Objective:Previous research established that white matter hyperintensities (WMH), a biomarker of small vessel cerebrovascular disease, are strong predictors of cognitive function in older adults and associated with clinical presentation of Alzheimer’s disease (AD), particularly when distributed in posterior brain regions. Secondary prevention clinical trials, such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, target amyloid accumulation in asymptomatic amyloid positive individuals, but it is unclear the extent to which small vessel cerebrovascular disease accounts for performance on the primary cognitive outcomes in these trials. The purpose of this study was to examine the relationship between regional WMH volume and performance on the Preclinical Alzheimer Cognitive Composite (PACC) among participants screened for participation in the A4 trial. We also determined whether the association between WMH and cognition is moderated by amyloid positivity status.Participants and Methods:We assessed demographic, amyloid PET status, cognitive screening, and raw MRI data for participants in the A4 trial and quantitated regional (by cerebral lobe) WMH volumes from T2-weighted FLAIR in amyloid positive and amyloid negative participants at screening. Cognition was assessed using PACC scores, a z-score sum of four cognitive tests: The Mini-Mental State Examination (MMSE), the Free and Cued Selective Reminding Test, Logical Memory Test, and Digit Symbol Substitution Test. We included 1329 amyloid positive and 329 amyloid negative individuals (981 women; mean age=71.79 years; mean education=16.58 years) at the time of the analysis. The sample included Latinx (n=50; 3%), non-Latinx (n=1590; 95.9%), or unspecified ethnicity (n=18; 1.1%) individuals who identified as American Indian/Alaskan Native (n=7; 0.4%), Asian (n=38; 2.3%), Black/African American (n=41; 2.5%), White (n=1551 ; 93.5%), or unspecified (n=21; 1.3%) race. We first examined the associations of total and regional WMH volume and amyloid positivity on PACC scores (the primary cognitive outcome measure for A4) using separate general linear models and then determined whether amyloid positivity status and regional WMH statistically interacted for those WMH regions that showed significant main effects.Results:Both increased WMH, in the frontal and parietal lobes particularly, and amyloid positivity were independently associated with poorer performance on the PACC, with similar magnitude. In subsequent models, WMH volume did not interact with amyloid positivity status on PACC scores.Conclusions:Regionally distributed WMH are independently associated with cognitive functioning in typical participants enrolled in a secondary prevention clinical trial for AD. These effects are of similar magnitude to the effects of amyloid positivity on cognition, highlighting the extent to which small vessel cerebrovascular disease potentially drives AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered explicitly when evaluating outcomes in trials, both as potential effect modifiers and as possible targets for intervention or prevention. The findings from this study cannot be generalized widely, as the participants are not representative of the overall population.

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13 区域白质高信号与前瞻性阿尔茨海默病临床试验参与者的认知相关

目的：先前的研究表明，白质高信号（WMH）是小血管脑血管疾病的生物标志物，是老年人认知功能的有力预测因子，并且与阿尔茨海默病（AD）的临床表现相关，特别是当分布在后脑区域时。二级预防临床试验，例如无症状阿尔茨海默病的抗淀粉样蛋白治疗（A4）研究，针对无症状淀粉样蛋白阳性个体中淀粉样蛋白的积累，但尚不清楚小血管脑血管疾病在多大程度上影响了无症状阿尔茨海默病的主要认知结果。这些试验。本研究的目的是研究筛选参加 A4 试验的参与者中区域 WMH 量与临床前阿尔茨海默氏症认知综合测试 (PACC) 表现之间的关系。我们还确定了 WMH 与认知之间的关联是否受到淀粉样蛋白阳性状态的调节。 参与者和方法：我们评估了 A4 试验参与者的人口统计学、淀粉样蛋白 PET 状态、认知筛查和原始 MRI 数据，并定量了区域（按脑叶）筛查时淀粉样蛋白阳性和淀粉样蛋白阴性参与者的 T2 加权 FLAIR 的 WMH 体积。使用 PACC 分数评估认知能力，这是四项认知测试的 z 分数总和：简易精神状态检查 (MMSE)、自由提示选择性提醒测试、逻辑记忆测试和数字符号替换测试。在分析时，我们纳入了 1329 名淀粉样蛋白阳性个体和 329 名淀粉样蛋白阴性个体（981 名女性；平均年龄 = 71.79 岁；平均受教育程度 = 16.58 岁）。样本包括拉丁裔 (n=50; 3%)、非拉丁裔 (n=1590; 95.9%) 或未指定种族 (n=18; 1.1%) 的美洲印第安人/阿拉斯加原住民 (n=7; 1.1%)。 0.4%）、亚洲人（n=38；2.3%）、黑人/非裔美国人（n=41；2.5%）、白人（n=1551；93.5%）或未指定种族（n=21；1.3%）。我们首先使用单独的一般线性模型检查了总和区域 WMH 体积以及淀粉样蛋白阳性与 PACC 评分（A4 的主要认知结果测量）之间的关联，然后确定淀粉样蛋白阳性状态和区域 WMH 是否在那些显示显着性的 WMH 区域中存在统计上的相互作用。结果：WMH（尤其是额叶和顶叶）的增加和淀粉样蛋白阳性均与 PACC 表现较差独立相关，且程度相似。在随后的模型中，WMH 体积与 PACC 评分上的淀粉样蛋白阳性状态没有相互作用。结论：区域分布的 WMH 与参加 AD 二级预防临床试验的典型参与者的认知功能独立相关。这些影响与淀粉样蛋白阳性对认知的影响相似，突显了小血管脑血管疾病潜在驱动 AD 相关认知特征的程度。在评估试验结果时，应明确考虑小血管脑血管疾病的测量，既作为潜在的效果调节剂，又作为干预或预防的可能目标。这项研究的结果不能广泛推广，因为参与者并不代表总体人群。