The relationship between serum uric acid (UA) and Alzheimer’s disease (AD) risk still remained ambiguous despite extensive attempts.
Objective:
Via the two-sample Mendelian randomization (MR) design, we aimed to examine the bidirectional causal relationships of serum UA, gout, and the risk of AD.
Methods:
Genetic variants of UA, gout, and AD were extracted from published genome-wide association summary statistics. The inverse-variance weighted (IVW, the primary method), and several sensitivity methods (MR-Egger, weighted median, and weighted mode) were used to calculate the effect estimates. Egger regression, MR-PRESSO and leave-one-SNP-out analysis were performed to identify potential violations.
Results:
Genetic proxies for serum UA concentration [odds ratio (ORIVW) = 1.09, 95% confidence interval (CI) = 1.01–1.19, p = 0.031] were related with an increased risk of AD using 25 single nucleotide polymorphisms (SNPs). This causal effect was confirmed by sensitivity analyses including MR-Egger (1.22, 1.06–1.42, p = 0.014), weighted median (1.18, 1.05–1.33, p = 0.006), and weighted mode (1.20, 1.07–1.35, p = 0.005) methods. No evidence of notable directional pleiotropy and heterogeneity were identified (p > 0.05). Three SNPs (rs2078267, rs2231142, and rs11722228) significantly drove the observed causal effects. Supportive causal effect of genetically determined gout on AD risk was demonstrated using two SNPs (ORIVW = 1.05, 95% CI = 1.00–1.11, p = 0.057). No reverse causal effects of AD on serum UA levels and gout risk were found.
Conclusion:
The findings revealed a causal relationship between elevated serum UA level and AD risk. However, further research is still warranted to investigate whether serum UA could be a reliable biomarker and therapeutic target for AD.
EuserSM, HofmanA, WestendorpRG, BretelerMM (2009) Serum uric acid and cognitive function and dementia. Brain132, 377–382.
13.
LatourteA, SoumaréA, BardinT, Perez-RuizF, DebetteS, RichetteP (2018) Uric acid and incident dementia over 12 years of follow-up: A population-based cohort study. Ann Rheum Dis77, 328–335.
14.
RichetteP, Perez-RuizF, DohertyM, JansenTL, NukiG, PascualE, PunziL, SoAK, BardinT (2014) Improving cardiovascular and renal outcomes in gout: What should we target?Nat Rev Rheumatol10, 654–661.
15.
LuN, DubreuilM, ZhangY, NeogiT, RaiSK, AscherioA, HernánMA, ChoiHK (2016) Gout and the risk of Alzheimer’s disease: A population-based, BMI-matched cohort study. Ann Rheum Dis75, 547–551.
16.
HongJ-Y, LanT-Y, TangG-J, TangC-H, ChenT-J, LinH-Y (2015) Gout and the risk of dementia: A nationwide population-based cohort study. Arthritis Res Ther17.
17.
SinghJA, ClevelandJD (2018) Gout and dementia in the elderly: A cohort study of Medicare claims. BMC Geriatr18, 281.
18.
WalkerVM, Davey SmithG, DaviesNM, MartinRM (2017) Mendelian randomization: A novel approach for the prediction of adverse drug events and drug repurposing opportunities. Int J Epidemiol46, 2078–2089.
19.
BaumeisterSE, KarchA, BahlsM, TeumerA, LeitzmannMF, BaurechtH (2020) Physical activity and risk of Alzheimer disease: A 2-sample mendelian randomization study. Neurology95, e1897–e1905.
20.
HuangJ, ZuberV, MatthewsPM, ElliottP, TzoulakiJ, DehghanA (2020) Sleep, major depressive disorder, and Alzheimer disease: A Mendelian randomization study. Neurology95, e1963–e1970.
21.
AndrewsSJ, GoateA, AnsteyKJ (2020) Association between alcohol consumption and Alzheimer’s disease: A Mendelian randomization study. Alzheimers Dement16, 345–353.
AndrewsSJ, Fulton-HowardB, O’ReillyP, MarcoraE, GoateAM (2021) Causal associations between modifiable risk factors and the Alzheimer’s phenome. Ann Neurol89, 54–65.
24.
WilliamsDM, HäggS, PedersenNL (2019) Circulating antioxidants and Alzheimer disease prevention: A Mendelian randomization study. Am J Clin Nutr109, 90–98.
25.
EfstathiadouA, GillD, McGraneF, QuinnT, DawsonJ (2019) Genetically determined uric acid and the risk of cardiovascular and neurovascular diseases: A Mendelian randomization study of outcomes investigated in randomized trials. J Am Heart Assoc8, e012738.
WangZ, MengL, ShenL, JiHF (2020) Impact of modifiable risk factors on Alzheimer’s disease: A two-sample Mendelian randomization study. Neurobiol Aging91, 167.e111–167.e119.
28.
Davey SmithG, HemaniG (2014) Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Hum Mol Genet23, R89–98.
29.
DaviesNM, HolmesMV, Davey SmithG (2018) Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ362, k601.
30.
KöttgenA, AlbrechtE, TeumerA, VitartV, KrumsiekJ, HundertmarkC, PistisG, RuggieroD, O’SeaghdhaCM, HallerT, etal. (2012) Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet45, 145–154.
31.
KunkleBW, Grenier-BoleyB, SimsR, BisJC, DamotteV, NajAC, BolandA, VronskayaM, van der LeeSJ, Amlie-WolfA,et al. (2019) Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet51, 414–430.
32.
BowdenJ, Davey SmithG, BurgessS (2015) Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression. Int J Epidemiol44, 512–525.
33.
BurgessS, ButterworthA, ThompsonSG (2013) Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol37, 658–665.
34.
HemaniG, BowdenJ, Davey SmithG (2018) Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet27, R195–R208.
35.
HartwigFP, Davey SmithG, BowdenJ (2017) Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol46, 1985–1998.
36.
BowdenJ, Del GrecoMF, MinelliC, Davey SmithG, SheehanN, ThompsonJ (2017) A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Stat Med36, 1783–1802.
37.
BowdenJ, Del GrecosMF, MinelliC, ZhaoQ, LawlorDA, SheehanNA, ThompsonJ, Davey SmithG (2019) Improving the accuracy of two-sample summary-data Mendelian randomization: Moving beyond the NOME assumption. Int J Epidemiol48, 728–742.
38.
VerbanckM, ChenCY, NealeB, DoR (2018) Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet50, 693–698.
39.
PichlerI, Del GrecoM F, GögeleM, LillCM, BertramL, DoCB, ErikssonN, ForoudT, MyersRH; PD GWAS Consortium, NallsM, KellerMF; International Parkinson’s Disease Genomics Consortium; Wellcome Trust Case Control Consortium 2, BenyaminB, WhitfieldJB; Genetics of Iron Status Consortium, PramstallerPP, HicksAA, ThompsonJR, MinelliC (2013) Serum iron levels and the risk of Parkinson disease: A Mendelian randomization study. PLoS Med10, e1001462.
40.
BurgessS, ThompsonSG, CRP CHD Genetics Collaboration (2011) Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol40, 755–764.
41.
DuN, XuD, HouX, SongX, LiuC, ChenY, WangY, LiX (2016) Inverse association between serum uric acid levels and Alzheimer’s disease risk. Mol Neurobiol53, 2594–2599.
42.
CaoZ, XuC, YangH, LiS, XuF, ZhangY, WangY (2020) Associations of BMI and serum urate with developingdementia: A prospective cohort study. J Clin Endocrinol Metab105.
43.
ScheepersL, JacobssonLTH, KernS, JohanssonL, DehlinM, SkoogI (2019) Urate and risk of Alzheimer’s disease and vascular dementia: A population-based study. Alzheimers Dement15, 754–763.
44.
VerhaarenBF, VernooijMW, DehghanA, VroomanHA, de BoerR, HofmanA, WittemanJC, NiessenWJ, BretelerMM, van der LugtA, IkramMA (2013) The relation of uric acid to brain atrophy and cognition: The Rotterdam Scan Study. Neuroepidemiology41, 29–34.
45.
BeydounMA, CanasJA, DoreGA, BeydounHA, RostantOS, Fanelli-KuczmarskiMT, EvansMK, ZondermanAB (2016) Serum uric acid and its association with longitudinal cognitive change among urban adults. J Alzheimers Dis52, 1415–1430.
46.
LinL, ZhengLJ, Joseph SchoepfU, Varga-SzemesA, SavageRH, WangYF, ZhangH, ZhangXY, LuGM, ZhangLJ (2019) Uric acid has different effects on spontaneous brain activities of males and females: A cross-sectional resting-state functional MR imaging study. Front Neurosci13, 763.
47.
CiceroAF, DesideriG, GrossiG, UrsoR, RosticciM, D’AddatoS, BorghiC (2015) Serum uric acid and impaired cognitive function in a cohort of healthy young elderly: Data from the Brisighella Study. Intern Emerg Med10, 25–31.
48.
ZhangJ, TangL, HuJ, WangY, XuY (2020) Uric acid is associated with cognitive impairment in the elderly patients receiving maintenance hemodialysis-A two-center study. Brain Behav10, e01542.
49.
SuzukiK, KoideD, FujiiK, YamazakiT, TsujiS, IwataA (2016) Elevated serum uric acid levels are related to cognitive deterioration in an elderly Japanese population. Dement Geriatr Cogn Dis Extra6, 580–588.
QiaoM, ChenC, LiangY, LuoY, WuW, XuY (2021) The influence of serum uric acid level on Alzheimer’s disease: A narrative review. BioMed Res Int2021, 5525710.
56.
FeigDI, KangDH, JohnsonRJ (2008) Uric acid and cardiovascular risk. N Engl J Med359, 1811–1821.
57.
VannorsdallTD, JinnahHA, GordonB, KrautM, SchretlenDJ (2008) Cerebral ischemia mediates the effect of serum uric acid on cognitive function. Stroke39, 3418–3420.
58.
BorghiC, Rodriguez-ArtalejoF, De BackerG, DallongevilleJ, MedinaJ, NuevoJ, GuallarE, PerkJ, BanegasJR, TubachF, RoyC, HalcoxJP (2018) Serum uric acid levels are associated with cardiovascular risk score: A} analysis of the EURIKA study. Int J Cardiol253, 167–173.
59.
KanellisJ, KangDH (2005) Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Semin Nephrol25, 39–42.
60.
HershfieldMS, RobertsLJ, 2nd, GansonNJ, KellySJ, SantistebanI, ScarlettE, JaggersD, SundyJS (2010) Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant}. Proc Natl Acad Sci U S A107, 14351–14356.
61.
GibsonJ, RussTC, ClarkeTK, HowardDM, HillaryRF, EvansKL, WalkerRM, BerminghamML, MorrisSW, CampbellA, HaywardC, MurrayAD, PorteousDJ, HorvathS, LuAT, McIntoshAM, WhalleyHC, MarioniRE (2019) A meta-analysis of genome-wide association studies of epigenetic age acceleration. PLoS Genet15, e1008104.
YangJ, ZhangX, CaoJ, XuP, ChenZ, WangS, LiB, ZhangL, XieL, FangL, XuZ (2021) Circular RNA UBE2Q2 promotes malignant progression of gastric cancer by regulating signal transducer and activator of transcription 3-mediated autophagy and glycolysis. Cell Death Dis12, 910.
67.
MandalAK, MountDB (2019) Interaction between ITM2B and GLUT9 links urate transport to neurodegenerative disorders. Front Physiol10, 1323.
68.
ZahediAS, AkbarzadehM, Sedaghati-KhayatB, SeyedhamzehzadehA, DaneshpourMS (2021) GCKR common functional polymorphisms are associated with metabolic syndrome and its components: A 10-year retrospective cohort study in Iranian adults. Diabetol Metab Syndr13, 20.
69.
JianC, WeiL, MoR, LiR, LiangL, ChenL, ZouC, MengY, LiuY, ZouD (2021) Microglia mediate the occurrence and development of Alzheimer’s disease through ligand-receptor axis communication. Front Aging Neurosci13, 731180.
70.
GaoC, PatelCJ, MichailidouK, PetersU, GongJ, SchildkrautJ, SchumacherFR, ZhengW, BoffettaP, StuckerI, WillettW, GruberS, EastonDF, HunterDJ, SellersTA, HaimanC, HendersonBE, HungRJ, AmosC, PierceBL, LindströmS, KraftP (2016) Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer. Int J Epidemiol45, 896–908.
