (PET) scan and structural brain magnetic resonance imaging scan along with longitudinal cognitive and clinical assessments. Amyloid burden was measured by tracer uptake during the PET scan and expressed as the mean cortical standardized uptake value ratio (SUVR) in brain regions involved in early Alzheimer disease. There were 236 participants with an average age of 66.5 years at the first PET scan.

In general agreement with previous studies, the researchers found that there was a tipping point at SUVR stage 1.2 after which the amyloid accumulation (the change in SUVR per year) increased in almost all participants. Between SUVR 1.2 and 3.0, the rate of amyloid accumulation was strongly but nonlinearly correlated to amyloid burden.

To estimate the age at which each participant had reached the tipping point, the researchers then aligned SUVR stages over time for the subset of 180 participants who had ≥1 amyloid PET scans taken between SUVR 1.2 and 3.0. The time interval between scans and changes in amyloid accumulation were significantly correlated (P <.0001). They estimated that participants reached SUVR 1.2 at an average age of 65.9 years.

The researchers aligned each participant’s age at SUVR 1.2 and longitudinal clinical data. They identified 22 participants who progressed to typical Alzheimer disease dementia by their last assessment, 3 of whom did not have amyloid on PET scans at the onset of symptoms and may have been misdiagnosed. When these 3 were omitted from the analysis, the researchers were able to make a prediction model for the age of symptom onset for a given age when SUVR 1.2 was reached (P <.0001).

The time interval between the tipping point and the onset of symptoms varied with the age at which a person reached the tipping point. In the prediction model, older people would develop symptoms at lower SUVR stages and thus lower amyloid burden. For example, the researchers estimated that a person who reaches the tipping point at age 45 years would develop symptoms of dementia at age 66 years. In contrast, a person who reaches the tipping point at age 85 years would develop symptoms at age 94 years. As the researchers described, other factors besides amyloid burden affect symptom onset in Alzheimer disease dementia, and these factors can change with age.

The researchers indicated that further studies are needed before the findings can be applied. They also emphasized the importance of predicting symptom onset for future clinical trials: “If specific therapies are most effective within a certain period of the disease course, precise staging is critical. Therefore, accurate prediction of symptom onset may accelerate efforts to develop effective preventative treatments for Alzheimer disease,” they wrote.


Schindler SE, Li Y, Buckles VD, et al. Predicting symptom onset in sporadic Alzheimer disease with amyloid PET. Neurology. 2021;97:e1823-e1834.

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