Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that predominantly affects elderly individuals across the globe. While genetic, environmental, and lifestyle factors are known to influence the onset of AD, the underlying mechanisms remain unclear.
Objective
To elucidate the intricate interplay between metabolites and immune cell activation in the ethology of AD, and to determine their collective impact on AD risk.
Methods
We conducted a comprehensive analysis of genome-wide association studies data to examine the relationships between metabolites, immune cell phenotypes, and the risk of AD. Our study encompassed a comprehensive examination involving 731 distinct immune cell types, 1400 metabolites, and a large cohort comprising10,520 AD cases with 401,661 controls. We employed univariate Mendelian randomization to assess bidirectional relationships between metabolites and AD, metabolites and immune cells, as well as immune cells and AD. Subsequently, multivariate Mendelian randomization was then applied to evaluate the potential mediating role of immune cells on the relationship between metabolites and AD.
Results
Specific metabolites, the histidine/pyruvate ratio and homoarginine, were positively associated with the risk of AD, mediated by immune cells. Conversely, 4-hydroxycoumarin and glycolithocholate sulfate showed protective associations against AD. Immune cell markers, CD64 on monocytes and HLA DR on CD14+ CD16− monocytes were linked to higher AD risk, while CD33dim HLA DR+ CD11b− myeloid cells and HLA DR on CD8+ T cells were protective.
Conclusions
This study highlights the critical role of immune cells in the pathogenesis of AD, demonstrating how their interaction with specific metabolites influences disease risk.
KorczynADGrinbergLT. Is Alzheimer disease a disease?Nat Rev Neurol2024; 20: 245–251.
4.
FernieARCarrariFSweetloveLJ. Respiratory metabolism: glycolysis, the TCA cycle and mitochondrial electron transport. Curr Opin Plant Biol2004; 7: 254–261.
5.
ZadkaLSochockaMHachiyaN, et al.Endocytosis and Alzheimer’s disease. Geroscience2024; 46: 71–85.
6.
PerluigiMDi DomenicoFButterfieldDA. Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease. Physiol Rev2024; 104: 103–197.
7.
GuoXYanLZhangD, et al.Passive immunotherapy for Alzheimer’s disease. Ageing Res Rev2024; 94: 102192.
8.
McMillanPJBenbowSJUhrichR, et al.Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change. Brain2023; 146: 3206–3220.
9.
BalusuSHorreKThruppN, et al.MEG3 Activates necroptosis in human neuron xenografts modeling Alzheimer’s disease. Science2023; 381: 1176–1182.
10.
BairamianDShaSRolhionN, et al.Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease. Mol Neurodegener2022; 17: 19.
11.
InoueYShueFBuG, et al.Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer’s disease. Mol Neurodegener2023; 18: 46.
12.
BrodatyHDonkinM. Family caregivers of people with dementia. Dialogues Clin Neurosci2009; 11: 217–228.
13.
BowdenJDavey SmithGBurgessS. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol2015; 44: 512–525.
14.
TeraoIKodamaW. Comparative efficacy, tolerability and acceptability of donanemab, lecanemab, aducanumab and lithium on cognitive function in mild cognitive impairment and Alzheimer’s disease: a systematic review and network meta-analysis. Ageing Res Rev2024; 94: 102203.
15.
MorrisMCEvansDABieniasJL, et al.Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA2002; 287: 3230–3237.
16.
ColcombeSJKramerAFEricksonKI, et al.Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U S A2004; 101: 3316–3321.
17.
LautenschlagerNTCoxKLFlickerL, et al.Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA2008; 300: 1027–1037.
18.
WilkinsJMTrushinaE. Application of metabolomics in Alzheimer’s disease. Front Neurol2017; 8: 719.
19.
AndersenJVSchousboeAVerkhratskyA. Astrocyte energy and neurotransmitter metabolism in Alzheimer’s disease: integration of the glutamate/GABA-glutamine cycle. Prog Neurobiol2022; 217: 102331.
20.
ChenZRHuangJBYangSL, et al.Role of cholinergic signaling in Alzheimer’s disease. Molecules2022; 27: 1816.
21.
CzapskiGAStrosznajderJB. Glutamate and GABA in microglia-neuron cross-talk in Alzheimer’s disease. Int J Mol Sci2021; 22: 11677.
22.
DejakaisayaHKwanPJonesNC. Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer’s disease. Epilepsia2021; 62: 1485–1493.
23.
AndersenJVMarkussenKHJakobsenE, et al.Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration. Neuropharmacology2021; 196: 108719.
24.
YinF. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. FEBS J2023; 290: 1420–1453.
25.
ColomboAVSadlerRKLloveraG, et al.Microbiota-derived short chain fatty acids modulate microglia and promote Abeta plaque deposition. Elife2021; 10: e59826.
26.
PantelopulosGAAbrahamCBStraubJE. Cholesterol and lipid rafts in the biogenesis of amyloid-beta protein and Alzheimer’s disease. Annu Rev Biophys2024; 53: 455–486.
27.
LeccaDJungYJScerbaMT, et al.Role of chronic neuroinflammation in neuroplasticity and cognitive function: a hypothesis. Alzheimers Dement2022; 18: 2327–2340.
28.
RijpmaAvan der GraafMLansbergenMM, et al.The medical food Souvenaid affects brain phospholipid metabolism in mild Alzheimer’s disease: results from a randomized controlled trial. Alzheimers Res Ther2017; 9: 51.
29.
BelangerMAllamanIMagistrettiPJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab2011; 14: 724–738.
30.
AshleighTSwerdlowRHBealMF. The role of mitochondrial dysfunction in Alzheimer’s disease pathogenesis. Alzheimers Dement2023; 19: 333–342.
31.
ChenXHoltzmanDM. Emerging roles of innate and adaptive immunity in Alzheimer’s disease. Immunity2022; 55: 2236–2254.
32.
KadryHNooraniBCuculloL. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS2020; 17: 69.
33.
ZenaroEPiacentinoGConstantinG. The blood-brain barrier in Alzheimer’s disease. Neurobiol Dis2017; 107: 41–56.
34.
YanPKimKWXiaoQ, et al.Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease. J Clin Invest2022; 132: e152565.
35.
LengFEdisonP. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?Nat Rev Neurol2021; 17: 157–172.
36.
JorfiMParkJHallCK, et al.Infiltrating CD8(+) T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model. Nat Neurosci2023; 26: 1489–1504.
37.
BowdenJHolmesMV. Meta-analysis and Mendelian randomization: a review. Res Synth Methods2019; 10: 486–496.
38.
Davey SmithGHemaniG. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet2014; 23: R89–R98.
39.
KurkiMIKarjalainenJPaltaP, et al.Finngen provides genetic insights from a well-phenotyped isolated population. Nature2023; 613: 508–518.
40.
SollisEMosakuAAbidA, et al.The NHGRI-EBI GWAS catalog: knowledgebase and deposition resource. Nucleic Acids Res2023; 51: D977–D985.
41.
ChenYLuTPettersson-KymmerU, et al.Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet2023; 55: 44–53.
42.
OrruVSteriMSidoreC, et al.Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet2020; 52: 1036–1045.
43.
LyonMSAndrewsSJElsworthB, et al.The variant call format provides efficient and robust storage of GWAS summary statistics. Genome Biol2021; 22: 32.
44.
VierstraJLazarJSandstromR, et al.Global reference mapping of human transcription factor footprints. Nature2020; 583: 729–736.
45.
HemaniGZhengJElsworthB, et al.The MR-base platform supports systematic causal inference across the human phenome. Elife2018; 7: e34408.
46.
BurgessSThompsonSG and CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol2011; 40: 755–764.
47.
BowdenJDavey SmithGHaycockPC, et al.Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol2016; 40: 304–314.
48.
BoehmFJZhouX. Statistical methods for Mendelian randomization in genome-wide association studies: a review. Comput Struct Biotechnol J2022; 20: 2338–2351.
49.
HemaniGTillingKDavey SmithG. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet2017; 13: e1007081.
50.
BogieJFJHaidarMKooijG, et al.Fatty acid metabolism in the progression and resolution of CNS disorders. Adv Drug Deliv Rev2020; 159: 198–213.
51.
YinFSanchetiHPatilI, et al.Energy metabolism and inflammation in brain aging and Alzheimer’s disease. Free Radic Biol Med2016; 100: 108–122.
52.
WangQDuanLLiX, et al.Glucose metabolism, neural cell senescence and Alzheimer’s disease. Int J Mol Sci2022; 23: 4351.
53.
JensenNJWodschowHZNilssonM, et al.Effects of ketone bodies on brain metabolism and function in neurodegenerative diseases. Int J Mol Sci2020; 21: 8767.
54.
HolecekM. Histidine in health and disease: metabolism, physiological importance, and use as a supplement. Nutrients2020; 12: 848.
55.
ShanLHofmanMAvan WamelenDJ, et al.Diurnal fluctuation in histidine decarboxylase expression, the rate limiting enzyme for histamine production, and its disorder in neurodegenerative diseases. Sleep2012; 35: 713–715.
56.
HirasawaN. Expression of histidine decarboxylase and its roles in inflammation. Int J Mol Sci2019; 20: 376.
57.
Martinez-ReyesIChandelNS. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun2020; 11: 102.
58.
Lepiarz-RabaIGbadamosiIFloreaR, et al.Metabolic regulation of microglial phagocytosis: implications for Alzheimer’s disease therapeutics. Transl Neurodegener2023; 12: 48.
59.
FuJLiJSunY, et al.In-depth investigation of the mechanisms of Schisandra chinensis polysaccharide mitigating Alzheimer’s disease rat via gut microbiota and feces metabolomics. Int J Biol Macromol2023; 232: 123488.
60.
WangCWangZZengB, et al.Fenton-like reaction of the iron(II)-histidine complex generates hydroxyl radicals: implications for oxidative stress and Alzheimer’s disease. Chem Commun (Camb)2021; 57: 12293–12296.
61.
RossiARigottoGValenteG, et al.Defective mitochondrial pyruvate flux affects cell bioenergetics in Alzheimer’s disease-related models. Cell Rep2020; 30: 2332–2348.e10.
62.
ChavaliVDAgarwalMVyasVK, et al.Neuroprotective effects of ethyl pyruvate against aluminum chloride-induced Alzheimer’s disease in rats via inhibiting toll-like receptor 4. J Mol Neurosci2020; 70: 836–850.
63.
PatelSDasAMeshramP, et al.Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein-protein interactions. Cell Biol Toxicol2021; 37: 653–678.
64.
ShaikhAYBjorklingFZabickaD, et al.Structure-activity study of oncocin: on-resin guanidinylation and incorporation of homoarginine, 4-hydroxyproline or 4,4-difluoroproline residues. Bioorg Chem2023; 141: 106876.
65.
ZyrekDWajdaACzechowiczP, et al.The antimicrobial activity of omiganan alone and in combination against Candida isolated from vulvovaginal candidiasis and bloodstream infections. Antibiotics (Basel)2021; 10: 1001.
66.
KochVGruenewaldLDGruber-RouhT, et al.Homoarginine in the cardiovascular system: pathophysiology and recent developments. Fundam Clin Pharmacol2023; 37: 519–529.
67.
AzargoonjahromiA. Dual role of nitric oxide in Alzheimer’s disease. Nitric Oxide2023; 134–135: 23–37.
68.
LiyPMPuziNNAJoseS, et al.Nitric oxide modulation in neuroinflammation and the role of mesenchymal stem cells. Exp Biol Med (Maywood)2021; 246: 2399–2406.
69.
SaresellaMMarventanoICalabreseE, et al.A complex proinflammatory role for peripheral monocytes in Alzheimer’s disease. J Alzheimers Dis2014; 38: 403–413.
70.
SicaAMantovaniA. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest2012; 122: 787–795.
71.
GeissmannFManzMGJungS, et al.Development of monocytes, macrophages, and dendritic cells. Science2010; 327: 656–661.
72.
AsmussenABuschHJHelbingT, et al.Monocyte subset distribution and surface expression of HLA-DR and CD14 in patients after cardiopulmonary resuscitation. Sci Rep2021; 11: 12403.
73.
MathanTSFigdorCGBuschowSI. Human plasmacytoid dendritic cells: from molecules to intercellular communication network. Front Immunol2013; 4: 372.
74.
YangYXWangQHuangHY, et al.New 5-methyl-4-hydroxycoumarin polyketide derivatives from Gerbera delavayi with anti-inflammatory activity. Fitoterapia2023; 169: 105568.
75.
ChenZZhongC. Oxidative stress in Alzheimer’s disease. Neurosci Bull2014; 30: 271–281.
76.
SweeneyMDMontagneASagareAP, et al.Vascular dysfunction-the disregarded partner of Alzheimer’s disease. Alzheimers Dement2019; 15: 158–167.
77.
Reszka-BlancoNJSivaramanVZhangL, et al.HIV-1 Env and Nef cooperatively contribute to plasmacytoid dendritic cell activation via CD4-dependent mechanisms. J Virol2015; 89: 7604–7611.
78.
CollinsSLPattersonAD. The gut microbiome: an orchestrator of xenobiotic metabolism. Acta Pharm Sin B2020; 10: 19–32.
79.
WangYXingXMaY, et al.Prevention of high-fat-diet-induced dyslipidemia by Lactobacillus plantarum LP104 through mediating bile acid enterohepatic axis circulation and intestinal flora. J Agric Food Chem2023; 71: 7334–7347.
80.
YinCXiaBTangS, et al.The effect of exogenous bile acids on antioxidant status and gut microbiota in heat-stressed broiler chickens. Front Nutr2021; 8: 747136.
81.
WuSRomero-RamirezLMeyJ. Taurolithocholic acid but not tauroursodeoxycholic acid rescues phagocytosis activity of bone marrow-derived macrophages under inflammatory stress. J Cell Physiol2022; 237: 1455–1470.
82.
CaiZQiaoPFWanCQ, et al.Role of blood-brain barrier in Alzheimer’s disease. J Alzheimers Dis2018; 63: 1223–1234.
83.
ArruvitoLPayaslianFBazP, et al.Identification and clinical relevance of naturally occurring human CD8 + HLA-DR+ regulatory T cells. J Immunol2014; 193: 4469–4476.
84.
WangYLuoYTangG, et al.HLA-DR Expression level in CD8(+) T cells correlates with the severity of children with acute infectious mononucleosis. Front Immunol2021; 12: 753290.
85.
LuegGGrossCCLohmannH, et al.Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer’s disease. Neurobiol Aging2015; 36: 81–89.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
