We previously found that the APOE genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies.

We analyzed APOE associations with the cognitive trajectories (Clinical Dementia Rating scale Sum of Boxes [CDR-SOB] and Mini-Mental State Examination [MMSE]) of more than 1,000 individuals from a national clinicopathologic sample who had either no, mild (sparse neuritic plaques and the Braak neurofibrillary tangle [NFT] stage I/II), or intermediate (moderate neuritic plaques and the Braak NFT stage III/IV) ADNC levels at autopsy via 2 latent classes reverse-time longitudinal modeling.

Carrying the APOE4 allele was associated with a faster rate of cognitive decline by both CDR-SOB and MMSE relative to APOE3 homozygotes. This association remained statistically significant after adjusting for ADNC severity, comorbid pathologies, and the effects of ADNC on the slope of cognitive decline. Our modeling strategy identified 2 latent classes in which APOE4 carriers declined faster than APOE3 homozygotes, with latent class 1 members representing slow decliners (CDR-SOB: 76.7% of individuals, 0.195 vs 0.146 points/y in APOE4 vs APOE3/3; MMSE: 88.6% of individuals, –0.303 vs –0.153 points/y in APOE4 vs APOE3/3), whereas latent class 2 members were fast decliners (CDR-SOB: 23.3% of participants, 1.536 vs 1.487 points/y in APOE4 vs APOE3/3; MMSE: 11.4% of participants, –2.538 vs –2.387 points/y in APOE4 vs APOE3/3). Compared with slow decliners, fast decliners were more likely to carry the APOE4 allele, younger at initial visit and death, more impaired at initial and last visits, and more likely to have intermediate (vs none or mild) ADNC levels, as well as concurrent Lewy bodies and hippocampal sclerosis at autopsy.

In a large national sample selected to represent the normal aging-early AD continuum, the APOE4 allele is associated with a modest but statistically significant acceleration of the cognitive decline rate even after controlling for its effects on ADNC and comorbid pathologies.

我们之前发现APOE基因型影响轻度至中度阿尔茨海默病 (AD) 痴呆的认知能力下降率，与其对 AD 神经病理学变化 (ADNC) 和共病学的影响无关。在这项研究中，我们检验了APOE等位基因对正常衰老-早期 AD 连续体的认知衰退速度有不同影响的假设，并且这种关联独立于它们对经典 ADNC 和共病的影响。

我们分析了APOE与认知轨迹（临床痴呆评定量表总和 [CDR-SOB] 和简易精神状态检查 [MMSE]）的关联，这些受试者来自全国临床病理样本，这些样本没有，轻度（稀疏神经炎）斑块和 Braak 神经原纤维缠结 [NFT] I/II 期）或中间（中度神经炎斑块和 Braak NFT III/IV 期）尸检时通过 2 个潜类别逆时纵向建模的 ADNC 水平。

携带APOE 4 等位基因与 CDR-SOB 和 MMSE 相对于APOE 3 纯合子的认知能力下降速度更快有关。在调整 ADNC 严重程度、合并症和 ADNC 对认知衰退斜率的影响后，这种关联仍然具有统计学意义。我们的建模策略确定了 2 个潜在类别，其中APOE 4 携带者下降速度快于APOE 3 纯合子，潜在类别 1 成员代表缓慢下降（CDR-SOB：76.7% 的个体，APOE 4 与APOE 3/中分别为 0.195 和 0.146 点/年3；MMSE：88.6% 的个体，–0.​​303 与 –0.153 点/年APOE 4 与APOE3/3)，而潜在的 2 类成员快速下降（CDR-SOB：23.3% 的参与者， APOE 4 和APOE 3/3中分别为 1.536 和 1.487 点/年；MMSE：11.4% 的参与者，–2.538对 –2.387 APOE 4 与APOE 3/3中的点/年）。与缓慢下降者相比，快速下降者更有可能携带APOE 4 等位基因，在初次就诊和死亡时更年轻，在初次和最后一次就诊时受损更大，更可能具有中等（相对于无或轻度）ADNC 水平，以及尸检时并发路易体和海马硬化。

在选择代表正常衰老-早期 AD 连续体的大型全国样本中，APOE 4 等位基因与适度但具有统计学意义的认知下降率加速相关，即使在控制其对 ADNC 和合并症的影响之后也是如此。