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Amyloid and Tau PET positive cognitively unimpaired individuals: Destined to decline?

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer disease (AD) neuropathological hallmarks (i.e., amyloid-beta 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+TMTL+) and/or in the neocortex (A+TNEO+) 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+TNEO+ (Hazard ratio [HR]=19.2[95% confidence interval: 10.9-33.7]), A+TMTL+ (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+TNEO+ (beta=-0.056+/-0.005, T=-11.55, p<0.001), A+TMTL+ (beta=-0.024+/-0.005, T=-4.72, p<0.001) and A+T- (beta=-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.