Linking alcohol use to Alzheimer’s disease: Interactions with aging and APOE along immune pathways
Main Article Content
Abstract
Although it is known that APOE genotype is the strongest genetic risk factor for late-onset Alzheimer’s disease, development is a multifactorial process. Alcohol use is a contributor to the epidemic of Alzheimer’s disease and related dementias in the US and globally, yet mechanisms are not fully understood. Carriers of the APOE ε 4 allele show elevated risk of dementia in relation to several lifestyle factors, including alcohol use. In this review, we describe how alcohol interacts with APOE genotype and aging with potential implications for Alzheimer’s disease promotion. Age-related immune senescence and “inflammaging” (i.e., low-grade inflammation associated with aging) are increasingly recognized as contributors to age-related disease. We focus on three immune pathways that are likely contributors to Alzheimer’s disease development, centering on alcohol and APOE genotype interactions, specifically: 1) microbial translocation and immune activation, 2) the senescence associated secretory phenotype, and 3) neuroinflammation. First, microbial translocation, the unphysiological movement of gut products into systemic circulation, elicits a proinflammatory response and increases with aging, with proposed links to Alzheimer’s disease. Second, the senescence associated secretory phenotype is a set of intercellular signaling factors, e.g., proinflammatory cytokines and chemokines, growth regulators, and proteases, that drives cellular aging when senescent cells remain metabolically active. The senescence associated secretory phenotype can drive development of aging-diseases such as Alzheimer’s disease. Third, neuroinflammation occurs via numerous mechanisms such as microglial activation and is gaining recognition as an etiological factor in the development of Alzheimer’s disease. This review focuses on interactions of alcohol with APOE genotype and aging along these three pathways that may promote Alzheimer’s disease. Further research on these processes may inform development of strategies to prevent onset and progression of Alzheimer’s disease and to delay associated cognitive decline.
Keywords:
alcohol, heavy drinking, moderate drinking, Alzheimer’s disease, APOE genotype, immune system, neuroinflammation, microbial translocation, senescence associated secretory phenotype
Article Details
How to Cite
MONNIG, Mollie; SHAH, Krish.
Linking alcohol use to Alzheimer’s disease: Interactions with aging and APOE along immune pathways.
Medical Research Archives, [S.l.], v. 12, n. 8, aug. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5228>. Date accessed: 04 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i8.5228.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Association A. 2023 Alzheimer's disease facts and figures. Alzheimers Dement. Apr 2023;19(4):15 98-1695. doi:10.1002/alz.13016
2. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. Aug 1993;43(8):1467-72. doi:10.1212/wnl.43.8.1467
3. Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. Oct 2009;41(10):1088-93. doi:10.1038/ng.440
4. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Jama. Oct 22-29 1997;278(16):1349-56.
5. Neu SC, Pa J, Kukull W, et al. Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol. Oct 1 2017;74(10):1178-1189. doi:10.1001/jamaneurol.2 017.2188
6. Rawle MJ, Davis D, Bendayan R, Wong A, Kuh D, Richards M. Apolipoprotein-E (Apoe) epsilon4 and cognitive decline over the adult life course. Transl Psychiatry. Jan 10 2018;8(1):18. doi:10.103 8/s41398-017-0064-8
7. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science (New York, NY). Apr 1992;256(5054):184-5. doi:10.1126/ science.1566067
8. Zhao Y, Cong L, Jaber V, Lukiw WJ. Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of Alzheimer's Disease Brain. Frontiers in immunology. 2017;8:1064. doi:10.3389/fimmu.2017.01064
9. Zhan X, Stamova B, Jin LW, DeCarli C, Phinney B, Sharp FR. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology. Nov 29 2016;87(22):2324-2332. doi:10.1212/wnl.0000000000003391
10. Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer's Disease. J Neurogastroenterol Motil. Jan 31 2019;25(1):48-60. doi:10.5056/jnm18087
11. Substance Abuse and Mental Health Services Administration (SAMHSA). 2018 National Survey on Drug Use and Health (NSDUH). Rockville, MD: SAMHSA; 2019.
12. Grant BF, Chou SP, Saha TD, et al. Prevalence of 12-Month Alcohol Use, High-Risk Drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: Results From the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry. 09 01 2017;74(9):911-923. doi:10.1001/jamapsychiatry.2 017.2161
13. Luján M, Gallego M, Belmonte Y, et al. Influence of pneumococcal serotype group on outcome in adults with bacteraemic pneumonia. Eur Respir J. Nov 2010;36(5):1073-9. doi:10.1183/ 09031936.00176309
14. Chosy EJ, Edland S, Launer L, White LR. Midlife alcohol consumption and later life cognitive impairment: Light drinking is not protective and APOE genotype does not change this relationship. PLoS One. 2022;17(3):e0264575. doi:10.1371/ journal.pone.0264575
15. Lao Y, Hou L, Li J, Hui X, Yan P, Yang K. Association between alcohol intake, mild cognitive impairment and progression to dementia: a dose-response meta-analysis. Aging Clin Exp Res. May 2021;33(5):1175-1185. doi:10.1007/s40520-020-01605-0
16. Holahan CJ, Schutte KK, Brennan PL, Holahan CK, Moos RH. Episodic heavy drinking and 20-year total mortality among late-life moderate drinkers. Alcohol Clin Exp Res. May 2014;38(5):1432-8. doi:10.1111/acer.12381
17. Lassen MCH, Skaarup KG, Sengeløv M, et al. Alcohol Consumption and the Risk of Acute Respiratory Distress Syndrome in COVID-19. Ann Am Thorac Soc. Jun 2021;18(6):1074-1076. doi:10.1513/AnnalsATS.202008-988RL
18. Ha VT, Nguyen TN, Nguyen TX, et al. Prevalence and Factors Associated with Falls among Older Outpatients. International journal of environmental research and public health. Apr 12 2021;18(8)doi:10.3390/ijerph18084041
19. Kojima G, Iliffe S, Liljas A, Walters K. Non-linear association between alcohol and incident frailty among community-dwelling older people: A dose-response meta-analysis. Biosci Trends. Nov 20 2017;11(5):600-602. doi:10.5582/bst.2017.01237
20. Merrick ES, Hodgkin D, Garnick DW, et al. Older adults' inpatient and emergency department utilization for ambulatory-care-sensitive conditions: relationship with alcohol consumption. J Aging Health. Feb 2011;23(1):86-111. doi:10.1177/08982 64310383156
21. Tan GJ, Tan MP, Luben RN, Wareham NJ, Khaw KT, Myint PK. The relationship between alcohol intake and falls hospitalization: Results from the EPIC-Norfolk. Geriatr Gerontol Int. Aug 2021;21(8):657-663. doi:10.1111/ggi.14219
22. Population Reference Bureau. Population Bulletin. vol 70, No. 2. 2015.
23. Schwarzinger M, Pollock BG, Hasan OSM, Dufouil C, Rehm J, Group QS. Contribution of alcohol use disorders to the burden of dementia in France 2008-13: a nationwide retrospective cohort study. Lancet Public Health. 03 2018;3(3):e124-e132. doi:10.1016/S2468-2667(18)30022-7
24. Zilkens RR, Bruce DG, Duke J, Spilsbury K, Semmens JB. Severe psychiatric disorders in mid-life and risk of dementia in late- life (age 65-84 years): a population based case-control study. Curr Alzheimer Res. 2014;11(7):681-93. doi:10.2174/1 567205011666140812115004
25. Harwood DG, Kalechstein A, Barker WW, et al. The effect of alcohol and tobacco consumption, and apolipoprotein E genotype, on the age of onset in Alzheimer's disease. Int J Geriatr Psychiatry. May 2010;25(5):511-8. doi:10.1002/ gps.2372
26. Guggenmos M, Schmack K, Sekutowicz M, et al. Quantitative neurobiological evidence for accelerated brain aging in alcohol dependence. Transl Psychiatry. Dec 11 2017;7(12):1279. doi:10.1038/s41398-017-0037-y
27. Xu W, Wang H, Wan Y, et al. Alcohol consumption and dementia risk: a dose-response meta-analysis of prospective studies. European journal of epidemiology. Jan 2017;32(1):31-42. doi:10.1007/s10654-017-0225-3
28. Anstey KJ, Mack HA, Cherbuin N. Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies. Am J Geriatr Psychiatry. Jul 2009;17(7):542 -55. doi:10.1097/JGP.0b013e3181a2fd07
29. Rehm J, Hasan OSM, Black SE, Shield KD, Schwarzinger M. Alcohol use and dementia: a systematic scoping review. Alzheimers Res Ther. 01 2019;11(1):1. doi:10.1186/s13195-018-0453-0
30. Love SM, North KE, Zeng D, et al. Nine-Year Ethanol Intake Trajectories and Their Association With 15-Year Cognitive Decline Among Black and White Adults. Am J Epidemiol. Aug 1 2020;189(8): 788-800. doi:10.1093/aje/kwaa006
31. Angebrandt A, Abulseoud OA, Kisner M, et al. Dose-dependent relationship between social drinking and brain aging. Neurobiol Aging. Mar 2022;111:71-81. doi:10.1016/j.neurobiolaging.202 1.11.008
32. Topiwala A, Allan CL, Valkanova V, et al. Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study. Bmj. Jun 6 2017;357:j23 53. doi:10.1136/bmj.j2353
33. Hassing LB. Light Alcohol Consumption Does Not Protect Cognitive Function: A Longitudinal Prospective Study. Front Aging Neurosci. 2018;10: 81. doi:10.3389/fnagi.2018.00081
34. Daviet R, Aydogan G, Jagannathan K, et al. Associations between alcohol consumption and gray and white matter volumes in the UK Biobank. Nat Commun. Mar 4 2022;13(1):1175. doi:10.1038 /s41467-022-28735-5
35. Corella D, Portoles O, Arriola L, et al. Saturated fat intake and alcohol consumption modulate the association between the APOE polymorphism and risk of future coronary heart disease: a nested case-control study in the Spanish EPIC cohort. J Nutr Biochem. May 2011;22(5):487-94. doi:10.1016/j.jnutbio.2010.04.003
36. Mukamal KJ, Chung H, Jenny NS, et al. Alcohol use and risk of ischemic stroke among older adults: the cardiovascular health study. Stroke. Sep 2005;36(9):1830-4. doi:10.1161/01.ST R.0000177587.76846.89
37. Kivipelto M, Rovio S, Ngandu T, et al. Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: a population-based study. J Cell Mol Med. Dec 2008;12(6b):2762-71. doi:10.1111/j.158 2-4934.2008.00296.x
38. Anttila T, Helkala EL, Viitanen M, et al. Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study. Bmj. Sep 4 2004;329(7465):539. doi:10.1136/bmj.38181.4189 58.BE
39. Mukamal KJ, Kuller LH, Fitzpatrick AL, Longstreth WT, Jr., Mittleman MA, Siscovick DS. Prospective study of alcohol consumption and risk of dementia in older adults. Jama. Mar 19 2003;28 9(11):1405-13. doi:10.1001/jama.289.11.1405
40. Dufouil C, Tzourio C, Brayne C, Berr C, Amouyel P, Alperovitch A. Influence of apolipoprotein E genotype on the risk of cognitive deterioration in moderate drinkers and smokers. Epidemiology (Cambridge, Mass). May 2000;11(3): 280-4. doi:10.1097/00001648-200005000-00009
41. Downer B, Zanjani F, Fardo DW. The relationship between midlife and late life alcohol consumption, APOE e4 and the decline in learning and memory among older adults. Alcohol Alcohol. Jan-Feb 2014;49(1):17-22. doi:10.1093/alcalc/agt144
42. Herring D, Paulson D. Moderate alcohol use and apolipoprotein E-4 (ApoE-4): Independent effects on cognitive outcomes in later life. J Clin Exp Neuropsychol. May 2018;40(4):326-337. doi:1 0.1080/13803395.2017.1343803
43. Reas ET, Laughlin GA, Bergstrom J, Kritz-Silverstein D, Barrett-Connor E, McEvoy LK. Effects of APOE on cognitive aging in community-dwelling older adults. Neuropsychology. Mar 2019;33(3):40 6-416. doi:10.1037/neu0000501
44. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. Jun 2014;69 Suppl 1:S4-9. doi:10.1093/gerona /glu057
45. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. Oct 2018;14(10):576-590. doi:10.1 038/s41574-018-0059-4
46. Sullivan EV, Pfefferbaum A. Brain-behavior relations and effects of aging and common comorbidities in alcohol use disorder: A review. Neuropsychology. Sep 2019;33(6):760-780. doi:10 .1037/neu0000557
47. Sklar AL, Gilbertson R, Boissoneault J, Prather R, Nixon SJ. Differential effects of moderate alcohol consumption on performance among older and younger adults. Alcohol Clin Exp Res. Dec 2012;36(12):2150-6. doi:10.1111/j.1530-0277.201 2.01833.x
48. Boissoneault J, Sklar A, Prather R, Nixon SJ. Acute effects of moderate alcohol on psychomotor, set shifting, and working memory function in older and younger social drinkers. J Stud Alcohol Drugs. Sep 2014;75(5):870-9. doi:10. 15288/jsad.2014.75.870
49. Garcia CC, Lewis B, Boissoneault J, Nixon SJ. Effects of Age and Acute Moderate Alcohol Consumption on Electrophysiological Indices of Attention. J Stud Alcohol Drugs. May 2020;81(3):3 72-383. doi:10.15288/jsad.2020.81.372
50. Lewis B, Boissoneault J, Gilbertson R, Prather R, Nixon SJ. Neurophysiological correlates of moderate alcohol consumption in older and younger social drinkers. Alcohol Clin Exp Res. Jun 2013;37(6):941-51. doi:10.1111/acer.12055
51. Keshavarzian A, Farhadi A, Forsyth CB, et al. Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. Journal of hepatology. Mar 2009;50:538-47. doi:10.1016/j.jhep.2008.10.028 10.1016/j.jhep.2008.10.028. Epub 2008 Dec 29.
52. Mutlu E, Keshavarzian A, Engen P, Forsyth CB, Sikaroodi M, Gillevet P. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol Clin Exp Res. Oct 2009;33:1836-46. doi:10.1111/j.1530 -0277.2009.01022.x 10.1111/j.1530-0277.2009.01 022.x. Epub 2009 Jul 23.
53. Banan A, Fields JZ, Decker H, Zhang Y, Keshavarzian A. Nitric oxide and its metabolites mediate ethanol-induced microtubule disruption and intestinal barrier dysfunction. The Journal of pharmacology and experimental therapeutics. Sep 2000;294(3):997-1008.
54. Bull-Otterson L, Feng W, Kirpich I, et al. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PloS one. 2013;8:e53028. doi:10.1371/ journal.pone.0053028 10.1371/journal.pone.0053 028. Epub 2013 Jan 9.
55. Park BS, Lee JO. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med. 2013;45:e66. doi:10.1038/emm. 2013.97
56. Wurfel MM, Wright SD. Lipopolysaccharide (LPS) binding protein catalyzes binding of LPS to lipoproteins. Progress in clinical and biological research. 1995;392:287-95.
57. Pugin J, Schürer-Maly CC, Leturcq D, Moriarty A, Ulevitch RJ, Tobias PS. Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci U S A. Apr 1993;90(7):2744-8. doi:10.1073/pnas.90.7.2744
58. De Groote D, Zangerle PF, Gevaert Y, et al. Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation. Cytokine. May 1992;4(3):239-48.
59. Colotta F, Borre A, Wang JM, et al. Expression of a monocyte chemotactic cytokine by human mononuclear phagocytes. J Immunol. Feb 01 1992;148(3):760-5.
60. Kirpich IA, McClain CJ, Vatsalya V, et al. Liver Injury and Endotoxemia in Male and Female Alcohol-Dependent Individuals Admitted to an Alcohol Treatment Program. Alcohol Clin Exp Res. Apr 2017;41(4):747-757. doi:10.1111/acer.13346
61. Schafer C, Parlesak A, Schutt C, Bode JC, Bode C. Concentrations of lipopolysaccharide-binding protein, bactericidal/permeability-increasing protein, soluble CD14 and plasma lipids in relation to endotoxaemia in patients with alcoholic liver disease. Alcohol Alcohol. Jan-Feb 2002;37(1):81-6.
62. Urbaschek R, McCuskey RS, Rudi V, et al. Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease. Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Alcohol Clin Exp Res. Feb 2001;25(2):261-8.
63. Leclercq S, Cani PD, Neyrinck AM, et al. Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. Brain Behav Immun. Aug 2012;26:911-8. doi:10.1016/j.bbi.2012.04.001 10. 1016/j.bbi.2012.04.001. Epub 2012 Apr 10.
64. Frank J, Witte K, Schrodl W, Schutt C. Chronic alcoholism causes deleterious conditioning of innate immunity. Alcohol Alcohol. Sep-Oct 2004;39(5):386-92. doi:10.1093/alcalc/agh083
65. Liangpunsakul S, Toh E, Ross RA, et al. Quantity of alcohol drinking positively correlates with serum levels of endotoxin and markers of monocyte activation. Sci Rep. Jun 2017;7(1):4462. doi:10.1038/s41598-017-04669-7
66. Afshar M, Richards S, Mann D, et al. Acute immunomodulatory effects of binge alcohol ingestion. Alcohol. Feb 2015;49(1):57-64. doi:10.1 016/j.alcohol.2014.10.002
67. Gonzalez-Quintela A, Dominguez-Santalla MJ, Perez LF, Vidal C, Lojo S, Barrio E. Influence of acute alcohol intake and alcohol withdrawal on circulating levels of IL-6, IL-8, IL-10 and IL-12. Cytokine. Sep 2000;12(9):1437-40. doi:10.1006/ cyto.2000.0715
68. Donnadieu-Rigole H, Pansu N, Mura T, et al. Beneficial Effect of Alcohol Withdrawal on Gut Permeability and Microbial Translocation in Patients with Alcohol Use Disorder. Alcohol Clin Exp Res. Jan 2018;42(1):32-40. doi:10.1111/acer.13527
69. Portelli J, Wiers CE, Li X, et al. Peripheral proinflammatory markers are upregulated in abstinent alcohol-dependent patients but are not affected by cognitive bias modification: Preliminary findings. Drug Alcohol Depend. Nov 1 2019;204: 107553. doi:10.1016/j.drugalcdep.2019.107553
70. Bala S, Marcos M, Gattu A, Catalano D, Szabo G. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PloS one. 2014;9(5):e96864. doi:10.1371/journal .pone.0096864
71. de Jong WJ, Cleveringa AM, Greijdanus B, Meyer P, Heineman E, Hulscher JB. The effect of acute alcohol intoxication on gut wall integrity in healthy male volunteers; a randomized controlled trial. Alcohol. Feb 2015;49(1):65-70. doi:10.1016/ j.alcohol.2014.09.033
72. Barr T, Helms C, Grant K, Messaoudi I. Opposing effects of alcohol on the immune system. Prog Neuropsychopharmacol Biol Psychiatry. Feb 4 2016;65:242-51. doi:10.1016/ j.pnpbp.2015.09.001
73. Mendenhall CL, Theus SA, Roselle GA, Grossman CJ, Rouster SD. Biphasic in vivo immune function after low- versus high-dose alcohol consumption. Alcohol. May-Jun 1997;14(3):255-60. doi:10.1016/s0741-8329(96)00150-4
74. Sureshchandra S, Raus A, Jankeel A, et al. Dose-dependent effects of chronic alcohol drinking on peripheral immune responses. Sci Rep. May 2019;9(1):7847. doi:10.1038/s41598-019-44302-3
75. de Bont N, Netea MG, Demacker PN, et al. Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection. J Lipid Res. Apr 1999;40(4):680-5.
76. Van Oosten M, Rensen PC, Van Amersfoort ES, et al. Apolipoprotein E protects against bacterial lipopolysaccharide-induced lethality. A new therapeutic approach to treat gram-negative sepsis. The Journal of biological chemistry. Mar 23 2001; 276(12):8820-4. doi:10.1074/jbc.M009915200
77. Vitek MP, Brown CM, Colton CA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging. Sep 2009;30( 9):1350-60. doi:10.1016/j.neurobiolaging.2007.11.014
78. Ringman JM, Elashoff D, Geschwind DH, et al. Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype. Arch Neurol. Jun 2012;69(6):757-64. doi:10.1001/archneurol.2012.277
79. den Hartigh LJ, Altman R, Hutchinson R, et al. Postprandial apoE isoform and conformational changes associated with VLDL lipolysis products modulate monocyte inflammation. PloS one. 2012; 7(11):e50513. doi:10.1371/journal.pone.0050513
80. Gale SC, Gao L, Mikacenic C, et al. APOepsilon4 is associated with enhanced in vivo innate immune responses in human subjects. J Allergy Clin Immunol. Jul 2014;134(1):127-34. doi:10.1016/j.jaci.2014.01.032
81. Tao Q, Ang TFA, DeCarli C, et al. Association of Chronic Low-grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers. JAMA Netw Open. 10 2018;1(6):e183597. doi:10.1001/jamanet workopen.2018.3597
82. Mukamal KJ, Jenny NS, Tracy RP, Siscovick DS. Alcohol consumption, interleukin-6 and apolipoprotein E genotypes, and concentrations of interleukin-6 and serum amyloid P in older adults. Am J Clin Nutr. Aug 2007;86(2):444-50. doi:10.10 93/ajcn/86.2.444
83. Kim KA, Jeong JJ, Yoo SY, Kim DH. Gut microbiota lipopolysaccharide accelerates inflamm -aging in mice. BMC Microbiol. Jan 16 2016;16:9. doi:10.1186/s12866-016-0625-7
84. Mitchell EL, Davis AT, Brass K, et al. Reduced Intestinal Motility, Mucosal Barrier Function, and Inflammation in Aged Monkeys. J Nutr Health Aging. 2017;21(4):354-361. doi:10.1007/s12603-016-0725-y
85. Walker EM, Slisarenko N, Gerrets GL, et al. Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells. Geroscience. Dec 2019;41(6):739-757. doi:10.1007 /s11357-019-00099-7
86. Wilson QN, Wells M, Davis AT, et al. Greater Microbial Translocation and Vulnerability to Metabolic Disease in Healthy Aged Female Monkeys. Sci Rep. Jul 27 2018;8(1):11373. doi:10.1038/s41598-018-29473-9
87. Chung KW, Lee EK, Kim DH, et al. Age-related sensitivity to endotoxin-induced liver inflammation: Implication of inflammasome/IL-1beta for steatohepatitis. Aging Cell. Aug 2015;14(4):524-33. doi:10.1111/acel.12305
88. Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F. Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PloS one. 2013;8(1):e54600. doi:10.1371/ journal.pone.0054600
89. Kavanagh K, Hsu FC, Davis AT, Kritchevsky SB, Rejeski WJ, Kim S. Biomarkers of leaky gut are related to inflammation and reduced physical function in older adults with cardiometabolic disease and mobility limitations. Geroscience. Dec 2019 ;41(6):923-933. doi:10.1007/s11357-019-00112-z
90. Stehle JR, Jr., Leng X, Kitzman DW, Nicklas BJ, Kritchevsky SB, High KP. Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults. J Gerontol A Biol Sci Med Sci. Nov 2012;67(11):1212-8. doi:10.1093/gerona/gls178
91. Reiner AP, Lange EM, Jenny NS, et al. Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults. Arteriosclerosis, thrombosis, and vascular biology. Jan 2013;33(1):158-64. doi:10.11 61/atvbaha.112.300421
92. Pinti M, Appay V, Campisi J, et al. Aging of the immune system: Focus on inflammation and vaccination. European journal of immunology. Oct 2016;46(10):2286-2301. doi:10.1002/eji.201546178
93. Zhang R, Miller RG, Gascon R, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). Journal of neuroimmunology. Jan 3 2009;206(1-2):121-4. doi:10.1016/j.jneuroim.2008.09.017
94. Vogt NM, Kerby RL, Dill-McFarland KA, et al. Gut microbiome alterations in Alzheimer's disease. Sci Rep. Oct 19 2017;7(1):13537. doi:10.1038/s 41598-017-13601-y
95. Vargas-Caraveo A, Sayd A, Maus SR, et al. Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions. Sci Rep. Oct 13 2017; 7(1):13113. doi:10.1038/s41598-017-13302-6
96. Zhao Y, Jaber V, Lukiw WJ. Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus. Frontiers in cellular and infection microbiology. 2017;7:318. doi:10.3389/fcimb.20 17.00318
97. Andre P, Samieri C, Buisson C, et al. Lipopolysaccharide-Binding Protein, Soluble CD14, and the Long-Term Risk of Alzheimer's Disease: A Nested Case-Control Pilot Study of Older Community Dwellers from the Three-City Cohort. J Alzheimers Dis. 2019;71(3):751-761. doi:10.3233/jad-190295
98. Pase MP, Himali JJ, Beiser AS, et al. Association of CD14 with incident dementia and markers of brain aging and injury. Neurology. Jan 21 2020;94(3):e254-e266. doi:10.1212/wnl.000000 0000008682
99. Ng A, Tam WW, Zhang MW, et al. IL-1beta, IL-6, TNF- alpha and CRP in Elderly Patients with Depression or Alzheimer's disease: Systematic Review and Meta-Analysis. Sci Rep. Aug 13 2018;8(1):12050. doi:10.1038/s41598-018-30487-6
100. Bradburn S, Sarginson J, Murgatroyd CA. Association of Peripheral Interleukin-6 with Global Cognitive Decline in Non-demented Adults: A Meta-Analysis of Prospective Studies. Front Aging Neurosci. 2017;9:438. doi:10.3389/fnagi.2017.00438
101. Kim JW, Stewart R, Kang HJ, et al. Longitudinal Associations Between Serum Cytokine Levels and Dementia. Frontiers in psychiatry. 2018;9:606. doi:10.3389/fpsyt.2018.00606
102. Lee WJ, Liao YC, Wang YF, Lin IF, Wang SJ, Fuh JL. Plasma MCP-1 and Cognitive Decline in Patients with Alzheimer's Disease and Mild Cognitive Impairment: A Two-year Follow-up Study. Sci Rep. 01 2018;8(1):1280. doi:10.1038/s4 1598-018-19807-y
103. Bettcher BM, Fitch R, Wynn MJ, et al. MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer's disease dementia phenotypes. Alzheimers Dement (Amst). 2016;3:91-7. doi:10.1016/j.dadm.2016.05.004
104. Chinta SJ, Woods G, Rane A, Demaria M, Campisi J, Andersen JK. Cellular senescence and the aging brain. Exp Gerontol. Aug 2015;68:3-7. doi:10.1016/j.exger.2014.09.018
105. Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118. doi:10.1146/annurev-path ol-121808-102144
106. Howcroft TK, Campisi J, Louis GB, et al. The role of inflammation in age-related disease. Aging (Albany NY). Jan 2013;5(1):84-93. doi:10.18632/ag ing.100531
107. Davalos AR, Coppe JP, Campisi J, Desprez PY. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev. Jun 2010;29(2):273-83. doi:10.1007/s10555-010-9220-9
108. Ferrucci L, Gonzalez-Freire M, Fabbri E, et al. Measuring biological aging in humans: A quest. Aging Cell. Feb 2020;19(2):e13080. doi:10.1111/ acel.13080
109. Brinkley TE, Leng X, Miller ME, et al. Chronic inflammation is associated with low physical function in older adults across multiple comorbidities. J Gerontol A Biol Sci Med Sci. Apr 2009;64(4):455-61. doi:10.1093/gerona/gln038
110. Puzianowska-Kuznicka M, Owczarz M, Wieczorowska-Tobis K, et al. Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immun Ageing. 2016;13:21. doi:10.1186/s12979-016-0076-x
111. Giovannini S, Onder G, Liperoti R, et al. Interleukin-6, C-reactive protein, and tumor necrosis factor-alpha as predictors of mortality in frail, community-living elderly individuals. J Am Geriatr Soc. Sep 2011;59(9):1679-85. doi:10.1111/j .1532-5415.2011.03570.x
112. Bailey KL, Smith LM, Heires AJ, Katafiasz DM, Romberger DJ, LeVan TD. Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists. Aging Clin Exp Res. Sep 2019;31(9):1185-1193. doi:10.1007/s40520-018-1064-0
113. Bettcher BM, Neuhaus J, Wynn MJ, et al. Increases in a Pro-inflammatory Chemokine, MCP-1, Are Related to Decreases in Memory Over Time. Front Aging Neurosci. 2019;11:25. doi:10.3389/fn agi.2019.00025
114. Magalhaes CA, Ferreira CN, Loures CMG, et al. Leptin, hsCRP, TNF-alpha and IL-6 levels from normal aging to dementia: Relationship with cognitive and functional status. J Clin Neurosci. Oct 2018;56:150-155. doi:10.1016/j.jocn.2018.08.027
115. Ong SM, Hadadi E, Dang TM, et al. The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence. Cell Death Dis. Feb 15 2018;9(3):266. doi:10.1038/s41419-018-0327-1
116. Wolf J, Weinberger B, Arnold CR, Maier AB, Westendorp RG, Grubeck-Loebenstein B. The effect of chronological age on the inflammatory response of human fibroblasts. Exp Gerontol. Sep 2012;47(9):749-53. doi:10.1016/j.exger.2012.07.001
117. Yousefzadeh MJ, Schafer MJ, Noren Hooten N, et al. Circulating levels of monocyte chemoattractant protein-1 as a potential measure of biological age in mice and frailty in humans. Aging Cell. Apr 2018;17(2)doi:10.1111/acel.12706
118. Lv S, Zhang Y, Lin Y, et al. ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl-CoA level. Aging Cell. Sep 2023;22(9):e13 932. doi:10.1111/acel.13932
119. Andriani GA, Almeida VP, Faggioli F, et al. Whole Chromosome Instability induces senescence and promotes SASP. Sci Rep. Oct 12 2016;6:35218 . doi:10.1038/srep35218
120. Zampino M, Ferrucci L, Semba RD. Biomarkers in the path from cellular senescence to frailty. Exp Gerontol. Jan 2020;129:110750. doi:10.1016/j.exg er.2019.110750
121. Leclercq S, De Saeger C, Delzenne N, de Timary P, Starkel P. Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry. Nov 1 2014;76:725-33. doi:10.1016/j.biopsych.201 4.02.003 10.1016/j.biopsych.2014.02.003. Epub 2014 Feb 14.
122. Neupane SP, Skulberg A, Skulberg KR, Aass HC, Bramness JG. Cytokine Changes following Acute Ethanol Intoxication in Healthy Men: A Crossover Study. Mediators Inflamm. 2016;201 6:3758590. doi:10.1155/2016/3758590
123. Pascual M, Montesinos J, Marcos M, et al. Gender differences in the inflammatory cytokine and chemokine profiles induced by binge ethanol drinking in adolescence. Addict Biol. Oct 4 2016;22(6):1829-1841. doi:10.1111/adb.12461
124. Qin L, He J, Hanes RN, Pluzarev O, Hong JS, Crews FT. Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. Journal of neuroinflammation. 2008;5:10. doi:10.1186/1742-2094-5-10 10.1186/1742-2094-5-10.
125. Crews FT, Sarkar DK, Qin L, Zou J, Boyadjieva N, Vetreno RP. Neuroimmune Function and the Consequences of Alcohol Exposure. Alcohol Research : Current Reviews. 2015;37(2):331-351.
126. Crews FT, Qin L, Sheedy D, Vetreno RP, Zou J. High mobility group box 1/Toll-like receptor danger signaling increases brain neuroimmune activation in alcohol dependence. Biol Psychiatry. Apr 1 2013;73(7):602-12. doi:10.1016/j.biopsych. 2012.09.030
127. Coleman LG, Jr., Zou J, Qin L, Crews FT. HMGB1/ IL-1beta complexes regulate neuroimmune responses in alcoholism. Brain Behav Immun. Aug 2018;72:61-77. doi:10.1016 /j.bbi.2017.10.027
128. Lawrimore CJ, Crews FT. Ethanol, TLR3, and TLR4 Agonists Have Unique Innate Immune Responses in Neuron-Like SH-SY5Y and Microglia-Like BV2. Alcohol Clin Exp Res. May 2017;41(5):93 9-954. doi:10.1111/acer.13368
129. Lowe PP, Gyongyosi B, Satishchandran A, et al. Reduced gut microbiome protects from alcohol-induced neuroinflammation and alters intestinal and brain inflammasome expression. Journal of neuroinflammation. Oct 27 2018;15(1):298. doi:10. 1186/s12974-018-1328-9
130. Lippai D, Bala S, Petrasek J, et al. Alcohol-induced IL-1beta in the brain is mediated by NLRP3/ ASC inflammasome activation that amplifies neuroinflammation. J Leukoc Biol. Jul 2013;94(1):171-82. doi:10.1189/jlb.1212659
131. Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal. Apr 2012;24(4):835-45. doi:10.1016/j.cellsig.2011.12.006
132. Aird KM, Iwasaki O, Kossenkov AV, et al. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J Cell Biol. Nov 7 2016;215(3):325-334. doi:10. 1083/jcb.201608026
133. Martins de Carvalho L, Wiers CE, Manza P, et al. Effect of alcohol use disorder on cellular aging. Psychopharmacology (Berl). Nov 2019;236(11):324 5-3255. doi:10.1007/s00213-019-05281-5
134. Chen X, Li M, Yan J, et al. Alcohol Induces Cellular Senescence and Impairs Osteogenic Potential in Bone Marrow-Derived Mesenchymal Stem Cells. Alcohol Alcohol. May 1 2017;52(3):289-297. doi:10.1093/alcalc/agx006
135. Epel ES, Merkin SS, Cawthon R, et al. The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men. Aging (Albany NY). Dec 4 2008;1(1):81-8. doi:10.18632/aging.100007
136. Harpaz T, Abumock H, Beery E, et al. The Effect of Ethanol on Telomere Dynamics and Regulation in Human Cells. Cells. Oct 15 2018;7(10)doi:10.3390/cells7100169
137. Strandberg TE, Strandberg AY, Saijonmaa O, Tilvis RS, Pitkala KH, Fyhrquist F. Association between alcohol consumption in healthy midlife and telomere length in older men. The Helsinki Businessmen Study. European journal of epidemiology. Oct 2012;27(10):815-22. doi:10.100 7/s10654-012-9728-0
138. Yamaki N, Matsushita S, Hara S, Yokoyama A, Hishimoto A, Higuchi S. Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde. J Psychiatr Res. Feb 2019;109:27-32. doi:10.1016/j.jpsychires.2018.11.007
139. Stephenson M, Bollepalli S, Cazaly E, et al. Associations of Alcohol Consumption With Epigenome-Wide DNA Methylation and Epigenetic Age Acceleration: Individual-Level and Co-twin Comparison Analyses. Alcohol Clin Exp Res. Feb 2021;45(2):318-328. doi:10.1111/acer.14528
140. Elliott DA, Weickert CS, Garner B. Apolipoproteins in the brain: implications for neurological and psychiatric disorders. Clin Lipidol. Aug 1 2010;51(4):555-573. doi:10.2217/clp.10.37
141. Rebeck GW. The role of APOE on lipid homeostasis and inflammation in normal brains. J Lipid Res. Aug 2017;58(8):1493-1499. doi:10.1194/ jlr.R075408
142. Chernick D, Ortiz-Valle S, Jeong A, Qu W, Li L. Peripheral versus central nervous system APOE in Alzheimer's disease: Interplay across the blood-brain barrier. Neurosci Lett. 08 2019;708:134306. doi:10.1016/j.neulet.2019.134306
143. Kloske CM, Wilcock DM. The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer's Disease. Frontiers in immunology. 2020;11:754. doi:10.33 89/fimmu.2020.00754
144. Brown GC. The endotoxin hypothesis of neurodegeneration. Journal of neuroinflammation. Sep 13 2019;16(1):180. doi:10.1186/s12974-019-1564-7
145. Erickson MA, Hartvigson PE, Morofuji Y, Owen JB, Butterfield DA, Banks WA. Lipopolysaccharide impairs amyloid β efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier. Journal of neuroinflammation. Jun 2012;9:150. doi:10.1186/1742-2094-9-150
146. Chang L, Munsaka SM, Kraft-Terry S, Ernst T. Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. Jun 2013;8(3):576-93. doi:10.1007/s11481-013-9460-x
147. Rae CD. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochemical research. Jan 2014;39(1):1-36. doi:10.1007/s11064-013-1199-5
148. Barrientos RM, Kitt MM, Watkins LR, Maier SF. Neuroinflammation in the normal aging hippocampus. Neuroscience. Nov 19 2015;309:84-99. doi:10.1016/j.neuroscience.2015.03.007
149. Clarke LE, Liddelow SA, Chakraborty C, Munch AE, Heiman M, Barres BA. Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci U S A. Feb 20 2018;115(8):E1896-e1905. doi:10.1073/ pnas.1800165115
150. Gulyas B, Vas A, Toth M, et al. Age and disease related changes in the translocator protein (TSPO) system in the human brain: positron emission tomography measurements with [11C] vinpocetine. Neuroimage. Jun 1 2011;56(3):1111-21. doi:10.1016/j.neuroimage.2011.02.020
151. Sparkman NL, Johnson RW. Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation. 2008;15(4-6):32 3-30. doi:10.1159/000156474
152. Waragai M, Moriya M, Nojo T. Decreased N-Acetyl Aspartate/Myo-Inositol Ratio in the Posterior Cingulate Cortex Shown by Magnetic Resonance Spectroscopy May Be One of the Risk Markers of Preclinical Alzheimer's Disease: A 7-Year Follow-Up Study. J Alzheimers Dis. 2017;60(4):1411-1427. doi:10.3233/JAD-170450
153. Kantarci K, Weigand SD, Przybelski SA, et al. MRI and MRS predictors of mild cognitive impairment in a population-based sample. Neurology. Jul 9 2013;81(2):126-33. doi:10.1212/ WNL.0b013e31829a3329
154. Kantarci K, Lowe V, Przybelski SA, et al. Magnetic resonance spectroscopy, beta-amyloid load, and cognition in a population-based sample of cognitively normal older adults. Neurology. Sep 6 2011;77(10):951-8. doi:10.1212/WNL.0b013e31 822dc7e1
155. Hupfeld KE, Hyatt HW, Alvarez Jerez P, et al. In Vivo Brain Glutathione is Higher in Older Age and Correlates with Mobility. Cereb Cortex. Aug 26 2021;31(10):4576-4594. doi:10.1093/cercor/bhab107
156. Voevodskaya O, Sundgren PC, Strandberg O, et al. Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease. Neurology. May 10 2016;86 (19):1754-61. doi:10.1212/wnl.0000000000002672
157. Lind A, Boraxbekk CJ, Petersen ET, Paulson OB, Siebner HR, Marsman A. Regional Myo-Inositol, Creatine, and Choline Levels Are Higher at Older Age and Scale Negatively with Visuospatial Working Memory: A Cross-Sectional Proton MR Spectroscopy Study at 7 Tesla on Normal Cognitive Ageing. J Neurosci. Oct 14 2020;40(42): 8149-8159. doi:10.1523/jneurosci.2883-19.2020
158. Sporn L, MacMillan EL, Ge R, Greenway K, Vila-Rodriguez F, Laule C. Longer Repetition Time Proton MR Spectroscopy Shows Increasing Hippocampal and Parahippocampal Metabolite Concentrations with Aging. J Neuroimaging. Sep 2019;29(5):592-597. doi:10.1111/jon.12648
159. Maghsudi H, Schütze M, Maudsley AA, Dadak M, Lanfermann H, Ding XQ. Age-related Brain Metabolic Changes up to Seventh Decade in Healthy Humans : Whole-brain Magnetic Resonance Spectroscopic Imaging Study. Clin Neuroradiol. Sep 2020;30(3):581-589. doi:10.1007 /s00062-019-00814-z
160. Marjańska M, McCarten JR, Hodges J, et al. Region-specific aging of the human brain as evidenced by neurochemical profiles measured noninvasively in the posterior cingulate cortex and the occipital lobe using (1)H magnetic resonance spectroscopy at 7 T. Neuroscience. Jun 23 2017;35 4:168-177. doi:10.1016/j.neuroscience.2017.04.035
161. Suri S, Emir U, Stagg CJ, et al. Effect of age and the APOE gene on metabolite concentrations in the posterior cingulate cortex. Neuroimage. May 15 2017;152:509-516. doi:10.1016/j.neuroimage.2 017.03.031
162. Ding XQ, Maudsley AA, Sabati M, et al. Physiological neuronal decline in healthy aging human brain - An in vivo study with MRI and short echo-time whole-brain (1)H MR spectroscopic imaging. Neuroimage. Aug 15 2016;137:45-51. doi:10.1016/j.neuroimage.2016.05.014
163. Gruber S, Pinker K, Riederer F, et al. Metabolic changes in the normal ageing brain: consistent findings from short and long echo time proton spectroscopy. Eur J Radiol. Nov 2008;68(2):320-7. doi:10.1016/j.ejrad.2007.08.038
164. Tunc-Skarka N, Meier S, Demirakca T, et al. Effects of normal aging and SCN1A risk-gene expression on brain metabolites: evidence for an association between SCN1A and myo-inositol. NMR Biomed. Feb 2014;27(2):228-34. doi:10.100 2/nbm.3057
165. Nedelska Z, Przybelski SA, Lesnick TG, et al. (1)H-MRS metabolites and rate of beta-amyloid accumulation on serial PET in clinically normal adults. Neurology. Sep 26 2017;89(13):1391-1399. doi:10.1212/wnl.0000000000004421
166. Wang H, Tan L, Wang HF, et al. Magnetic Resonance Spectroscopy in Alzheimer's Disease: Systematic Review and Meta-Analysis. J Alzheimers Dis. 2015;46(4):1049-70. doi:10.3233/jad-143225
167. Li BS, Wang H, Gonen O. Metabolite ratios to assumed stable creatine level may confound the quantification of proton brain MR spectroscopy. Magnetic resonance imaging. Oct 2003;21(8):923-8. doi:10.1016/s0730-725x(03)00181-4
168. Zahr NM, Pfefferbaum A. Alcohol's Effects on the Brain: Neuroimaging Results in Humans and Animal Models. Alcohol Res. 2017;38(2):183-206.
169. Ende G, Walter S, Welzel H, et al. Alcohol consumption significantly influences the MR signal of frontal choline-containing compounds. Neuroimage. Aug 15 2006;32(2):740-6. doi:10.1016/j.neuroimag e.2006.03.049
170. Ende G, Hermann D, Demirakca T, et al. Loss of control of alcohol use and severity of alcohol dependence in non-treatment-seeking heavy drinkers are related to lower glutamate in frontal white matter. Alcohol Clin Exp Res. Oct 2013;37 (10):1643-9. doi:10.1111/acer.12149
171. Tunc-Skarka N, Weber-Fahr W, Ende G. Recreational alcohol use induces changes in the concentrations of choline-containing compounds and total creatine in the brain: a (1)H MRS study of healthy subjects. Magma (New York, NY). Oct 2015;28(5):503-10. doi:10.1007/s10334-015-0486-3
172. Kirkland AE, Browning BD, Green R, Leggio L, Meyerhoff DJ, Squeglia LM. Brain metabolite alterations related to alcohol use: a meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry. May 4 2022;doi:10.1038/s 41380-022-01594-8
173. Monnig MA, Woods AJ, Walsh E, et al. Cerebral Metabolites on the Descending Limb of Acute Alcohol: A Preliminary 1H MRS Study. Alcohol Alcohol. Jul 2019;doi:10.1093/alcalc/agz062
174. Biller A, Bartsch AJ, Homola G, Solymosi L, Bendszus M. The effect of ethanol on human brain metabolites longitudinally characterized by proton MR spectroscopy. J Cereb Blood Flow Metab. May 2009;29(5):891-902. doi:10.1038/jcbfm.2009.12
175. Gomez R, Behar KL, Watzl J, et al. Intravenous ethanol infusion decreases human cortical gamma-aminobutyric acid and N-acetylaspartate as measured with proton magnetic resonance spectroscopy at 4 tesla. Biol Psychiatry. Feb 1 2012 ;71(3):239-46. doi:10.1016/j.biopsych.2011.06.026
176. Piers RJ. Structural brain volume differences between cognitively intact ApoE4 carriers and non-carriers across the lifespan. Neural regeneration research. Aug 2018;13(8):1309-1312. doi:10.4103/ 1673-5374.235408
177. Bussy A, Snider BJ, Coble D, et al. Effect of apolipoprotein E4 on clinical, neuroimaging, and biomarker measures in noncarrier participants in the Dominantly Inherited Alzheimer Network. Neurobiol Aging. Mar 2019;75:42-50. doi:10.1016/ j.neurobiolaging.2018.10.011
178. Gonneaud J, Arenaza-Urquijo EM, Fouquet M, et al. Relative effect of APOE ε4 on neuroimaging biomarker changes across the lifespan. Neurology. Oct 2016;87(16):1696-1703. doi:10.1212/WNL.0 000000000003234
179. Glorioso CA, Pfenning AR, Lee SS, et al. Rate of brain aging and APOE ε4 are synergistic risk factors for Alzheimer's disease. Life Sci Alliance. Jun 2019;2(3)doi:10.26508/lsa.201900303
180. Gomar JJ, Gordon ML, Dickinson D, et al. APOE genotype modulates proton magnetic resonance spectroscopy metabolites in the aging brain. Biol Psychiatry. May 1 2014;75(9):686-92. doi:10.1016/j.biopsych.2013.05.022
181. Montesinos J, Alfonso-Loeches S, Guerri C. Impact of the Innate Immune Response in the Actions of Ethanol on the Central Nervous System. Alcohol Clin Exp Res. Nov 2016;40(11):2260-2270. doi:10.1111/acer.13208
182. Crews FT, Zou J, Qin L. Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun. Jun 2011;25 Suppl 1:S4-S12. doi:10.1016/j.bbi.2011.03.003
183. Szabo G, Saha B. Alcohol’s Effect on Host Defense. Alcohol Research : Current Reviews. 2015;37(2):159-170.
184. Mandrekar P, Catalano D, White B, Szabo G. Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of nuclear regulatory factor kappa B and induction of interleukin 10. Alcohol Clin Exp Res. Jan 2006;30(1 ):135-9. doi:10.1111/j.1530-0277.2006.00012.x
185. Mandrekar P, Jeliazkova V, Catalano D, Szabo G. Acute alcohol exposure exerts anti-inflammatory effects by inhibiting IkappaB kinase activity and p65 phosphorylation in human monocytes. J Immunol. Jun 15 2007;178(12):7686-93.
186. Mandrekar P, Bala S, Catalano D, Kodys K, Szabo G. The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes. J Immunol. Jul 2009;183(2):1320-7. doi:10.4049/jimmunol.0803206
187. Muralidharan S, Ambade A, Fulham MA, Deshpande J, Catalano D, Mandrekar P. Moderate alcohol induces stress proteins HSF1 and hsp70 and inhibits proinflammatory cytokines resulting in endotoxin tolerance. J Immunol. Aug 15 2014;1 93:1975-87. doi:10.4049/jimmunol.1303468 10.40 49/jimmunol.1303468. Epub 2014 Jul 14.
188. Varadhan R, Yao W, Matteini A, et al. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. J Gerontol A Biol Sci Med Sci. Feb 2014;69(2):165-73. doi:10.1093/gerona/glt023
189. Schram MT, Euser SM, de Craen AJ, et al. Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc. May 2007;55 (5):708-16. doi:10.1111/j.1532-5415.2007.01159.x
190. Trollor JN, Smith E, Baune BT, et al. Systemic inflammation is associated with MCI and its subtypes: the Sydney Memory and Aging Study. Dement Geriatr Cogn Disord. 2010;30(6):569-78. doi:10.1159/000322092
191. Cesari M, Kritchevsky SB, Nicklas B, et al. Oxidative damage, platelet activation, and inflammation to predict mobility disability and mortality in older persons: results from the health aging and body composition study. J Gerontol A Biol Sci Med Sci. Jun 2012;67(6):671-6. doi:10.1 093/gerona/glr246
192. Tangestani Fard M, Stough C. A Review and Hypothesized Model of the Mechanisms That Underpin the Relationship Between Inflammation and Cognition in the Elderly. Front Aging Neurosci. 2019;11:56. doi:10.3389/fnagi.2019.00056
193. Villeda SA, Luo J, Mosher KI, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. Aug 31 2011;477 (7362):90-4. doi:10.1038/nature10357
194. McKechnie DGJ, Papacosta AO, Lennon LT, Ramsay SE, Whincup PH, Wannamethee SG. Associations between inflammation, cardiovascular biomarkers and incident frailty: the British Regional Heart Study. Age Ageing. Nov 10 2021;50(6):1979-1987. doi:10.1093/ageing/afab143
195. Dugué PA, Hodge AM, Ulvik A, et al. Association of markers of inflammation, the kynurenine pathway and B vitamins with age and mortality, and a signature of inflammaging. J Gerontol A Biol Sci Med Sci. Jun 12 2021;doi :10.1093/gerona/glab163
196. Adriaensen W, Matheï C, Vaes B, van Pottelbergh G, Wallemacq P, Degryse JM. Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: A regression and CART approach in the BELFRAIL study. Exp Gerontol. Sep 2015;6 9:53-61. doi:10.1016/j.exger.2015.06.005
2. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. Aug 1993;43(8):1467-72. doi:10.1212/wnl.43.8.1467
3. Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. Oct 2009;41(10):1088-93. doi:10.1038/ng.440
4. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Jama. Oct 22-29 1997;278(16):1349-56.
5. Neu SC, Pa J, Kukull W, et al. Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol. Oct 1 2017;74(10):1178-1189. doi:10.1001/jamaneurol.2 017.2188
6. Rawle MJ, Davis D, Bendayan R, Wong A, Kuh D, Richards M. Apolipoprotein-E (Apoe) epsilon4 and cognitive decline over the adult life course. Transl Psychiatry. Jan 10 2018;8(1):18. doi:10.103 8/s41398-017-0064-8
7. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science (New York, NY). Apr 1992;256(5054):184-5. doi:10.1126/ science.1566067
8. Zhao Y, Cong L, Jaber V, Lukiw WJ. Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of Alzheimer's Disease Brain. Frontiers in immunology. 2017;8:1064. doi:10.3389/fimmu.2017.01064
9. Zhan X, Stamova B, Jin LW, DeCarli C, Phinney B, Sharp FR. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology. Nov 29 2016;87(22):2324-2332. doi:10.1212/wnl.0000000000003391
10. Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer's Disease. J Neurogastroenterol Motil. Jan 31 2019;25(1):48-60. doi:10.5056/jnm18087
11. Substance Abuse and Mental Health Services Administration (SAMHSA). 2018 National Survey on Drug Use and Health (NSDUH). Rockville, MD: SAMHSA; 2019.
12. Grant BF, Chou SP, Saha TD, et al. Prevalence of 12-Month Alcohol Use, High-Risk Drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: Results From the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry. 09 01 2017;74(9):911-923. doi:10.1001/jamapsychiatry.2 017.2161
13. Luján M, Gallego M, Belmonte Y, et al. Influence of pneumococcal serotype group on outcome in adults with bacteraemic pneumonia. Eur Respir J. Nov 2010;36(5):1073-9. doi:10.1183/ 09031936.00176309
14. Chosy EJ, Edland S, Launer L, White LR. Midlife alcohol consumption and later life cognitive impairment: Light drinking is not protective and APOE genotype does not change this relationship. PLoS One. 2022;17(3):e0264575. doi:10.1371/ journal.pone.0264575
15. Lao Y, Hou L, Li J, Hui X, Yan P, Yang K. Association between alcohol intake, mild cognitive impairment and progression to dementia: a dose-response meta-analysis. Aging Clin Exp Res. May 2021;33(5):1175-1185. doi:10.1007/s40520-020-01605-0
16. Holahan CJ, Schutte KK, Brennan PL, Holahan CK, Moos RH. Episodic heavy drinking and 20-year total mortality among late-life moderate drinkers. Alcohol Clin Exp Res. May 2014;38(5):1432-8. doi:10.1111/acer.12381
17. Lassen MCH, Skaarup KG, Sengeløv M, et al. Alcohol Consumption and the Risk of Acute Respiratory Distress Syndrome in COVID-19. Ann Am Thorac Soc. Jun 2021;18(6):1074-1076. doi:10.1513/AnnalsATS.202008-988RL
18. Ha VT, Nguyen TN, Nguyen TX, et al. Prevalence and Factors Associated with Falls among Older Outpatients. International journal of environmental research and public health. Apr 12 2021;18(8)doi:10.3390/ijerph18084041
19. Kojima G, Iliffe S, Liljas A, Walters K. Non-linear association between alcohol and incident frailty among community-dwelling older people: A dose-response meta-analysis. Biosci Trends. Nov 20 2017;11(5):600-602. doi:10.5582/bst.2017.01237
20. Merrick ES, Hodgkin D, Garnick DW, et al. Older adults' inpatient and emergency department utilization for ambulatory-care-sensitive conditions: relationship with alcohol consumption. J Aging Health. Feb 2011;23(1):86-111. doi:10.1177/08982 64310383156
21. Tan GJ, Tan MP, Luben RN, Wareham NJ, Khaw KT, Myint PK. The relationship between alcohol intake and falls hospitalization: Results from the EPIC-Norfolk. Geriatr Gerontol Int. Aug 2021;21(8):657-663. doi:10.1111/ggi.14219
22. Population Reference Bureau. Population Bulletin. vol 70, No. 2. 2015.
23. Schwarzinger M, Pollock BG, Hasan OSM, Dufouil C, Rehm J, Group QS. Contribution of alcohol use disorders to the burden of dementia in France 2008-13: a nationwide retrospective cohort study. Lancet Public Health. 03 2018;3(3):e124-e132. doi:10.1016/S2468-2667(18)30022-7
24. Zilkens RR, Bruce DG, Duke J, Spilsbury K, Semmens JB. Severe psychiatric disorders in mid-life and risk of dementia in late- life (age 65-84 years): a population based case-control study. Curr Alzheimer Res. 2014;11(7):681-93. doi:10.2174/1 567205011666140812115004
25. Harwood DG, Kalechstein A, Barker WW, et al. The effect of alcohol and tobacco consumption, and apolipoprotein E genotype, on the age of onset in Alzheimer's disease. Int J Geriatr Psychiatry. May 2010;25(5):511-8. doi:10.1002/ gps.2372
26. Guggenmos M, Schmack K, Sekutowicz M, et al. Quantitative neurobiological evidence for accelerated brain aging in alcohol dependence. Transl Psychiatry. Dec 11 2017;7(12):1279. doi:10.1038/s41398-017-0037-y
27. Xu W, Wang H, Wan Y, et al. Alcohol consumption and dementia risk: a dose-response meta-analysis of prospective studies. European journal of epidemiology. Jan 2017;32(1):31-42. doi:10.1007/s10654-017-0225-3
28. Anstey KJ, Mack HA, Cherbuin N. Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies. Am J Geriatr Psychiatry. Jul 2009;17(7):542 -55. doi:10.1097/JGP.0b013e3181a2fd07
29. Rehm J, Hasan OSM, Black SE, Shield KD, Schwarzinger M. Alcohol use and dementia: a systematic scoping review. Alzheimers Res Ther. 01 2019;11(1):1. doi:10.1186/s13195-018-0453-0
30. Love SM, North KE, Zeng D, et al. Nine-Year Ethanol Intake Trajectories and Their Association With 15-Year Cognitive Decline Among Black and White Adults. Am J Epidemiol. Aug 1 2020;189(8): 788-800. doi:10.1093/aje/kwaa006
31. Angebrandt A, Abulseoud OA, Kisner M, et al. Dose-dependent relationship between social drinking and brain aging. Neurobiol Aging. Mar 2022;111:71-81. doi:10.1016/j.neurobiolaging.202 1.11.008
32. Topiwala A, Allan CL, Valkanova V, et al. Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study. Bmj. Jun 6 2017;357:j23 53. doi:10.1136/bmj.j2353
33. Hassing LB. Light Alcohol Consumption Does Not Protect Cognitive Function: A Longitudinal Prospective Study. Front Aging Neurosci. 2018;10: 81. doi:10.3389/fnagi.2018.00081
34. Daviet R, Aydogan G, Jagannathan K, et al. Associations between alcohol consumption and gray and white matter volumes in the UK Biobank. Nat Commun. Mar 4 2022;13(1):1175. doi:10.1038 /s41467-022-28735-5
35. Corella D, Portoles O, Arriola L, et al. Saturated fat intake and alcohol consumption modulate the association between the APOE polymorphism and risk of future coronary heart disease: a nested case-control study in the Spanish EPIC cohort. J Nutr Biochem. May 2011;22(5):487-94. doi:10.1016/j.jnutbio.2010.04.003
36. Mukamal KJ, Chung H, Jenny NS, et al. Alcohol use and risk of ischemic stroke among older adults: the cardiovascular health study. Stroke. Sep 2005;36(9):1830-4. doi:10.1161/01.ST R.0000177587.76846.89
37. Kivipelto M, Rovio S, Ngandu T, et al. Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: a population-based study. J Cell Mol Med. Dec 2008;12(6b):2762-71. doi:10.1111/j.158 2-4934.2008.00296.x
38. Anttila T, Helkala EL, Viitanen M, et al. Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study. Bmj. Sep 4 2004;329(7465):539. doi:10.1136/bmj.38181.4189 58.BE
39. Mukamal KJ, Kuller LH, Fitzpatrick AL, Longstreth WT, Jr., Mittleman MA, Siscovick DS. Prospective study of alcohol consumption and risk of dementia in older adults. Jama. Mar 19 2003;28 9(11):1405-13. doi:10.1001/jama.289.11.1405
40. Dufouil C, Tzourio C, Brayne C, Berr C, Amouyel P, Alperovitch A. Influence of apolipoprotein E genotype on the risk of cognitive deterioration in moderate drinkers and smokers. Epidemiology (Cambridge, Mass). May 2000;11(3): 280-4. doi:10.1097/00001648-200005000-00009
41. Downer B, Zanjani F, Fardo DW. The relationship between midlife and late life alcohol consumption, APOE e4 and the decline in learning and memory among older adults. Alcohol Alcohol. Jan-Feb 2014;49(1):17-22. doi:10.1093/alcalc/agt144
42. Herring D, Paulson D. Moderate alcohol use and apolipoprotein E-4 (ApoE-4): Independent effects on cognitive outcomes in later life. J Clin Exp Neuropsychol. May 2018;40(4):326-337. doi:1 0.1080/13803395.2017.1343803
43. Reas ET, Laughlin GA, Bergstrom J, Kritz-Silverstein D, Barrett-Connor E, McEvoy LK. Effects of APOE on cognitive aging in community-dwelling older adults. Neuropsychology. Mar 2019;33(3):40 6-416. doi:10.1037/neu0000501
44. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. Jun 2014;69 Suppl 1:S4-9. doi:10.1093/gerona /glu057
45. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. Oct 2018;14(10):576-590. doi:10.1 038/s41574-018-0059-4
46. Sullivan EV, Pfefferbaum A. Brain-behavior relations and effects of aging and common comorbidities in alcohol use disorder: A review. Neuropsychology. Sep 2019;33(6):760-780. doi:10 .1037/neu0000557
47. Sklar AL, Gilbertson R, Boissoneault J, Prather R, Nixon SJ. Differential effects of moderate alcohol consumption on performance among older and younger adults. Alcohol Clin Exp Res. Dec 2012;36(12):2150-6. doi:10.1111/j.1530-0277.201 2.01833.x
48. Boissoneault J, Sklar A, Prather R, Nixon SJ. Acute effects of moderate alcohol on psychomotor, set shifting, and working memory function in older and younger social drinkers. J Stud Alcohol Drugs. Sep 2014;75(5):870-9. doi:10. 15288/jsad.2014.75.870
49. Garcia CC, Lewis B, Boissoneault J, Nixon SJ. Effects of Age and Acute Moderate Alcohol Consumption on Electrophysiological Indices of Attention. J Stud Alcohol Drugs. May 2020;81(3):3 72-383. doi:10.15288/jsad.2020.81.372
50. Lewis B, Boissoneault J, Gilbertson R, Prather R, Nixon SJ. Neurophysiological correlates of moderate alcohol consumption in older and younger social drinkers. Alcohol Clin Exp Res. Jun 2013;37(6):941-51. doi:10.1111/acer.12055
51. Keshavarzian A, Farhadi A, Forsyth CB, et al. Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. Journal of hepatology. Mar 2009;50:538-47. doi:10.1016/j.jhep.2008.10.028 10.1016/j.jhep.2008.10.028. Epub 2008 Dec 29.
52. Mutlu E, Keshavarzian A, Engen P, Forsyth CB, Sikaroodi M, Gillevet P. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol Clin Exp Res. Oct 2009;33:1836-46. doi:10.1111/j.1530 -0277.2009.01022.x 10.1111/j.1530-0277.2009.01 022.x. Epub 2009 Jul 23.
53. Banan A, Fields JZ, Decker H, Zhang Y, Keshavarzian A. Nitric oxide and its metabolites mediate ethanol-induced microtubule disruption and intestinal barrier dysfunction. The Journal of pharmacology and experimental therapeutics. Sep 2000;294(3):997-1008.
54. Bull-Otterson L, Feng W, Kirpich I, et al. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PloS one. 2013;8:e53028. doi:10.1371/ journal.pone.0053028 10.1371/journal.pone.0053 028. Epub 2013 Jan 9.
55. Park BS, Lee JO. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med. 2013;45:e66. doi:10.1038/emm. 2013.97
56. Wurfel MM, Wright SD. Lipopolysaccharide (LPS) binding protein catalyzes binding of LPS to lipoproteins. Progress in clinical and biological research. 1995;392:287-95.
57. Pugin J, Schürer-Maly CC, Leturcq D, Moriarty A, Ulevitch RJ, Tobias PS. Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci U S A. Apr 1993;90(7):2744-8. doi:10.1073/pnas.90.7.2744
58. De Groote D, Zangerle PF, Gevaert Y, et al. Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation. Cytokine. May 1992;4(3):239-48.
59. Colotta F, Borre A, Wang JM, et al. Expression of a monocyte chemotactic cytokine by human mononuclear phagocytes. J Immunol. Feb 01 1992;148(3):760-5.
60. Kirpich IA, McClain CJ, Vatsalya V, et al. Liver Injury and Endotoxemia in Male and Female Alcohol-Dependent Individuals Admitted to an Alcohol Treatment Program. Alcohol Clin Exp Res. Apr 2017;41(4):747-757. doi:10.1111/acer.13346
61. Schafer C, Parlesak A, Schutt C, Bode JC, Bode C. Concentrations of lipopolysaccharide-binding protein, bactericidal/permeability-increasing protein, soluble CD14 and plasma lipids in relation to endotoxaemia in patients with alcoholic liver disease. Alcohol Alcohol. Jan-Feb 2002;37(1):81-6.
62. Urbaschek R, McCuskey RS, Rudi V, et al. Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease. Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Alcohol Clin Exp Res. Feb 2001;25(2):261-8.
63. Leclercq S, Cani PD, Neyrinck AM, et al. Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. Brain Behav Immun. Aug 2012;26:911-8. doi:10.1016/j.bbi.2012.04.001 10. 1016/j.bbi.2012.04.001. Epub 2012 Apr 10.
64. Frank J, Witte K, Schrodl W, Schutt C. Chronic alcoholism causes deleterious conditioning of innate immunity. Alcohol Alcohol. Sep-Oct 2004;39(5):386-92. doi:10.1093/alcalc/agh083
65. Liangpunsakul S, Toh E, Ross RA, et al. Quantity of alcohol drinking positively correlates with serum levels of endotoxin and markers of monocyte activation. Sci Rep. Jun 2017;7(1):4462. doi:10.1038/s41598-017-04669-7
66. Afshar M, Richards S, Mann D, et al. Acute immunomodulatory effects of binge alcohol ingestion. Alcohol. Feb 2015;49(1):57-64. doi:10.1 016/j.alcohol.2014.10.002
67. Gonzalez-Quintela A, Dominguez-Santalla MJ, Perez LF, Vidal C, Lojo S, Barrio E. Influence of acute alcohol intake and alcohol withdrawal on circulating levels of IL-6, IL-8, IL-10 and IL-12. Cytokine. Sep 2000;12(9):1437-40. doi:10.1006/ cyto.2000.0715
68. Donnadieu-Rigole H, Pansu N, Mura T, et al. Beneficial Effect of Alcohol Withdrawal on Gut Permeability and Microbial Translocation in Patients with Alcohol Use Disorder. Alcohol Clin Exp Res. Jan 2018;42(1):32-40. doi:10.1111/acer.13527
69. Portelli J, Wiers CE, Li X, et al. Peripheral proinflammatory markers are upregulated in abstinent alcohol-dependent patients but are not affected by cognitive bias modification: Preliminary findings. Drug Alcohol Depend. Nov 1 2019;204: 107553. doi:10.1016/j.drugalcdep.2019.107553
70. Bala S, Marcos M, Gattu A, Catalano D, Szabo G. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PloS one. 2014;9(5):e96864. doi:10.1371/journal .pone.0096864
71. de Jong WJ, Cleveringa AM, Greijdanus B, Meyer P, Heineman E, Hulscher JB. The effect of acute alcohol intoxication on gut wall integrity in healthy male volunteers; a randomized controlled trial. Alcohol. Feb 2015;49(1):65-70. doi:10.1016/ j.alcohol.2014.09.033
72. Barr T, Helms C, Grant K, Messaoudi I. Opposing effects of alcohol on the immune system. Prog Neuropsychopharmacol Biol Psychiatry. Feb 4 2016;65:242-51. doi:10.1016/ j.pnpbp.2015.09.001
73. Mendenhall CL, Theus SA, Roselle GA, Grossman CJ, Rouster SD. Biphasic in vivo immune function after low- versus high-dose alcohol consumption. Alcohol. May-Jun 1997;14(3):255-60. doi:10.1016/s0741-8329(96)00150-4
74. Sureshchandra S, Raus A, Jankeel A, et al. Dose-dependent effects of chronic alcohol drinking on peripheral immune responses. Sci Rep. May 2019;9(1):7847. doi:10.1038/s41598-019-44302-3
75. de Bont N, Netea MG, Demacker PN, et al. Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection. J Lipid Res. Apr 1999;40(4):680-5.
76. Van Oosten M, Rensen PC, Van Amersfoort ES, et al. Apolipoprotein E protects against bacterial lipopolysaccharide-induced lethality. A new therapeutic approach to treat gram-negative sepsis. The Journal of biological chemistry. Mar 23 2001; 276(12):8820-4. doi:10.1074/jbc.M009915200
77. Vitek MP, Brown CM, Colton CA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging. Sep 2009;30( 9):1350-60. doi:10.1016/j.neurobiolaging.2007.11.014
78. Ringman JM, Elashoff D, Geschwind DH, et al. Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype. Arch Neurol. Jun 2012;69(6):757-64. doi:10.1001/archneurol.2012.277
79. den Hartigh LJ, Altman R, Hutchinson R, et al. Postprandial apoE isoform and conformational changes associated with VLDL lipolysis products modulate monocyte inflammation. PloS one. 2012; 7(11):e50513. doi:10.1371/journal.pone.0050513
80. Gale SC, Gao L, Mikacenic C, et al. APOepsilon4 is associated with enhanced in vivo innate immune responses in human subjects. J Allergy Clin Immunol. Jul 2014;134(1):127-34. doi:10.1016/j.jaci.2014.01.032
81. Tao Q, Ang TFA, DeCarli C, et al. Association of Chronic Low-grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers. JAMA Netw Open. 10 2018;1(6):e183597. doi:10.1001/jamanet workopen.2018.3597
82. Mukamal KJ, Jenny NS, Tracy RP, Siscovick DS. Alcohol consumption, interleukin-6 and apolipoprotein E genotypes, and concentrations of interleukin-6 and serum amyloid P in older adults. Am J Clin Nutr. Aug 2007;86(2):444-50. doi:10.10 93/ajcn/86.2.444
83. Kim KA, Jeong JJ, Yoo SY, Kim DH. Gut microbiota lipopolysaccharide accelerates inflamm -aging in mice. BMC Microbiol. Jan 16 2016;16:9. doi:10.1186/s12866-016-0625-7
84. Mitchell EL, Davis AT, Brass K, et al. Reduced Intestinal Motility, Mucosal Barrier Function, and Inflammation in Aged Monkeys. J Nutr Health Aging. 2017;21(4):354-361. doi:10.1007/s12603-016-0725-y
85. Walker EM, Slisarenko N, Gerrets GL, et al. Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells. Geroscience. Dec 2019;41(6):739-757. doi:10.1007 /s11357-019-00099-7
86. Wilson QN, Wells M, Davis AT, et al. Greater Microbial Translocation and Vulnerability to Metabolic Disease in Healthy Aged Female Monkeys. Sci Rep. Jul 27 2018;8(1):11373. doi:10.1038/s41598-018-29473-9
87. Chung KW, Lee EK, Kim DH, et al. Age-related sensitivity to endotoxin-induced liver inflammation: Implication of inflammasome/IL-1beta for steatohepatitis. Aging Cell. Aug 2015;14(4):524-33. doi:10.1111/acel.12305
88. Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F. Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PloS one. 2013;8(1):e54600. doi:10.1371/ journal.pone.0054600
89. Kavanagh K, Hsu FC, Davis AT, Kritchevsky SB, Rejeski WJ, Kim S. Biomarkers of leaky gut are related to inflammation and reduced physical function in older adults with cardiometabolic disease and mobility limitations. Geroscience. Dec 2019 ;41(6):923-933. doi:10.1007/s11357-019-00112-z
90. Stehle JR, Jr., Leng X, Kitzman DW, Nicklas BJ, Kritchevsky SB, High KP. Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults. J Gerontol A Biol Sci Med Sci. Nov 2012;67(11):1212-8. doi:10.1093/gerona/gls178
91. Reiner AP, Lange EM, Jenny NS, et al. Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults. Arteriosclerosis, thrombosis, and vascular biology. Jan 2013;33(1):158-64. doi:10.11 61/atvbaha.112.300421
92. Pinti M, Appay V, Campisi J, et al. Aging of the immune system: Focus on inflammation and vaccination. European journal of immunology. Oct 2016;46(10):2286-2301. doi:10.1002/eji.201546178
93. Zhang R, Miller RG, Gascon R, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). Journal of neuroimmunology. Jan 3 2009;206(1-2):121-4. doi:10.1016/j.jneuroim.2008.09.017
94. Vogt NM, Kerby RL, Dill-McFarland KA, et al. Gut microbiome alterations in Alzheimer's disease. Sci Rep. Oct 19 2017;7(1):13537. doi:10.1038/s 41598-017-13601-y
95. Vargas-Caraveo A, Sayd A, Maus SR, et al. Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions. Sci Rep. Oct 13 2017; 7(1):13113. doi:10.1038/s41598-017-13302-6
96. Zhao Y, Jaber V, Lukiw WJ. Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus. Frontiers in cellular and infection microbiology. 2017;7:318. doi:10.3389/fcimb.20 17.00318
97. Andre P, Samieri C, Buisson C, et al. Lipopolysaccharide-Binding Protein, Soluble CD14, and the Long-Term Risk of Alzheimer's Disease: A Nested Case-Control Pilot Study of Older Community Dwellers from the Three-City Cohort. J Alzheimers Dis. 2019;71(3):751-761. doi:10.3233/jad-190295
98. Pase MP, Himali JJ, Beiser AS, et al. Association of CD14 with incident dementia and markers of brain aging and injury. Neurology. Jan 21 2020;94(3):e254-e266. doi:10.1212/wnl.000000 0000008682
99. Ng A, Tam WW, Zhang MW, et al. IL-1beta, IL-6, TNF- alpha and CRP in Elderly Patients with Depression or Alzheimer's disease: Systematic Review and Meta-Analysis. Sci Rep. Aug 13 2018;8(1):12050. doi:10.1038/s41598-018-30487-6
100. Bradburn S, Sarginson J, Murgatroyd CA. Association of Peripheral Interleukin-6 with Global Cognitive Decline in Non-demented Adults: A Meta-Analysis of Prospective Studies. Front Aging Neurosci. 2017;9:438. doi:10.3389/fnagi.2017.00438
101. Kim JW, Stewart R, Kang HJ, et al. Longitudinal Associations Between Serum Cytokine Levels and Dementia. Frontiers in psychiatry. 2018;9:606. doi:10.3389/fpsyt.2018.00606
102. Lee WJ, Liao YC, Wang YF, Lin IF, Wang SJ, Fuh JL. Plasma MCP-1 and Cognitive Decline in Patients with Alzheimer's Disease and Mild Cognitive Impairment: A Two-year Follow-up Study. Sci Rep. 01 2018;8(1):1280. doi:10.1038/s4 1598-018-19807-y
103. Bettcher BM, Fitch R, Wynn MJ, et al. MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer's disease dementia phenotypes. Alzheimers Dement (Amst). 2016;3:91-7. doi:10.1016/j.dadm.2016.05.004
104. Chinta SJ, Woods G, Rane A, Demaria M, Campisi J, Andersen JK. Cellular senescence and the aging brain. Exp Gerontol. Aug 2015;68:3-7. doi:10.1016/j.exger.2014.09.018
105. Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118. doi:10.1146/annurev-path ol-121808-102144
106. Howcroft TK, Campisi J, Louis GB, et al. The role of inflammation in age-related disease. Aging (Albany NY). Jan 2013;5(1):84-93. doi:10.18632/ag ing.100531
107. Davalos AR, Coppe JP, Campisi J, Desprez PY. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev. Jun 2010;29(2):273-83. doi:10.1007/s10555-010-9220-9
108. Ferrucci L, Gonzalez-Freire M, Fabbri E, et al. Measuring biological aging in humans: A quest. Aging Cell. Feb 2020;19(2):e13080. doi:10.1111/ acel.13080
109. Brinkley TE, Leng X, Miller ME, et al. Chronic inflammation is associated with low physical function in older adults across multiple comorbidities. J Gerontol A Biol Sci Med Sci. Apr 2009;64(4):455-61. doi:10.1093/gerona/gln038
110. Puzianowska-Kuznicka M, Owczarz M, Wieczorowska-Tobis K, et al. Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immun Ageing. 2016;13:21. doi:10.1186/s12979-016-0076-x
111. Giovannini S, Onder G, Liperoti R, et al. Interleukin-6, C-reactive protein, and tumor necrosis factor-alpha as predictors of mortality in frail, community-living elderly individuals. J Am Geriatr Soc. Sep 2011;59(9):1679-85. doi:10.1111/j .1532-5415.2011.03570.x
112. Bailey KL, Smith LM, Heires AJ, Katafiasz DM, Romberger DJ, LeVan TD. Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists. Aging Clin Exp Res. Sep 2019;31(9):1185-1193. doi:10.1007/s40520-018-1064-0
113. Bettcher BM, Neuhaus J, Wynn MJ, et al. Increases in a Pro-inflammatory Chemokine, MCP-1, Are Related to Decreases in Memory Over Time. Front Aging Neurosci. 2019;11:25. doi:10.3389/fn agi.2019.00025
114. Magalhaes CA, Ferreira CN, Loures CMG, et al. Leptin, hsCRP, TNF-alpha and IL-6 levels from normal aging to dementia: Relationship with cognitive and functional status. J Clin Neurosci. Oct 2018;56:150-155. doi:10.1016/j.jocn.2018.08.027
115. Ong SM, Hadadi E, Dang TM, et al. The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence. Cell Death Dis. Feb 15 2018;9(3):266. doi:10.1038/s41419-018-0327-1
116. Wolf J, Weinberger B, Arnold CR, Maier AB, Westendorp RG, Grubeck-Loebenstein B. The effect of chronological age on the inflammatory response of human fibroblasts. Exp Gerontol. Sep 2012;47(9):749-53. doi:10.1016/j.exger.2012.07.001
117. Yousefzadeh MJ, Schafer MJ, Noren Hooten N, et al. Circulating levels of monocyte chemoattractant protein-1 as a potential measure of biological age in mice and frailty in humans. Aging Cell. Apr 2018;17(2)doi:10.1111/acel.12706
118. Lv S, Zhang Y, Lin Y, et al. ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl-CoA level. Aging Cell. Sep 2023;22(9):e13 932. doi:10.1111/acel.13932
119. Andriani GA, Almeida VP, Faggioli F, et al. Whole Chromosome Instability induces senescence and promotes SASP. Sci Rep. Oct 12 2016;6:35218 . doi:10.1038/srep35218
120. Zampino M, Ferrucci L, Semba RD. Biomarkers in the path from cellular senescence to frailty. Exp Gerontol. Jan 2020;129:110750. doi:10.1016/j.exg er.2019.110750
121. Leclercq S, De Saeger C, Delzenne N, de Timary P, Starkel P. Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry. Nov 1 2014;76:725-33. doi:10.1016/j.biopsych.201 4.02.003 10.1016/j.biopsych.2014.02.003. Epub 2014 Feb 14.
122. Neupane SP, Skulberg A, Skulberg KR, Aass HC, Bramness JG. Cytokine Changes following Acute Ethanol Intoxication in Healthy Men: A Crossover Study. Mediators Inflamm. 2016;201 6:3758590. doi:10.1155/2016/3758590
123. Pascual M, Montesinos J, Marcos M, et al. Gender differences in the inflammatory cytokine and chemokine profiles induced by binge ethanol drinking in adolescence. Addict Biol. Oct 4 2016;22(6):1829-1841. doi:10.1111/adb.12461
124. Qin L, He J, Hanes RN, Pluzarev O, Hong JS, Crews FT. Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. Journal of neuroinflammation. 2008;5:10. doi:10.1186/1742-2094-5-10 10.1186/1742-2094-5-10.
125. Crews FT, Sarkar DK, Qin L, Zou J, Boyadjieva N, Vetreno RP. Neuroimmune Function and the Consequences of Alcohol Exposure. Alcohol Research : Current Reviews. 2015;37(2):331-351.
126. Crews FT, Qin L, Sheedy D, Vetreno RP, Zou J. High mobility group box 1/Toll-like receptor danger signaling increases brain neuroimmune activation in alcohol dependence. Biol Psychiatry. Apr 1 2013;73(7):602-12. doi:10.1016/j.biopsych. 2012.09.030
127. Coleman LG, Jr., Zou J, Qin L, Crews FT. HMGB1/ IL-1beta complexes regulate neuroimmune responses in alcoholism. Brain Behav Immun. Aug 2018;72:61-77. doi:10.1016 /j.bbi.2017.10.027
128. Lawrimore CJ, Crews FT. Ethanol, TLR3, and TLR4 Agonists Have Unique Innate Immune Responses in Neuron-Like SH-SY5Y and Microglia-Like BV2. Alcohol Clin Exp Res. May 2017;41(5):93 9-954. doi:10.1111/acer.13368
129. Lowe PP, Gyongyosi B, Satishchandran A, et al. Reduced gut microbiome protects from alcohol-induced neuroinflammation and alters intestinal and brain inflammasome expression. Journal of neuroinflammation. Oct 27 2018;15(1):298. doi:10. 1186/s12974-018-1328-9
130. Lippai D, Bala S, Petrasek J, et al. Alcohol-induced IL-1beta in the brain is mediated by NLRP3/ ASC inflammasome activation that amplifies neuroinflammation. J Leukoc Biol. Jul 2013;94(1):171-82. doi:10.1189/jlb.1212659
131. Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal. Apr 2012;24(4):835-45. doi:10.1016/j.cellsig.2011.12.006
132. Aird KM, Iwasaki O, Kossenkov AV, et al. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J Cell Biol. Nov 7 2016;215(3):325-334. doi:10. 1083/jcb.201608026
133. Martins de Carvalho L, Wiers CE, Manza P, et al. Effect of alcohol use disorder on cellular aging. Psychopharmacology (Berl). Nov 2019;236(11):324 5-3255. doi:10.1007/s00213-019-05281-5
134. Chen X, Li M, Yan J, et al. Alcohol Induces Cellular Senescence and Impairs Osteogenic Potential in Bone Marrow-Derived Mesenchymal Stem Cells. Alcohol Alcohol. May 1 2017;52(3):289-297. doi:10.1093/alcalc/agx006
135. Epel ES, Merkin SS, Cawthon R, et al. The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men. Aging (Albany NY). Dec 4 2008;1(1):81-8. doi:10.18632/aging.100007
136. Harpaz T, Abumock H, Beery E, et al. The Effect of Ethanol on Telomere Dynamics and Regulation in Human Cells. Cells. Oct 15 2018;7(10)doi:10.3390/cells7100169
137. Strandberg TE, Strandberg AY, Saijonmaa O, Tilvis RS, Pitkala KH, Fyhrquist F. Association between alcohol consumption in healthy midlife and telomere length in older men. The Helsinki Businessmen Study. European journal of epidemiology. Oct 2012;27(10):815-22. doi:10.100 7/s10654-012-9728-0
138. Yamaki N, Matsushita S, Hara S, Yokoyama A, Hishimoto A, Higuchi S. Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde. J Psychiatr Res. Feb 2019;109:27-32. doi:10.1016/j.jpsychires.2018.11.007
139. Stephenson M, Bollepalli S, Cazaly E, et al. Associations of Alcohol Consumption With Epigenome-Wide DNA Methylation and Epigenetic Age Acceleration: Individual-Level and Co-twin Comparison Analyses. Alcohol Clin Exp Res. Feb 2021;45(2):318-328. doi:10.1111/acer.14528
140. Elliott DA, Weickert CS, Garner B. Apolipoproteins in the brain: implications for neurological and psychiatric disorders. Clin Lipidol. Aug 1 2010;51(4):555-573. doi:10.2217/clp.10.37
141. Rebeck GW. The role of APOE on lipid homeostasis and inflammation in normal brains. J Lipid Res. Aug 2017;58(8):1493-1499. doi:10.1194/ jlr.R075408
142. Chernick D, Ortiz-Valle S, Jeong A, Qu W, Li L. Peripheral versus central nervous system APOE in Alzheimer's disease: Interplay across the blood-brain barrier. Neurosci Lett. 08 2019;708:134306. doi:10.1016/j.neulet.2019.134306
143. Kloske CM, Wilcock DM. The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer's Disease. Frontiers in immunology. 2020;11:754. doi:10.33 89/fimmu.2020.00754
144. Brown GC. The endotoxin hypothesis of neurodegeneration. Journal of neuroinflammation. Sep 13 2019;16(1):180. doi:10.1186/s12974-019-1564-7
145. Erickson MA, Hartvigson PE, Morofuji Y, Owen JB, Butterfield DA, Banks WA. Lipopolysaccharide impairs amyloid β efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier. Journal of neuroinflammation. Jun 2012;9:150. doi:10.1186/1742-2094-9-150
146. Chang L, Munsaka SM, Kraft-Terry S, Ernst T. Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. Jun 2013;8(3):576-93. doi:10.1007/s11481-013-9460-x
147. Rae CD. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochemical research. Jan 2014;39(1):1-36. doi:10.1007/s11064-013-1199-5
148. Barrientos RM, Kitt MM, Watkins LR, Maier SF. Neuroinflammation in the normal aging hippocampus. Neuroscience. Nov 19 2015;309:84-99. doi:10.1016/j.neuroscience.2015.03.007
149. Clarke LE, Liddelow SA, Chakraborty C, Munch AE, Heiman M, Barres BA. Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci U S A. Feb 20 2018;115(8):E1896-e1905. doi:10.1073/ pnas.1800165115
150. Gulyas B, Vas A, Toth M, et al. Age and disease related changes in the translocator protein (TSPO) system in the human brain: positron emission tomography measurements with [11C] vinpocetine. Neuroimage. Jun 1 2011;56(3):1111-21. doi:10.1016/j.neuroimage.2011.02.020
151. Sparkman NL, Johnson RW. Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation. 2008;15(4-6):32 3-30. doi:10.1159/000156474
152. Waragai M, Moriya M, Nojo T. Decreased N-Acetyl Aspartate/Myo-Inositol Ratio in the Posterior Cingulate Cortex Shown by Magnetic Resonance Spectroscopy May Be One of the Risk Markers of Preclinical Alzheimer's Disease: A 7-Year Follow-Up Study. J Alzheimers Dis. 2017;60(4):1411-1427. doi:10.3233/JAD-170450
153. Kantarci K, Weigand SD, Przybelski SA, et al. MRI and MRS predictors of mild cognitive impairment in a population-based sample. Neurology. Jul 9 2013;81(2):126-33. doi:10.1212/ WNL.0b013e31829a3329
154. Kantarci K, Lowe V, Przybelski SA, et al. Magnetic resonance spectroscopy, beta-amyloid load, and cognition in a population-based sample of cognitively normal older adults. Neurology. Sep 6 2011;77(10):951-8. doi:10.1212/WNL.0b013e31 822dc7e1
155. Hupfeld KE, Hyatt HW, Alvarez Jerez P, et al. In Vivo Brain Glutathione is Higher in Older Age and Correlates with Mobility. Cereb Cortex. Aug 26 2021;31(10):4576-4594. doi:10.1093/cercor/bhab107
156. Voevodskaya O, Sundgren PC, Strandberg O, et al. Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease. Neurology. May 10 2016;86 (19):1754-61. doi:10.1212/wnl.0000000000002672
157. Lind A, Boraxbekk CJ, Petersen ET, Paulson OB, Siebner HR, Marsman A. Regional Myo-Inositol, Creatine, and Choline Levels Are Higher at Older Age and Scale Negatively with Visuospatial Working Memory: A Cross-Sectional Proton MR Spectroscopy Study at 7 Tesla on Normal Cognitive Ageing. J Neurosci. Oct 14 2020;40(42): 8149-8159. doi:10.1523/jneurosci.2883-19.2020
158. Sporn L, MacMillan EL, Ge R, Greenway K, Vila-Rodriguez F, Laule C. Longer Repetition Time Proton MR Spectroscopy Shows Increasing Hippocampal and Parahippocampal Metabolite Concentrations with Aging. J Neuroimaging. Sep 2019;29(5):592-597. doi:10.1111/jon.12648
159. Maghsudi H, Schütze M, Maudsley AA, Dadak M, Lanfermann H, Ding XQ. Age-related Brain Metabolic Changes up to Seventh Decade in Healthy Humans : Whole-brain Magnetic Resonance Spectroscopic Imaging Study. Clin Neuroradiol. Sep 2020;30(3):581-589. doi:10.1007 /s00062-019-00814-z
160. Marjańska M, McCarten JR, Hodges J, et al. Region-specific aging of the human brain as evidenced by neurochemical profiles measured noninvasively in the posterior cingulate cortex and the occipital lobe using (1)H magnetic resonance spectroscopy at 7 T. Neuroscience. Jun 23 2017;35 4:168-177. doi:10.1016/j.neuroscience.2017.04.035
161. Suri S, Emir U, Stagg CJ, et al. Effect of age and the APOE gene on metabolite concentrations in the posterior cingulate cortex. Neuroimage. May 15 2017;152:509-516. doi:10.1016/j.neuroimage.2 017.03.031
162. Ding XQ, Maudsley AA, Sabati M, et al. Physiological neuronal decline in healthy aging human brain - An in vivo study with MRI and short echo-time whole-brain (1)H MR spectroscopic imaging. Neuroimage. Aug 15 2016;137:45-51. doi:10.1016/j.neuroimage.2016.05.014
163. Gruber S, Pinker K, Riederer F, et al. Metabolic changes in the normal ageing brain: consistent findings from short and long echo time proton spectroscopy. Eur J Radiol. Nov 2008;68(2):320-7. doi:10.1016/j.ejrad.2007.08.038
164. Tunc-Skarka N, Meier S, Demirakca T, et al. Effects of normal aging and SCN1A risk-gene expression on brain metabolites: evidence for an association between SCN1A and myo-inositol. NMR Biomed. Feb 2014;27(2):228-34. doi:10.100 2/nbm.3057
165. Nedelska Z, Przybelski SA, Lesnick TG, et al. (1)H-MRS metabolites and rate of beta-amyloid accumulation on serial PET in clinically normal adults. Neurology. Sep 26 2017;89(13):1391-1399. doi:10.1212/wnl.0000000000004421
166. Wang H, Tan L, Wang HF, et al. Magnetic Resonance Spectroscopy in Alzheimer's Disease: Systematic Review and Meta-Analysis. J Alzheimers Dis. 2015;46(4):1049-70. doi:10.3233/jad-143225
167. Li BS, Wang H, Gonen O. Metabolite ratios to assumed stable creatine level may confound the quantification of proton brain MR spectroscopy. Magnetic resonance imaging. Oct 2003;21(8):923-8. doi:10.1016/s0730-725x(03)00181-4
168. Zahr NM, Pfefferbaum A. Alcohol's Effects on the Brain: Neuroimaging Results in Humans and Animal Models. Alcohol Res. 2017;38(2):183-206.
169. Ende G, Walter S, Welzel H, et al. Alcohol consumption significantly influences the MR signal of frontal choline-containing compounds. Neuroimage. Aug 15 2006;32(2):740-6. doi:10.1016/j.neuroimag e.2006.03.049
170. Ende G, Hermann D, Demirakca T, et al. Loss of control of alcohol use and severity of alcohol dependence in non-treatment-seeking heavy drinkers are related to lower glutamate in frontal white matter. Alcohol Clin Exp Res. Oct 2013;37 (10):1643-9. doi:10.1111/acer.12149
171. Tunc-Skarka N, Weber-Fahr W, Ende G. Recreational alcohol use induces changes in the concentrations of choline-containing compounds and total creatine in the brain: a (1)H MRS study of healthy subjects. Magma (New York, NY). Oct 2015;28(5):503-10. doi:10.1007/s10334-015-0486-3
172. Kirkland AE, Browning BD, Green R, Leggio L, Meyerhoff DJ, Squeglia LM. Brain metabolite alterations related to alcohol use: a meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry. May 4 2022;doi:10.1038/s 41380-022-01594-8
173. Monnig MA, Woods AJ, Walsh E, et al. Cerebral Metabolites on the Descending Limb of Acute Alcohol: A Preliminary 1H MRS Study. Alcohol Alcohol. Jul 2019;doi:10.1093/alcalc/agz062
174. Biller A, Bartsch AJ, Homola G, Solymosi L, Bendszus M. The effect of ethanol on human brain metabolites longitudinally characterized by proton MR spectroscopy. J Cereb Blood Flow Metab. May 2009;29(5):891-902. doi:10.1038/jcbfm.2009.12
175. Gomez R, Behar KL, Watzl J, et al. Intravenous ethanol infusion decreases human cortical gamma-aminobutyric acid and N-acetylaspartate as measured with proton magnetic resonance spectroscopy at 4 tesla. Biol Psychiatry. Feb 1 2012 ;71(3):239-46. doi:10.1016/j.biopsych.2011.06.026
176. Piers RJ. Structural brain volume differences between cognitively intact ApoE4 carriers and non-carriers across the lifespan. Neural regeneration research. Aug 2018;13(8):1309-1312. doi:10.4103/ 1673-5374.235408
177. Bussy A, Snider BJ, Coble D, et al. Effect of apolipoprotein E4 on clinical, neuroimaging, and biomarker measures in noncarrier participants in the Dominantly Inherited Alzheimer Network. Neurobiol Aging. Mar 2019;75:42-50. doi:10.1016/ j.neurobiolaging.2018.10.011
178. Gonneaud J, Arenaza-Urquijo EM, Fouquet M, et al. Relative effect of APOE ε4 on neuroimaging biomarker changes across the lifespan. Neurology. Oct 2016;87(16):1696-1703. doi:10.1212/WNL.0 000000000003234
179. Glorioso CA, Pfenning AR, Lee SS, et al. Rate of brain aging and APOE ε4 are synergistic risk factors for Alzheimer's disease. Life Sci Alliance. Jun 2019;2(3)doi:10.26508/lsa.201900303
180. Gomar JJ, Gordon ML, Dickinson D, et al. APOE genotype modulates proton magnetic resonance spectroscopy metabolites in the aging brain. Biol Psychiatry. May 1 2014;75(9):686-92. doi:10.1016/j.biopsych.2013.05.022
181. Montesinos J, Alfonso-Loeches S, Guerri C. Impact of the Innate Immune Response in the Actions of Ethanol on the Central Nervous System. Alcohol Clin Exp Res. Nov 2016;40(11):2260-2270. doi:10.1111/acer.13208
182. Crews FT, Zou J, Qin L. Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun. Jun 2011;25 Suppl 1:S4-S12. doi:10.1016/j.bbi.2011.03.003
183. Szabo G, Saha B. Alcohol’s Effect on Host Defense. Alcohol Research : Current Reviews. 2015;37(2):159-170.
184. Mandrekar P, Catalano D, White B, Szabo G. Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of nuclear regulatory factor kappa B and induction of interleukin 10. Alcohol Clin Exp Res. Jan 2006;30(1 ):135-9. doi:10.1111/j.1530-0277.2006.00012.x
185. Mandrekar P, Jeliazkova V, Catalano D, Szabo G. Acute alcohol exposure exerts anti-inflammatory effects by inhibiting IkappaB kinase activity and p65 phosphorylation in human monocytes. J Immunol. Jun 15 2007;178(12):7686-93.
186. Mandrekar P, Bala S, Catalano D, Kodys K, Szabo G. The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes. J Immunol. Jul 2009;183(2):1320-7. doi:10.4049/jimmunol.0803206
187. Muralidharan S, Ambade A, Fulham MA, Deshpande J, Catalano D, Mandrekar P. Moderate alcohol induces stress proteins HSF1 and hsp70 and inhibits proinflammatory cytokines resulting in endotoxin tolerance. J Immunol. Aug 15 2014;1 93:1975-87. doi:10.4049/jimmunol.1303468 10.40 49/jimmunol.1303468. Epub 2014 Jul 14.
188. Varadhan R, Yao W, Matteini A, et al. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. J Gerontol A Biol Sci Med Sci. Feb 2014;69(2):165-73. doi:10.1093/gerona/glt023
189. Schram MT, Euser SM, de Craen AJ, et al. Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc. May 2007;55 (5):708-16. doi:10.1111/j.1532-5415.2007.01159.x
190. Trollor JN, Smith E, Baune BT, et al. Systemic inflammation is associated with MCI and its subtypes: the Sydney Memory and Aging Study. Dement Geriatr Cogn Disord. 2010;30(6):569-78. doi:10.1159/000322092
191. Cesari M, Kritchevsky SB, Nicklas B, et al. Oxidative damage, platelet activation, and inflammation to predict mobility disability and mortality in older persons: results from the health aging and body composition study. J Gerontol A Biol Sci Med Sci. Jun 2012;67(6):671-6. doi:10.1 093/gerona/glr246
192. Tangestani Fard M, Stough C. A Review and Hypothesized Model of the Mechanisms That Underpin the Relationship Between Inflammation and Cognition in the Elderly. Front Aging Neurosci. 2019;11:56. doi:10.3389/fnagi.2019.00056
193. Villeda SA, Luo J, Mosher KI, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. Aug 31 2011;477 (7362):90-4. doi:10.1038/nature10357
194. McKechnie DGJ, Papacosta AO, Lennon LT, Ramsay SE, Whincup PH, Wannamethee SG. Associations between inflammation, cardiovascular biomarkers and incident frailty: the British Regional Heart Study. Age Ageing. Nov 10 2021;50(6):1979-1987. doi:10.1093/ageing/afab143
195. Dugué PA, Hodge AM, Ulvik A, et al. Association of markers of inflammation, the kynurenine pathway and B vitamins with age and mortality, and a signature of inflammaging. J Gerontol A Biol Sci Med Sci. Jun 12 2021;doi :10.1093/gerona/glab163
196. Adriaensen W, Matheï C, Vaes B, van Pottelbergh G, Wallemacq P, Degryse JM. Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: A regression and CART approach in the BELFRAIL study. Exp Gerontol. Sep 2015;6 9:53-61. doi:10.1016/j.exger.2015.06.005