O2-06-06: SNPS in MAPT are associated with cerebrospinal fluid Tau levels, MAPT mRNA levels, and age at onset of late-onset Alzheimer's disease

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.

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Alterations in T-Cell Transcription Factors and Cytokine Gene Expression in Late-Onset Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210480 ◽

2021 ◽

pp. 1-21

Author(s):

Masoud Neshan ◽

Seyed Kazem Malakouti ◽

Leila Kamalzadeh ◽

Mina Makvand ◽

Arezoo Campbell ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transcription Factors ◽

T Cell ◽

Late Onset ◽

Cytokine Gene Expression ◽

Mrna Levels ◽

Tnf Α ◽

Significant Difference ◽

Ifn Γ

Background: Late-onset Alzheimer’s disease (LOAD) is associated with many environmental and genetic factors. The effect of systemic inflammation on the pathogenesis of neurodegenerative diseases such as AD has been strongly suggested. T helper cells (Th) are one of the important components of the immune system and can easily infiltrate the brain in pathological conditions. The development of each Th-subset depends on the production of unique cytokines and their main regulator. Objective: This study aimed to compare the mRNA levels of Th-related genes derived from peripheral blood mononuclear cells of LOAD patients with control. Also, the identification of the most important Th1/Th2 genes and downstream pathways that may be involved in the pathogenesis of AD was followed by computational approaches. Methods: This study invloved 30 patients with LOAD and 30 non-demented controls. The relative expression of T-cell cytokines (IFN-γ, TNF-α, IL-4, and IL-5) and transcription factors (T-bet and GATA-3) were assessed using real-time PCR. Additionally, protein-protein interaction (PPI) was investigated by gene network construction. Results: A significant decrease at T-bet, IFN-γ, TNF-α, and GATA-3 mRNA levels was detected in the LOAD group, compared to the controls. However, there was no significant difference in IL-4 or IL-5 mRNA levels. Network analysis revealed a list of the highly connected protein (hubs) related to mitogen-activated protein kinase (MAPK) signaling and Th17 cell differentiation pathways. Conclusion: The findings point to a molecular dysregulation in Th-related genes, which can promising in the early diagnosis or targeted interventions of AD. Furthermore, the PPI analysis showed that upstream off-target stimulation may involve MAPK cascade activation and Th17 axis induction.

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Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/617420 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Peter Wostyn ◽

Debby Van Dam ◽

Kurt Audenaert ◽

Peter Paul De Deyn

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Late Onset ◽

Senile Plaques ◽

Protective Effects ◽

Caffeine Consumption ◽

Neuroprotective Effects ◽

Csf Production

Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na+-K+ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis.

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Cerebrospinal Fluid Aβ43 Is Reduced in Early-Onset Compared to Late-Onset Alzheimer’s Disease, But Has Similar Diagnostic Accuracy to Aβ42

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2017.00210 ◽

2017 ◽

Vol 9 ◽

Cited By ~ 9

Author(s):

Camilla Lauridsen ◽

Sigrid B. Sando ◽

Ina Møller ◽

Guro Berge ◽

Precious K. Pomary ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Diagnostic Accuracy ◽

Early Onset ◽

Late Onset

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O2-06-03: Late-onset Alzheimer's Disease-associated SNPS in TOMM40 and APOE have different effects on cerebrospinal fluid amyloid-beta levels

Alzheimer s & Dementia ◽

10.1016/j.jalz.2008.05.351 ◽

2008 ◽

Vol 4 ◽

pp. T144-T144

Author(s):

Alison M. Goate ◽

John S.K. Kauwe ◽

Kevin Mayo ◽

Sarah Bertelsen ◽

Aarti R. Shah ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Beta ◽

Late Onset

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Alpha1-Antichymotrypsin Level in Cerebrospinal Fluid Is Closely Associated with Late Onset Alzheimer's Disease.

Internal Medicine ◽

10.2169/internalmedicine.34.481 ◽

1995 ◽

Vol 34 (6) ◽

pp. 481-484 ◽

Cited By ~ 23

Author(s):

Yasuo HARIGAYA ◽

Mikio SHOJI ◽

Tamiko NAKAMURA ◽

Etsuro MATSUBARA ◽

Kenji HOSODA ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Late Onset

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Association of Polygenic Risk Score with Age at Onset and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease in a Chinese Cohort

Neuroscience Bulletin ◽

10.1007/s12264-020-00469-8 ◽

2020 ◽

Vol 36 (7) ◽

pp. 696-704 ◽

Cited By ~ 3

Author(s):

Wei-Wei Li ◽

Zhen Wang ◽

Dong-Yu Fan ◽

Ying-Ying Shen ◽

Dong-Wan Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Risk Score ◽

Age At Onset ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Cerebrospinal Fluid Biomarkers ◽

Chinese Cohort

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Choroidal Proteins Involved in Cerebrospinal Fluid Production may be Potential Drug Targets for Alzheimer's Disease Therapy

Perspectives in Medicinal Chemistry ◽

10.4137/pmc.s6509 ◽

2011 ◽

Vol 5 ◽

pp. PMC.S6509 ◽

Cited By ~ 5

Author(s):

Peter Wostyn ◽

Kurt Audenaert ◽

Peter Paul De Deyn

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Late Onset ◽

Future Research ◽

Caffeine Consumption ◽

Research Attention ◽

Fluid Production ◽

Β Amyloid

Alzheimer's disease is known to be the most common form of dementia in the elderly. It is clinically characterized by impairment of cognitive functions, as well as changes in personality, behavioral disturbances and an impaired ability to perform activities of daily living. To date, there are no effective ways to cure or reverse the disease. Genetic studies of early-onset familial Alzheimer's disease cases revealed causative mutations in the genes encoding β-amyloid precursor protein and the γ-secretase-complex components presenilin-1 and presenilin-2, supporting an important role of β-amyloid in the pathogenesis of Alzheimer's disease. Compromised function of the choroid plexus and defective cerebrospinal fluid production and turnover, with diminished clearance of β-amyloid, may play an important role in late-onset forms of Alzheimer's disease. If reduced cerebrospinal fluid turnover is a risk factor for Alzheimer's disease, then therapeutic strategies to improve cerebrospinal fluid flow are reasonable. However, the role of deficient cerebrospinal fluid dynamics in Alzheimer's disease and the relevance of choroidal proteins as potential therapeutic targets to enhance cerebrospinal fluid turnover have received relatively little research attention. In this paper, we discuss several choroidal proteins, such as Na+-K+ ATPase, carbonic anhydrase, and aquaporin 1, that may be targets for pharmacological up-regulation of cerebrospinal fluid formation. The search for potentially beneficial drugs useful to ameliorate Alzheimer's disease by facilitating cerebrospinal fluid production and turnover may be an important area for future research. However, the ultimate utility of such modulators in the management of Alzheimer's disease remains to be determined. Here, we hypothesize that caffeine, the most commonly used psychoactive drug in the world, may be an attractive therapeutic candidate for treatment of Alzheimer's disease since long-term caffeine consumption may augment cerebrospinal fluid production. Other potential mechanisms of cognitive protection by caffeine have been suggested by recent studies.

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