Summary: Researchers made a significant advance in understanding Alzheimer’s disease (AD) by pinpointing how specific brain cells contribute to different stages of the disease.
Employing single nucleus RNA sequencing, they analyzed genetic risks in microglia and astrocytes, revealing distinct roles these cells play in AD progression. Astrocytes were found to impact early stages like amyloid-β buildup, while microglia influenced later stages, including plaque and tau tangle accumulation and cognitive decline.
This study, leveraging autopsy and neuroimaging data across various stages of AD, offers crucial insights for developing targeted therapies.
Cell-Type Specific Genetic Risks: The study identifies how genetic risks in astrocytes and microglia correlate with different phases of Alzheimer’s disease progression.
Advanced Sequencing Technique: Single nucleus RNA sequencing was utilized to assess cell-specific AD polygenic risk scores, enhancing the understanding of disease mechanisms.
Implications for Targeted Treatments: These findings open new avenues for developing treatments that specifically target the genetic risks associated with different cell types in the brain.
Source: Brigham and Women’s Hospital
Developing treatments for Alzheimer’s disease (AD) is difficult because complex underlying mechanisms drive different types of cells that may contribute to the disorder.
Microglia and astrocytes, resident immune and support cells in the central nervous system, are known to exclusively express several genes linked to risk of AD — particularly AD dementia.
However, it was previously unclear exactly how and when these genetic risk factors contributed to other, distinct stages of AD progression, such as the accumulation of amyloid-β plaques and tau tangles.
Researchers led by a team at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, identified the impact of AD genetic risk specific to each major brain cell type on key disease processes.
They implemented single nucleus RNA sequencing to calculate cell-type-specific AD polygenic risk scores from two large clinical research study datasets.
Using autopsy data spanning all stages of disease severity, along with independent neuroimaging data from asymptomatic, preclinical stages of AD, the investigators were able to characterize the contributions of cell-specific risk genes.
Astrocyte-specific genetic risk contributed to earlier stages of disease progress, like amyloid-β accumulation, while microglia-specific risk played a part in later phases of plaque and tau tangle accumulation, and cognitive decline.
“Our results provide human evidence for how genetic risk in specific brain cells affects AD processes, some even before the onset of clinical symptoms.,” said Hyun-Sik Yang, MD, of the Department of Neurology. “Future studies could extend our technique to other aspects of AD or even other diseases, in order to help develop targeted treatments.”
About this Alzheimer’s disease and genetics research news
Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease
Many of the Alzheimer’s disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear.
Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes.
In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-β), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline.
In an independent neuroimaging dataset of cognitively unimpaired elderly (n = 2921), astrocytic ADPRS was associated with amyloid-β, and microglial ADPRS was associated with amyloid-β and tau, connecting cell-type-specific genetic risk with AD pathology even before symptom onset.
Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.