Tharick Pascoal, MD, PhD (Associate Professor of Psychiatry) is an internationally recognized expert on the imaging and fluid biomarkers of Alzheimer’s disease and related dementias. He recently published two papers examining the multifaceted but interactive nature of Alzheimer’s disease pathology.

“Microglia and astrocytes are glial cells that act together and play a major role in the immune response in the human brain. From clinical research, it has long been postulated reactivity microglia and astrocyte as downstream phenomenon to the key features of Alzheimer’s disease—amyloid and tau—and that targeting glial pathologies with therapeutic interventions would not be useful because they were merely consequences of Alzheimer’s disease pathological cascade,” said Dr. Pascoal. “In these two papers, we propose that disturbances in the immune system such as microglial and astrocyte reactivity are upstream in the Alzheimer’s disease process and key to determining disease progression.”

Dr. Pascoal continued, “These two papers are totally aligned with prior work suggesting that disturbance in the neuroimmune systems (microglial activation and astrocyte reactivity) is a major player (and an upstream event) in the Alzheimer’s disease process, and that medications targeting neuroimmune cells have the potential to mitigate the development of tau pathology, and consequently halt Alzheimer’s disease progression. In addition, our work suggests that biomarkers of these glial cells receivability should be included in the biological definition of Alzheimer’s disease and biomarker models of Alzheimer’s disease progression, which currently entire excludes these biomarkers, suggesting that amyloid, tau, and neurodegeneration are the only key processes that matter to model the progression of the disease.”

Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease (Nature Medicine)
An unresolved question for the understanding of Alzheimer’s disease pathophysiology is why a significant percentage of amyloid-β-positive cognitively unimpaired individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In a biomarker study across three cohorts, Dr. Pascoal and a team of scientists tested whether astrocyte reactivity modulates the association of amyloid-β with tau phosphorylation in cognitively unimpaired individuals. The investigators found that amyloid-β was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an Alzheimer’s disease-like pattern of tau tangle accumulation as a function of amyloid-β only in cognitively unimpaired, positive-for-astrocyte-reactivity individuals.

Bellaver B, Povala G, Ferreira PCL, Ferrari-Souza JP, Leffa DT, Lussier FZ, Benedet AL, Ashton NJ, Triana-Baltzer G, Kolb HC, Tissot C, Therriault J, Servaes S, Stevenson J, Rahmouni N, Lopez OL, Tudorascu DL, Villemagne VL, Ikonomovic MD, Gauthier S, Zimmer ER, Zetterberg H, Blennow K, Aizenstein HJ, Klunk WE, Snitz BE, Maki P, Thurston RC, Cohen AD, Ganguli M, Karikari TK, Rosa-Neto P, Pascoal TA.
Nature Medicine, May 2023.

APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles (Science Advances)

Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer’s disease. Dr. Pascoal and a team of investigators tested the association between APOEε4 status and microglial activation in living individuals across the aging and Alzheimer’s disease spectrum by studying 118 individuals with positron emission tomography for amyloid-β, tau, and microglial activation. They showed that APOE, the most important genetic risk factor to Alzheimer’s disease, exerts an effect of microglial activation independent of amyloid and this led to downstream tau pathology, which drives disease progression. 

Ferrari-Souza JP, Lussier FZ, Leffa DT, Therriault J, Tissot C, Bellaver B, Ferreira PCL, Malpetti M, Wang YT, Povala G, Benedet AL, Ashton NJ, Chamoun M, Servaes S, Bezgin G, Kang MS, Stevenson J, Rahmouni N, Pallen V, Poltronetti NM, O’Brien JT, Rowe JB, Cohen AD, Lopez OL, Tudorascu DL, Karikari TK, Klunk WE, Villemagne VL, Soucy JP, Gauthier S, Souza DO, Zetterberg H, Blennow K, Zimmer ER, Rosa-Neto P, Pascoal TA.
Science Advances, 5 Apr 202. Vol 9, Issue 14.