Dynamic deposition of tau protein and the risk of Alzheimer’s Disease progression from Mild Cognitive Impairment: a multilevel joint model study

Our study aimed to identify key brain regions of tau protein deposition that predict the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD), and to further quantify the association of these regions with the risk of progression. We conducted a study using longitudinal tau-PET data from 126 MCI participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The penalized generalized estimating equation (PGEE), mixed effects gradient boosting (MEGB), and mixed effects random forest (MERF) methods were applied to identify key brain regions with tau deposition. A multilevel joint model based on the screened brain regions was constructed to analyze the longitudinal trajectory of tau deposition and its dynamic association with the risk of progression from MCI to AD. The entorhinal cortex, amygdala, inferior parietal cortex, middle temporal gyrus, parahippocampal gyrus, and ventral posterior cingulate cortex were jointly identified by all three methods. The joint model revealed substantial heterogeneity in hazard ratios across regions. The entorhinal cortex demonstrated the highest risk (HR = 3.763, 95% CI: 2.237–6.801), followed by the amygdala (HR = 3.732, 95% CI: 2.326–6.164) and the inferior parietal cortex (HR = 3.511, 95% CI: 2.109–6.013). The middle temporal gyrus (HR = 2.770, 95% CI: 1.972–3.955) and parahippocampal gyrus (HR = 2.522, 95% CI: 1.833–3.529) also showed significant associations, whereas the ventral posterior cingulate cortex was not significantly associated with progression risk (HR = 1.354, 95% CI: 0.858–2.164). Tau deposition in five key brain regions—the entorhinal cortex, amygdala, inferior parietal cortex, middle temporal gyrus, and parahippocampal gyrus—is significantly associated with the risk of progression from MCI to AD, with substantial heterogeneity in hazard ratios across regions. Current tau burden, rather than its accumulation rate, emerged as the dominant factor associated with progression risk. Not applicable.