Sex Differences in Blood of Alzheimer’s and Parkinson’s Patients

Despite 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.

  • 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.

“The study by Grandke et al. makes a significant contribution to our understanding of sex-specific immune signatures in neurodegenerative diseases,” Enrico Glaab at the University of Luxembourg wrote to Alzforum. He believes the database could allow scientists to identify new blood biomarkers as well as to generate hypotheses about the effects of the peripheral immune system on neurodegeneration (comment below).

Sex Delta by Cell Type. 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).

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.]

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).

The authors next compared expression changes in blood of living patients with those measured in postmortem brain in two neurodegenerative disease datasets, the Religious Orders Study and Memory and Aging Project (ROSMAP) and ZEBRA, a meta-analysis of 33 scRNA-Seq studies (Flotho et al., 2024). Both include people with AD and PD, allowing for direct comparisons. Generally, there was little overlap between expression changes in blood and brain in MCI, AD, or PD. Even so, in men, 32 genes were altered from healthy control levels in all three datasets, though not always in the same direction. In women, eight genes were. Most of these are known AD risk factors, including those involved in the immune system, blood-brain barrier, microglia, and trafficking of proteins to the cell membrane.

“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

Comments

  1. This study makes a significant contribution to our understanding of sex-specific immune signatures in neurodegenerative diseases. The authors have created a comprehensive single-cell atlas of peripheral blood mononuclear cells from patients with Alzheimer's and Parkinson's diseases and mild cognitive impairment, as well as healthy controls.

    Of particular value is the scale of this resource, which surpasses previous datasets in both depth and breadth, with over 909,000 cells from 257 individuals in 290 samples. The finding that PD shows more pronounced sex differences than AD in peripheral immune cells is intriguing, especially the observation of opposite directional changes in cell types such as CD8+ T cells and plasma cells between men and women with PD.

    The identification of common pathways in both diseases suggests potential shared systemic mechanisms that could be further explored. The authors' efforts to integrate their peripheral findings with brain transcriptome data also provide valuable insights into potential communication between these compartments.

    The public web portal for this dataset will be a useful resource for researchers to generate and test hypotheses about immune contributions to neurodegeneration. While future analyses will need to further explore the influence of common confounders, such as body mass index and comorbidities, on the relevant molecular signatures, this dataset provides a strong foundation for such investigations. This resource may be particularly useful for identifying peripheral biomarkers with sex-specific relevance, developing more tailored therapeutic approaches, and understanding systemic contributions to neuroinflammation in these diseases.

    View all comments by Enrico Glaab

  2. A wealth of literature demonstrates that the arsenal of inflammatory responses in males is radically different from that in females. If one acknowledges that females experience giving birth, and that pain tolerance is regulated by inflammatory signaling loops, then it is less surprising that overall sex differences exist. Sex differences have previously been reported in the immune system of both preclinical animal models and clinical samples of PD; for example, it has been documented that there are more DEGs in PBMCs from female PD patients relative to HCs than the DEGs identified in males. The inclusion of other neurodegenerative diseases is particularly informative of sex-dependent disease processes.

    What is particularly striking from this manuscript is that PD appears to be the disease with the most sex-dependent PBMC phenotypes described. Particularly surprising is that male and female PD patients often exhibit phenotypes that do not positively correlate, and actually negatively correlate. For example, nearly all cell type frequencies reported in female PD PBMCs relative to HC PBMCs are downregulated, whereas a large majority of these are upregulated in male PD PBMCs. This is also reflected in the pathway enrichment analysis, with little to no overlap in enriched pathways identified in male versus female PD PBMCs. In contrast, AD and MCI, whilst exhibiting some sex-dependent differences, show a large degree of correlation between the sexes within disease group.

    One caveat is that the study does not compare ND to household non-ND controls, and our experience has been that comparisons with someone living in the same environment definitely influence the outcomes (Houser et al., 2018).

    Overall, this highlights the importance of understanding and appreciating sex-dependent phenotypes and underlying mechanisms in different neurodegenerative disease states, especially when considering the role of the immune system in disease etiology as a potential therapeutic target. It is likely there will be specific sex-dependent differences in the immune system that we will have to consider when targeting the immune system with potential therapy. 

    The web server that has been developed from this dataset will be a great benefit to the research community. It will allow fast, easy and relatively uncomplicated access to these large-scale findings. It will allow for easy visualization of gene-expression values and fast hypothesis testing. Furthermore, a small number of longitudinal samples existed for some patients which have been made accessible on this webserver, allowing researchers to easily monitor changes in DEGs overtime for quick hypothesis testing regarding contributions to disease progression.

    References:

    Houser MC, Chang J, Factor SA, Molho ES, Zabetian CP, Hill-Burns EM, Payami H, Hertzberg VS, Tansey MG. Stool immune profiles evince gastrointestinal inflammation in Parkinson's disease. Mov Disord. 2018 Mar 23; PubMed.

    View all comments by Malu G. Tansey View all comments by Rebecca Wallings

  3. I commend Grandke et al. for highlighting that their strongest pathway-level signal, "SRP-dependent cotranslational protein targeting to membrane," aligns with the gingipain hypothesis. This pathway primarily comprises ribosomal proteins, e.g. RPL*, RPS*, which are often dismissed as uninteresting or flagged as quality control artifacts.

    Some studies of Alzheimer’s disease and related neurodegenerative disorders even exclude these proteins from analyses despite their robust expression. However, the repeated appearance of these genes across multiple studies suggests a meaningful connection to Alzheimer’s disease. In my research on cholinergic nuclei and AD-associated hypometabolism (Patel et al., 2020; Patel et al., 2021), we observed elevated expression of this pathway. Furthermore, ribosomal protein-encoding genes mark dystrophic microglia (Nguyen et al., 2020) and microglia actively phagocytosing plaques (Grubman et al., 2021). While recent single-nucleus studies have not reported an increase in these microglia in AD brains, two independent spatial transcriptomics studies—recently covered by Alzforum—found enrichment of such microglia near plaques in human brains (Aug 2024 conference news; preprint: Avey et al., 2024). 

    The gingipain hypothesis posits that Porphyromonas gingivalis, a bacterium, and its gingipain proteases play a causal role in AD pathology (Dominy et al., 2019). Though controversial, the upregulation of ribosomal proteins in AD supports this hypothesis. A conservative study of the blood microbiome identified P. gingivalis as a transient member (Tan et al., 2023), supporting Grandke and colleagues' findings in blood. More directly, Niño et al. used spatial transcriptomics and single-cell RNA sequencing to link P. gingivalis infection in cancer cells to gene expression changes (Galeano Niño et al., 2022). They observed strong upregulation of ribosomal protein expression in infected cells, alongside ferritin chains (FTL and FTH1), which are also markers of dystrophic/ribosomal microglia.

    Notably, ribosomal proteins are short and enriched for the arginine and lysine residues that gingipains cleave (Patel et al., 2021), providing a perfect meal for this intracellular pathogen that’s on a protein diet. Another connection is the expression of ferritin chains that sequester iron, which P. gingivalis relies on for its characteristic black iron coat. Interestingly, Grandke et al. also found that the SRP ribosome pathway was the most frequently enriched pathway in males with Parkinson’s disease. Gingipains have been identified in the substantia nigra of Parkinson’s disease patients (Ermini et al., 2024) and interact with α-synuclein, suggesting a broader role in neurodegeneration.

    Given the presence of P. gingivalis in the blood, it’s worth considering whether Grandke et al. are detecting infected cells that contribute to neurodegenerative disease. Encouragingly, the Phase 2 SPRING Trial of LHP588 in P. gingivalis-positive Alzheimer’s disease has just recently started by Lighthouse Pharmaceuticals, offering potential clinical insights into targeting gingipains as a therapeutic strategy.

    From a data perspective, I applaud the authors for openly sharing their data on the Sequence Read Archive and providing a web-accessible browser. However, for bioinformaticians like myself, I recommend they also release intermediate count matrices and cell annotations. This would facilitate computational reuse without requiring others to process the raw reads from scratch.

    Conflict of Interest Statement: I have received consulting fees from Cortexyme Inc. and Keystone Bio, which focused on treating Alzheimer's disease by targeting P. gingivalis and its gingipain proteases.

    References:

    Patel S, Howard D, Man A, Schwartz D, Jee J, Felsky D, Pausova Z, Paus T, French L. Donor-Specific Transcriptomic Analysis of Alzheimer's Disease-Associated Hypometabolism Highlights a Unique Donor, Ribosomal Proteins and Microglia. eNeuro. 2020 Nov-Dec;7(6) Print 2020 Nov-Dec PubMed.

    Patel S, Howard D, Chowdhury N, Derieux C, Wellslager B, Yilmaz Ö, French L. Characterization of Human Genes Modulated by Porphyromonas gingivalis Highlights the Ribosome, Hypothalamus, and Cholinergic Neurons. Front Immunol. 2021;12:646259. Epub 2021 Jun 14 PubMed.

    Nguyen AT, Wang K, Hu G, Wang X, Miao Z, Azevedo JA, Suh E, Van Deerlin VM, Choi D, Roeder K, Li M, Lee EB. APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer's disease. Acta Neuropathol. 2020 Oct;140(4):477-493. Epub 2020 Aug 25 PubMed. Correction.

    Grubman A, Choo XY, Chew G, Ouyang JF, Sun G, Croft NP, Rossello FJ, Simmons R, Buckberry S, Landin DV, Pflueger J, Vandekolk TH, Abay Z, Zhou Y, Liu X, Chen J, Larcombe M, Haynes JM, McLean C, Williams S, Chai SY, Wilson T, Lister R, Pouton CW, Purcell AW, Rackham OJ, Petretto E, Polo JM. Transcriptional signature in microglia associated with Aβ plaque phagocytosis. Nat Commun. 2021 May 21;12(1):3015. PubMed.

    Avey DR, Ng B, Vialle RA, Kearns NA, Lopes Kd, Iatrou A, Tissera SD, Vyas H, Saunders DM, Flood DJ, Xu J, Tasaki S, Gaiteri C, Bennett DA, Wang Y. Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics. 2024 Sep 10 10.1101/2024.09.05.611566 (version 1) bioRxiv.

    Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, Nguyen M, Haditsch U, Raha D, Griffin C, Holsinger LJ, Arastu-Kapur S, Kaba S, Lee A, Ryder MI, Potempa B, Mydel P, Hellvard A, Adamowicz K, Hasturk H, Walker GD, Reynolds EC, Faull RL, Curtis MA, Dragunow M, Potempa J. Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019 Jan;5(1):eaau3333. Epub 2019 Jan 23 PubMed.

    Tan CC, Ko KK, Chen H, Liu J, Loh M, SG10K_Health Consortium, Chia M, Nagarajan N. No evidence for a common blood microbiome based on a population study of 9,770 healthy humans. Nat Microbiol. 2023 May;8(5):973-985. Epub 2023 Mar 30 PubMed.

    Galeano Niño JL, Wu H, LaCourse KD, Kempchinsky AG, Baryiames A, Barber B, Futran N, Houlton J, Sather C, Sicinska E, Taylor A, Minot SS, Johnston CD, Bullman S. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature. 2022 Nov;611(7937):810-817. Epub 2022 Nov 16 PubMed.

    Ermini F, Low VF, Song JJ, Tan AY, Faull RL, Dragunow M, Curtis MA, Dominy SS. Ultrastructural localization of Porphyromonas gingivalis gingipains in the substantia nigra of Parkinson's disease brains. NPJ Parkinsons Dis. 2024 Apr 25;10(1):90. PubMed.

    View all comments by Leon French

  4. Neurodegenerative diseases such as Alzheimer's dementia and Parkinson's disease are recognized as having a significant immune component, with many studies linking alterations in the peripheral immune system to disease progression (Hammond et al., 2019; Navarro et al., 2021; Pike et al., 2024; Parkinson Progression Marker Initiative, 2011). Various research groups have investigated the immune contributions from the genetics perspective by linking GWAS to cell-specific molecular mechanisms and candidate pathways. For instance, Fairfax et al. used purified monocytes and B cells to map cell-type-specific regulatory mechanisms, shedding light on immune-related disease susceptibility (Fairfax et al., 2012). Raj et al. further demonstrated that disease-associated genetic variants exhibit a polarization of cis-regulatory effects, with AD and PD susceptibility alleles being particularly enriched in monocyte-specific regulatory regions (Raj et al., 2014). 

    This study by Grandke et al. has generated a valuable resource by identifying cell-type-specific changes in peripheral blood mononuclear cells from individuals with AD and PD. The authors compared brain biomarkers with blood-derived cell-type-specific results, providing insights into how sex influences immune cell composition and gene expression patterns in neurodegenerative diseases. Sex differences in common neuropathologies have also been studied extensively and are of great importance in our search for biomarkers. To cite a few examples, Eissman et al.’s GWAS analysis identified a female-specific locus on chromosome 10, where the minor allele was associated with higher resilience scores among women (Eissman et al., 2022). More recently, they identified three sex-specific loci, including an X-chromosome locus associated with memory (Eissman et al., 2024). 

    The ability to explore blood gene expression at the single-cell level opens new avenues for identifying peripheral biomarkers for early disease detection and monitoring disease progression. This kind of research advances the field, as biomarkers are essential for treating people.

    References:

    Eissman JM, Archer DB, Mukherjee S, Lee ML, Choi SE, Scollard P, Trittschuh EH, Mez JB, Bush WS, Kunkle BW, Naj AC, Gifford KA, Alzheimer's Disease Neuroimaging Initiative (ADNI) | Alzheimer's Disease Genetics Consortium (ADGC) | The Alzheimer's Disease Sequencing Project (ADSP), Cuccaro ML, Cruchaga C, Pericak-Vance MA, Farrer LA, Wang LS, Schellenberg GD, Mayeux RP, Haines JL, Jefferson AL, Kukull WA, Keene CD, Saykin AJ, Thompson PM, Martin ER, Bennett DA, Barnes LL, Schneider JA, Crane PK, Hohman TJ, Dumitrescu L. Sex-specific genetic architecture of late-life memory performance. Alzheimers Dement. 2024 Feb;20(2):1250-1267. Epub 2023 Nov 20 PubMed.

    Eissman JM, Dumitrescu L, Mahoney ER, Smith AN, Mukherjee S, Lee ML, Scollard P, Choi SE, Bush WS, Engelman CD, Lu Q, Fardo DW, Trittschuh EH, Mez J, Kaczorowski CC, Hernandez Saucedo H, Widaman KF, Buckley RF, Properzi MJ, Mormino EC, Yang HS, Harrison TM, Hedden T, Nho K, Andrews SJ, Tommet D, Hadad N, Sanders RE, Ruderfer DM, Gifford KA, Zhong X, Raghavan NS, Vardarajan BN, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Alzheimer’s Disease Genetics Consortium (ADGC), A4 Study Team, Pericak-Vance MA, Farrer LA, Wang LS, Cruchaga C, Schellenberg GD, Cox NJ, Haines JL, Keene CD, Saykin AJ, Larson EB, Sperling RA, Mayeux R, Cuccaro ML, Bennett DA, Schneider JA, Crane PK, Jefferson AL, Hohman TJ. Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease. Brain. 2022 Jul 29;145(7):2541-2554. PubMed.

    Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A, Ellis P, Langford C, Vannberg FO, Knight JC. Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nat Genet. 2012 Mar 25;44(5):502-10. PubMed.

    Hammond TR, Marsh SE, Stevens B. Immune Signaling in Neurodegeneration. Immunity. 2019 Apr 16;50(4):955-974. PubMed.

    Parkinson Progression Marker Initiative. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol. 2011 Dec;95(4):629-35. Epub 2011 Sep 14 PubMed.

    Navarro E, Udine E, Lopes KP, Parks M, Riboldi G, Schilder BM, Humphrey J, Snijders GJ, Vialle RA, Zhuang M, Sikder T, Argyrou C, Allan A, Chao MJ, Farrell K, Henderson B, Simon S, Raymond D, Elango S, Ortega RA, Shanker V, Swan M, Zhu CW, Ramdhani R, Walker RH, Tse W, Sano M, Pereira AC, Ahfeldt T, Goate AM, Bressman S, Crary JF, de Witte L, Frucht S, Saunders-Pullman R, Raj T. Dysregulation of mitochondrial and proteolysosomal genes in Parkinson's disease myeloid cells. Nat Aging. 2021 Sep;1(9):850-863. Epub 2021 Sep 14 PubMed.

    Pike SC, Havrda M, Gilli F, Zhang Z, Salas LA. Immunological shifts during early-stage Parkinson's disease identified with DNA methylation data on longitudinally collected blood samples. NPJ Parkinsons Dis. 2024 Jan 11;10(1):21. PubMed.

    Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, Replogle JM, Feng T, Lee M, Asinovski N, Frohlich I, Imboywa S, Von Korff A, Okada Y, Patsopoulos NA, Davis S, McCabe C, Paik HI, Srivastava GP, Raychaudhuri S, Hafler DA, Koller D, Regev A, Hacohen N, Mathis D, Benoist C, Stranger BE, De Jager PL. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science. 2014 May 2;344(6183):519-23. PubMed.

    View all comments by Katia Lopes View all comments by David Bennett

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References

Paper Citations

  1. Carlisle SM, Qin H, Hendrickson RC, Muwanguzi JE, Lefkowitz EJ, Kennedy RE, Yan Z, Yacoubian TA, Benveniste EN, West AB, Harms AS, Standaert DG. Sex-based differences in the activation of peripheral blood monocytes in early Parkinson disease. NPJ Parkinsons Dis. 2021 Apr 13;7(1):36. PubMed.
  2. Flotho M, Amand J, Hirsch P, Grandke F, Wyss-Coray T, Keller A, Kern F. ZEBRA: a hierarchically integrated gene expression atlas of the murine and human brain at single-cell resolution. Nucleic Acids Res. 2024 Jan 5;52(D1):D1089-D1096. PubMed.

External Citations

  1. database

Further Reading

Primary Papers

  1. Grandke F, Fehlmann T, Kern F, Gate DM, Wolff TW, Leventhal O, Channappa D, Hirsch P, Wilson EN, Meese E, Liu C, Shi Q, Flotho M, Li Y, Chen C, Yu Y, Xu J, Junkin M, Wang Z, Wu T, Liu L, Hou Y, Andreasson KI, Gansen JS, Mass E, Poston K, Wyss-Coray T, Keller A. A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration. Nat Commun. 2025 Feb 25;16(1):1965. PubMed.

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