Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy.
Eur J Neurol. 2024 Sep;31(9):e16374. doi: 10.1111/ene.16374. Epub 2024 Jun 10.
Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aβ and tau proteins with cognitive and motor phenotype in ALS.
APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aβ42, Aβ40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype.
APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aβ42 (-0.8 vs. 0.1, log-transformed values) and Aβ42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aβ42 levels, possibly reflecting cerebral Aβ deposition. While lower Aβ42/40 correlated with lower memory score (β = 0.20), Aβ42 positively correlated with both ALS-specific (β = 0.24) and ALS-nonspecific (β = 0.24) scores. Although Aβ42/40 negatively correlated with T-tau (β = -0.29) and P-tau181 (β = -0.33), we found an unexpected positive association of Aβ42 and Aβ40 with both tau proteins. Regarding motor phenotype, lower levels of Aβ species were associated with lower motor neuron (LMN) signs (Aβ40: β = 0.34; Aβ42: β = 0.22).
APOE haplotype and CSF Aβ biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.
肌萎缩侧索硬化症（ALS）的非特异性认知缺陷（尤其是记忆障碍）及其生物学基础知之甚少。我们研究了阿尔茨海默病（AD）遗传风险因子 APOE 以及脑脊液（CSF）生物标志物 Aβ和 tau 蛋白与 ALS 的认知和运动表型之间的关联。
在 281 名 ALS 患者中确定了 APOE 单倍型；对于其中的 105 名患者，通过化学发光酶免疫分析（CLEIA）定量测定 CSF 中的 Aβ42、Aβ40、总 tau（T-tau）和磷酸化 tau（P-tau181）水平。采用爱丁堡认知和行为 ALS 筛查（ECAS）评估神经心理学表型。
APOE-E4 等位基因与 ECAS 记忆评分较差相关（携带者中位数为 14.0，而非携带者中位数为 16.0），CSF 中 Aβ42 水平较低（-0.8 对 0.1，对数转换值），Aβ42/40 比值较低（-0.1 对 0.3）。约 37.1%的 ALS 患者出现 Aβ42 水平较低，可能反映了脑内 Aβ沉积。尽管 Aβ42/40 与记忆评分较低呈负相关（β=0.20），但 Aβ42 与 ALS 特异性评分（β=0.24）和 ALS 非特异性评分（β=0.24）均呈正相关。尽管 Aβ42/40 与 T-tau（β=-0.29）和 P-tau181（β=-0.33）呈负相关，但我们发现 Aβ42 和 Aβ40 与两种 tau 蛋白呈意外的正相关。关于运动表型，较低的 Aβ 水平与较低的运动神经元（LMN）体征相关（Aβ40：β=0.34；Aβ42：β=0.22）。
APOE 单倍型和 CSF Aβ 生物标志物与 ALS 中的认知缺陷相关，尤其是与记忆障碍相关。这可能部分反映了 AD 样的病理生理过程，但也可能涉及其他 ALS 特异性机制。
