The role of cortical microstructural changes on longitudinal accumulation of tau and cognitive decline in at risk older adults

Abstract

AbstractBackgroundNon‐invasive diffusion‐weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) was recently shown to be cross‐sectionally associated with tau in cognitively‐normal older adults (Rodriguez‐Vieitez et al., Mol. Psych. 2021), suggesting that it might be an early marker of neuronal injury. However, the impact of cMD on longitudinal accumulation of tau pathology is currently unknown. Moreover, APOE‐e4 — the strongest genetic risk factor for sporadic AD — has been shown to be related to tau aggregation (Therriault et al.,JAMA Network 2019) and cognitive impairment in older adults. Here, we investigated whether cMD at baseline can predict longitudinal accumulation of tau as well as cognitive decline in cognitively‐normal adults with and without an APOE‐e4.Methods122 cognitively‐normal participants from the Harvard Aging Brain Study (71.0±9.7 years; 79 women[64.8%]), 30.3% APOE‐e4‐carriers, 16.0±2.9 years of education; Table 1) underwent DWI, T1w‐MRI, 18F‐flortaucipir(FTP)‐PET imaging and cognitive assessments at baseline. All participants had at least one longitudinal follow‐up FTP‐PET scan (average follow‐up time of 2.4±0.55 years). PET data were normalized to cerebellar grey‐matter. FTP‐PET was quantified using PVC‐corrected SUVR. Longitudinal measures of Preclinical Alzheimer Cognitive Composite (PACC5) were available for all individuals over a 7.2±2.4 years follow‐up interval. We assessed whether the interaction of APOE‐e4 and cMD (in entorhinal and inferior‐temporal cortices) was associated with longitudinal local tau accumulation and with longitudinal PACC5 using separate linear mixed‐effects models. Models were corrected for demographics and baseline tau or PACC5 as appropriate.ResultsThe APOE‐e4 carriers and non‐carriers had similar baseline demographics and imaging characteristics (Table 1). We found significant interaction effects of APOE‐e4 status and cMD in predicting longitudinal tau (entorhinal p=0.008 and inferior‐temporal p=0.032) and longitudinal PACC5 (both entorhinal and inferior‐temporal p<0.001), such that baseline cMD predicted the accumulation of tau and cognitive decline in APOE‐e4‐carriers only (Figures 1 and 2).ConclusionsOur results demonstrate that the cortical microstructual changes measured by cMD are related to accumulation of longitudinal local tau and cognitive decline in at‐risk individuals. The combination of APOE‐e4 and elevated cMD may help identify individuals at short‐term risk of tau accumulation and AD‐related cognitive decline, suggesting utility in therapeutic trials.