The kynurenine pathway in Alzheimer's disease: a meta-analysis of central and peripheral levels

Fernandes, Brisa Simões; Inam, Mehmet Enes; Enduru, Nitesh; Quevedo, João; Zhao, Zhongming

doi:10.47626/1516-4446-2022-2962

Cited by 6 publications

(3 citation statements)

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“…In our study, some pathophysiology mechanisms have been identified and several biological pathways, both in each condition in isolation and shared between AD and frailty are reported, such as the inflammation pathway, which reported kynurenine pathway in association with AD (Fernandes et al, 2023) and frailty (Kim et al, 2020). Several observational studies reported the relationship between brain pathologies and frailty.…”

Section: Discussionmentioning

confidence: 61%

Dissecting the shared genetic architecture between Alzheimer’s disease and frailty: a cross-trait meta-analyses of genome-wide association studies

Enduru,

Fernandes,

Zhao

2024

Front. Genet.

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Introduction: Frailty is the most common medical condition affecting the aging population, and its prevalence increases in the population aged 65 or more. Frailty is commonly diagnosed using the frailty index (FI) or frailty phenotype (FP) assessments. Observational studies have indicated the association of frailty with Alzheimer’s disease (AD). However, the shared genetic and biological mechanism of these comorbidity has not been studied.Methods: To assess the genetic relationship between AD and frailty, we examined it at single nucleotide polymorphism (SNP), gene, and pathway levels.Results: Overall, 16 genome-wide significant loci (15 unique loci) (pmeta-analysis < 5 × 10−8) and 22 genes (21 unique genes) were identified between AD and frailty using cross-trait meta-analysis. The 8 shared loci implicated 11 genes: CLRN1-AS1, CRHR1, FERMT2, GRK4, LINC01929, LRFN2, MADD, RP11-368P15.1, RP11-166N6.2, RNA5SP459, and ZNF652 between AD and FI, and 8 shared loci between AD and FFS implicated 11 genes: AFF3, C1QTNF4, CLEC16A, FAM180B, FBXL19, GRK4, LINC01104, MAD1L1, RGS12, ZDHHC5, and ZNF521. The loci 4p16.3 (GRK4) was identified in both meta-analyses. The colocalization analysis supported the results of our meta-analysis in these loci. The gene-based analysis revealed 80 genes between AD and frailty, and 4 genes were initially identified in our meta-analyses: C1QTNF4, CRHR1, MAD1L1, and RGS12. The pathway analysis showed enrichment for lipoprotein particle plasma, amyloid fibril formation, protein kinase regulator, and tau protein binding.Conclusion: Overall, our results provide new insights into the genetics of AD and frailty, suggesting the existence of non-causal shared genetic mechanisms between these conditions.

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Section: Discussionmentioning

confidence: 61%

Dissecting the shared genetic architecture between Alzheimer’s disease and frailty: a cross-trait meta-analyses of genome-wide association studies

Enduru,

Fernandes,

Zhao

2024

Front. Genet.

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“…The magnitude of the shift is inversely proportional to the CD8+ T cell count (T cell lymphopenia=>increased dysbiosis) and autoimmune risk [94]. The kynurenine-to-tryptophan ratio is also directly predictive of Covid severity [95], AD [96], and cancer risk [97].…”

Section: Bbutyratementioning

confidence: 99%

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

W. Chambers

2024

JNNS

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The dermatological manifestations of Long Covid (LC) have languished in the shadows of chronic fatigue and brain fog. Yet they are all linked by gut dysbiosis and the cytokine triad of TNF-α, IL-1β, and IL-6. The gut microbiome common not only to LC, psoriasis, AA, and vitiligo but also to neurodegenerative disease has been recently described. This gut microbiome induces an altered tryptophan metabolism linked to autoimmune disease. SARS CoV2, Mycobacteria, and many intestinal parasites protectively upregulate IFN-γ (less Covid in BCG and in subSaharan Africa), triggering the characteristic altered tryptophan metabolism and curtailing synthesis of serotonin and melatonin. Chronic inflammation due to persistent spike protein S exhausts IFN-γ and leads to gut dysbiosis and autoimmune risk. Butyrate immunomodulates IFN-γ and TGF-β, which counterbalance each other (reciprocal relationship). Low IFN-γ (LC) translates to high TGF-β (organ fibrosis). This review suggests that an etiologic prebiotic (d-mannose)/probiotic (lactobacilli, bifidobacteria)/postbiotic (butyrate) approach to autoimmune skin disease that improves intestinal barrier integrity and that suppresses the triad of TNF-α, IL-6, and IL-1β may enhance or even eliminate the traditional immunotherapy of targeted monoclonal antibodies, Janus kinase inhibitors, and steroids. Health benefits of this approach extend well beyond suppression of autoimmune skin disease. Societal benefits include relief to those most affected - women (LC), especially of color (AA, psoriasis, vitiligo).

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“…The kynurenine-to-tryptophan ratio is also directly predictive of Covid severity 95 , AD 96 , and cancer risk 97 .…”

Section: Prevention and Therapymentioning

confidence: 99%

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

Chambers,

Chambers

2023

Preprint

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The dermatological manifestations of Long Covid (LC) have languished in the shadows of chronic fatigue and brain fog. Yet they are all linked by gut dysbiosis and the cytokine triad of TNF-α, IL-1β, and IL-6. The gut microbiome common not only to LC, psoriasis, AA, and vitiligo but also to neurodegenerative disease has been recently described. This gut microbiome induces an altered tryptophan metabolism linked to autoimmune disease. SARS CoV2 invades enterochromaffin cells rich in ACE2 receptors and curtails absorption of the essential amino acid tryptophan and subsequent synthesis of serotonin and melatonin. This review suggests that an etiologic prebiotic (d-mannose)/probiotic (lactobacilli, bifidobacteria)/postbiotic (butyrate) approach to autoimmune skin disease that improves intestinal barrier integrity and that suppresses the triad of TNF-α, IL-6, and IL-1β may enhance or even eliminate the traditional immunotherapy of targeted monoclonal antibodies, Janus kinase inhibitors, and steroids. Health benefits of this approach extend well beyond suppression of autoimmune skin disease.

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The kynurenine pathway in Alzheimer's disease: a meta-analysis of central and peripheral levels

Cited by 6 publications

References 50 publications

Dissecting the shared genetic architecture between Alzheimer’s disease and frailty: a cross-trait meta-analyses of genome-wide association studies

Dissecting the shared genetic architecture between Alzheimer’s disease and frailty: a cross-trait meta-analyses of genome-wide association studies

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

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