Nat Med

. 2023 May 29.

doi: 10.1038/s41591-023-02380-x. Online ahead of print.

Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer's disease

Bruna Bellaver ^{1 2}, Guilherme Povala ¹, Pamela C L Ferreira ¹, João Pedro Ferrari-Souza ^{1 2}, Douglas T Leffa ¹, Firoza Z Lussier ¹, Andréa L Benedet ³, Nicholas J Ashton ^{3 4 5}, Gallen Triana-Baltzer ⁶, Hartmuth C Kolb ⁶, Cécile Tissot ⁷, Joseph Therriault ⁷, Stijn Servaes ⁷, Jenna Stevenson ⁷, Nesrine Rahmouni ⁷, Oscar L Lopez ⁸, Dana L Tudorascu ^{1 9}, Victor L Villemagne ¹, Milos D Ikonomovic ^{1 8 10}, Serge Gauthier ⁷, Eduardo R Zimmer ^{2 11 12 13}, Henrik Zetterberg ^{3 14 15 16 17 18}, Kaj Blennow ^{3 14}, Howard J Aizenstein ^{1 19}, William E Klunk ¹, Beth E Snitz ⁸, Pauline Maki ²⁰, Rebecca C Thurston ^{1 21 22}, Ann D Cohen ¹, Mary Ganguli ^{1 8 22}, Thomas K Karikari ^{1 3}, Pedro Rosa-Neto ^{7 23}, Tharick A Pascoal ^{24 25}

Affiliations expand

• PMID: 37248300

DOI: 10.1038/s41591-023-02380-x

Abstract

An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast⁺). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast⁺ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.



This seems to be well related to what is written on the page of Florey institute:"In AD, microglia become increasingly inefficient in their response to accumulating toxins in the AD brain and while stuck in a long-term dysregulated state contribute to neuronal loss in the decades between onset of pathology and dementia".

But even more, it is IMO a good explanation of why the Imagine study failed when selecting the study population.