Geroscience-guided approaches for Alzheimer’s disease: targeting aging mechanisms for therapeutic intervention

Khaled A. Abdel-Sater

For citation:

Abstract

Background. The biggest risk factor for Alzheimer's disease (AD) is aging, contributing to impaired clearance of tau and amyloid-beta proteins, microglial senescence, endoplasmic reticulum stress, lipid dysregulation, and excitotoxicity.

Objective. This review investigates how aging speeds up the pathophysiology of AD and evaluates emerging geroscience-based interventions targeting biological aging mechanisms to delay or prevent cognitive decline.

Methods. A narrative review of the literature from 2015 to 2025 was conducted, integrating longitudinal studies, meta-analyses, and preclinical models that examine the aging-AD interface. The MEDLINE, Embase, Cochrane, Google Scholar, and PubMed databases were searched using specifically related keywords, such as ageing, AD, AD pathology, anti-aging strategies, and AD therapies.

Results. From the initial search, more than 150 studies were excluded, and only 100 studies were selected for this review. After revision also duplicated 30 studies were removed. Ultimately, the review comprised seventy studies. Most of these studies discussed aging-related mechanisms – glymphatic dysfunction, APOE ε4-associated lipid transport impairment, BDNF depletion, and glutamate excitotoxicity, and anti-ageing strategies such as lifestyle interventions (e.g., physical activity, sleep optimization, cognitive engagement) and medical and biological therapies for AD.

Conclusion. Targeting aging mechanisms offers a paradigm shift in AD prevention and treatment; however, multidisciplinary collaboration is essential to translate geroscience into clinical practice. The integration of lifestyle and pharmacological strategies may yield synergistic neuroprotective benefits. Future research should focus on integrated, multimodal interventions that combine lifestyle modification with pharmacological and biological therapies. Tailored approaches–based on genetic risk profiles (e.g., APOE status), comorbidities, and individual aging trajectories–may optimize clinical outcomes. To evaluate the long-term safety and effectiveness of innovative treatments like senolytics, epigenetic modulators, and stem cell-based therapies in older populations, extensive, longitudinal clinical trials are also required. Developments in biological age biomarkers, machine learning, and systems biology have the potential to improve risk assessment and therapy customization.

Keywords: Alzheimer’s disease, aging, neuroinflammation, senolytics, epigenetics, stem cell therapy.

References

1. Scheltens P, De Strooper B, Kivipelto M et al. Alzheimer's disease. Lancet 2021;397(10284):1577-90. DOI: 10.1016/S0140-6736(20)32205-4 2. Bellenguez C, Küçükali F, Jansen IE et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet 2022;54(4):412-36. DOI: 10.1038/s41588-022-01024-z

3. Lopez-Lee C, Torres ERS, Carling G, Gan L. Mechanisms of sex differences in Alzheimer's disease. Neuron 2024;112(8):1208-21. DOI: 10.1016/j.Neuron.2024.01.024

4. Jiang Q, Liu J, Huang S et al. Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances. Signal Transduct Target Ther 2025;(10):76. DOI: 10.1038/s41392-025-02145-7

5. Zhang XX, Tian Y, Wang ZT et al. The Epidemiology of Alzheimer's Disease Modifiable Risk Factors and Prevention. J Prev Alzheimers Dis 2021;8(3):313-21. DOI: 10.14283/jpad.2021.15

6. Sehar U, Rawat P, Reddy AP et al. Amyloid Beta in Aging and Alzheimer's Disease. Int J Mol Sci 2022;23(21):12924-7. DOI: 10.3390/ijms232112924

7. Kelliny S, Zhou XF, Bobrovskaya L. Alzheimer's Disease and Frontotemporal Dementia: A Review of Pathophysiology and Therapeutic Approaches. J Neurosci Res 2025;103(5):e70046-e70050. DOI: 10.1002/jnr.70046

8. Liu RM. Aging, Cellular Senescence, and Alzheimer's Disease. Int J Mol Sci 2022;23(4):1989-92. DOI: 10.3390/ijms23041989

9. Yoo HJ, Kwon MS. Aged Microglia in Neurodegenerative Diseases: Microglia Lifespan and Culture Methods. Front Aging Neurosci 2022;(13):766267. DOI: 10.3389/fnagi.2021.766267

10. Ana B. Aged-Related Changes in Microglia and Neurodegenerative Diseases: Exploring the Connection. Biomedicines 2024;12(8):1737-41. DOI: 10.3390/biomedicines12081737

11. Heavener KS, Bradshaw EM. The aging immune system in Alzheimer's and Parkinson's diseases. Semin Immunopathol 2022;44(5):649-57. DOI: 10.1007/s00281-022-00944-6

12. Picca A, Ferri E, Calvani R et al. Age-Associated Glia Remodeling and Mitochondrial Dysfunction in Neurodegeneration: Antioxidant Supplementation as a Possible Intervention. Nutrients 2022;14(12):2406-10. DOI: 10.3390/nu14122406

13. Ajoolabady A, Lindholm D, Ren J, Pratico D. ER stress and UPR in Alzheimer's disease: mechanisms, pathogenesis, treatments. Cell Death Dis 2022;13(8):706. DOI: 10.1038/s41419-022-05153-5

14. Kumari S, Dhapola R, Reddy DH. Apoptosis in Alzheimer's disease: insight into the signaling pathways and therapeutic avenues. Apoptosis 2023;28(7-8):943-57. DOI: 10.1007/s10495-023-01848-y

15. Liu Y, Xu C, Gu R et al. Endoplasmic reticulum stress in diseases. MedComm 2024;5(9):e701. DOI: 10.1002/mco2.701

16. Liu CC, Zhao J, Fu Y et al. Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function. Nat Neurosci 2022;25(8):1020-33. DOI: 10.1038/s41593-022-01127-0

17. Tai LM, Ghura S, Koster KP et al. APOE-modulated Aβ-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. J Neurochem 2015;133(4):465-88. DOI: 10.1111/jnc.13072

18. Ibrahim AM, Chauhan L, Bhardwaj A et al. Brain-Derived Neurotropic Factor in Neurodegenerative Disorders. Biomedicines 2022;10(5):1143. DOI: 10.3390/biomedicines10051143

19. Koya PC, Kolla SC, Madala V, Sayana SB. Potential of Nerve Growth Factor (NGF)- and Brain-Derived Neurotrophic Factor (BDNF)-Targeted Gene Therapy for Alzheimer's Disease: A Narrative Review. Cureus 2025;17(6):e85814. DOI: 10.7759/cureus.85814

20. Verma M, Lizama BN, Chu CT. Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration. Transl Neurodegener 2022;11(1):3. DOI: 10.1186/s40035-021-00278-7

21. Mizoguchi Y, Yao H, Imamura Y et al. Lower brain-derived neurotrophic factor levels are associated with age-related memory impairment in community-dwelling older adults: the Sefuri study. Sci Rep 2020;10(1):16442. DOI: 10.1038/s41598-020-73576-1

22. Sun S, Ma S, Cai Y et al. A single-cell transcriptomic atlas of exercise-induced anti-inflammatory and geroprotective effects across the body [published correction appears in Innovation (Camb). 2025; 6(2):100806. DOI: 10.1016/j.xinn.2025.100806.]. Innovation (Camb) 2023;4(1):100380. DOI: 10.1016/j.xinn.2023.100380

23. Kępka A, Ochocińska A, Borzym-Kluczyk M et al. Healthy Food Pyramid as Well as Physical and Mental Activity in the Prevention of Alzheimer's Disease. Nutrients 2022;14(8):1534. DOI: 10.3390/nu 14081534

24. Khalil MH. The BDNF-Interactive Model for Sustainable Hippocampal Neurogenesis in Humans: Synergistic Effects of Environmentally-Mediated Physical Activity, Cognitive Stimulation, and Mindfulness. Int J Mol Sci 2024;25(23):12924. DOI: 10.3390/ijms252312924

25. Barad Z, Augusto J, Kelly ÁM. Exercise-induced modulation of neuroinflammation in ageing. J Physiol 2023;601(11):2069-83. DOI: 10.1113/JP282894

26. Abraham MJ, El Sherbini A, El-Diasty M et al. Restoring Epigenetic Reprogramming with Diet and Exercise to Improve Health-Related Metabolic Diseases. Biomolecules 2023;13(2):318. DOI: 10.3390/biom 13020318

27. Sawda C, Moussa C, Turner RS. Resveratrol for Alzheimer's disease. Ann N Y Acad Sci 2017;1403(1):142-9. DOI: 10.1111/nyas.13431

28. Grant WB, Blake SM. Diet's Role in Modifying Risk of Alzheimer's Disease: History and Present Understanding. J Alzheimers Dis 2023;96(4):1353-82. DOI: 10.3233/JAD-230418

29. Ali AM, Kunugi H. Royal Jelly as an Intelligent Anti-Aging Agent-A Focus on Cognitive Aging and Alzheimer's Disease: A Review. Antioxidants (Basel) 2020;9(10):937. DOI: 10.3390/antiox9100937

30. Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr 2016;(36):211-39. DOI: 10.1146/annurev-nutr-071715-050947

31. Liu S, Gao J, Zhu M et al. Gut Microbiota and Dysbiosis in Alzheimer's Disease: Implications for Pathogenesis and Treatment. Mol Neurobiol 2020;57(12):5026-43. DOI: 10.1007/s12035-020-02073-3

32. Wiciński M, Erdmann J, Nowacka A et al. Natural Phytochemicals as SIRT Activators-Focus on Potential Biochemical Mechanisms. Nutrients 2023;15(16):3578. DOI: 10.3390/nu15163578

33. Mattson MP, Moehl K, Ghena N et al. Intermittent metabolic switching, neuroplasticity and brain health [published correction appears in Nat Rev Neurosci. 2020 Aug;21(8):445. DOI: 10.1038/s41583-020-0342-y.]. Nat Rev Neurosci 2018;19(2):63-80. DOI: 10.1038/nrn.2017.156

34. Yang Y, Zhang L. The effects of caloric restriction and its mimetics in Alzheimer's disease through autophagy pathways. Food Funct 2020;11(2):1211-24. DOI: 10.1039/c9fo02611h

35. Park S, Zhang T, Wu X, Yi Qiu J. Ketone production by ketogenic diet and by intermittent fasting has different effects on the gut microbiota and disease progression in an Alzheimer's disease rat model. J Clin Biochem Nutr 2020;67(2):188-98. DOI: 10.3164/jcbn.19-87

36. Trisal A, Singh AK. Clinical Insights on Caloric Restriction Mimetics for Mitigating Brain Aging and Related Neurodegeneration. Cell Mol Neurobiol 2024;44(1):67-70. DOI: 10.1007/s10571-024-01493-2

37. Nowell J, Blunt E, Gupta D, Edison P. Antidiabetic agents as a novel treatment for Alzheimer's and Parkinson's disease. Ageing Res Rev 2023;(89):101979. DOI: 10.1016/j.arr.2023.101979

38. Satarker S, Wilson J, Kolathur KK et al. Spermidine as an epigenetic regulator of autophagy in neurodegenerative disorders. Eur J Pharmacol 2024;(979):176823. DOI: 10.1016/j.ejphar.2024.176823

39. Abdul-Rahman T, Awuah WA, Mikhailova T et al. Antioxidant, anti-inflammatory and epigenetic potential of curcumin in Alzheimer's disease. Biofactors 2024;50(4):693-708. DOI: 10.1002/biof.2039

40. Fan L, Zhang Z. Therapeutic potential of curcumin on the cognitive decline in animal models of Alzheimer's disease: a systematic review and meta-analysis. Naunyn Schmiedebergs Arch Pharmacol 2024;397(7):4499-509. DOI: 10.1007/s00210-024-02946-7

41. Alsaleem MA, Al-Kuraishy HM, Al-Gareeb AI et al. Molecular Signaling Pathways of Quercetin in Alzheimer's Disease: A Promising Arena. Cell Mol Neurobiol 2024;45(1):8. DOI: 10.1007/s10571-024-01526-w

42. Sabogal-Guáqueta AM, Muñoz-Manco JI, Ramírez-Pineda JR et al. The flavonoid quercetin ameliorates Alzheimer's disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer's disease model mice. Neuropharmacology 2015;(93):134-45. DOI: 10.1016/j.neuropharm.2015.01.027

43. Khan H, Ullah H, Aschner M et al. Neuroprotective Effects of Quercetin in Alzheimer's Disease. Biomolecules 2019;10(1):59. DOI: 10.3390/biom10010059

44. Mas-Bargues C, Borrás C, Viña J. The multimodal action of genistein in Alzheimer's and other age-related diseases. Free Radic Biol Med 2022;(183):127-37. DOI: 10.1016/j.freeradbiomed.2022.03.021

45. Zaa CA, Marcelo ÁJ, An Z et al. Anthocyanins: Molecular Aspects on Their Neuroprotective Activity. Biomolecules 2023;13(11):1598. DOI: 10.3390/biom13111598

46. Afzal M, Redha A, AlHasan R. Anthocyanins Potentially Contribute to Defense against Alzheimer's Disease. Molecules 2019;24(23):4255. DOI: 10.3390/molecules24234255

47. Peng S, Liu J, Liang C et al. Aquaporin-4 in glymphatic system, and its implication for central nervous system disorders. Neurobiol Dis 2023;(179):106035. DOI: 10.1016/j.nbd.2023.106035

48. Parhizkar S, Gent G, Chen Y et al. Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice. Sci Transl Med 2023;15(693):eade6285. DOI: 10.1126/scitranslmed.ade6285

49. Lv Y-N, Cui Y, Zhang B, Huang S. Sleep deficiency promotes Alzheimer’s disease development and progression. Front Neurol 2022;(13):1053942. DOI: 10.3389/fneur.2022.1053942

50. Yang L, Zhou H, Huang L et al. Stress level of glucocorticoid exacerbates neuronal damage and Aβ production through activating NLRP1 inflammasome in primary cultured hippocampal neurons of APP-PS1 mice. Int Immunopharmacol 2022;(110):108972. DOI: 10.1016/j.intimp.2022.108972

51. Calcia MA, Bonsall DR, Bloomfield PS et al. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl) 2016;233(9):1637-50. DOI: 10.1007/s00213-016-4218-9

52. Mostafa M, Disouky A, Lazarov O. Therapeutic modulation of neurogenesis to improve hippocampal plasticity and cognition in aging and Alzheimer's disease. Neurotherapeutics 2025;22(3):e00580. DOI: 10.1016/j.neurot.2025.e00580

53. Iordan AD, Cooke KA, Moored KD et al. Aging and Network Properties: Stability Over Time and Links with Learning during Working Memory Training. Front Aging Neurosci 2018;(9):419. DOI: 10.3389/fnagi.2017.00419

54. Gao L, Zhang Y, Sterling K, Song W. Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential. Transl Neurodegener 2022;11(1):4. DOI: 10.1186/s40035-022-00279-0

55. Emblad SYM, Mukaetova-Ladinska EB. Creative Art Therapy as a Non-Pharmacological Intervention for Dementia: A Systematic Review. J Alzheimers Dis Rep 2021;5(1):353-64. DOI: 10.3233/ADR-201002

56. Ji S, Duan J, Hou X et al. The Role of Acupuncture Improving Cognitive Deficits due to Alzheimer's Disease or Vascular Diseases through Regulating Neuroplasticity. Neural Plast 2021;(2021):8868447. DOI: 10.1155/2021/8868447

57. Ristori S, Bertoni G, Bientinesi E, Monti D. The Role of Nutraceuticals and Functional Foods in Mitigating Cellular Senescence and Its Related Aspects: A Key Strategy for Delaying or Preventing Aging and Neurodegenerative Disorders. Nutrients 2025;17(11):1837. DOI: 10.3390/nu17111837

58. Schweiger A, Diniz B, Nicol G et al. Protocol for a pilot clinical trial of the senolytic drug combination Dasatinib Plus Quercetin to mitigate age-related health and cognitive decline in mental disorders. F1000Res 2025;(13):1072. DOI: 10.12688/f1000research.151963.2

59. Horvath S. DNA methylation age of human tissues and cell types [published correction appears in Genome Biol. 2015 May 13;16:96. DOI: 10.1186/s13059-015-0649-6.]. Genome Biol 2013;14(10):R115. DOI: 10.1186/gb-2013-14-10-r115

60. Shukla S, Tekwani BL. Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation. Front Pharmacol 2020;(11):537. DOI: 10.3389/fphar.2020.00537

61. Macip CC, Hasan R, Hoznek V et al. Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice. Cell Reprogram 2024;26(1):24-32. DOI: 10.1089/cell.2023.0072

62. Zhu D, Montagne A, Zhao Z. Alzheimer's pathogenic mechanisms and underlying sex difference. Cell Mol Life Sci 2021;78(11):4907-20. DOI: 10.1007/s00018-021-03830-w

63. Fitzgerald GS, Chuchta TG, McNay EC. Insulin-like growth factor-2 is a promising candidate for the treatment and prevention of Alzheimer's disease. CNS Neurosci Ther 2023;29(6):1449-69. DOI: 10.1111/cns.14160 64. Chen KS, Noureldein MH, McGinley LM et al. Human neural stem cells restore spatial memory in a transgenic Alzheimer's disease mouse model by an immunomodulating mechanism. Front Aging Neurosci 2023;(15):1306004. DOI: 10.3389/fnagi.2023.1306004

65. Shigematsu K, Takeda T, Komori N et al. Hypothesis: Intravenous administration of mesenchymal stem cells is effective in the treatment of Alzheimer's disease. Med Hypotheses 2021;(150):110572. DOI: 10.1016/j.mehy.2021.110572

66. Kovina MV, Karnaukhov AV, Krasheninnikov ME et al. Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice. Front Genet 2019;(10):310. DOI: 10.3389/fgene.2019.00310 67. Urayama A, Moreno-Gonzalez I, Morales-Scheihing D et al. Preventive and therapeutic reduction of amyloid deposition and behavioral impairments in a model of Alzheimer's disease by whole blood exchange. Mol Psychiatry 2022;27(10):4285-96. DOI: 10.1038/s41380-022-01679-4 68. Sha SJ, Deutsch GK, Tian L et al. Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA Neurol 2019;76(1):35-40. DOI: 10.1001/jamaneurol.2018.3288

69. Boehme M, Guzzetta KE, Bastiaanssen TFS et al. Microbiota from young mice counteracts selective age-associated behavioral deficits. Nat Aging 2021;1(8):666-76. DOI: 10.1038/s43587-021-00093-9

For citation: Abdel-Sater K.A. Geroscience-guided approaches for Alzheimer’s disease: targeting aging mechanisms for therapeutic intervention. Clinical review for general practice. 2025; 6 (8): 22–30 (In Russ.). DOI: 10.47407/kr2025.6.8.00654

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Clinical review for general practice