AbstractA 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.