Hayes-Larson Eleanor, Andrews Ryan M, Kezios Katrina L, Bercu Ariane, Rouanet Anaïs, Helmer Catherine, Crane Paul K, Gibbons Laura E, Klinedinst Brandon S, McEvoy Linda K, Nichols Emma, Weuve Jennifer, Rajan Kumar B, Hwang Phillip H, Mez Jesse, Farina Mateo, Shaw Crystal, Sims Kendra D, Therneau Terry, Petersen Ronald C, Bouteloup Vincent, Gross Alden L, Albert Marilyn, Morris John C, Masters Colin L, Resnick Susan M, Maruff Paul, Manly Jennifer J, Turney Indira C, Vonk Jet M J, Avila-Rieger Justina, Weigand Alexandra, Chen Ruijia, Wang Jingxuan, Proust-Lima Cécile, Mayeda Elizabeth Rose
From the Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA.
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA.
Epidemiology. 2025 Jul 1;36(4):560-571. doi: 10.1097/EDE.0000000000001859. Epub 2025 Mar 31.
Cognitive change is an important factor in understanding dementia. Estimating effects of exposures on cognitive change requires choosing an analytical timescale, typically time on study or current age. There is limited consensus regarding timescale choice in epidemiologic cognitive aging research.
Using a coordinated analytic approach in 10 cohorts of older adults, we evaluated whether estimated effects of two exposures on memory change differed depending on timescale (time on study or current age). We modeled effects of apolipoprotein-E ( APOE ) ε4 genotype (a time-invariant exposure) and diabetes (a potentially time-varying/acquired exposure evaluated at baseline) using mixed-effects models with linear and nonlinear time specifications for both timescales.
Among APOE ε4 carriers, model-estimated memory scores at baseline (time on study timescale) or at each cohort's median baseline age (current age timescale) were lower, and the average rate of decline was faster than among APOE ε4 noncarriers. Model-estimated memory scores at baseline or at median baseline age were generally similar across baseline diabetes status, with variability across cohorts in the diabetes-memory change association. In some cohorts, trends in diabetes-memory change associations differed in direction across timescales.
Timescale was largely inconsequential for estimated effects of APOE genotype, but yielded differences in estimated diabetes effects, raising questions about the appropriate scale. The current age scale may be problematic because diabetes was measured heterogeneously in age across individuals, a common issue in aging cohorts. Our work demonstrates approaches to evaluate alternative timescales, including in multicohort analyses, and highlights potential implications for estimated exposure effects on cognitive change.
认知变化是理解痴呆症的一个重要因素。估计暴露因素对认知变化的影响需要选择一个分析时间尺度，通常是研究时长或当前年龄。在流行病学认知老化研究中，关于时间尺度的选择，人们的共识有限。
我们采用协调分析方法，对10个老年人群队列进行研究，评估两种暴露因素对记忆变化的估计影响是否因时间尺度（研究时长或当前年龄）而异。我们使用混合效应模型，对载脂蛋白E（APOE）ε4基因型（一种时间不变的暴露因素）和糖尿病（一种在基线时评估的潜在时间变化/后天获得的暴露因素）的影响进行建模，两种时间尺度均采用线性和非线性时间规范。
在APOE ε4携带者中，模型估计的基线时（研究时长时间尺度）或每个队列的基线年龄中位数时（当前年龄时间尺度）的记忆分数较低，且平均下降速度比APOE ε4非携带者更快。基线时或基线年龄中位数时的模型估计记忆分数在基线糖尿病状态之间总体相似，糖尿病与记忆变化的关联在各队列之间存在差异。在一些队列中，糖尿病与记忆变化关联的趋势在不同时间尺度上方向不同。
时间尺度对APOE基因型估计影响的影响在很大程度上无关紧要，但在糖尿病估计影响方面产生了差异，这引发了关于合适尺度的问题。当前年龄尺度可能存在问题，因为糖尿病在个体年龄方面的测量存在异质性，这是老年人群队列中的一个常见问题。我们的工作展示了评估替代时间尺度的方法，包括在多队列分析中，并强调了对估计暴露因素对认知变化影响的潜在影响。
