Scientists reveal cellular changes unique to early Alzheimer’s disease
A study of brain tissue from living adults provides a rare look into the earliest stages of the neurodegenerative disease and highlights cell types involved in plaque production.
Finally, the researchers identified microglia — cells that help clear the amyloid-beta peptide from the brain — that were functioning in two different kinds of activated states. Some of these states have not been detected previously in microglia in animal models, though the researchers recently confirmed several of these diverse states in induced pluripotent stem cells. In the present study, the team found cells in one of these states in tissue from both patients with Alzheimer’s and those with Parkinson’s — a finding that could provide clues about similarities between the conditions.
In the future, Macosko and Stevens plan to identify proteins that are correlated with these cell states in pairs of blood and cerebrospinal fluid samples, which could serve as markers of disease progression. They hope, too, that other researchers will use their approach to analyze datasets from different kinds of samples and sequencing methods together.
“One of the biggest challenges in this field is the fact that every data set is analyzed separately,” Macosko said. “We’re hopeful that this cohort can be useful as a reference for others to align and integrate their own data so that it becomes easier to compare and contrast different diseases or cohorts.”
Already, the findings have provided a launching point for a new research effort coordinated by Stevens, Macosko, and members of the International Neuroimmune Consortium, which brings together researchers from the Broad, the University of Eastern Finland, Stanford University, the UK Dementia Research Institute, and others. The collaboration aims to determine how neuro-immune interactions contribute to cell vulnerability and neurodegeneration in Alzheimer’s and other brain diseases.
“This cohort provides us with ground truth on changes in neurons and glia in the brains of living patients at early stages of disease progression,” said Stevens. “That could lead to new neuroimmune biomarkers and improvements in biomarkers discovery in the blood and CSF.”
This work was supported in part by the Alzheimer’s Association, the National Institutes of Health, the Sigrid Juselius Foundation, the Strategic Neuroscience Funding of the University of Eastern Finland, the Finnish Cultural Foundation, the North Savo Regional Fund, and the European Union.
Gazestani V, Kamath T, et al. Early Alzheimer’s disease pathology in human cortex is associated with a transient phase of distinct cell states. Cell. Online September 28, 2023. DOI:10.1016/j.cell.2023.08.005.