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.

痴呆领域一个尚未解答的主要问题是，具有阿尔茨海默氏病神经病理学特征（即淀粉样蛋白斑块和 tau 神经原纤维缠结）的认知未受损个体能否随着时间的推移保持其认知能力，或者注定会下降。在这项大型多中心淀粉样蛋白和 tau 正电子发射断层扫描 (PET) 研究（n  = 1,325）中，我们检查了淀粉样蛋白 PET 阳性的认知未受损个体未来发展为轻度认知障碍的风险以及随时间推移认知能力下降的速度（ A ⁺ ) 和 tau PET 阳性 (T ⁺ ) 位于内侧颞叶 (A ⁺ T _MTL ⁺ ) 和/或颞新皮质 (A ⁺ T_NEO-T ⁺ ) 并将它们与 A ⁺ T ⁻和 A ⁻ T ⁻组进行比较。^{Cox 比例风险模型显示，A +} T _NEO-T ⁺中进展为轻度认知障碍的风险显着增加（风险比 (HR) = 19.2，95% 置信区间 (CI) = 10.9–33.7），A ⁺ T _MTL ⁺（HR = 14.6，95% CI = 8.1–26.4）和 A ⁺ T ⁻（HR = 2.4，95% CI = 1.4–4.3）组与 A ⁻ T ⁻（参考）组。两者 A ⁺ T _MTL ⁺(HR = 6.0, 95% CI = 3.4–10.6) 和 A ⁺ T _NEO-T ^{+ (HR = 7.9, 95% CI = 4.7–13.5) 组也比 A +} T组表现出更快的轻度认知障碍临床进展^-团体。线性混合效应模型表明，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) 和 A ⁺ T ⁻ ( β  = −0.008 ± 0.002， 与 A ⁻ T ⁻（参考）组相比（所有P < 0.001）， T  = −3.46，P  < 0.001）组的纵向整体认知能力下降明显更快。A ⁺ T _NEO-T ⁺ ( P  < 0.001) 和 A ⁺ T _MTL ⁺ ( P  = 0.002) 组的进展也比 A ⁺ T ⁻团体。总之，异常淀粉样蛋白和 tau PET 检查相结合提供的晚期阿尔茨海默病病理变化证据与认知未受损个体的短期（即 3-5 年）认知能力下降密切相关，因此具有很高的临床相关性。