Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline

ABSTRACT A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer’s disease (AD) neuropathological hallmarks (i.e., amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multi-center amyloid and tau PET study (n=1325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET positive (T+) in the medial temporal lobe (A+T MTL +) and/or in the neocortex (A+T NEO +) and compared them with A+T- and A-T-groups. Cox proportional hazard models showed a substantially increased risk for progression to mild cognitive impairment in the A+T NEO + (Hazard ratio [HR]=19.2[95% confidence interval: 10.9-33.7]), A+T MTL + (HR=14.6[8.1-26.4) and A+T-(HR=2.4[1.4-4.3]) groups vs the A-T-(reference) group. Linear mixed effect models indicated that the A+T NEO + (β=-0.056±0.005, T=-11.55, p<0.001), A+T MTL + (β=-0.024±0.005, T=-4.72, p<0.001) and A+T-(β=-0.008±0.002, T=-3.46, p<0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T-(reference) group (all p<0.001). Evidence of advanced AD pathological changes provided by amyloid and tau PET is strongly associated with short-term (i.e., 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.