Alzheimer's disease (AD) is influenced by a complex interplay of genetic, immune, and metabolic factors. Identifying plasma proteins causally linked to AD could help clarify these pathways and uncover potential therapeutic targets.
Objective
This study aims to investigate the causal relationships between AD and plasma proteins.
Methods
We conducted a two-stage, two-sample Mendelian randomization (MR) analysis to explore the causal relationships between plasma protein levels and AD risk. In both stages, we used non-overlapping genome-wide association study datasets for exposures (plasma protein levels) and outcome (AD) to ensure robust and independent analyses. We examined both forward (from plasma proteins to AD risk) and reverse (from AD to plasma protein expression) causal effects to elucidate potential bidirectional relationships.
Results
Our MR analysis identified 25 plasma proteins with causal associations to AD, with many implicated in immune and lipid metabolic pathways. These findings reinforce the roles of inflammation and lipid metabolism in AD pathogenesis and offer novel insights into specific proteins that may serve as biomarkers or therapeutic targets.
Conclusions
This study provides further support for the relationship between immune and lipid metabolic dysregulation and AD, advancing our understanding of the molecular mechanisms underlying disease progression and highlighting key proteins for future research and therapeutic development.
ScheltensPDe StrooperBKivipeltoM, et al.Alzheimer's disease. Lancet2021; 397: 1577–1590.
3.
BatemanRJXiongCBenzingerTL, et al.Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med2012; 367: 795–804.
4.
VillemagneVLBurnhamSBourgeatP, et al.Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol2013; 12: 357–367.
5.
McDadeEWangGGordonBA, et al.Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology2018; 91: e1295–e1306.
6.
TherriaultJSchindlerSESalvadoG, et al.Biomarker-based staging of Alzheimer disease: rationale and clinical applications. Nat Rev Neurol2024; 20: 232–244.
7.
VillemagneVLDoreVBurnhamSC, et al.Imaging tau and amyloid-beta proteinopathies in Alzheimer disease and other conditions. Nat Rev Neurol2018; 14: 225–236.
8.
JohnsonECBBianSHaqueRU, et al.Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease. Nat Med2023; 29: 1979–1988.
9.
van der EndeELIn ‘t VeldSHanskampI, et al.CSF Proteomics in autosomal dominant Alzheimer's disease highlights parallels with sporadic disease. Brain2023; 146: 4495–4507.
10.
ShenYTimsinaJHeoG, et al.CSF Proteomics identifies early changes in autosomal dominant Alzheimer's disease. Cell2024; 187: 6309–6326.
11.
GunesSAizawaYSugashiT, et al.Biomarkers for Alzheimer's disease in the current state: a narrative review. Int J Mol Sci2022; 23: 4962.
12.
TeunissenCEVerberkIMWThijssenEH, et al.Blood-based biomarkers for Alzheimer's disease: towards clinical implementation. Lancet Neurol2022; 21: 66–77.
13.
HampelHO'BryantSEMolinuevoJL, et al.Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol2018; 14: 639–652.
14.
JanelidzeSMattssonNPalmqvistS, et al.Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Nat Med2020; 26: 379–386.
15.
OlssonBLautnerRAndreassonU, et al.CSF And blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol2016; 15: 673–684.
16.
OecklPHalbgebauerSAnderl-StraubS, et al.Glial fibrillary acidic protein in serum is increased in Alzheimer's disease and correlates with cognitive impairment. J Alzheimers Dis2019; 67: 481–488.
17.
PalmqvistSTidemanPMattsson-CarlgrenN, et al.Blood biomarkers to detect Alzheimer disease in primary care and secondary care. JAMA2024; 332: 1245–1257.
18.
LuYPikeJRChenJ, et al.Changes in Alzheimer disease blood biomarkers and associations with Incident all-cause dementia. JAMA2024; 332: 1258–1269.
19.
BurgessSButterworthAThompsonSG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol2013; 37: 658–665.
20.
Davey SmithGHemaniG. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet2014; 23: R89–R98.
21.
KunkleBWGrenier-BoleyBSimsR, et al.Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates abeta, tau, immunity and lipid processing. Nat Genet2019; 51: 414–430.
22.
BellenguezCKucukaliFJansenIE, et al.New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet2022; 54: 412–436.
23.
SunBBChiouJTraylorM, et al.Plasma proteomic associations with genetics and health in the UK Biobank. Nature2023; 622: 329–338.
24.
FerkingstadESulemPAtlasonBA, et al.Large-scale integration of the plasma proteome with genetics and disease. Nat Genet2021; 53: 1712–1721.
25.
WuYZhangCYLiuX, et al.Shared genetic architecture and causal relationship between sleep behaviors and lifespan. Transl Psychiatry2024; 14: 108.
26.
WuFHuangYHuJ, et al.Mendelian randomization study of inflammatory bowel disease and bone mineral density. BMC Med2020; 18: 312.
27.
YaoSZhangMDongSS, et al.Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression. Nat Hum Behav2022; 6: 1569–1576.
28.
PurcellSNealeBTodd-BrownK, et al.PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet2007; 81: 559–575.
29.
1000 Genomes Project Consortium, AutonABrooksLD, et al.A global reference for human genetic variation. Nature2015; 526: 68–74.
30.
LiuMJiangYWedowR, et al.Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet2019; 51: 237–244.
31.
VerbanckMChenCYNealeB, et al.Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet2018; 50: 693–698.
32.
BurgessSThompsonSGCollaborationCCG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol2011; 40: 755–764.
33.
GuoJYuKDongSS, et al.Mendelian randomization analyses support causal relationships between brain imaging-derived phenotypes and risk of psychiatric disorders. Nat Neurosci2022; 25: 1519–1527.
34.
PalmerTMLawlorDAHarbordRM, et al.Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res2012; 21: 223–242.
35.
HemaniGTillingKDavey SmithG. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet2017; 13: e1007081.
36.
HemaniGZhengJElsworthB, et al.The MR-Base platform supports systematic causal inference across the human phenome. Elife2018; 7: e34408.
37.
BowdenJSmithDHaycockG, , et al.Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol2016; 40: 304–314.
38.
BowdenJDavey SmithGBurgessS. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol2015; 44: 512–525.
39.
ZhaoQWangJHemaniG, et al.Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. Ann Stat2020; 48: 1742–1769.
40.
HartwigFPDavey SmithGBowdenJ. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol2017; 46: 1985–1998.
41.
BowdenJDel GrecoMFMinelliC, et al.Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol2019; 48: 728–742.
42.
BurgessSThompsonSG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol2017; 32: 377–389.
43.
OhMJangSYLeeJY, et al.The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism. Nat Commun2023; 14: 5728.
44.
FergusonJFHinkleCCMehtaNN, et al.Translational studies of lipoprotein-associated phospholipase A(2) in inflammation and atherosclerosis. J Am Coll Cardiol2012; 59: 764–772.
45.
HallstrandTSLaiYHooperKA, et al.Endogenous secreted phospholipase A2 group X regulates cysteinyl leukotrienes synthesis by human eosinophils. J Allergy Clin Immunol2016; 137: 268–277.
46.
AstudilloAMBalboaMABalsindeJ. Compartmentalized regulation of lipid signaling in oxidative stress and inflammation: plasmalogens, oxidized lipids and ferroptosis as new paradigms of bioactive lipid research. Prog Lipid Res2023; 89: 101207.
47.
BatraRKrumsiekJWangX, et al.Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy. Alzheimers Dement2024; 20: 8294–8307.
48.
MengHElliottAMansfieldJ, et al.Identification of tauopathy-associated lipid signatures in Alzheimer's disease mouse brain using label-free chemical imaging. Commun Biol2024; 7: 1341.
49.
Do CarmoSKautzmannMIBhattacharjeeS, et al.Differential effect of an evolving amyloid and tau pathology on brain phospholipids and bioactive lipid mediators in rat models of Alzheimer-like pathology. J Neuroinflammation2024; 21: 185.
50.
WangLYangZSatoshiF, et al.Membrane remodeling by FAM92A1 during brain development regulates neuronal morphology, synaptic function, and cognition. Nat Commun2024; 15: 6209.
51.
IncontroSMusellaMLSammariM, et al.Lipids shape brain function through ion channel and receptor modulations: physiological mechanisms and clinical perspectives. Physiol Rev2025; 105: 137–207.
52.
Campos-PenaVPichardo-RojasPSanchez-BarbosaT, et al.Amyloid beta, lipid metabolism, basal cholinergic system, and therapeutics in Alzheimer's disease. Int J Mol Sci2022; 23: 12092.
53.
LvSLZengZFGanWQ, et al.Lp-PLA2 inhibition prevents Ang II-induced cardiac inflammation and fibrosis by blocking macrophage NLRP3 inflammasome activation. Acta Pharmacol Sin2021; 42: 2016–2032.
54.
MurakamiMSatoHTaketomiY. Modulation of immunity by the secreted phospholipase A(2) family. Immunol Rev2023; 317: 42–70.
55.
ElahiFMCasalettoKBLa JoieR, et al.Plasma biomarkers of astrocytic and neuronal dysfunction in early- and late-onset Alzheimer's disease. Alzheimers Dement2020; 16: 681–695.
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