Exploration of Neuroprotective Therapy

Declarations

Acknowledgments

We thank Ms. Nuria de la Torre Alonso for technical and editorial assistance. Figure 1 was created with Biorender (BioRender.com).

Author contributions

JA: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. MP, MAV, ISM and FH: Conceptualization, Investigation. All authors read and approved the submitted version.

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work has been supported by grants from the Spanish Ministry of Science and Innovation [PID2020-113204GB-I00] (FH) and [PID2021-123859OB-100] from MCIN /AEI/10.13039/501100011033/FEDER, UE (JA). This work was supported by CSIC through an intramural grant [201920E104] (JA). The Centro de Biología Molecular Severo Ochoa (CBMSO) is a Severo Ochoa Center of Excellence (MICIN, award CEX2021-001154-S). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Primers. 2015;1:15056. [DOI] [PubMed]

Jensen AMG, Kitago Y, Fazeli E, Vaegter CB, Small SA, Petsko GA, et al. Dimerization of the Alzheimer’s disease pathogenic receptor SORLA regulates its association with retromer. Proc Natl Acad Sci U S A. 2023;120:e2212180120. [DOI] [PubMed]

Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007;39:168–77. [DOI] [PubMed] [PMC]

Fernandez-Nogales M, Santos-Galindo M, Hernandez IH, Cabrera JR, Lucas JJ. Faulty splicing and cytoskeleton abnormalities in Huntington’s disease. Brain Pathol. 2016;26:772–8. [DOI] [PubMed] [PMC]

Goutagny R, Gu N, Cavanagh C, Jackson J, Chabot JG, Quirion R, et al. Alterations in hippocampal network oscillations and theta-gamma coupling arise before Aβ overproduction in a mouse model of Alzheimer’s disease. Eur J Neurosci. 2013;37:1896–902. [DOI] [PubMed]

Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6. [DOI] [PubMed]

Du X, Wang X, Geng M. Alzheimer’s disease hypothesis and related therapies. Transl Neurodegener. 2018;7:2. [DOI] [PubMed] [PMC]

Davies P. Challenging the cholinergic hypothesis in Alzheimer disease. JAMA. 1999;281:1433–4. [DOI] [PubMed]

Khachaturian ZS. Calcium hypothesis of Alzheimer’s disease and brain aging. Ann N Y Acad Sci. 1994;747:1–11. [DOI] [PubMed]

10.

Zhu X, Raina AK, Perry G, Smith MA. Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol. 2004;3:219–26. [DOI] [PubMed]

11.

Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17:157–72. [DOI] [PubMed]

12.

Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975;72:1858–62. [DOI] [PubMed] [PMC]

13.

Chen Z, Zhong C. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol. 2013;108:21–43. [DOI] [PubMed]

14.

Arnsten AFT, Datta D, Del Tredici K, Braak H. Hypothesis: tau pathology is an initiating factor in sporadic Alzheimer’s disease. Alzheimers Dement. 2021;17:115–24. [DOI] [PubMed] [PMC]

15.

Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol. 2019;15:565–81. [DOI] [PubMed]

16.

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] [PubMed] [PMC]

17.

Liang W, Chen Q, Cheng S, Wei R, Li Y, Yao C, et al. Skin chronological aging drives age-related bone loss via secretion of cystatin-A. Nature Aging. 2022;2:906–22. [DOI] [PubMed]

18.

Gupta DP, Lee YS, Choe Y, Kim KT, Song GJ, Hwang SC. Knee osteoarthritis accelerates amyloid beta deposition and neurodegeneration in a mouse model of Alzheimer’s disease. Mol Brain. 2023;16:1. [DOI] [PubMed] [PMC]

19.

Eiser AR, Fulop T. Alzheimer’s disease is a multi-organ disorder: it may already be preventable. J Alzheimers Dis. 2023;91:1277–81. [DOI] [PubMed]

20.

Jorfi M, Maaser-Hecker A, Tanzi RE. The neuroimmune axis of Alzheimer’s disease. Genome Med. 2023;15:6. [DOI] [PubMed] [PMC]

21.

Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791–800. [DOI] [PubMed]

22.

Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59. [DOI] [PubMed]

23.

Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev. 2004;84:361–84. [DOI] [PubMed]

24.

Cha HJ, Shen J, Kang J. Regulation of gene expression by the APP family in the adult cerebral cortex. Sci Rep. 2022;12:66. [DOI] [PubMed] [PMC]

25.

Guo Q, Li H, Gaddam SS, Justice NJ, Robertson CS, Zheng H. Amyloid precursor protein revisited: neuron-specific expression and highly stable nature of soluble derivatives. J Biol Chem. 2012;287:2437–45. [DOI] [PubMed] [PMC]

26.

Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018;217:459–72. [DOI] [PubMed] [PMC]

27.

Paolicelli RC, Sierra A, Stevens B, Tremblay ME, Aguzzi A, Ajami B, et al. Microglia states and nomenclature: a field at its crossroads. Neuron. 2022;110:3458–83. [DOI] [PubMed] [PMC]

28.

Zhang G, Wang Z, Hu H, Zhao M, Sun L. Microglia in Alzheimer’s disease: a target for therapeutic intervention. Front Cell Neurosci. 2021;15:749587. [DOI] [PubMed] [PMC]

29.

Perea JR, Bolos M, Avila J. Microglia in Alzheimer’s disease in the context of tau pathology. Biomolecules. 2020;10:1439. [DOI] [PubMed] [PMC]

30.

Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016;213:667–75. [DOI] [PubMed] [PMC]

31.

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7. [DOI] [PubMed] [PMC]

32.

Qian X, Yue L, Mellor D, Robbins NM, Li W, Xiao S. Reduced peripheral nerve conduction velocity is associated with Alzheimer’s disease: a cross-sectional study from China. Neuropsychiatr Dis Treat. 2022;18:231–42. [DOI] [PubMed] [PMC]

33.

Barthelemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TLS, et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med. 2020;26:398–407. [DOI] [PubMed] [PMC]

34.

Blennow K, Dubois B, Fagan AM, Lewczuk P, de Leon MJ, Hampel H. Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Alzheimers Dement. 2015;11:58–69. [DOI] [PubMed] [PMC]

35.

Avila J, Perry G. A multilevel view of the development of Alzheimer’s disease. Neuroscience. 2021;457:283–93. [DOI] [PubMed]

36.

Ma YH, Shen LX, Li YZ, Leng Y, Yang L, Chen SD, et al. Lung function and risk of incident dementia: a prospective cohort study of 431,834 individuals. Brain Behav Immun. 2023;109:321–30. [DOI] [PubMed]

37.

Tublin JM, Adelstein JM, Del Monte F, Combs CK, Wold LE. Getting to the heart of Alzheimer disease. Circ Res. 2019;124:142–9. [DOI] [PubMed] [PMC]

38.

Peikert A, Cunningham JW. Amyloid-β and the risk of heart failure: cause or only association? JACC Heart Fail. 2023;11:103–5. [DOI] [PubMed]

39.

Troncone L, Luciani M, Coggins M, Wilker EH, Ho CY, Codispoti KE, et al. Aβ amyloid pathology affects the hearts of patients with Alzheimer’s disease: mind the heart. J Am Coll Cardiol. 2016;68:2395–407. [DOI] [PubMed] [PMC]

40.

Cardiogenic dementia. Lancet. 1977;309:27–8. [PubMed]

41.

SPRINT MIND Investigators for the SPRINT Research Group; Nasrallah IM, Pajewski NM, Auchus AP, Chelune G, Cheung AK, Cleveland ML, et al. Association of intensive vs. standard blood pressure control with cerebral white matter lesions. JAMA. 2019;322:524–34. [DOI] [PubMed] [PMC]

42.

Moreno-Jimenez EP, Flor-Garcia M, Terreros-Roncal J, Rabano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med. 2019;25:554–60. [DOI] [PubMed]

43.

Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477:90–4. [DOI] [PubMed] [PMC]

44.

Liu ZH, Wang YJ, Bu XL. Alzheimer’s disease: targeting the peripheral circulation. Mol Neurodegener. 2023;18:3. [DOI] [PubMed] [PMC]

45.

Bu XL, Xiang Y, Jin WS, Wang J, Shen LL, Huang ZL, et al. Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies. Mol Psychiatry. 2018;23:1948–56. [DOI] [PubMed]

46.

Sun HL, Chen SH, Yu ZY, Cheng Y, Tian DY, Fan DY, et al. Blood cell-produced amyloid-β induces cerebral Alzheimer-type pathologies and behavioral deficits. Mol Psychiatry. 2021;26:5568–77. [DOI] [PubMed]

47.

Kowalski K, Mulak A. Brain-gut-microbiota axis in Alzheimer’s disease. J Neurogastroenterol Motil. 2019;25:48–60. [DOI] [PubMed] [PMC]

48.

Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, et al. The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS One. 2010;5:e9505. [DOI] [PubMed] [PMC]

49.

Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med. 2016;8:340ra72. [DOI] [PubMed] [PMC]

50.

Chen C, Zhou Y, Wang H, Alam A, Kang SS, Ahn EH, et al. Gut inflammation triggers C/EBPβ/δ-secretase-dependent gut-to-brain propagation of Aβ and Tau fibrils in Alzheimer’s disease. EMBO J. 2021;40:e106320. [DOI] [PubMed] [PMC]

51.

Jin J, Xu Z, Zhang L, Zhang C, Zhao X, Mao Y, et al. Gut-derived β-amyloid: likely a centerpiece of the gut-brain axis contributing to Alzheimer’s pathogenesis. Gut Microbes. 2023;15:2167172. [DOI] [PubMed] [PMC]

52.

Sun Y, Sommerville NR, Liu JYH, Ngan MP, Poon D, Ponomarev ED, et al. Intra-gastrointestinal amyloid-β1-42 oligomers perturb enteric function and induce Alzheimer’s disease pathology. J Physiol. 2020;598:4209–23. [DOI] [PubMed] [PMC]

53.

Carloni S, Bertocchi A, Mancinelli S, Bellini M, Erreni M, Borreca A, et al. Identification of a choroid plexus vascular barrier closing during intestinal inflammation. Science. 2021;374:439–48. [DOI] [PubMed]

54.

Dai CL, Liu F, Iqbal K, Gong CX. Gut microbiota and immunotherapy for Alzheimer’s disease. Int J Mol Sci. 2022;23:15230. [DOI] [PubMed] [PMC]

55.

Mawe GM, Hoffman JM. Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol. 2013;10:473–86. [DOI] [PubMed] [PMC]

56.

Avila-Villanueva M, Gomez-Ramirez J, Avila J, Fernandez-Blazquez MA. Alzheimer’s disease and empathic abilities: the proposed role of the cingulate cortex. J Alzheimers Dis Rep. 2021;5:345–52. [DOI] [PubMed] [PMC]

57.

Canton-Habas V, Rich-Ruiz M, Romero-Saldana M, Carrera-Gonzalez MDP. Depression as a risk factor for dementia and Alzheimer’s disease. Biomedicines. 2020;8:457. [DOI] [PubMed] [PMC]

58.

Konopelski P, Mogilnicka I. Biological effects of indole-3-propionic acid, a gut microbiota-derived metabolite, and its precursor tryptophan in mammals’ health and disease. Int J Mol Sci. 2022;23:1222. [DOI] [PubMed] [PMC]

59.

Gheorghe CE, Martin JA, Manriquez FV, Dinan TG, Cryan JF, Clarke G. Focus on the essentials: tryptophan metabolism and the microbiome-gut-brain axis. Curr Opin Pharmacol. 2019;48:137–45. [DOI] [PubMed]

60.

Seo DO, O’Donnell D, Jain N, Ulrich JD, Herz J, Li Y, et al. ApoE isoform– and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science. 2023;379:eadd1236. [DOI] [PubMed]

61.

Agirman G, Hsiao EY. Gut microbes shape athletic motivation. Nature. 2022;612:633–4. [DOI] [PubMed]

62.

Goncalves RA, Sudo FK, Lourenco MV, Drummond C, Assuncao N, Vanderborght B, et al. Cerebrospinal fluid irisin and lipoxin A4 are reduced in elderly Brazilian individuals with depression: insight into shared mechanisms between depression and dementia. Alzheimers Dement. 2023;19:2595–604. [DOI] [PubMed]

63.

Peng J, Wu J. Effects of the FNDC5/irisin on elderly dementia and cognitive impairment. Front Aging Neurosci. 2022;14:863901. [DOI] [PubMed] [PMC]

64.

Bassendine MF, Taylor-Robinson SD, Fertleman M, Khan M, Neely D. Is Alzheimer’s disease a liver disease of the brain? J Alzheimers Dis. 2020;75:1–14. [DOI] [PubMed] [PMC]

65.

Liu YH, Wang YR, Xiang Y, Zhou HD, Giunta B, Manucat-Tan NB, et al. Clearance of amyloid-beta in Alzheimer’s disease: shifting the action site from center to periphery. Mol Neurobiol. 2015;51:1–7. [DOI] [PubMed]

66.

Xiang Y, Bu XL, Liu YH, Zhu C, Shen LL, Jiao SS, et al. Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer’s disease. Acta Neuropathol. 2015;130:487–99. [DOI] [PubMed] [PMC]

67.

Cheng Y, He CY, Tian DY, Chen SH, Ren JR, Sun HL, et al. Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease. Acta Neuropathol. 2023;145:717–31. [DOI] [PubMed]

68.

Nho K, Kueider-Paisley A, Ahmad S, MahmoudianDehkordi S, Arnold M, Risacher SL, et al.; Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium. Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers. JAMA Netw Open. 2019;2:e197978. [DOI] [PubMed] [PMC]

69.

Giannisis A, Patra K, Edlund AK, Nieto LA, Benedicto-Gras J, Moussaud S, et al. Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice. Mol Psychiatry. 2022;27:3533–43. [DOI] [PubMed] [PMC]

70.

Liu CC, Zhao J, Fu Y, Inoue Y, Ren Y, Chen Y, et al. Peripheral apoE4 enhances Alzheimer’s pathology and impairs cognition by compromising cerebrovascular function. Nat Neurosci. 2022;25:1020–33. [DOI] [PubMed] [PMC]

71.

Lam V, Takechi R, Hackett MJ, Francis R, Bynevelt M, Celliers LM, et al. Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype. PLoS Biol. 2021;19:e3001358. [DOI] [PubMed] [PMC]

72.

Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25:1822–32. [DOI] [PubMed] [PMC]

73.

Xue YH, Peng YS, Ting HF, Peijer Hsieh J, Huang YK, Wang YH, et al. Etoricoxib and diclofenac might reduce the risk of dementia in patients with osteoarthritis: a nation-wide, population-based retrospective cohort study. Dement Geriatr Cogn Disord. 2018;45:262–71. [DOI] [PubMed]

74.

Tian DY, Cheng Y, Zhuang ZQ, He CY, Pan QG, Tang MZ, et al. Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer’s disease. Mol Psychiatry. 2021;26:6074–82. [DOI] [PubMed]

75.

Montejo de Garcini E, Diez JC, Avila J. Quantitation and characterization of tau factor in porcine tissues. Biochim Biophys Acta. 1986;881:456–61. [DOI] [PubMed]

76.

Valles-Saiz L, Peinado-Cahuchola R, Avila J, Hernandez F. Microtubule-associated protein tau in murine kidney: role in podocyte architecture. Cell Mol Life Sci. 2022;79:97. [DOI] [PubMed] [PMC]

77.

Doran M, du Plessis DG, Ghadiali EJ, Mann DM, Pickering-Brown S, Larner AJ. Familial early-onset dementia with tau intron 10 + 16 mutation with clinical features similar to those of Alzheimer disease. Arch Neurol. 2007;64:1535–9. [DOI] [PubMed]

78.

Stocker H, Beyer L, Trares K, Perna L, Rujescu D, Holleczek B, et al. Association of kidney function with development of Alzheimer disease and other dementias and dementia-related blood biomarkers. JAMA Netw Open. 2023;6:e2252387. [DOI] [PubMed]

79.

Wang S, Wang J, Dove A, Guo J, Yang W, Qi X, et al. Association of impaired kidney function with dementia and brain pathologies: a community-based cohort study. Alzheimers Dement. 2022;[Epub ahead of print]. [DOI] [PubMed]

80.

Xu H, Garcia-Ptacek S, Bruchfeld A, Fu EL, Shori TD, Lindholm B, et al. Association between cholinesterase inhibitors and kidney function decline in patients with Alzheimer’s dementia. Kidney Int. 2023;103:166–76. [DOI] [PubMed]

81.

Chen F, Wang N, Tian X, Qin Y, Su J, He R, et al. The potential diagnostic accuracy of urine formaldehyde levels in Alzheimer’s disease: a systematic review and meta-analysis. Front Aging Neurosci. 2022;14:1057059. [DOI] [PubMed] [PMC]

82.

Mathieu C, Martens PJ, Vangoitsenhoven R. One hundred years of insulin therapy. Nat Rev Endocrinol. 2021;17:715–25. [DOI] [PubMed]

83.

Neumann KF, Rojo L, Navarrete LP, Farias G, Reyes P, Maccioni RB. Insulin resistance and Alzheimer’s disease: molecular links & clinical implications. Curr Alzheimer Res. 2008;5:438–47. [DOI] [PubMed]

84.

Li L, Holscher C. Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res Rev. 2007;56:384–402. [DOI] [PubMed]

85.

Desai GS, Zheng C, Geetha T, Mathews ST, White BD, Huggins KW, et al. The pancreas-brain axis: insight into disrupted mechanisms associating type 2 diabetes and Alzheimer’s disease. J Alzheimers Dis. 2014;42:347–56. [DOI] [PubMed]

86.

de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008;2:1101–13. [DOI] [PubMed] [PMC]

87.

Reish NJ, Jamshidi P, Stamm B, Flanagan ME, Sugg E, Tang M, et al. Multiple cerebral hemorrhages in a patient receiving lecanemab and treated with t-PA for stroke. N Engl J Med. 2023;388:478–9. [DOI] [PubMed] [PMC]

88.

Alves F, Kallinowski P, Ayton S. Accelerated brain volume loss caused by anti-beta-amyloid drugs: a systematic review and meta-analysis. Neurology. 2023;100:e2114–24. [DOI] [PubMed]

89.

Moutinho S. The long road to a cure for Alzheimer’s disease is paved with failures. Nat Med. 2022;28:2228–31. [DOI] [PubMed]

90.

Cummings J, Lee G, Nahed P, Kambar M, Zhong K, Fonseca J, et al. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement (N Y). 2022;8:e12295. [DOI] [PubMed] [PMC]

91.

Aguillon D, Langella S, Chen Y, Sanchez JS, Su Y, Vila-Castelar C, et al. Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer’s disease. Alzheimers Dement. 2023;19:2585–94. [DOI] [PubMed]

92.

Zhao A, Jiao Y, Ye G, Kang W, Tan L, Li Y, et al. Soluble TREM2 levels associate with conversion from mild cognitive impairment to Alzheimer’s disease. J Clin Invest. 2022;132:e158708. [DOI] [PubMed] [PMC]

93.

Franco R, Cedazo-Minguez A. Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans? Front Pharmacol. 2014;5:146. [DOI] [PubMed] [PMC]

94.

Perez-Olives C, Rivas-Santisteban R, Lillo J, Navarro G, Franco R. Recent advances in the potential of cannabinoids for neuroprotection in Alzheimer’s, Parkinson’s, and Huntington’s diseases. Adv Exp Med Biol. 2021;1264:81–92. [DOI] [PubMed]

95.

Levert S, Pilliod J, Aumont E, Armanville S, Tremblay C, Calon F, et al. Direct and indirect effects of filamin A on tau pathology in neuronal cells. Mol Neurobiol. 2023;60:1021–39. [DOI] [PubMed] [PMC]

96.

Else H. Alzheimer’s drug saga prompts journal to scrutinize whistle-blowers. Nature. 2023;613:618–9. [DOI] [PubMed]

97.

Yu H, Liu Y, He B, He T, Chen C, He J, et al. Platelet biomarkers for a descending cognitive function: a proteomic approach. Aging Cell. 2021;20:e13358. [DOI] [PubMed] [PMC]

98.

Huang YM, Ma YH, Gao PY, Wang ZB, Huang LY, Hou JH, et al. Plasma β₂-microglobulin and cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact older adults: the CABLE study. Alzheimers Res Ther. 2023;15:69. [DOI] [PubMed] [PMC]

99.

Bu XL, Sun PY, Fan DY, Wang J, Sun HL, Cheng Y, et al. Associations of plasma soluble CD22 levels with brain amyloid burden and cognitive decline in Alzheimer’s disease. Sci Adv. 2022;8:eabm5667. [DOI] [PubMed]

100.

Avila-Villanueva M, Gomez-Ramirez J, Maestu F, Venero C, Avila J, Fernandez-Blazquez MA. The role of chronic stress as a trigger for the Alzheimer disease continuum. Front Aging Neurosci. 2020;12:561504. [DOI] [PubMed] [PMC]

101.

Rocca WA, Petersen RC, Knopman DS, Hebert LE, Evans DA, Hall KS, et al. Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cognitive impairment in the United States. Alzheimers Dement. 2011;7:80–93. [DOI] [PubMed] [PMC]

102.

Wolters FJ, Chibnik LB, Waziry R, Anderson R, Berr C, Beiser A, et al. Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium. Neurology. 2020;95:e519–31. [DOI] [PubMed] [PMC]

103.

Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement. 2015;11:1007–14. [DOI] [PubMed] [PMC]

104.

Rodriguez-Matellan A, Alcazar N, Hernandez F, Serrano M, Avila J. In vivo reprogramming ameliorates aging features in dentate gyrus cells and improves memory in mice. Stem Cell Reports. 2020;15:1056–66. [DOI] [PubMed] [PMC]

105.

Han X, Zhang T, Liu H, Mi Y, Gou X. Astrocyte senescence and Alzheimer’s disease: a review. Front Aging Neurosci. 2020;12:148. [DOI] [PubMed] [PMC]

106.

Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288:518–36. [DOI] [PubMed] [PMC]

107.

Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer’s disease. J Alzheimers Dis. 2017;58:1–15. [DOI] [PubMed]

108.

Varesi A, Pierella E, Romeo M, Piccini GB, Alfano C, Bjørklund G, et al. The potential role of gut microbiota in Alzheimer’s disease: from diagnosis to treatment. Nutrients. 2022;14:668. [DOI] [PubMed] [PMC]

109.

Hampel H, Vergallo A, Perry G, Lista S; Alzheimer Precision Medicine Initiative (APMI). The Alzheimer Precision Medicine Initiative. J Alzheimers Dis. 2019;68:1–24. [DOI] [PubMed] [PMC]