2021 Alzheimer’s disease facts and figures. Alzheimers Dement. 2021;17(3):327–406. https://alz-journals.onlinelibrary.wiley.com/action/showCitFormats?doi=10.1002%2Falz.12328.

Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science (New York, NY). 2002;297(5580):353–6.

Article  CAS  Google Scholar 

Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement. 2021;17(4):696–701.

Article  PubMed  Google Scholar 

Knopman DS, Perlmutter JS. Prescribing aducanumab in the face of meager efficacy and real risks. Neurology. 2021;97(11):545–7.

Article  PubMed  PubMed Central  Google Scholar 

van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in Early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21.

Article  PubMed  Google Scholar 

Le Page A, Dupuis G, Frost EH, Larbi A, Pawelec G, Witkowski JM, et al. Role of the peripheral innate immune system in the development of Alzheimer’s disease. Exp Gerontol. 2018;107:59–66.

Article  PubMed  Google Scholar 

Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21(3):383–421.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat TJ, Medeiros R. Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease. J Neuroinflammation. 2018;15(1):276.

Article  PubMed  PubMed Central  Google Scholar 

Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 2011;12(12):723–38.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Hong MS, Dan JM, Choi JY, Kang I. Age-associated changes in the frequency of naive, memory and effector CD8+ T cells. Mech Ageing Dev. 2004;125(9):615–8.

Article  PubMed  Google Scholar 

Lee N, Shin MS, Kang I. T-cell biology in aging, with a focus on lung disease. J Gerontol A Biol Sci Med Sci. 2012;67(3):254–63.

Article  PubMed  Google Scholar 

Keaney J, Campbell M. The dynamic blood-brain barrier. FEBS J. 2015;282(21):4067–79.

Article  PubMed  CAS  Google Scholar 

Kim HR, Hong MS, Dan JM, Kang I. Altered IL-7Ralpha expression with aging and the potential implications of IL-7 therapy on CD8+ T-cell immune responses. Blood. 2006;107(7):2855–62.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kim HR, Hwang KA, Kim KC, Kang I. Down-regulation of IL-7Ralpha expression in human T cells via DNA methylation. J Immunol. 2007;178(9):5473–9.

Article  PubMed  CAS  Google Scholar 

Shin MS, You S, Kang Y, Lee N, Yoo SA, Park K, et al. DNA Methylation regulates the differential expression of CX3CR1 on human IL-7Ralphalow and IL-7Ralphahigh effector memory CD8+ T cells with distinct migratory capacities to the fractalkine. J Immunol. 2015;195(6):2861–9.

Article  PubMed  CAS  Google Scholar 

Shin MS, Yim K, Moon K, Park HJ, Mohanty S, Kim JW, et al. Dissecting alterations in human CD8+ T cells with aging by high-dimensional single cell mass cytometry. Clin Immunol. 2019;200:24–30.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Shin MS, Park H-J, Young J, Kang I. Implication of IL-7 receptor alpha chain expression by CD8+ T cells and its signature in defining biomarkers in aging. Immunity Ageing. 2022;19(1):66.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Lee WW, Shin MS, Kang Y, Lee N, Jeon S, Kang I. The relationship of cytomegalovirus (CMV) infection with circulatory IFN-alpha levels and IL-7 receptor alpha expression on CD8+ T cells in human aging. Cytokine. 2012;58(3):332–5.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Park HJ, Shin MS, Kim M, Bilsborrow JB, Mohanty S, Montgomery RR, et al. Transcriptomic analysis of human IL-7 receptor alpha (low) and (high) effector memory CD8(+) T cells reveals an age-associated signature linked to influenza vaccine response in older adults. Aging Cell. 2019;18(4): e12960.

Article  PubMed  PubMed Central  Google Scholar 

Frisoni GB, Altomare D, Thal DR, Ribaldi F, van der Kant R, Ossenkoppele R, et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci. 2022;23(1):53–66.

Article  PubMed  CAS  Google Scholar 

Bettcher BM, Tansey MG, Dorothée G, Heneka MT. Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus. Nat Rev Neurol. 2021;17(11):689–701.

Article  PubMed  PubMed Central  Google Scholar 

Gate D, Saligrama N, Leventhal O, Yang AC, Unger MS, Middeldorp J, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature. 2020;577(7790):399–404.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Sood S, Gallagher IJ, Lunnon K, Rullman E, Keohane A, Crossland H, et al. A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status. Genome Biol. 2015;16:185.

Article  PubMed  PubMed Central  Google Scholar 

Nachun D, Ramos E, Karydas A, Dokuru D, Gao F, Yang Z, et al. Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders. bioRxiv. 2019:2019.12.13.875112. https://www.biorxiv.org/content/10.1101/2019.12.13.875112v1, https://doi.org/10.1101/2019.12.13.875112.

Niculescu AB, Le-Niculescu H, Roseberry K, Wang S, Hart J, Kaur A, et al. Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs. Mol Psychiatry. 2020;25(8):1651–72.

Article  PubMed  CAS  Google Scholar 

Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011;27(12):1739–40.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Shin HJ, Kim SH, Park HJ, Shin MS, Kang I, Kang MJ. Nucleotide-binding domain and leucine-rich-repeat-containing protein X1 deficiency induces nicotinamide adenine dinucleotide decline, mechanistic target of rapamycin activation, and cellular senescence and accelerates aging lung-like changes. Aging Cell. 2021;20(7): e13410.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Shin MS, Park HJ, Salahuddin S, Montgomery RR, Emu B, Shaw AC, et al. Alterations in high-dimensional T-cell profile and gene signature of immune aging in HIV-infected older adults without viremia. Aging Cell. 2022;21(10): e13702.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Zheng C, Zhou X-W, Wang J-Z. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Transl Neurodegener. 2016;5(1):7.

Article  PubMed  PubMed Central  Google Scholar 

Ng A, Tam WW, Zhang MW, Ho CS, Husain SF, McIntyre RS, et al. IL-1β, IL-6, TNF- α and CRP in Elderly patients with depression or Alzheimer’s disease: systematic review and meta-analysis. Sci Rep. 2018;8(1):12050.

Article  PubMed  PubMed Central  Google Scholar 

Krance SH, Wu C-Y, Zou Y, Mao H, Toufighi S, He X, et al. The complement cascade in Alzheimer’s disease: a systematic review and meta-analysis. Mol Psychiatry. 2021;26(10):5532–41.

Article  PubMed  Google Scholar 

Zuena AR, Casolini P, Lattanzi R, Maftei D. Chemokines in Alzheimer’s disease: new insights into prokineticins chemokine-like proteins. Front Pharmacol. 2019;10:622.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Reimand J, Isserlin R, Voisin V, Kucera M, Tannus-Lopes C, Rostamianfar A, et al. Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA Cytoscape and EnrichmentMap. Nat Protoc. 2019;14(2):482–517.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Ishigami A, Ohsawa T, Hiratsuka M, Taguchi H, Kobayashi S, Saito Y, et al. Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer’s disease. J Neurosci Res. 2005;80(1):120–8.

Article  PubMed  CAS  Google Scholar 

von Bernhardi R, Cornejo F, Parada GE, Eugenin J. Role of TGFbeta signaling in the pathogenesis of Alzheimer’s disease. Front Cell Neurosci. 2015;9:426.

Google Scholar 

Bachovchin DA, Cravatt BF. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat Rev Drug Discov. 2012;11(1):52–68.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular