Synergistic underpinning of global amyloid and cingulate neuroinflammation underlies tau propagation in Alzheimer's disease: Neuroimaging: Neuroimaging predictors of cognitive decline.

Background: Understanding the underling pathophysiology of tau burden and its propagation through Braak stages is imperative in Alzheimer's disease (AD) and its clinical trial strategy. This multimodal PET study aimed to reveal the Aβ ([18F]AZD4694) and activated microglia ([11C]PBR28) converges to potentiate the NFTs ([18F]MK6240) deposition in AD in Braak stages. We hypothesized that the NFTs deposition driven by Aβ and neuroinflammation leads to cognitive. Method: A total of 108 participants (70 CN, 25 MCI, and 13 AD) with a high‐affinity binder for TSPO underwent 3 PET scans, MMSE and CDR‐SB. Static [18F]AZD4694, [18F]MK6240, and [11C]PBR28 SUVR images were generated. All PET images were normalized to the ADNI template, used cerebellar grey as a reference region. A total of 35 anatomical based regions including Braak stage 1 – 6 and its combination, 23 anatomical regions, and local‐to‐local interactive region were used to evaluate the important regional effect of amyloid and neuroinflammation on tau. All analyses were corrected for age, sex, education, APOE, and multiple correction using FDR. Result: We showed a significant synergistic local‐to‐local effect between Aβ and neuroinflammation on NFTs in Precuneus/PCC, basolateral temporal, and medial frontal cortices. Moreover, 3D cross‐regional regressions showed signification interactions between amyloid and neuroinflammation on tau on all Braak stages. Importantly, neuroinflammation in cingulate /precuneus demonstrated the greatest number of interactive effects on tau in the presence of amyloid. Last, global amyloid, cingulate neuroinflammation, and Braak stage 4 tau together led to worse MMSE (p = 0.03) while global amyloid and Braak stage 4 tau together led to worse CDR‐SB (p = 0.003). Conclusion: This study demonstrated the imperative role of microglia on tau propagation in the presence of amyloid. The microglial activation in the cingulate/precuneus, epicenter of the archetypical brain network, showed the most frequent effect together with global amyloid on tau loads on all Braak stages. Last, all 3 major targets of AD clinical trials led to worse cognitive score compared to its independent effect. This study underscores the local and distal effects of neuroinflammation and amyloid on Braak staging in AD, and shows molecular underpinnings for a promising combination therapy in AD. [ABSTRACT FROM AUTHOR]