Bayesian genome-wide TWAS with reference transcriptomic data of brain and blood tissues identified 141 risk genes for Alzheimer's disease dementia.

BACKGROUND: Transcriptome-wide association study (TWAS) is an influential tool for identifying genes associated with complex diseases whose genetic effects are likely mediated through transcriptome. TWAS utilizes reference genetic and transcriptomic data to estimate effect sizes of genetic variants on gene expression (i.e., effect sizes of a broad sense of expression quantitative trait loci, eQTL). These estimated effect sizes are employed as variant weights in gene-based association tests, facilitating the mapping of risk genes with genome-wide association study (GWAS) data. However, most existing TWAS of Alzheimer's disease (AD) dementia are limited to studying only cis-eQTL proximal to the test gene. To overcome this limitation, we applied the Bayesian Genome-wide TWAS (BGW-TWAS) method to leveraging both cis- and trans- eQTL of brain and blood tissues, in order to enhance mapping risk genes for AD dementia. METHODS: We first applied BGW-TWAS to the Genotype-Tissue Expression (GTEx) V8 dataset to estimate cis- and trans- eQTL effect sizes of the prefrontal cortex, cortex, and whole blood tissues. Estimated eQTL effect sizes were integrated with the summary data of the most recent GWAS of AD dementia to obtain BGW-TWAS (i.e., gene-based association test) p-values of AD dementia per gene per tissue type. Then we used the aggregated Cauchy association test to combine TWAS p-values across three tissues to obtain omnibus TWAS p-values per gene. RESULTS: We identified 85 significant genes in prefrontal cortex, 82 in cortex, and 76 in whole blood that were significantly associated with AD dementia. By combining BGW-TWAS p-values across these three tissues, we obtained 141 significant risk genes including 34 genes primarily due to trans-eQTL and 35 mapped risk genes in GWAS Catalog. With these 141 significant risk genes, we detected functional clusters comprised of both known mapped GWAS risk genes of AD in GWAS Catalog and our identified TWAS risk genes by protein-protein interaction network analysis, as well as several enriched phenotypes related to AD. CONCLUSION: We applied BGW-TWAS and aggregated Cauchy test methods to integrate both cis- and trans- eQTL data of brain and blood tissues with GWAS summary data, identifying 141 TWAS risk genes of AD dementia. These identified risk genes provide novel insights into the underlying biological mechanisms of AD dementia and potential gene targets for therapeutics development.

Role of vitamin B12 and folic acid in treatment of Alzheimer's disease: a meta-analysis of randomized control trials.

Vitamin B12 and folic acid could reduce blood homocysteine levels, which was thought to slow down the progression of Alzheimer's disease (AD), but previous studies regarding the effect of vitamin B12 and folic acid in treatment of AD have not reached conclusive results. We searched PubMed and Embase until January 12, 2023. Only randomized control trials involving participants clearly diagnosed with AD and who received vitamin B12 and folic acid were enrolled. Five studies that met the criteria were selected for inclusion in the meta-analysis. Changes in cognitive function were measured based on either the Mini-Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Changes in daily life function and the level of blood homocysteine were also investigated. After a 6-month treatment, administration of vitamin B12 and folic acid improved the MMSE scores more than placebo did (SMD = 0.21, 95% CI = 0.01 to 0.32, p = 0.04) but did not significantly affect ADAS-Cog scores (SMD = 0.06, 95% CI = -0.22 to 0.33, p = 0.68) or measures of daily life function. Blood homocysteine levels were significantly decreased after vitamin B12 and folic acid treatment. Participants with AD who received 6 months of vitamin B12 and folic acid supplementation had better MMSE scores but had no difference in ADAS-Cog scores. Daily life function did not improve after treatment.

Towards early diagnosis of Alzheimer's disease: advances in immune-related blood biomarkers and computational approaches.

Alzheimer's disease has an increasing prevalence in the population world-wide, yet current diagnostic methods based on recommended biomarkers are only available in specialized clinics. Due to these circumstances, Alzheimer's disease is usually diagnosed late, which contrasts with the currently available treatment options that are only effective for patients at an early stage. Blood-based biomarkers could fill in the gap of easily accessible and low-cost methods for early diagnosis of the disease. In particular, immune-based blood-biomarkers might be a promising option, given the recently discovered cross-talk of immune cells of the central nervous system with those in the peripheral immune system. Here, we give a background on recent advances in research on brain-immune system cross-talk in Alzheimer's disease and review machine learning approaches, which can combine multiple biomarkers with further information (e.g. age, sex, APOE genotype) into predictive models supporting an earlier diagnosis. In addition, mechanistic modeling approaches, such as agent-based modeling open the possibility to model and analyze cell dynamics over time. This review aims to provide an overview of the current state of immune-system related blood-based biomarkers and their potential for the early diagnosis of Alzheimer's disease.

Future perspective and clinical applicability of the combined use of plasma phosphorylated tau 181 and neurofilament light chain in Subjective Cognitive Decline and Mild Cognitive Impairment.

We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer's Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aß1-42, Aß1-42/1-40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP-) when they were A-, A+/T-/N-, or A+/T-/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP- patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn's k = 0.50, p < 0.001). Based on a logistic regression model, we estimated the risk of AD pathology considering the two biomarkers: 10.91% if both p-tau181 and NfL were negative; 41.10 and 76.49% if only one biomarker was positive (respectively p-tau18 and NfL); 94.88% if both p-tau181 and NfL were positive. Considering the moderate concordance and the risk of presenting an underlying AD pathology according to the positivity of plasma p-tau181 and NfL, we proposed a flow chart to guide the combined use of plasma p-tau181 and NfL and the interpretation of biomarker results to detect AD pathology.

Nucleic acid aptamer-based electrochemical sensor for the detection of serum P-tau231 and the instant screening test of Alzheimer's disease.

The instant screening of patients with a tendency towards developing Alzheimer's disease (AD) is significant for providing preventive measures and treatment. However, the current imaging-based technology cannot meet the requirements in the early stage. Developing biosensor-based liquid biopsy technology could be overcoming this bottleneck problem. Herein, we developed a simple, low-cost, and sensitive electrochemical aptamer biosensor for detecting phosphorylated tau protein threonine 231 (P-tau231), the earliest and one of the most efficacious abnormally elevated biomarkers of AD. Gold nanoparticles (AuNPs) were electrochemically synthesized on a glassy carbon electrode as the transducer, exhibiting excellent conductivity, and were applied to amplify the electrochemical signal. A nucleic acid aptamer was designed as the receptor to capture the P-tau231 protein, specifically through the formation of an aptamer-antigen complex. The proposed biosensor showed excellent sensitivity in detecting P-tau 231, with a broad linear detection range from 10 to 107 pg/mL and a limit of detection (LOD) of 2.31 pg/mL. The recoveries of the biosensor in human serum ranged from 97.59 to 103.26%, demonstrating that the biosensor could be used in complex practical samples. In addition, the results showed that the developed biosensor has good repeatability, reproducibility, and stability, which provides a novel method for the early screening of AD.

[Human tau N-terminal domain-specific monoclonal antibodies: screening and application in blood detection].

The antibodies to the microtubule-associated protein tau play a role in basic and clinical studies of Alzheimer's disease (AD) and other tauopathies. With the recombinant human tau441 as the immunogen, the hybridoma cell strains secreting the anti-human tau N-terminal domain (NTD-tau) monoclonal antibodies were generated by cell fusion and screened by limiting dilution. The purified monoclonal antibodies were obtained by inducing the mouse ascites and affinity chromatography. The sensitivity and specificity of the monoclonal antibodies were examined by indirect ELISA and Western blotting, respectively. A double antibody sandwich ELISA method for detecting human tau protein was established and optimized. The results showed that the positive cloning rate of hybridoma cells was 83.6%. A stable cell line producing ZD8F7 antibodies was established, and the antibody titer in the supernatant of the cell line was 1:16 000. The antibody titer in the ascitic fluid was higher than 1:256 000; and the titer of purified ZD8F7 monoclonal antibodies was higher than 1:128 000. The epitope analysis showed that the ZD8F7 antibody recognized tau21-37 amino acid in the N-terminal domain. The Western blotting results showed that the ZD8F7 antibody recognized the recombinant human tau protein of 50-70 kDa and the human tau protein of 50 kDa in the brain tissue of transgenic AD model mice (APP/PS1/tau). With ZD8F7 as a capture antibody, a quantitative detection method for human tau protein was established, which showed a linear range of 7.8-500.0 pg/mL and could identify human tau protein in the brain tissue of AD transgenic mice and human plasma but not recognize the mouse tau protein. In conclusion, the human NTD-tau-specific monoclonal antibody and the double antibody sandwich ELISA method established in this study are highly sensitive and can serve as a powerful tool for the detection of tau protein in neurodegenerative diseases.

Relationship between Plasma Lipid Profile and Cognitive Status in Early Alzheimer Disease.

Alzheimer disease (AD) is a heterogeneous and complex disease in which different pathophysiological mechanisms are involved. This heterogenicity can be reflected in different atrophy patterns or clinical manifestations. Regarding biochemical pathways involved in early AD, lipid metabolism plays an important role; therefore, lipid levels have been evaluated as potential AD diagnosis biomarkers, and their levels could be related to different AD clinical manifestations. Therefore, the aim of this work is to study AD lipid profiles from early AD patients and evaluate their clinical significance. For this purpose, untargeted plasma lipidomic analysis was carried out in early AD patients (n = 31) diagnosed with cerebrospinal fluid (CSF) biomarkers. Cluster analysis was carried out to define early AD subgroups according to the lipid levels. Then, the clinical significance of each lipid profile subgroup was studied, analyzing differences for other variables (cognitive status, CSF biomarkers, medication, comorbidities, age, and gender). The cluster analysis revealed two different groups of AD patients. Cluster 1 showed higher levels of plasma lipids and better cognitive status than Cluster 2. However, no differences were found for the other variables (age, gender, medication, comorbidities, cholesterol, and triglycerides levels) between both groups. Plasma lipid levels could differentiate two early AD subgroups, which showed different cognitive statuses. However, further research with a large cohort and longitudinal study evaluating the clinical evolution of these patients is required. In general, it would involve a relevant advance in the knowledge of AD pathological mechanisms, potential treatments, and precision medicine.

Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting.

Alzheimer's disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms. Several blood-based biomarkers have shown high potential for accurately detecting AD pathophysiology. As a result, there has been considerable interest in applying these biomarkers for diagnosis and prognosis, as surrogate metrics to investigate the impact of various covariates on AD pathophysiology and to accelerate AD therapeutic trials and monitor treatment effects. However, the lack of standardization of how blood samples and collected, processed, stored analyzed and reported can affect the reproducibility of these biomarker measurements, potentially hindering progress toward their widespread use in clinical and research settings. To help address these issues, we provide fundamental guidelines developed according to recent research findings on the impact of sample handling on blood biomarker measurements. These guidelines cover important considerations including study design, blood collection, blood processing, biobanking, biomarker measurement, and result reporting. Furthermore, the proposed guidelines include best practices for appropriate blood handling procedures for genetic and ribonucleic acid analyses. While we focus on the key blood-based AD biomarkers for the AT(N) criteria (e.g., amyloid-beta [Aß]40, Aß42, Aß42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau and glial fibrillary acidic protein), we anticipate that these guidelines will generally be applicable to other types of blood biomarkers. We also anticipate that these guidelines will assist investigators in planning and executing biomarker research, enabling harmonization of sample handling to improve comparability across studies.

Causal effect of blood osteocalcin on the risk of Alzheimer's disease and the mediating role of energy metabolism.

Growing evidence suggests an association between osteocalcin (OCN), a peptide derived from bone and involved in regulating glucose and lipid metabolism, and the risk of Alzheimer's disease (AD). However, the causality of these associations and the underlying mechanisms remain uncertain. We utilized a Mendelian randomization (MR) approach to investigate the causal effects of blood OCN levels on AD and to assess the potential involvement of glucose and lipid metabolism. Independent instrumental variables strongly associated (P < 5E-08) with blood OCN levels were obtained from three independent genome-wide association studies (GWAS) on the human blood proteome (N = 3301 to 35,892). Two distinct summary statistics datasets on AD from the International Genomics of Alzheimer's Project (IGAP, N = 63,926) and a recent study including familial-proxy AD patients (FPAD, N = 472,868) were used. Summary-level data for fasting glucose (FG), 2h-glucose post-challenge, fasting insulin, HbA1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol (TC), and triglycerides were incorporated to evaluate the potential role of glucose and lipid metabolism in mediating the impact of OCN on AD risk. Our findings consistently demonstrate a significantly negative correlation between genetically determined blood OCN levels and the risk of AD (IGAP: odds ratio [OR, 95%CI] = 0.83[0.72-0.96], P = 0.013; FPAD: OR = 0.81 [0.70-0.93], P = 0.002). Similar estimates with the same trend direction were obtained using other statistical approaches. Furthermore, employing multivariable MR analysis, we found that the causal relationship between OCN levels and AD was disappeared after adjustment of FG and TC (IGAP: OR = 0.97[0.80-1.17], P = 0.753; FPAD: OR = 0.98 [0.84-1.15], P = 0.831). There were no apparent instances of horizontal pleiotropy, and leave-one-out analysis showed good stability of the estimates. Our study provides evidence supporting a protective effect of blood OCN levels on AD, which is primarily mediated through regulating FG and TC levels. Further studies are warranted to elucidate the underlying physio-pathological mechanisms.

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly.

BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aß deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample. METHODS: Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aß-PET ([11C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aß accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex). RESULTS: Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aß pathology. Plasma t-tau concentration did not associate with any of the measured pathologies. CONCLUSIONS: Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.

Lipoproteins and metabolites in diagnosing and predicting Alzheimer's disease using machine learning.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that poses a substantial economic burden. The Random forest algorithm is effective in predicting AD; however, the key factors influencing AD onset remain unclear. This study aimed to analyze the key lipoprotein and metabolite factors influencing AD onset using machine-learning methods. It provides new insights for researchers and medical personnel to understand AD and provides a reference for the early diagnosis, treatment, and early prevention of AD. METHODS: A total of 603 participants, including controls and patients with AD with complete lipoprotein and metabolite data from the Alzheimer's disease Neuroimaging Initiative (ADNI) database between 2005 and 2016, were enrolled. Random forest, Lasso regression, and CatBoost algorithms were employed to rank and filter 213 lipoprotein and metabolite variables. Variables with consistently high importance rankings from any two methods were incorporated into the models. Finally, the variables selected from the three methods, with the participants' age, sex, and marital status, were used to construct a random forest predictive model. RESULTS: Fourteen lipoprotein and metabolite variables were screened using the three methods, and 17 variables were included in the AD prediction model based on age, sex, and marital status of the participants. The optimal random forest modeling was constructed with "mtry" set to 3 and "ntree" set to 300. The model exhibited an accuracy of 71.01%, a sensitivity of 79.59%, a specificity of 65.28%, and an AUC (95%CI) of 0.724 (0.645-0.804). When Mean Decrease Accuracy and Gini were used to rank the proteins, age, phospholipids to total lipids ratio in intermediate-density lipoproteins (IDL_PL_PCT), and creatinine were among the top five variables. CONCLUSIONS: Age, IDL_PL_PCT, and creatinine levels play crucial roles in AD onset. Regular monitoring of lipoproteins and their metabolites in older individuals is significant for early AD diagnosis and prevention.

The Associations Between Serum Insulin-like Growth Factor-I, Brain White Matter Volumes, and Cognition in Mild Cognitive Impairment and Alzheimer's Disease.

Background: Insulin-like growth factor-I (IGF-I) regulates myelin, but little is known whether IGF-I associates with white matter functions in subjective and objective mild cognitive impairment (SCI/MCI) or Alzheimer's disease (AD). Objective: To explore whether serum IGF-I is associated with magnetic resonance imaging - estimated brain white matter volumes or cognitive functions. Methods: In a prospective study of SCI/MCI (n = 106) and AD (n = 59), we evaluated the volumes of the total white matter, corpus callosum (CC), and white matter hyperintensities (WMHs) as well as Mini-Mental State Examination (MMSE), Trail Making Test A and B (TMT-A/B), and Stroop tests I-III at baseline, and after 2 years. Results: IGF-I was comparable in SCI/MCI and AD (113 versus 118 ng/mL, p = 0.44). In SCI/MCI patients, the correlations between higher baseline IGF-I and greater baseline and 2-year volumes of the total white matter and total CC lost statistical significance after adjustment for intracranial volume and other covariates. However, after adjustment for covariates, higher baseline IGF-I correlated with better baseline scores of MMSE and Stroop test II in SCI/MCI and with better baseline results of TMT-B and Stroop test I in AD. IGF-I did not correlate with WMH volumes or changes in any of the variables. Conclusions: Both in SCI/MCI and AD, higher IGF-I was associated with better attention/executive functions at baseline after adjustment for covariates. Furthermore, the baseline associations between IGF-I and neuropsychological test results in AD may argue against significant IGF-I resistance in the AD brain.

Unraveling the genetic architecture of blood unfolded p-53 among non-demented elderlies: novel candidate genes for early Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a heritable neurodegenerative disease whose long asymptomatic phase makes the early diagnosis of it pivotal. Blood U-p53 has recently emerged as a superior predictive biomarker for AD in the early stages. We hypothesized that genetic variants associated with blood U-p53 could reveal novel loci and pathways involved in the early stages of AD. RESULTS: We performed a blood U-p53 Genome-wide association study (GWAS) on 484 healthy and mild cognitively impaired subjects from the ADNI cohort using 612,843 Single nucleotide polymorphisms (SNPs). We performed a pathway analysis and prioritized candidate genes using an AD single-cell gene program. We fine-mapped the intergenic SNPs by leveraging a cell-type-specific enhancer-to-gene linking strategy using a brain single-cell multimodal dataset. We validated the candidate genes in an independent brain single-cell RNA-seq and the ADNI blood transcriptome datasets. The rs279686 between AASS and FEZF1 genes was the most significant SNP (p-value = 4.82 × 10-7). Suggestive pathways were related to the immune and nervous systems. Twenty-three candidate genes were prioritized at 27 suggestive loci. Fine-mapping of 5 intergenic loci yielded nine cell-specific candidate genes. Finally, 15 genes were validated in the independent single-cell RNA-seq dataset, and five were validated in the ADNI blood transcriptome dataset. CONCLUSIONS: We underlined the importance of performing a GWAS on an early-stage biomarker of AD and leveraging functional omics datasets for pinpointing causal genes in AD. Our study prioritized nine genes (SORCS1, KIF5C, TMEFF2, TMEM63C, HLA-E, ATAT1, TUBB, ARID1B, and RUNX1) strongly implicated in the early stages of AD.

Plasma Neurofilament Light Relates to Divergent Default and Salience Network Connectivity in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia.

Background: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) show differential vulnerability to large-scale brain functional networks. Plasma neurofilament light (NfL), a promising biomarker of neurodegeneration, has been linked in AD patients to glucose metabolism changes in AD-related regions. However, it is unknown whether plasma NfL would be similarly associated with disease-specific functional connectivity changes in AD and bvFTD. Objective: Our study examined the associations between plasma NfL and functional connectivity of the default mode and salience networks in patients with AD and bvFTD. Methods: Plasma NfL and neuroimaging data from patients with bvFTD (n = 16) and AD or mild cognitive impairment (n = 38; AD + MCI) were analyzed. Seed-based functional connectivity maps of key regions within the default mode and salience networks were obtained and associated with plasma NfL in these patients. RESULTS: We demonstrated divergent associations between NfL and functional connectivity in AD + MCI and bvFTD patients. Specifically, AD + MCI patients showed lower default mode network functional connectivity with higher plasma NfL, while bvFTD patients showed lower salience network functional connectivity with higher plasma NfL. Further, lower NfL-related default mode network connectivity in AD + MCI patients was associated with lower Montreal Cognitive Assessment scores and higher Clinical Dementia Rating sum-of-boxes scores, although NfL-related salience network connectivity in bvFTD patients was not associated with Neuropsychiatric Inventory Questionnaire scores. CONCLUSIONS: Our findings indicate that plasma NfL is differentially associated with brain functional connectivity changes in AD and bvFTD.

Search in the Periphery for Potential Inflammatory Biomarkers of Dementia with Lewy Bodies and Alzheimer's Disease.

Background: Neuroinflammation, with altered peripheral proinflammatory cytokine production, plays a major role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), while the role of inflammation in dementia with Lewy bodies (DLB) is less known and the results of different studies are often in disagreement. Objective: The present study aimed to investigate the levels of TNFα and IL-6 in serum and supernatants, and the related DNA methylation in patients affected by DLB and AD compared to healthy controls (HCs), to clarify the role of epigenetic mechanisms of DNA promoter methylation on of pro-inflammatory cytokines overproduction. Methods: Twenty-one patients with DLB and fourteen with AD were frequency-matched for age and sex with eleven HCs. Clinical evaluation, TNFα and IL-6 gene methylation status, cytokine gene expression levels and production in serum and peripheral blood mononuclear cell (PBMC) supernatants were performed. Results: In AD and DLB patients, higher serum levels of IL-6 and TNFα were detected than in HCs. Differences in LPS-stimulated versus spontaneous PBMCs were observed between DLB, AD, and HC in the levels of TNFα (p = 0.027) and IL-6 (p < 0.001). Higher levels were also revealed for sIL-6R in DLB (p < 0.001) and AD (p < 0.001) in comparison with HC.DNA hypomethylation in IL-6 and TNFα CpG promoter sites was detected for DLB and AD patients compared to the corresponding site in HCs. Conclusions: Our preliminary study documented increased levels of IL-6 and TNFα in DLB and AD patients to HCs. This overproduction can be due to epigenetic mechanisms regarding the hypomethylation of DNA promoters.

Prognostic Power? Do the Plasma Biomarkers, Neurofilament Light and Phospho-Tau 181, Improve Prediction of Progression to Alzheimer's Disease Using a Machine Learning Approach in the ADNI Cohort?

With the advent of therapeutics with potential to slow Alzheimer's disease progression the necessity of understanding the diagnostic value of plasma biomarkers is critical, not only for understanding the etiology and progression of Alzheimer's disease, but also for access and response to potentially disease modifying therapeutic agents. Multiple studies are currently assessing the sensitivity and specificity of plasma biomarkers in large cohorts such as the Alzheimer's Disease Neuroimaging Initiative. This study uses machine learning to predict the progression from mild cognitive impairment using plasma biomarkers in conjunction with well-established cerebrospinal fluid and imaging biomarkers of disease progression.

[Blood biomarkers open a window to brain pathophysiology in Alzheimer's disease]. / Blodtest ­ fönster till hjärnan vid Alzheimers sjukdom.

Technical developments have paved the way for the development of ultrasensitive analytical methods that allow for precise quantification of brain-specific proteins in blood samples. Plasma levels of amyloid ß, specifically the Aß42/40 ratio, are reduced in Alzheimer's disease (AD) and show concordance with brain amyloidosis assessed by PET, but the overlap with normal elderly may be too large for reliable use in clinical applications. Plasma phosphorylated tau (P-tau), especially a variant called P-tau217, is markedly increased in the early symptomatic stages of AD but remains normal in other neurodegenerative disorders. Total tau (T-tau) is measurable in blood and shows most promise as a biomarker for acute neuronal injury (e.g. acute traumatic or hypoxic brain injury), where T-tau shows a fast and dramatic increase but does not work well as an AD biomarker due to contributions to blood levels from peripheral tissues. Instead, a novel method for tau protein produced only in the CNS called brain-derived tau (BD-tau) shows promise as a biomarker for AD-type neurodegeneration. Neurofilament light (NFL) levels in blood correlate tightly with levels in CSF and reflect axonal injury irrespective of the underlying cause. Increased blood NFL concentration is found in several neurodegenerative disorders, including AD, but even more so in disorders such as motor neuron disease and frontotemporal dementia. Glial fibrillary acidic protein (GFAP) is expressed with activation of astrocytes, and is mildly increased in AD, but is also very high also in acute brain disorders. These blood tests show promise as tools to identify AD pathophysiology in the first assessment of patients with early cognitive symptoms, also in primary care, to guide clinical management and possible admission to the specialist clinic. A two-step model will result in a very high accuracy to either predict or exclude brain amyloidosis of the Alzheimer type.

Association of Vascular Endothelial Growth Factor Levels with Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative illness that leads to impairment of cognitive functions and memory loss. Even though there is a plethora of research reporting the abnormal regulation of VEGF expression in AD pathogenesis, whether the CSF and serum VEGF are increased in AD is an open question yet. In this study, the association of CSF and serum VEGF concentrations with the risk of Alzheimer's disease was investigated using systematic review and meta-analysis. METHODS: A systematic literature search was carried out using online specialized biomedical databases of Web of Science, Pubmed, Scopus, Embase, and Google Scholar until Feb 2023 without restriction to the beginning time. The meta-analysis was performed using the random-effects model and only case-control publications describing VEGF concentrations in Alzheimer's patients were considered for calculating the pooled effect size. RESULTS: In the systematic literature search, 6 and 13 studies met the inclusion criteria to evaluate CSF and serum VEGF concentrations of Alzheimer's patients, respectively. This meta-analysis retrieved a total number of 2380 Alzheimer's patients and 5368 healthy controls. Under the random-effects model in the meta-analysis, the pooled SMD for CSF and serum VEGF concentrations of Alzheimer's patients were -0.13 (95%CI,-0.42-0.16) and 0.23 (95%CI,-0.27-0.73), respectively. Results of meta-regression analysis showed that the quality scores of papers and female sex ratios of participants did not affect the associations of VEGF concentrations with the risk of Alzheimer's disease. However, the age average of patients significantly affects the associations of CSF VEGF concentrations with the risk of Alzheimer's disease (P=0.051). There was a statistically significant subgroup effect for the disease severity of Alzheimer's patients which modifies the associations of serum VEGF concentrations with the risk of Alzheimer's disease (P<0.01) and subgroup analysis shows that study location modifies the associations of CSF and serum VEGF concentrations with the risk of Alzheimer's disease (P<0.01). CONCLUSION: The results show that the serum VEGF concentrations increased for Alzheimer's patients in accordance with the increased expression of VEGF and the VEGF levels of Alzheimer's patients decreased by increasing their disease severities. Therefore, in addition to detecting AD in the earliest stages of the disease, serum VEGF could be a promising biomarker to follow up on the disease and evaluate the clinical course of the disease.

Serum Tau-A and Tau-C Levels and Their Association with Cognitive Impairment and Dementia Progression in a Memory Clinic Derived Cohort.

BACKGROUND: Serum-measured fragments of Tau cleaved by ADAM-10 (Tau-A) and Caspase-3 (Tau-C) have been found linked to change in cognitive function and risk of dementia. OBJECTIVES: 1) To determine the discriminatory abilities of Tau-A, and Tau-C in subjects with either mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or AD dementia compared to a control group. 2) To determine if there is a relation between Tau-A, and Tau-C and established cerebrospinal fluid (CSF) markers of AD- ß-Amyloid1-42 (AB42), Phosphorylated-tau-181 (p-tau), and total-tau. 3) To determine if Tau-A and Tau-C are associated with progression rate from MCI due to AD to AD dementia. DESIGN: Cross-sectional and a substudy using a retrospective cohort design. SETTING: Memory clinic derived subjects contributing to the Danish Dementia Biobank. PARTICIPANTS: Cognitively unimpaired subjects (n=49), patients with mild cognitive impairment (MCI) due to AD (n=45), and Alzheimer's dementia (n=52). MEASUREMENTS: Competitive enzyme-linked immunosorbent assay (ELISA)-measured serum levels of Tau-A, and Tau-C. RESULTS: The ratio between Tau-A and Tau-C differed between the three groups (p=0.015). Age- and sex-adjusted Tau-A differed between groups with lower ratios being associated with more severe disease (p=0.023). Tau-C was trending towards significant correlation to CSF-levels of AB42 (Pearson correlation coefficient 0.164, p=0.051). Those with Tau-C-levels in the 2nd quartile had a hazard ratio (HR) of 2.91 (95% CI 1.01 - 8.44, p=0.04) of progression compared to those in the 1st quartile. Those in the 3rd quartile was found to have a borderline significant (p=0.055) HR of 2.63 (95% CI 0.98 - 7.05) when compared to those in the lowest quartile. CONCLUSIONS: Tau-A and the ratio between Tau-A and Tau-C showed significant differences between groups and were correlated to CSF-AB42. Tau-C values in the middle range were associated with faster progression from MCI to dementia. This pilot study adds to the mounting data suggesting serum-measured Tau-A and Tau-C as biomarkers useful in relation to diagnosis and progression rate in AD but need further validation.

Plasma biomarkers increase diagnostic confidence in patients with Alzheimer's disease or frontotemporal lobar degeneration.

BACKGROUND: The recent development of techniques to assess plasma biomarkers has changed the way the research community envisions the future of diagnosis and management of Alzheimer's disease (AD) and other neurodegenerative disorders. This work aims to provide real world evidence on the clinical impact of plasma biomarkers in an academic tertiary care center. METHODS: Anonymized clinical reports of patients diagnosed with AD or Frontotemporal Lobar Degeneration with available plasma biomarkers (Aß42, Aß42/Aß40, p-tau181, p-tau231, NfL, GFAP) were independently assessed by two neurologists who expressed diagnosis and diagnostic confidence three times: (T0) at baseline based on the information collected during the first visit, (T1) after plasma biomarkers, and (T2) after traditional biomarkers (when available). Finally, we assessed whether clinicians' interpretation of plasma biomarkers and the consequent clinical impact are consistent with the final diagnosis, determined after the conclusion of the diagnostic clinical and instrumental work-up by the actual managing physicians who had complete access to all available information. RESULTS: Clinicians assessed 122 reports, and their concordance ranged from 81 to 91% at the three time points. At T1, the presentation of plasma biomarkers resulted in a change of diagnosis in 2% (2/122, p = 1.00) of cases, and in increased diagnostic confidence in 76% (91/120, p < 0.001) of cases with confirmed diagnosis. The change in diagnosis and the increase in diagnostic confidence after plasma biomarkers were consistent with the final diagnosis in 100% (2/2) and 81% (74/91) of cases, respectively. At T2, the presentation of traditional biomarkers resulted in a further change of diagnosis in 13% (12/94, p = 0.149) of cases, and in increased diagnostic confidence in 88% (72/82, p < 0.001) of cases with confirmed diagnosis. CONCLUSIONS: In an academic tertiary care center, plasma biomarkers supported clinicians by increasing their diagnostic confidence in most cases, despite a negligible impact on diagnosis. Future prospective studies are needed to assess the full potential of plasma biomarkers on clinical grounds.