Print This PostDespite growing recognition of the importance of the peripheral immune system in neurodegenerative disease, little is known about how these blood cells change in Alzheimer’s and Parkinson’s diseases. In the February 25 Nature Communications, scientists led by Andreas Keller at Saarland University, Saarbrücken, Germany, and Tony Wyss-Coray at Stanford University, California, presented an overview. They analyzed gene expression in peripheral blood mononuclear cells (PBMCs) from 257 people using single-cell RNA-Seq. With nearly 1 million cells in the dataset, this is the largest study yet of PBMCs in AD, PD, and healthy controls.
Headlines
- scRNA-Seq study finds sex-specific changes in blood from Parkinson’s patients.
- Men and women with Alzheimer’s had similar expression changes in their blood.
- The data, covering almost 1 million blood cells, is available online.
Because AD is more prevalent in women, and PD in men, the authors paid particular attention to sex differences. For both diseases, the relative proportion of certain blood cell types changed in sex-specific ways. When the authors homed in on gene expression, they found few differences between men and women in AD, whereas in PD, many genes changed in opposite directions in each sex. The database is available online and includes a web interface that allows scientists to browse the findings for genes and pathways of interest. Scientists can also download the raw data.
In men with Alzheimer’s (top left), B cells (red boxes) were fewer (blue), while NK cells (blue boxes) were more abundant (red). In women (bottom), it was the opposite. Shown on the right are cell clusters determined by gene expression. [Courtesy of Grandke et al., Nature Communications, 2025.]
A previous bulk RNA-Seq analysis of peripheral monocytes from PD patients had reported that these cells were more inflamed in women than men (Carlisle et al., 2021), but there has not been a comprehensive survey of sex differences in blood from AD and PD patients.
To undertake this, first author Friederike Grandke at Saarland University used data from patients who were seen at the Stanford Alzheimer’s Disease Research Center. The cohort comprised 48 people clinically diagnosed with mild cognitive impairment, 46 with PD, 27 with AD, and 15 with MCI due to PD, as well as 121 healthy controls. Participants were predominantly white and in their early 70s.
The authors ran scRNA-Seq on a total of 909,322 blood cells. They identified 13 different cell types, with the predominant ones being T cells, B cells, natural killer and natural killer T-like cells, and monocytes. Many cell types were more, or less, prevalent in disease compared with healthy control blood, and several sex differences emerged. For example, in PD, the numbers of CD8+ T cells went up in men, but down in women. In AD, monocyte and NK cells went up in men but not women, while B cells went up in women but not men (image above).
Comparing gene expression in these cells to that of healthy controls, the authors found additional sex-specific effects. In AD and MCI patients, sex differences were minor. Most genes changed similarly in men and women. In PD, however, expression changes in the two sexes were either uncorrelated, or even moved in opposite directions. Overall, many more biological processes were perturbed in blood cells from men with PD than women (image above).
Malú Tansey and Rebecca Wallings at the University of Florida, Gainesville, found the extreme sex differences in PD surprising. However, they noted that the immune system is particularly prone to sex differences. “There is a wealth of literature demonstrating that the arsenal of inflammatory responses in males versus females is radically different,” they wrote (comment below).
PD Hits Men Harder. In blood from AD and MCI patients, gene expression changes versus healthy controls (HC) were similar in men and women, but in Parkinson’s patients (right), most changes were in men. [Courtesy of Grandke et al., Nature Communications, 2025.]
“Sex is a key factor influencing the molecular landscape of AD and PD,” Keller wrote to Alzforum. “These differences should be considered when investigating disease etiology and developing targeted therapies.”
Still, the authors noted that teasing out sex- and disease-specific gene signatures for Alzheimer’s disease will require even larger datasets. They are expanding the cohort and adding more matched blood and brain data from the same patients, in order to better integrate findings from these compartments into a comprehensive view of disease progression.—Madolyn Bowman Rogers
Shared from the Alz Forum – find the original and more at https://www.alzforum.org/news/research-news/sex-differences-blood-alzheimers-and-parkinsons-patients
Dementia Researcher
Alzheimer's Association