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

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), 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 temporal neocortex (A + T NEO-T + ) and compared them with A + T - and A - T - groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A + T NEO-T + (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A + T MTL + (HR = 14.6, 95% CI = 8.1-26.4) and A + T - (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A - T - (reference) group. Both A + T MTL + (HR = 6.0, 95% CI = 3.4-10.6) and A + T NEO-T + (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A + T - group. Linear mixed-effect models indicated that the A + T NEO-T + (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). Both A + T NEO-T + (P < 0.001) and A + T MTL + (P = 0.002) groups also progressed faster than the A + T - group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.