Alzheimer's disease (AD) is highly associated with aging, typically presenting with amnestic, multi-domain cognitive impairment and greater medial temporal lobe (MTL) atrophy relative to cortex. However, approximately 15 % of AD cases present atypically, often at younger ages and with greater cortical involvement relative to MTL. This association between age and AD presentation is imperfect: some younger-onset cases are typical, amnestic presentations while some older-onset cases present less typically. We hypothesize that this discordance may be partially modulated by discordance between chronological age and biological age, defined epigenetically. Participants from the Alzheimer's Disease Neuroimaging Initiative with MRI and known amyloid status were selected (n = 1011, 44.4 % female, 75.33 ± 7.28 years) and classified as amyloid-negative, cognitively unimpaired (n = 329) or amyloid-positive, symptomatic individuals with mild cognitive impairment or dementia (n = 682). Biological age was estimated in individuals with DNA methylation (n = 448) using established epigenetic clocks. Biological age gap (BAG) was calculated to categorize individuals into "accelerated" (biological age > chronological age) or "decelerated" (biological age < chronological age) groups. We define the Cortico-Medial Temporal index (CoMeT), derived from MRI, to quantify age-adjusted relative differences between cortical and MTL structures. Lower CoMeT scores indicate relatively greater cortical involvement. BAG and CoMeT were significantly correlated (Pearson R=0.13, p = 0.023). Symptomatic individuals with decelerated BAG exhibited significantly lower CoMeT scores than individuals with accelerated BAG, with a large effect size, reflecting greater cortical involvement relative to MTL (Wilcoxon p = 0.023, rank-biserial correlation=-0.98). We conclude that biological aging modulates AD presentation beyond chronological age, providing novel insights into mechanisms underlying AD heterogeneity.

Keywords: Alzheimer’s disease; Biological aging; DNA methylation; Epigenetics; MRI; Neurodegeneration.

Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

阿尔茨海默病（AD）与老龄化高度相关，通常表现为记忆障碍和多领域认知功能下降，并且相对于大脑皮层，内侧颞叶（MTL）萎缩更为明显。然而，大约15%的AD病例表现出非典型症状，往往在较年轻时发病，并且相对于MTL，皮层受累更严重。年龄与AD表现之间的这种关联并不完美：一些年轻的患者表现为典型的记忆障碍症状，而一些年长的患者则表现为不太典型的症状。我们假设这种不一致可能部分受到实际年龄和表观遗传定义的生物年龄之间差异的影响。

从阿尔茨海默病神经影像学倡议项目中选择了具有MRI图像和已知淀粉样蛋白状态的参与者（n=1011，44.4%为女性，平均年龄75.33±7.28岁），并将其分类为淀粉样蛋白阴性、认知未受损（n=329）或淀粉样蛋白阳性、伴有轻度认知障碍或痴呆的有症状个体（n=682）。在具有DNA甲基化数据（n=448）的个体中，使用已建立的表观遗传时钟估算生物年龄。通过计算“生物年龄差距”（BAG），将个体分为“加速老化”（生物年龄>实际年龄）或“减速老化”（生物年龄<实际年龄）。我们定义了从MRI数据衍生出的皮质-内侧颞叶指数（CoMeT），以量化调整年龄后的皮层和MTL结构之间的相对差异。较低的CoMeT分数表示相对较严重的皮层受累。BAG与CoMeT显著相关（Pearson R=0.13，p = 0.023）。减速老化个体比加速老化的有症状个体表现出显著更低的CoMeT分数，并且这种效应具有较大的效应量，这反映了相对于MTL更严重的皮层受累（Wilcoxon p = 0.023，等级双列相关=-0.98）。我们得出结论，生物老化在实际年龄之外影响AD的表现形式，为理解AD异质性的机制提供了新的见解。

关键词：阿尔茨海默病；生物老化；DNA甲基化；表观遗传学；MRI；神经退行性变。