Amyloid-β, p-tau, and reactive microglia load are correlates of MRI cortical atrophy in Alzheimer’s disease

Frigerio, Irene; Boon, Baayla D.C.; Lin, Cheng-Xian; Graaf, Yvon Galis-de; Bol, John G.J.M.; Preziosa, Paolo; Twisk, Jos W. R.; Barkhof, Frederik; Hoozemans, Jeroen J. M.; Bouwman, Femke H.; Rozemüller, Annemieke; Berg, Wilma D. J. van de; Jonkman, Laura E.

doi:10.1101/2021.06.16.448650

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“…Some investigations attributed equal influence of Aβ and tau to microglial activation (24), while others supported the interaction of Aβ and microglia activation to set the pace for subsequent tau spread (12, 25). The effects of microglial activation on cognition are thought to be strongly mediated by gray matter atrophy (26), and activated microglia have been correlated with parietal atrophy post mortem (27). Thus, we aimed to investigate the interplay between ATI(N) biomarkers and microglial activation in a cohort composed of primary and secondary tauopathies, including atypical and typical AD.…”

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confidence: 99%

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

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β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1) and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT= 0.412 ± 0.196 vs. βA= 0.142 ± 0.123, p < 0.001; AD-CBS: βT= 0.385 ± 0.176 vs. βA= 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT= 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. An index of tau- and Aβ-associated microglia activation accounts for regional heterogeneity and allows for clinical and biomarker correlations with ATN-specific neuroinflammation.

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