ImportanceFactors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement.ObjectivesTo examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy.Design, Setting, and ParticipantsThis cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses.Main Outcomes and MeasuresClinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET).ResultsOf the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = −0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02).Conclusions and RelevanceFindings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

中文翻译：

---

阿尔茨海默病的临床病理异质性和神经胶质激活模式

与阿尔茨海默病 (AD) 临床异质性相关的重要因素沿着一个连续体分布，假设与缠结分布相关，并且与理解治疗进展中的神经胶质激活考虑因素相关。 目的使用皮质边缘指数 (CLix) 来解释尸检中发现的空间分布缠结的个体性。 设计、设置和参与者这项横断面研究是对 1991 年至 2020 年加入的佛罗里达尸检多民族 (FLAME) 队列进行的回顾性医疗记录审查。 数据对 2022 年 12 月至 2023 年 12 月进行了分析。在独立的神经影像组中对结构磁共振成像 (MRI) 和 tau 正电子发射断层扫描 (PET) 进行了评估。 FLAME 队列包括 2809 名尸检个体；这项研究包括神经病理学诊断的 AD 病例 (FLAME-AD)。衍生出 FLAME-AD 病例的数字病理学亚组用于神经胶质激活分析。主要结果和测量异质性的临床病理因素，可告知患者病史和 AD 的神经病理学评估； CLix 评分（较低的相对皮质优势/海马保留与较高的相对皮质保留/边缘优势病例）；神经影像学测量（即结构 MRI 和 tau-PET）。 结果 在 FLAME 队列中的 2809 例尸检个体中，评估了 1361 例神经病理学诊断的 AD 病例。数字病理亚组包括 60 个 FLAME-AD 病例。独立神经影像组包括93例。在 1361 例 FLAME-AD 病例中，633 例为男性（47%；中位[范围]死亡年龄，81[54-96]岁），728 例为女性（53%；中位[范围]死亡年龄，81[53]岁）。 -102]年）。症状发作较年轻（Spearman ρ = 0.39，磷< .001) 以及简易精神状态检查的更快下降 (Spearman ρ = 0.27;磷< .001) 与 FLAME-AD 系列中较低的 CLix 分数相关。患有非记忆删除综合征的病例的 CLix 评分（中位数 [IQR]，13 [9-18]）低于非记忆删除综合征病例（中位数 [IQR]，21 [15-27]）；磷< .001）。海马 MRI 体积（Spearman ρ = -0.45；磷< .001) 和后扣带回和楔前叶皮层中 flartaucipir tau-PET 的摄取 (Spearman ρ = -0.74;磷< .001) 与 CLix 分数呈负相关。尽管 CLix 评分低于 10 的 AD 病例具有较高的皮质缠结计数，但我们发现与 CLix 的病例相比，CD68 激活的小胶质细胞/巨噬细胞负担百分比较低（中位数 [IQR]，0.46% [0.32%-0.75%]）分数为 10 至 30（中位数 [IQR]，0.75% [0.51%-0.98%]），与 CLix 分数 30 或更高（中位数 [IQR]，0.40% [0.32%-0.57%]）相当；磷= .02)。结论和相关性发现表明 AD 异质性沿着皮质边缘缠结分布的连续体存在。 CD68 负荷减少可能意味着 tau 积累与小胶质细胞/巨噬细胞激活之间的关联未被充分认识，在免疫失调的个体化治疗中应考虑这一关联。