Association of functional brain alterations with β-amyloid, tau, and cognitive decline in Alzheimer’s disease

Regional functional activity plays a critical role in the cognitive performance of both aging individuals and Alzheimer’s disease (AD). To better understand the pathologies and clinical progression patterns of AD, the investigation of the associations of regional functional brain alterations with β-amyloid (Aβ) plaques, tau tangles, and cognitive decline in AD is essential. We recruited 179 participants (mean age of 69.7 years, 61% female) who underwent concurrent 18F-Florbetapir Aβ PET imaging, 18F-PI-2620 tau PET imaging, resting functional MRI, and cognitive assessments, after which we classified these participants into A-/T- (N = 35), A-/T+ (N = 11), A+/T- (N = 53), and A+/T+ (N = 80) groups according to the thresholds of the Aβ and tau PET standardized uptake value ratio (SUVR). We subsequently compared the group differences in mean regional homogeneity (ReHo) values and explored the correlations between ReHo index scores and Aβ burden, tau deposition, and cognitive scores using general linear models, including age, sex, education, hippocampus volume, and total intracranial volume as covariates. We detected neuronal hyperactivity and hypoactivity in the angular gyrus, cuneus, lingual gyrus, and parahippocampal gyrus, which are mainly distributed across the default mode and salience networks; moreover, they are associated with regional Aβ burden and tau deposition encompassing the AD spectrum. Furthermore, we confirmed that elevated cortical Aβ accumulation and tau deposition mainly induce decreases in regional functional activity in AD. Finally, we observed that Aβ- and tau-related regional functional brain alterations showed significant indirect associations with the relationships between Aβ burden (β = -0.08, 95% ci, -4.22~ -0.75, p = 0.01), tau deposition (β = -0.17, 95% ci, -11.04~-4.07, p < 0.0001), and cognitive performance. These findings indicate that abnormal functional activity is associated with both AD hallmark pathologies and cognitive decline, in a manner consistent with a potential mediating role. This study revealed that cortical Aβ and tau aggregation may alter functional activity (as reflected by ReHo), thus further leading to cognitive decline in patients with AD. These findings provide novel insights into how Aβ and tau-associated functional activity affect cognitive decline in AD patients.