Sreepada Lasya P, Brown Christopher A, Das Sandhitsu R, Yushkevich Paul A, Wolk David A, McMillan Corey T
Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104, United States; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
Neurobiol Aging. 2025 Sep;153:21-29. doi: 10.1016/j.neurobiolaging.2025.06.003. Epub 2025 Jun 4.
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.
阿尔茨海默病（AD）与衰老高度相关，通常表现为遗忘性、多领域认知障碍，且相对于皮质而言，内侧颞叶（MTL）萎缩更为明显。然而，约15%的AD病例表现不典型，发病年龄往往较轻，且相对于MTL而言，皮质受累更严重。年龄与AD表现之间的这种关联并不完美：一些早发型病例表现为典型的遗忘症状，而一些晚发型病例的表现则不太典型。我们推测，这种不一致可能部分受按表观遗传学定义的实足年龄与生物学年龄之间的不一致所调节。从阿尔茨海默病神经影像倡议组织中选取有MRI数据且已知淀粉样蛋白状态的参与者（n = 1011，44.4%为女性，75.33±7.28岁），并将其分为淀粉样蛋白阴性、认知未受损组（n = 329）或淀粉样蛋白阳性、有轻度认知障碍或痴呆症状的个体组（n = 682）。使用已建立的表观遗传时钟对有DNA甲基化的个体（n = 448）估计生物学年龄。计算生物学年龄差距（BAG），将个体分为“加速型”（生物学年龄>实足年龄）或“减速型”（生物学年龄<实足年龄）组。我们定义了源自MRI的皮质-内侧颞叶指数（CoMeT），以量化皮质和MTL结构之间经年龄调整的相对差异。较低的CoMeT分数表明皮质受累相对更严重。BAG与CoMeT显著相关（Pearson相关系数R = 0.13，p = 0.023）。BAG为减速型的有症状个体的CoMeT分数显著低于BAG为加速型的个体，效应量较大，这反映出相对于MTL而言，皮质受累更严重（Wilcoxon检验p = 0.023，等级二列相关系数=-0.98）。我们得出结论，生物学衰老对AD表现的调节作用超出了实足年龄，这为AD异质性的潜在机制提供了新的见解。
