Minimal levels of amyloid accumulation in the brains of cognitively unimpaired individuals are associated with long-term cognitive impairment up to 20 years later

The minimal amyloid accumulation (MAA) in cognitively unimpaired individuals that predicts the onset of cognitive impairment remains unknown. In a multi-center amyloid positron emission tomography (PET) study of 1834 cognitively unimpaired participants with longitudinal clinical/cognitive assessments for up to 20.3 years, we found that 48.7% of the amyloid-negative participants with MAA starting from an amyloid PET centiloid of 1.03 had a higher risk of cognitive impairment than those with the lowest centiloid values (<1.03; hazards ratio (HR)=1.40, p=0.0046), although their risk was clearly lower than amyloid-positive participants (centiloid>20; HR=0.47, p<0.0001). Amyloid positivity was also associated with the fastest longitudinal amyloid accumulation and cognitive decline, followed by the MAA, and finally by the lowest amyloid. These findings suggest that current thresholds of amyloid positivity used for Alzheimer disease diagnosis may be overly restrictive, potentially excluding a large portion of amyloid-negative participants at elevated risk of developing cognitive impairment from prevention trials.