DNA methylation age (MA), brain age (BA), and frailty index (FI) are putative aging biomarkers linked to dementia risk. We investigated their relationship and combined potential for prediction of cognitive impairment and future dementia risk using the ADNI database. Of several MA algorithms, DunedinPACE and GrimAge2, associated with memory, were combined in a composite MA alongside BA and a data-driven FI in predictive analyses. Pairwise correlations between age- and sex-adjusted measures for MA (aMA), aBA, and aFI were low. FI outperformed BA and MA in all diagnostic tasks. A model including age, sex, and aFI achieved an area under the curve (AUC) of 0.94 for differentiating cognitively normal controls (CN) from dementia patients in a held-out test set. When combined with clinical biomarkers (apolipoprotein E ε4 allele count, memory, executive function), a model including aBA and aFI predicted 5-year dementia risk among MCI patients with an out-of-sample AUC of 0.88. In the prognostic model, BA and FI offered complementary value (both βs 0.50). The tested MAs did not improve predictions. Results were consistent across FI algorithms, with data-driven health deficit selection yielding the best performance. FI had a stronger adverse effect on prognosis in males, while BA’s impact was greater in females. Our findings highlight the complementary value of BA and FI in dementia prediction. The results support a multidimensional view of dementia, including an intertwined relationship between the biomarkers, sex, and prognosis. The tested MA’s limited contribution suggests caution in their use for individual risk assessment of dementia.

DNA 甲基化年龄 （MA）、脑年龄 （BA） 和虚弱指数 （FI） 是与痴呆风险相关的推定衰老生物标志物。我们使用 ADNI 数据库调查了它们之间的关系以及预测认知障碍和未来痴呆风险的综合潜力。在几种 MA 算法中，与记忆相关的 DunedinPACE 和 GrimAge2 在预测分析中与 BA 和数据驱动的 FI 一起组合成一个复合 MA。MA （aMA） 、 aBA 和 aFI 的年龄和性别校正指标之间的成对相关性较低。FI 在所有诊断任务中均优于 BA 和 MA。包括年龄、性别和 aFI 的模型实现了 0.94 的曲线下面积 （AUC），用于区分认知正常对照 （CN） 和持有测试集中的痴呆患者。当与临床生物标志物 （载脂蛋白 E ε4 等位基因计数、记忆、执行功能） 相结合时，包括 aBA 和 aFI 的模型预测样本外 AUC 为 0.88 的 MCI 患者的 5 年痴呆风险。在预后模型中，BA 和 FI 提供互补价值 （均βs 0.50）。测试的 MA 并没有改善预测。结果在 FI 算法之间是一致的，数据驱动的健康缺陷选择产生了最佳性能。FI 对男性预后的不良影响更强，而 BA 对女性的影响更大。我们的研究结果强调了 BA 和 FI 在痴呆预测中的互补价值。结果支持痴呆的多维观点，包括生物标志物、性别和预后之间的交织关系。经过测试的 MA 的有限贡献表明，在用于痴呆的个体风险评估时应谨慎。