Analysis of Alzheimer’s pathology in brain cells finds deterioration in two stages

Key takeaways:

• Cell transformation begins with slow degeneration and progresses rapidly.
• The data confirmed results from previous studies of Alzheimer’s-related cell pathology.

A genetic analysis of postmortem brains from individuals in various stages of Alzheimer’s disease revealed two distinct phases of cell deterioration, according to research published in Nature Neuroscience.

“Single cell and spatial genomics technologies now offer a dramatically higher resolution analysis of complex brain tissues,” Mariano I. Gabitto, PhD, assistant investigator at the Allen Institute in Seattle, and colleagues wrote. “Multiple studies have now begun to apply them to identify cellular vulnerabilities and molecular changes with AD.”

Gabitto and colleagues, including researchers from the NIH, utilized multiomics and spatial genomics to study cell types in those with AD and determine which types may be damaged due to AD-related disease pathology.

Their study examined postmortem brain tissue of 84 older adults with differing AD pathologies (average age at time of death, 88 years; 61% women) from the University of Washington BioRepository and Integrated Neuropathology labs from the Kaiser Permanente Washington Health Research Institute ACT study as well as from the University of Washington Alzheimer’s Disease Research Center.

The researchers cut the tissue blocks from the cells of the middle temporal gyrus — which controls language memory and vision — into five micrometer portions, utilized chromogenic staining for preservation, then performed quantitative neuropathology to place donors along a disease pseudoprogression score.

Their analysis of the brain tissue of those affected by AD, combined with comparisons of data from controls, allowed for the creation of a progressive timeline that showed the effects of the disease course, according to an NIH press release.

The pseudoprogression analysis revealed two disease-related phases of cell transformation: an early phase marked by a slow increase in disease pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin and inhibitory neurons, along with a remyelination response by oligodendrocyte precursor cells; and a later phase defined by an exponential increase in disease pathology, loss of excitatory neurons and inhibitory neuron subtypes.

Through these data, Gabitto and colleagues confirmed what had previously been replicated in prior studies of AD-related cell pathology.

“With these tools, scientists were able to detect the earliest cellular changes to the brain to create a more complete picture of what happens over the entire course of the disease,” John Ngai, PhD, director of the NIH’s Brain Research Through Advancing Innovative Neurotechnologies Initiative, said in the release. “The new knowledge provided by this study may help scientists and drug developers around the world develop diagnostics and treatments targeted to specific stages of Alzheimer’s and other dementias.”

Reference:

Alzheimer’s disease may damage the brain in two phases. https://www.nih.gov/news-events/news-releases/alzheimer-s-disease-may-damage-brain-two-phases. Published Oct. 15, 2024. Accessed Oct. 17, 2024.