Chronic Stress as A Catalyst for Cognitive Decline and Alzheimer’s Disease: Integrating Neuroendocrine, Neuroinflammatory, And Gut-Brain Axis Mechanisms
DOI:
https://doi.org/10.54097/8g4rj375Keywords:
Chronic stress, Alzheimer’s disease, HPA axis, Neuroinflammation, Gut–brain axis, Glucocorticoid, Microbiota.Abstract
Chronic stress is an increasingly recognized, pivotal modifiable risk factor for accelerating cognitive decline and Alzheimer's disease (AD) pathogenesis. This review systematically synthesizes evidence from the past decade (2015–2025) on the underlying mechanisms and emerging interventions. We delineate how chronic stress triggers a cascade of events, beginning with the sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to glucocorticoid dysregulation. This, in turn, directly promotes the core pathologies of AD: amyloid-beta (Aβ) deposition and tau hyperphosphorylation. Concurrently, stress induces microglia-mediated neuroinflammation and disrupts the gut-brain axis, exacerbating neuronal damage through systemic and central inflammatory responses. In terms of intervention, promising strategies include pharmacological approaches like the glucocorticoid receptor modulator dazucorilant, natural compounds such as quercetin, and non-pharmacological strategies encompassing specific probiotics, mindfulness-based stress reduction, and multidomain lifestyle interventions. Integrating these multimodal strategies, which target the neuroendocrine, inflammatory, and gut-brain pathways, holds substantial promise for delaying AD onset and mitigating its progression.
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[1] Tasha Rhoads et al. Differential associations of neighborhood disadvantage, race/ethnicity, and cognitive status with experiences of psychosocial distress in the HABS‐HD cohort. Alzheimers Dement. 2024 Dec 23;21(1): e14257.
[2] Chen, Y., Dang, M., and Zhang, Z. (2021). Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer’s disease: A systematic review of symptom- general and –specific lesion patterns. Mol. Neurodegener. 16:38
[3] Qin Zhao et al. Systematic evaluation of the associations between mental disorders and dementia: An umbrella review of systematic reviews and meta-analyses. J Affect Disord. 2022.
[4] Jean Stafford et al. Psychiatric disorders and risk of subsequent dementia: Systematic review and meta-analysis of longitudinal studies. Int J Geriatr Psychiatry. 2022 May.
[5] Weijia Dang et al.Investigating shared risk variants and genetic etiology between Alzheimer’s disease and three stress-related psychiatric disorders: a large-scale genome-wide cross-strait analysis. Front Aging. 2025 Feb 5; 6:1488528
[6] Jean Stafford et al. Psychiatric disorders and risk of subsequent dementia: Systematic review and meta-analysis of longitudinal studies. Int J Geriatr Psychiatry. 2022 May.
[7] Emmal L Twait et al. Late-life depression, allostatic load, and risk of dementia: The AGES-Reykjavik Study.Psychoneuroendocrinology. 2022 Nov 17; 148:105975.
[8] Nicole K Zhang et al. The neural basis of neuropsychiatric symptoms in Alzheimer's disease.Front Aging Neurosci. 2024.
[9] Joanna Poszwa et al. Integration of Neuroimaging and Molecular Biomarkers in the Diagnosis of Alzheimer’s Disease and Frontotemporal Dementia: The Promise of fMRI.Current Alzheimer Research, 2025
[10] Helmet T Karim et al.Hippocampal subfield volume in older adults with and without mild cognitive impairment: effects of worry and cognitive reappraisal.Neurobiol Aging. 2024 May 28; 141:55–65.
[11] Faborode OS et al.Inescapable footshocks induce molecular changes in the prefrontal cortex of rats in an amyloid-beta-42 model of Alzheimer’s disease.Behavioural Brain Research 419, 113679, 2022
[12] Filip Kosel.Aberrant cortical activity in 5xFAD mice in response to social and non-social olfactory stimuli.Journal of Alzheimer’s Disease 97 (2), 659-677, 2024
[13] Nicole C Reyna et al.Anxiety and Alzheimer’s disease pathogenesis: focus on 5-HT and CRF systems in 3xTg-AD and TgF344-AD animal models.Front Aging Neurosci. 2023 Nov 10; 15:1251075.
[14] Joanna Dunacka et al.High Behavioral Reactivity to Novelty as a Susceptibility Factor for Memory and Anxiety Disorders in Streptozotocin-Induced Neuroinflammation as a Rat Model of Alzheimer’s Disease.Int J Mol Sci. 2024 Oct 28;25(21):11562.
[15] Nazmus S Khan et al.Behavioral and Neurophysiological Implications of Pathological Human Tau Expression in Serotonin Neurons.ACS Chem Neurosci. 2024.
[16] Dishary Sharmin et al. Synthesis and Receptor Binding Studies of α5 GABAAR Selective Novel Imidazodiazepines Targeted for Psychiatric and Cognitive Disorders.Molecules. 2023.
[17] Carey E Lyons et al. Chronic Social and Psychological Stress Impact Select Neuropathologies in the PS19 Mouse Model of Tauopathy.Psychosom Med. 2024.
[18] M G Garcia et al. Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer's disease-transgenic mice.Brain Behav Immun Health. 2023.
[19] Cryan et al.The gut microbiome in neurological disorders.The Lancet Neurology 19 (2), 179-194, 2020
[20] Shabbir et al.Curcumin, quercetin, catechins and metabolic diseases: the role of gut microbiota.Nutrients 13 (1), 206, 2021
[21] Van Ameringen et al.The gut microbiome in psychiatry: A primer for clinicians.Depression and Anxiety 36 (11), 1004- 1025, 2019
[22] Rajoka et al.Interaction between diet composition and gut microbiota and its impact on gastrointestinal tract health.Food Science and Human Wellness 6 (3), 121-130, 2017
[23] Feng, W.; Ao, H.; Peng, C. Gut microbiota, short-chain fatty acids, and herbal medicines. Front. Pharmacol. 2018, 9, 1354.
[24] Agus et al.Gut microbiota-derived metabolites as central regulators in metabolic disorders.Gut 70 (6), 1174-1182, 2021
[25] Fooks, L.; Gibson, G.R. Probiotics as modulators of the gut flora. Br. J. Nutr. 2002, 88, s39–s49.
[26] Kang, D.-W.; Adams, J.B.; Coleman, D.M.; Pollard, E.L.; Maldonado, J.; McDonough-Means, S.; Caporaso, J.G.; Krajmalnik-Brown, R. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Sci. Rep. 2019, 9, 5821.
[27] Das, B.C.; Nandwana, N.K.; Das, S.; Nandwana, V.; Shareef, M.A.; Das, Y.; Saito, M.; Weiss, L.M.; Almaguel, F.; Hosmane, N.S. Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective. Molecules 2022, 27, 2615.
[28] Lu, C.-J.; Hu, J.; Wang, Z.; Xie, S.; Pan, T.; Huang, L.; Li, X. Discovery of boron-containing compounds as Aβ aggregation inhibitors and antioxidants for the treatment of Alzheimer’s disease. MedChemComm 2018, 9, 1862–1870.
[29] Majid T et al.Perturbations in Microbiota Composition as a Novel Mediator in Neuropsychiatric, Neurological and Mental Disorders: Preventive and Therapeutic Complementary Therapies to Balance the Change.Current Alzheimer Research 20 (4), 213-223, 2023
[30] Sixin Li et al.Bibliometric analysis of Alzheimer's disease and depression.Current Neuropharmacology 23 (1), 98-115, 2025
[31] Georgia E Hodes et al. Sex Differences in Stress Response: Classical Mechanisms and Beyond.Curr Neuropharmacol. 2024.
[32] Alyssa Kniffin et al. Septohippocampal cholinergic system at the intersection of stress and cognition: Current trends and translational implications.Eur J Neurosci. 2024 May.
[33] Canet G.Advancing Alzheimer's disease pharmacotherapy: efficacy of glucocorticoid modulation with dazucorilant (CORT113176) in preclinical mouse models.British journal of pharmacology 182 (9), 1930-1956, 2025
[34] Safarzadeh E.Quercetin ameliorates cognitive deficit, expression of amyloid precursor gene, and pro-inflammatory cytokines in an experimental models of Alzheimer's disease in Wistar rats.Experimental Gerontology 193, 112466, 2024
[35] Carabotti, M.; Scirocco, A.; Maselli, M.A.; Severi, C. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann. Gastroenterol. 2015, 28, 203–209.
[36] Mayer, E.A.; Tillisch, K.; Gupta, A. Gut/brain axis and the microbiota. J. Clin. Investig. 2015, 125, 926–938.
[37] Sharma, R.; Gupta, D.; Mehrotra, R.; Mago, P. Psychobiotics: The next-generation probiotics for the brain. Curr. Microbiol. 2021, 78, 449–463.
[38] Kash, T.L.; Baucum, A.J., 2nd; Conrad, K.L.; Colbran, R.J.; Winder, D.G. Alcohol exposure alters NMDAR function in the bed nucleus of the stria terminalis. Neuropsychopharmacology 2009, 34, 2420–2429.
[39] Bonfili, L.; Cecarini, V.; Cuccioloni, M.; Angeletti, M.; Berardi, S.; Scarpona, S.; Rossi, G.; Eleuteri, A.M. SLAB51 Probiotic formulation activates SIRT1 pathway promoting antioxidant and neuroprotective effects in an AD mouse model. Mol. Neurobiol. 2018, 55, 7987–8000.
[40] Castelli, V.; d’Angelo, M.; Lombardi, F.; Alfonsetti, M.; Antonosante, A.; Catanesi, M.; Benedetti, E.; Palumbo, P.; Cifone, M.G.; Giordano, A.; et al. Effects of the probiotic formulation SLAB51 in in vitro and in vivo Parkinson’s disease models. Aging 2020, 912, 4641–4659.
[41] Friedrich Leblhuber etal. Commentary: effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: a randomized, double-blind and controlled trial. Frontiers in Aging Neuroscience 10, 54, 2018
[42] Rostamzadeh A. Psychotherapeutic interventions in individuals at risk for Alzheimer’s dementia: a systematic review. Alzheimer's research & therapy 14 (1), 18, 2022
[43] Maxfield M.“Why miss today worrying about tomorrow?” A qualitative investigation of ways middle-aged and older adults manage dementia-related anxiety.Anxiety, Stress, & Coping 38 (2), 219-233, 2025
[44] Shiyi Li.Association between Obesity and Cognitive Function in Chinese Older Adults: The Mediating Effects of Sleep Quality and Blood Pressure.Current Alzheimer Research, 2025
[45] ShaKhawat R et al.Early tactile stimulation influences the development of Alzheimer's disease in gestationally stressed APP NL-G-F adult offspring NL-G-F/NL-G-F mice.Exp Neurol. 2023 Oct.
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