Biological Significance of the Protein Changes Occurring in the Cerebrospinal Fluid of Alzheimer’s Disease Patients: Getting Clues from Proteomic Studies

The fact that cerebrospinal fluid (CSF) deeply irrigates the brain together with the relative simplicity of sample extraction from patients make this biological fluid the best target for biomarker discovery in neurodegenerative diseases. During the last decade, biomarker discovery has been especially fruitful for the identification new proteins that appear in the CSF of Alzheimer’s disease (AD) patients together with amyloid-β (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau). Thus, several proteins have been already stablished as important biomarkers, due to an increase (i.e., CHI3L1) or a decrease (i.e., VGF) in AD patients’ CSF. Notwithstanding this, only a deep analysis of a database generated with all the changes observed in CSF across multiple proteomic studies, and especially those using state-of-the-art methodologies, may expose those components or metabolic pathways disrupted at different levels in AD. Deep comparative analysis of all the up- and down-regulated proteins across these studies revealed that 66% of the most consistent protein changes in CSF correspond to intracellular proteins. Interestingly, processes such as those associated to glucose metabolism or RXR signaling appeared inversely represented in CSF from AD patients in a significant manner. Herein, we discuss whether certain cellular processes constitute accurate indicators of AD progression by examining CSF. Furthermore, we uncover new CSF AD markers, such as ITAM, PTPRZ or CXL16, identified by this study.

Download Full-text

Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15606141 ◽

2015 ◽

Vol 36 (3) ◽

pp. 621-628 ◽

Cited By ~ 23

Author(s):

Sara Shams ◽

Tobias Granberg ◽

Juha Martola ◽

Xiaozhen Li ◽

Mana Shams ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Serum Albumin ◽

Amyloid Β ◽

Cerebral Microbleeds ◽

Csf Biomarkers ◽

Barrier Dysfunction ◽

T Tau

Cerebral microbleeds (CMBs) are hypothesised to have an important yet unknown role in the dementia disease pathology. In this study we analysed increasing number of CMBs and their independent associations with routine cerebrospinal fluid (CSF) biomarkers in a continuum of cognitive impairment. A total of 1039 patients undergoing dementia investigation were analysed and underwent lumbar puncture, and an MRI scan. CSF samples were analysed for amyloid β (Aβ) 42, total tau (T-tau), tau phosphorylated at threonine 18 (P-tau) and CSF/serum albumin ratios. Increasing number of CMBs were independently associated with low Aβ42 levels, in the whole cohort, Alzheimer’s disease and mild cognitive impairment ( p < 0.05). CSF/serum albumin ratios were high with multiple CMBs ( p < 0.001), reflecting accompanying blood–brain barrier dysfunction. T-tau and P-tau levels were lower in Alzheimer’s patients with multiple CMBs when compared to zero CMBs, but did not change in the rest of the cohort. White matter hyperintensities were associated with low Aβ42 in the whole cohort and Alzheimer’s disease ( p < 0.05). Aβ42 is the routine CSF-biomarker mainly associated with CMBs in cognitive impairment, and there is an accumulative effect with increasing number of CMBs.

Download Full-text

The Associations of Cerebrospinal Fluid ApoE and Biomarkers of Alzheimer’s Disease: Exploring Interactions With Sex

Frontiers in Neuroscience ◽

10.3389/fnins.2021.633576 ◽

2021 ◽

Vol 15 ◽

Author(s):

Ying Liu ◽

Jing-Hui Song ◽

Wei Xu ◽

Xiao-He Hou ◽

Jie-Qiong Li ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Multiple Linear Regression Model ◽

Linear Mixed Effects ◽

Longitudinal Changes ◽

Apoe Isoforms ◽

T Tau ◽

Normal Cognition

BackgroundSex-related difference in Alzheimer’s disease (AD) has been proposed, and apolipoprotein E (ApoE) isoforms have been suggested to be involved in the pathogenesis of AD.ObjectiveWe aimed to explore whether cerebrospinal fluid (CSF) ApoE is associated with AD biomarkers and whether the associations are different (between sexes).MethodsData of 309 participants [92 with normal cognition, 148 with mild cognitive impairment (MCI), and 69 with AD dementia] from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were cross-sectionally evaluated with the multiple linear regression model and longitudinally with the multivariate linear mixed-effects model for the associations of CSF ApoE with AD biomarkers. Sex–ApoE interaction was used to estimate whether sex moderates the associations of CSF ApoE and AD biomarkers.ResultsSignificant interactions between CSF ApoE and sex on AD biomarkers were observed [amyloid-β (Aβ): p = 0.0169 and phosphorylated-tau (p-tau): p = 0.0453]. In women, baseline CSF ApoE levels were significantly associated with baseline Aβ (p = 0.0135) and total-tau (t-tau) (p < 0.0001) as well as longitudinal changes of the biomarkers (Aβ: p = 0.0104; t-tau: p = 0.0110). In men, baseline CSF ApoE levels were only correlated with baseline p-tau (p < 0.0001) and t-tau (p < 0.0001) and did not aggravate AD biomarkers longitudinally.ConclusionThe associations between CSF ApoE and AD biomarkers were sex-specific. Elevated CSF ApoE was associated with longitudinal changes of AD biomarkers in women, which indicates that CSF ApoE might be involved in the pathogenesis of AD pathology in a sex-specific way.

Download Full-text

Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment

Psychological Medicine ◽

10.1017/s0033291712001870 ◽

2012 ◽

Vol 43 (5) ◽

pp. 911-920 ◽

Cited By ~ 54

Author(s):

I. H. G. B. Ramakers ◽

F. R. J. Verhey ◽

P. Scheltens ◽

H. Hampel ◽

H. Soininen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Neuropsychiatric Symptoms ◽

Amyloid Β ◽

Screening Guidelines ◽

Symptoms Of Depression ◽

T Tau

BackgroundAnxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI.MethodSubjects with MCI (n=268) were selected from the ‘Development of screening guidelines and criteria for pre-dementia Alzheimer's disease’ (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid β(1-42)protein (Aβ42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory.ResultsDepressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aβ42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6–3.3] and t-tau (OR 2.6, 95% CI 1.9–3.6) concentrations and with the combination of abnormal concentrations of both Aβ42 and t-tau (OR 3.1, 95% CI 2.0–4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aβ42 (agitation: OR 1.6, 95% CI 1.1–2.3; irritability: OR 2.2, 95% CI 1.5–3.3). Symptoms of depression and apathy were not related to any of the CSF markers.ConclusionsIn subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not.

Download Full-text

Cognitive Dispersion Is Not Associated with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Results from the European Prevention of Alzheimer’s Dementia (EPAD) v500.0 Cohort

Journal of Alzheimer s Disease ◽

10.3233/jad-200514 ◽

2020 ◽

Vol 78 (1) ◽

pp. 185-194

Author(s):

Tam Watermeyer ◽

Alejandra Marroig ◽

Craig W. Ritchie ◽

Karen Ritchie ◽

Kaj Blennow ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Aging ◽

Amyloid Β ◽

Cost Effective ◽

Csf Levels ◽

T Tau

Background: Cognitive dispersion, variation in performance across cognitive domains, is posited as a non-invasive and cost-effective marker of early neurodegeneration. Little work has explored associations between cognitive dispersion and Alzheimer’s disease (AD) biomarkers in healthy older adults. Even less is known about the influence or interaction of biomarkers reflecting brain pathophysiology or other risk factors on cognitive dispersion scores. Objective: The main aim of this study was to examine whether higher cognitive dispersion was associated with cerebrospinal fluid (CSF) levels of amyloid-β (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), and amyloid positivity in a cohort of older adults at various severities of AD. A secondary aim was to explore which AD risk factors were associated with cognitive dispersion scores. Methods: Linear and logistic regression analyses explored the associations between dispersion and CSF levels of Aβ42, t-tau, and p-tau and amyloid positivity (Aβ42 < 1000 pg/ml). Relationships between sociodemographics, APOE ɛ4 status, family history of dementia, and levels of depression and dispersion were also assessed. Results: Dispersion did not emerge as associated with any of the analytes nor amyloid positivity. Older (β= –0.007, SE = 0.002, p = 0.001) and less educated (β= –0.009, SE = 0.003, p = 0.009) individuals showed greater dispersion. Conclusion: Dispersion was not associated with AD pathology, but was associated with age and years of education, highlighting individual differences in cognitive aging. The use of this metric as a screening tool for existing AD pathology is not supported by our analyses. Follow-up work will determine if dispersion scores can predict changes in biomarker levels and/or positivity status longitudinally.

Download Full-text

Social Networks and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Pathology in Cognitively Intact Older Adults: The CABLE Study

Journal of Alzheimer s Disease ◽

10.3233/jad-201426 ◽

2021 ◽

pp. 1-10

Author(s):

Ya-Hui Ma ◽

Ya-Yu Wang ◽

Lan Tan ◽

Wei Xu ◽

Xue-Ning Shen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Social Networks ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Cognitive Status ◽

Tau Proteins ◽

Preclinical Ad ◽

T Tau ◽

Cognitively Intact

Background: Although social networks are deemed as moderators of incident Alzheimer’s disease (AD), few data are available on the mechanism relevant to AD pathology. Objective: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD). Methods: We studied participants from the Chinese Alzheimer’s disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-β (Aβ 1–42 and Aβ 1–40) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were measured using self-reported questionnaires about social ties. Linear regression models were used. Results: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aβ 1–42 and T-tau/Aβ 1–42 and high Aβ 1–42/Aβ 1–40). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE 4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (β= –0.005, p < 0.001), Aβ 1–42/Aβ 1–40 (β= 0.481, p = 0.001), and T-tau/Aβ 1–42 (β= –0.047, p < 0.001) were noted in preclinical AD stage than controls. Conclusion: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations.

Download Full-text

A Non-APOE Polygenic Risk Score for Alzheimer’s Disease Is Associated With Cerebrospinal Fluid Neurofilament Light in a Representative Sample of Cognitively Unimpaired 70-Year Olds

The Journals of Gerontology Series A ◽

10.1093/gerona/glab030 ◽

2021 ◽

Author(s):

Ingmar Skoog ◽

Silke Kern ◽

Jenna Najar ◽

Rita Guerreiro ◽

Jose Bras ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Enzyme Linked Immunosorbent Assay ◽

Polygenic Risk Score ◽

Neurofilament Light ◽

Polygenic Risk ◽

Apoe Ε4 ◽

T Tau

Abstract The effect of Alzheimer’s disease (AD) polygenic risk scores (PRS) on amyloid and tau pathophysiology and neurodegeneration in cognitively unimpaired older adults is not known in detail. This study aims to investigate non-APOE AD-PRS and APOE ε4 in relation to AD pathophysiology evaluated by cerebrospinal fluid (CSF) biomarkers in a population-based sample of 70-year olds. A total of 303 dementia-free individuals from the Gothenburg H70 Birth Cohort Studies were included. Genotyping was performed using the NeuroChip, and AD-PRS were calculated. CSF levels of amyloid-β (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), neurogranin (Ng), and neurofilament light (NfL) were measured with enzyme-linked immunosorbent assay. Associations were found between non-APOE PRS and both NfL (p = .001) and Aβ42 (p = .02), and between APOE ε4 and Aβ42 (p = 1e−10), t-tau (p = 5e−4), and p-tau (p = .002). Similar results were observed when only including individuals with CDR = 0, except for no evidence of an association between non-APOE PRS and Aβ42. There was an interaction between non-APOE PRS and Aβ42 pathology status in relation to NfL (p = .005); association was only present in individuals without Aβ42 pathology (p = 3e-4). In relation to Aβ42, there was a borderline interaction (p = .06) between non-APOE PRS and APOE ε4; association was present in ε4 carriers only (p = .03). Similar results were observed in individuals with CDR = 0 (n = 246). In conclusion, among cognitively healthy 70-year olds from the general population, genetic risk of AD beyond the APOE locus was associated with NfL in individuals without Aβ42 pathology, and with Aβ42 in APOE ε4 carriers, suggesting these associations are driven by different mechanisms.

Download Full-text

White Matter Hyperintensities Are No Major Confounder for Alzheimer’s Disease Cerebrospinal Fluid Biomarkers

Journal of Alzheimer s Disease ◽

10.3233/jad-200496 ◽

2021 ◽

Vol 79 (1) ◽

pp. 163-175

Author(s):

Linda J.C. van Waalwijk van Doorn ◽

Mohsen Ghafoorian ◽

Esther M.C. van Leijsen ◽

Jurgen A.H.R. Claassen ◽

Andrea Arighi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

White Matter ◽

White Matter Hyperintensities ◽

Linear Regression Analysis ◽

Amyloid Β ◽

Csf Biomarkers ◽

Csf Biomarker ◽

T Tau

Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1–42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer’s disease (AD). However, CSF biomarker levels can be affected by confounding factors. Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels. Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis. Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group. Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.

Download Full-text

Follow-up study on plasma and cerebrospinal fluid levels of B amyloids and tau proteins in patients with alzheimer's disease

European Psychiatry ◽

10.1016/s0924-9338(11)72213-1 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 506-506

Author(s):

Y. Fu ◽

S. Xiao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Tau Proteins ◽

Enzyme Linked Immunosorbent Assay ◽

Csf Levels ◽

Severity Of Dementia ◽

T Tau

AimsCompare baseline and 6-month follow-up plasma and cerebrospinal fluid (CSF) levels of amyloid β peptides 1–40 (Aβ1–40) and 1–42 (Aβ1–42), total tau protein (T-tau) and phosphorylated tau at threonine 231 (P-tau231) in patients with Alzheimer's disease (AD) and vascular dementia (VD).Methods21 patients with AD and 7 patients with VD based on the criteria of Diagnostic Statistical Manual 4th edition were assessed at baseline and 7 with AD and 6 with VD were re-assessed 6 months later. Assessments included the Mini-Mental State Exam (MMSE), the Global Deteriorate Scale (GDS), plasma and CSF levels of Aβ1–40 and Aβ1–42, and CSF levels of T-tau and P-tau231 (using a sandwich enzyme-linked immunosorbent assay).ResultsAt baseline there were significant differences between AD and VD patients in the mean CSF levels of T-tau (t=2.580, P=0.016), P-tau231 (t=4.014, P=0.000) and Aβ1–40 (t=2.766, P=0.010). At baseline in AD patients, duration of illness was negatively correlated with CSF P-tau231 levels (r=-0.485, P=0.026), MMSE scores (r=-0.565, P=0.008) and GDS scores (r=-0.482, P=0.027); and CSF Aβ1–42 levels were positively correlated to MMSE scores (r=0.565, P=0.008) and negatively correlated with GDS scores (r=-0.634, P=0.002). In the AD patients plasma Aβ1–40 levels increased significantly over the 6-month follow-up period (t=-2.735, P=0.041).ConclusionsPlasma Aβ1–40 levels increased significantly in AD patients after 6-months of follow-up, that means levels of plasma Aβ1–40 could imply the development of Alzheimer disease. Moreover, CSF P-tau231 and CSF Aβ1–42 levels are associated with the severity of dementia and cognitive impairment.

Download Full-text

Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

Brain Sciences ◽

10.3390/brainsci11020215 ◽

2021 ◽

Vol 11 (2) ◽

pp. 215

Author(s):

Donovan A. McGrowder ◽

Fabian Miller ◽

Kurt Vaz ◽

Chukwuemeka Nwokocha ◽

Cameil Wilson-Clarke ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Late Onset ◽

Amyloid Β ◽

Current Evidence ◽

Csf Biomarkers ◽

Diagnostic Efficacy ◽

Neurofilament Light ◽

New Biomarkers

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.

Download Full-text