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The roles of complement 1q (C1q) and Apolipoprotein E (ApoE) in driving Alzheimer's disease (AD) progression might be explained by their associations with neuroinflammation and AD pathology which were previously reported. We examined the associations of cerebrospinal fluid (CSF) C1q and ApoE with CSF neuroinflammatory biomarkers and AD core biomarkers, as well as explore whether C1q mediated the associations of CSF ApoE with these biomarkers. Here, we analyzed CSF proteomics data using two different proteomics datasets-SomaScan(n = 579) and multiple reaction monitoring (MRM[n = 207]). Linear regression analyses were conducted to explore the association of CSF ApoE and C1q. The mediation model and structural equation model (SEM) were conducted to explore the associations of ApoE and C1q with AD biomarkers. Multiple linear regression showed that CSF ApoE was positively associated with CSF C1q in total participants and Alzheimer's continuum participants. Mediation analyses indicated that C1q mediated the associations of CSF ApoE with CSF totau tau(T-tau), phosphorylated tau(p-tau), glial fibrillary acidic protein(sTREM2) and GFAP(glial fibrillary acidic protein) (all the p values <0.05) but not with CSF amyloid-β and progranulin (PGRN). The SEM yielded similar results. Our findings suggest that C1q is linked to ApoE and it mediates the associations of ApoE with T-tau, p-tau, sTREM2, GFAP, indicating C1q association with ApoE might be involved in AD progression.

Alzheimer’s disease (AD) is the most common neurodegenerative disorders presenting with the pathological hallmarks of amyloid plaques and tau tangles. Over the past few years, great efforts have been made to explore reliable biomarkers of AD. High-throughput omics are a technology driven by multiple levels of unbiased data to detect the complex etiology of AD, and it provides us with new opportunities to better understand the pathophysiology of AD and thereby identify potential biomarkers. Through revealing the interaction networks between different molecular levels, the ultimate goal of multi-omics is to improve the diagnosis and treatment of AD. In this review, based on the current AD pathology and the current status of AD diagnostic biomarkers, we summarize how genomics, transcriptomics, proteomics and metabolomics are all conducing to the discovery of reliable AD biomarkers that could be developed and used in clinical AD management.

Tau is a microtubule-associated protein widely distributed in the central nervous system (CNS). The main function of tau is to promote the assembly of microtubules and stabilize their structure. After a long period of research on neurodegenerative diseases, the function and dysfunction of the microtubule-associated protein tau in neurodegenerative diseases and tau neurotoxicity have attracted increasing attention. Tauopathies are a series of progressive neurodegenerative diseases caused by pathological changes in tau, such as abnormal phosphorylation. The pathological features of tauopathies are the deposition of abnormally phosphorylated tau proteins and the aggregation of tau proteins in neurons. This article first describes the normal physiological function and dysfunction of tau proteins and then discusses the enzymes and proteins involved in tau phosphorylation and dephosphorylation, the role of tau in cell dysfunction, and the relationships between tau and several neurodegenerative diseases. The study of tau neurotoxicity provides new directions for the treatment of tauopathies.

Multimorbidity (the presence of two or more long-term conditions [LTCs]) was suggested to exacerbate the neuronal injuries. The impact of multimorbidity on dementia has not been fully elucidated. We aimed to investigate the association between multimorbidity and dementia risk. We used the prospective data from 245,483 UK Biobank participants during a 9-year follow-up. Multimorbidity status was evaluated based on the LTC counts and multimorbidity patterns. Cox regression models adjusted for potential confounders were used to examine the associations of multimorbidity status with all-cause dementia (ACD), Alzheimer’s disease (AD) and vascular dementia (VD). Participants with multimorbidity at baseline had higher risks of ACD and VD, and the risks were elevated with the increase of LTC counts (ACD: hazard ratios [HR] = 1.15, 95% confidence intervals [CI] = 1.01–1.31 with 2 LTCs; HR = 1.18, CI = 1.01–1.39 with 3 LTCs; HR = 1.65, CI = 1.44–1.88 with ≥4 LTCs; VD: HR = 1. 66, CI = 1.24–2.21 with 2 LTCs; HR = 2.10, CI = 1.53–2.88 with 3 LTCs; HR = 3.17, CI = 2.43–4.13 with ≥4 LTCs). Participants with ≥4 LTCs also had a higher risk of AD (HR = 1.34, CI = 1.08–1.66]. Participants with the cardio-cerebrovascular/respiratory/metabolic/musculoskeletal/depressive multimorbidity were 1.46, 1.28, and 2.50 times more likely to develop ACD (HR = 1.46, 95% CI = 1.28–1.67), AD (HR = 1.28, CI = 1.04–1.58), and VD (HR = 2.50, CI = 1.90–3.27), respectively. Those with tumor/genitourinary/digestive disorders had a 11% higher hazard of ACD (HR = 1.11, CI = 1.00–1.24) and a 73% elevated risk of VD (HR = 1.73, CI = 1.37–2.18). The prevention of LTC accumulation and the identification of specific multimorbidity patterns might be beneficial to the prevention of dementia and its subtypes, AD as well as VD.

The rapid emergence of SARS-CoV-2 variants of concern (VOCs) calls for efforts to study broadly neutralizing antibodies elicited by infection or vaccination so as to inform the development of vaccines and antibody therapeutics with broad protection. Here, we identified two convalescents of breakthrough infection with relatively high neutralizing titers against all tested viruses. Among 50 spike-specific monoclonal antibodies (mAbs) cloned from their B cells, the top 6 neutralizing mAbs (KXD01-06) belong to previously defined IGHV3-53/3-66 public antibodies. Although most antibodies in this class are dramatically escaped by VOCs, KXD01-06 all exhibit broad neutralizing capacity, particularly KXD01-03, which neutralize SARS-CoV-2 from prototype to the emerging EG.5.1 and FL.1.5.1. Deep mutational scanning reveals that KXD01-06 can be escaped by current and prospective variants with mutations on D420, Y421, L455, F456, N460, A475 and N487. Genetic and functional analysis further indicates that the extent of somatic hypermutation is critical for the breadth of KXD01-06 and other IGHV3-53/3-66 public antibodies. Overall, the prevalence of broadly neutralizing IGHV3-53/3-66 public antibodies in these two convalescents provides rationale for novel vaccines based on this class of antibodies. Meanwhile, KXD01-06 can be developed as candidates of therapeutics against SARS-CoV-2 through further affinity maturation.

Background Hepatocyte growth factor (HGF) plays a role in neuronal survival and development, and has been implicated in neurodegenerative diseases. We sought to examine the associations of the CSF HGF with Alzheimer’s disease (AD) pathology and cognitive function. Methods A total of 238 participants (including 90 cognitively normal (CN) and 148 mild cognitive impairment (MCI)) who had measurements of CSF HGF were included from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Multiple linear regression models were utilized to explore the cross-sectional associations of CSF HGF with AD biomarkers (including Aβ42, pTau, and tTau proteins) in non-demented participants. Moreover, linear mixed-effects regression models were utilized to explore the longitudinal associations of HGF subgroups with cognitive function. Mediation analyses were utilized to explore the mediation effects of AD markers. Results MCI individuals had significantly increased CSF HGF compared with the CN individuals. Results of multiple linear regressions showed significant correlations of CSF HGF with CSF Aβ42, pTau, and tTau in non-demented participants. Higher level of baseline CSF HGF was associated with faster cognitive decline. Influences of the baseline CSF HGF on cognition were partially mediated by Aβ42, pTau, and tTau pathologies. Conclusions High concentrations of HGF in CSF may be related to faster cognitive decline. The cognitive consequences of higher CSF HGF partly stem from AD pathology, which suggests that the CSF HGF may be an attractive biomarker candidate to track AD progression.

Background We aimed to investigate the tau biomarker discrepancies of Alzheimer’s disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET). Methods In the Alzheimer’s Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-β (Aβ) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared. Results Across different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF− 15.6%, plasma−/CSF+ 15.3%, plasma+/PET− 22.4%, and plasma−/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aβ pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF− and plasma−/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aβ burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aβ pathology. Conclusions Our results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.

Complement C1q initiates the classical complement pathway and becomes activated in Alzheimer’s disease (AD), contributing to the association between amyloid-β (Aβ) and tau pathologies. However, whether C1q influences AD pathology by modulating glial cell communication is unclear. We included 217 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to explore the associations of cerebrospinal fluid (CSF) C1q with soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP) and AD biomarkers. Additionally, we incorporated data from 535 participants in the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study to explore associations. We employed 10,000 bootstrapped iterations of causal mediation analysis to examine the possible mediating role of sTREM2 or GFAP in the relationship between CSF C1q and AD pathology. We found that CSF rather than serum C1q were positively associated with CSF sTREM2, GFAP, Aβ 42 , phosphorylated-tau (P-tau) and total tau (T-tau) at baseline. CSF C1q was only longitudinally associated with CSF T-tau levels and AD assessment scale-cognitive subscale 13 (ADAS-Cog 13) scores. Mediation analysis demonstrated that Aβ pathology partly mediated the association between CSF C1q and sTREM2 levels, which in turn impacted tau pathology progression. Serum C1q showed a significant association with CSF sTREM2 at baseline as well. Conclusions C1q is associated with CSF sTREM2 and mediates the relationship between Aβ and tau pathologies. This suggests that C1q may play a crucial role in the progression from Aβ pathology to tau pathology.

Introduction and aims Genetic variations play a significant role in determining an individual's AD susceptibility. Research on the connection between AD and TREM1 gene polymorphisms (SNPs) remained lacking. We sought to examine the associations between TREM1 SNPs and AD. Methods Based on the 1000 Genomes Project data, linkage disequilibrium (LD) analyses were utilized to screen for candidate SNPs in the TREM1 gene. AD cases (1081) and healthy control subjects (870) were collected and genotyped, and the associations between candidate SNPs and AD risk were analyzed. We explored the associations between target SNP and AD biomarkers. Moreover, 842 individuals from ADNI were selected to verify these results. Linear mixed models were used to estimate associations between the target SNP and longitudinal cognitive changes. Results The rs2062323 was identified to be associated with AD risk in the Han population, and rs2062323T carriers had a lower AD risk (co‐dominant model: OR, 0.67, 95% CI, 0.51–0.88, p = 0.0037; additive model: OR, 0.82, 95% CI, 0.72–0.94, p = 0.0032). Cerebrospinal fluid (CSF) sTREM2 levels were significantly increased in middle‐aged rs2062323T carriers (additive model: β = 0.18, p = 0.0348). We also found significantly elevated levels of CSF sTREM2 in the ADNI. The rate of cognitive decline slowed down in rs2062323T carriers. Conclusions This study is the first to identify significant associations between TREM1 rs2062323 and AD risk. The rs2062323T may be involved in AD by regulating the expression of TREM1, TREML1, TREM2, and sTREM2. The TREM family is expected to be a potential therapeutic target for AD. This study is the first to identify significant associations between TREM1 rs2062323 and AD risk. The rs2062323T may be involved in AD by regulating the expression of TREM1, TREML1, TREM2, and sTREM2. The TREM family is expected to be a potential therapeutic target for AD.

Previous observational studies reported that midlife clustering of cardiovascular risk factors and lifestyle behaviors were associated with neurodegenerative disease; however, these findings might be biased by confounding and reverse causality. This study aimed to investigate the causal associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease, using the two-sample Mendelian randomization design. Genetic variants for the modifiable risk factors and neurodegenerative disease were extracted from large-scale genome-wide association studies. The inverse-variance weighted method was used as the main analysis method, and MR-Egger regression and leave-one-out analyses were performed to identify potential violations. Genetically predicted diastolic blood pressure (DBP: OR per 1 mmHg, 0.990 [0.979–1.000]), body mass index (BMI: OR per 1 SD, 0.880 [0.825–0.939]), and educational level (OR per 1 SD, 0.698 [0.602–0.810]) were associated with lower risk of late-onset Alzheimer’s disease (LOAD), while genetically predicted low-density lipoprotein (LDL: OR per 1 SD, 1.302 [1.066–1.590]) might increase LOAD risk. Genetically predicted exposures (including LDL and BMI) applied to familial AD showed the same effect. The association of LDL was also found with Amyotrophic lateral sclerosis (ALS) (LDL: OR per 1 SD, 1.180 [1.080–1.289]). This MR analysis showed that LDL, BMI, BP, and educational level were causally related to AD; a significant association between LDL and ALS risk, as well as the potential effect of sleep duration on PD risk, were also revealed. Targeting these modifiable factors was a promising strategy of neurodegenerative disease prevention.