Amyloid Tipping Point Helps Predict Alzheimer’s Dementia Onset
Clear symptoms of Alzheimer’s dementia in cognitively normal people were strongly tied to an amyloid accumulation tipping point, researchers reported.
The tipping point was identified at a standardized uptake value ratio (SUVR) of 1.2 on Pittsburgh compound B PET. After that point, amyloid levels increased at a relatively consistent rate until reaching a high amyloid burden (SUVR 3.0), said Suzanne Schindler, MD, PhD, of Washington University in St. Louis, and colleagues.
Among people who progressed from cognitively normal to typical Alzheimer’s dementia syndrome, the estimated age when they reached SUVR 1.2 predicted their age at symptom onset (R2=0.54, P<0.0001, root mean square error of 4.5 years).
Accuracy was boosted to an R2 of 0.84 (P<0.0001, root mean square error of 2.8 years), after excluding people who likely were misdiagnosed, Schindler and colleagues wrote in Neurology.
The algorithm required only one amyloid PET scan plus a person’s age to estimate time to dementia symptom onset, the researchers noted.
“The predicted age at onset had a correlation of 0.92 with the actual age at onset,” Schindler told MedPage Today. “This is in the same range or even better than the age of symptom onset predicted by family age of onset in autosomal dominant Alzheimer’s disease.”
Alzheimer’s disease treatments will most likely be effective before symptoms start, Schindler pointed out. “However, when will symptoms start? In clinical trials of cognitively normal individuals with positive amyloid PET scans, many do not develop symptoms, making trials longer and more expensive,” she said.
Better estimations of dementia onset could help researchers identify people likely to develop symptoms during the course of a study, making trials more efficient, she observed.
“More broadly, there has long been controversy about how, and even if, amyloid plaques are related to dementia,” Schindler added.
“This is partly because some cognitively normal individuals have high levels of amyloid burden,” she said. “This study shows that amyloid burden is strongly associated with onset of dementia, but the relationship is not linear and age is a major modifying factor.”
Schindler and colleagues analyzed amyloid PET scans from 236 people participating in Alzheimer’s research studies at the Washington University Knight Alzheimer Disease Research Center. Participants had mean baseline age of 66.5 and all had two or more amyloid PET scans. The time between the last and first scans averaged 4.8 years.
The researchers also reviewed over 1,300 clinical assessments from 180 of the participants, which typically were performed every 1 to 3 years. Most participants were cognitively normal when data collection started.
Amyloid accumulated at a non-linear but relatively consistent rate from SUVR 1.2 until SUVR 3.0, an approximately 17-year period that spanned much of the preclinical Alzheimer’s phase for most participants.
Participants hit the tipping point at different ages. Based on the model, a 45-year-old who reached SUVR 1.2 would develop symptoms 21 years later at SUVR greater than 3.0. An 85-year-old would develop symptoms in 9 years, at SUVR of about 2.2. This difference may be related to lower cognitive reserve from normal aging processes or comorbidities, the researchers noted.
People with two copies of the high-risk APOE4 allele hit the tipping point about 10 years earlier than people with no copies, but after that point, they followed the same trajectory as others.
Additional studies involving both late-onset and autosomal dominant Alzheimer’s disease cohorts are needed to refine these approaches and validate these findings, the researchers noted.
“Obviously, we’ll have to see whether this approach works as well in other cohorts,” Schindler said. “Based on other work, I am very optimistic it will replicate well across cohorts.”
The study was supported by the National Institute on Aging.
Schindler disclosed no relationships with industry. Co-authors disclosed relationships with Janssen, Eli Lilly, Pfizer, Biogen, Roche, American Society for Neuroradiology, Alzheimer’s Association, People’s Republic of China, NIH, University of Pittsburgh, GE Healthcare, Centene, Fujirebio, Genentech, AbbVie, Araclon/Grifols, Diadem Res, DiamiR, Otsuka, C2N Diagnostics, Denali, Cajal Neurosciences, Takeda, NextCure, Novartis, Boehringer-Ingelheim, and Merck.
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