Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
Alzheimers Res Ther. 2022 Jul 15;14(1):95. doi: 10.1186/s13195-022-01038-z.
We previously identified four Alzheimer's disease (AD) subgroups with increasingly higher cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 181 (p-tau). These subgroups included individuals across the cognitive spectrum, suggesting p-tau subgroups could reflect distinct biological changes in AD, rather than disease severity. Therefore, in the current study, we further investigated which potential processes may be related with p-tau subgroups, by comparing individuals on CSF markers for presynaptic structure [vesicle-associated membrane protein 2 (VAMP2)], postsynaptic structure [neurogranin (NRGN)], axonal damage [neurofilament light (NfL)], and amyloid production [beta-secretase 1 (BACE1) and amyloid-beta 1-40 (Aβ40)].
We selected 348 amyloid-positive (A+) individuals (53 preclinical, 102 prodromal, 193 AD dementia) and 112 amyloid-negative (A-) cognitively normal (CN) individuals from the Amsterdam Dementia Cohort (ADC). Individuals were labeled according to their p-tau subgroup (subgroup 1: p-tau ≤ 56 pg/ml; subgroup 2: 57-96 pg/ml; subgroup 3: 97-159 pg/ml; subgroup 4: > 159 pg/ml). CSF protein levels were measured with ELISA (NRGN, BACE1, Aβ40, NfL) or single-molecule array (Simoa) (VAMP2). We tested whether protein levels differed between the p-tau subgroups within A+ individuals with linear models corrected for age and sex and whether disease stage influenced these relationships.
Among A+ individuals, higher p-tau subgroups showed a higher percentage of AD dementia [subgroup 1: n = 41/94 (44%); subgroup 2: n = 81/147 (55%); subgroup 3: n = 59/89 (66%); subgroup 4: n = 7/11 (64%)]. Relative to controls, subgroup 1 showed reduced CSF levels of BACE1, Aβ40, and VAMP2 and higher levels of NfL. Subgroups 2 to 4 showed gradually increased CSF levels of all measured proteins, either across the first three (NfL and Aβ40) or across all subgroups (VAMP2, NRGN, BACE1). The associations did not depend on the clinical stage (interaction p-values ranging between 0.19 and 0.87).
The results suggest that biological heterogeneity in p-tau levels in AD is related to amyloid metabolism and synaptic integrity independent of clinical stage. Biomarkers reflecting amyloid metabolism and synaptic integrity may be useful outcome measures in clinical trials targeting tau pathology.
我们之前发现，有四个阿尔茨海默病（AD）亚组的脑脊液（CSF）中 tau 第 181 位苏氨酸磷酸化（p-tau）水平逐渐升高。这些亚组包括认知谱上的个体，表明 p-tau 亚组可能反映了 AD 中不同的生物学变化，而不是疾病的严重程度。因此，在当前的研究中，我们通过比较脑脊液中突触前结构标志物[囊泡相关膜蛋白 2（VAMP2）]、突触后结构标志物[神经颗粒蛋白（NRGN）]、轴突损伤标志物[神经丝轻链（NfL）]和淀粉样蛋白产生标志物[β-分泌酶 1（BACE1）和淀粉样蛋白-β1-40（Aβ40）]，进一步研究了哪些潜在的过程可能与 p-tau 亚组有关。
我们从阿姆斯特丹痴呆队列（ADC）中选择了 348 名淀粉样蛋白阳性（A+）个体（53 名临床前，102 名前驱期，193 名 AD 痴呆）和 112 名淀粉样蛋白阴性（A-）认知正常（CN）个体。根据 p-tau 亚组（亚组 1：p-tau ≤ 56 pg/ml；亚组 2：57-96 pg/ml；亚组 3：97-159 pg/ml；亚组 4：> 159 pg/ml）对个体进行标记。使用 ELISA（NRGN、BACE1、Aβ40、NfL）或单分子阵列（Simoa）（VAMP2）测量 CSF 蛋白水平。我们测试了在 A+个体中，p-tau 亚组内的蛋白水平是否因线性模型而有所不同，该模型校正了年龄和性别，并且疾病阶段是否影响了这些关系。
在 A+个体中，较高的 p-tau 亚组显示出更高比例的 AD 痴呆[亚组 1：n = 41/94（44%）；亚组 2：n = 81/147（55%）；亚组 3：n = 59/89（66%）；亚组 4：n = 7/11（64%）]。与对照组相比，亚组 1 显示 BACE1、Aβ40 和 VAMP2 的 CSF 水平降低，NfL 的水平升高。亚组 2 到 4 则显示出所有测量蛋白的 CSF 水平逐渐升高，要么跨越前三（NfL 和 Aβ40），要么跨越所有亚组（VAMP2、NRGN、BACE1）。这些关联与临床阶段无关（交互 p 值在 0.19 到 0.87 之间）。
结果表明，AD 中 p-tau 水平的生物学异质性与淀粉样蛋白代谢和突触完整性有关，而与临床阶段无关。反映淀粉样蛋白代谢和突触完整性的生物标志物可能是针对 tau 病理学的临床试验中的有用结局指标。
