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Background: The N-glycan structure bisecting N-acetylglucosamine (bisecting GlcNAc) is present on several N-glycans that are elevated in Alzheimer's disease (AD), and previous studies have shown that bisecting GlcNAc levels correlate with total tau and phospho-tau181 in cerebrospinal fluid at early stages of AD. A recent population-based study showed that bisecting GlcNAc correlates with total tau also in blood and that this correlation could predict conversion to dementia. Objective: In this study, we have further investigated how bisecting GlcNAc relates to total tau and phospho-tau 181 in cerebrospinal fluid samples from controls and cases with early cognitive deficits, stratified by amyloid/tau status and gender. Methods: Relative levels of bisecting GlcNAc in cerebrospinal fluid were measured by an enzyme-linked lectin assay in individuals with subjective cognitive decline, mild cognitive impairment and controls from the Norwegian Dementia Disease Initiation cohort. Results: As in our previous study, the correlation between bisecting GlcNAc and total tau or phospho-tau181 was particularly strong in the subjective cognitive decline group. The correlation was observed in amyloid negative and tau negative as well as amyloid positive and tau positive individuals, both in females and in males. Interestingly, among the amyloid negative and tau negative individuals, the correlation was observed in individuals with subjective cognitive decline but not in the controls. Conclusions: Thus, bisecting GlcNAc could be a biomarker for early cognitive decline. [ABSTRACT FROM AUTHOR]

Background: The relationship between Alzheimer's disease (AD)-related pathology and cognition was not exactly consistent. Objective: To explore whether the association between AD pathology and cognition can be moderated by frailty. Methods: We included 1711 participants from the Alzheimer's Disease Neuroimaging Initiative database. Levels of cerebrospinal fluid amyloid-β, p-tau, and t-tau were identified for AD-related pathology based on the amyloid-β/tau/neurodegeneration (AT[N]) framework. Frailty was measured using a modified Frailty Index-11 (mFI-11). Regression and interaction models were utilized to assess the relationship among frailty, AT(N) profiles, and cognition. Moderation models analyzed the correlation between AT(N) profiles and cognition across three frailty levels. All analyses were corrected for age, sex, education, and APOEɛ4 status. Results: In this study, frailty (odds ratio [OR] = 1.71, p < 0.001) and AT(N) profiles (OR = 2.00, p < 0.001) were independently associated with cognitive status. The model fit was improved when frailty was added to the model examining the relationship between AT(N) profiles and cognition (p < 0.001). There was a significant interaction between frailty and AT(N) profiles in relation to cognitive status (OR = 1.12, pinteraction = 0.028). Comparable results were obtained when Mini-Mental State Examination scores were utilized as the measure of cognitive performance. The association between AT(N) profiles and cognition was stronger with the levels of frailty. Conclusions: Frailty may diminish patients' resilience to AD pathology and accelerate cognitive decline resulting from abnormal AD-related pathology. In summary, frailty contributes to elucidating the relationship between AD-related pathology and cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. Objective: We investigated genetic heterogeneity in AD risk through a multi-step analysis. Methods: We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases = 2,739, controls = 5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (AD cases = 500, controls = 470). We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n = 399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories. Results: PCA revealed three distinct clusters ("constellations") driven primarily by different correlation patterns in a region of strong LD surrounding the MAPT locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased cerebrospinal fluid p-tau and cognitive decline over time. Conclusions: This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. Objective: We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42, p-tau181), cognitive function, and NPS. Methods: Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOEɛ4. Results: The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aβ1-42 ratio was no longer associated with the NPI-Q. Conclusions: NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia. [ABSTRACT FROM AUTHOR]

Background: The identification of biomarkers for different dementias in plasma and cerebrospinal fluid (CSF) has made substantial progress. However, they are observational studies, and there remains a lack of research on dementias with low incidence rates. Objective: We performed a comprehensive Mendelian randomization to identify potential biomarkers for different dementia type. Methods: The summary-level datasets encompassed 734 plasma and 154 cerebrospinal fluid proteins sourced from recently published genome-wide association studies (GWAS). Summary statistics for different dementias, including any dementia (refering to any type of dementia symptoms, 218,792 samples), Alzheimer's disease (AD, 63,926 samples), vascular dementia (212,389 samples), frontotemporal dementia (3,024 samples), dementia with Lewy bodies (DLB, 6,618 samples), and dementia in Parkinson's disease (216,895 samples), were collected from large GWAS. The primary method is inverse variance weighting, with additional sensitivity analyses conducted to ensure the robustness of the findings. Results: The molecules released into CSF, namely APOE2 for any dementia, APOE2 and Siglec-3 for AD, APOE2 for vascular dementia, and APOE2 for DLB, might be potential biomarkers. CD33 for AD and SNCA for DLB in plasma could be promising biomarkers. Conclusions: This is the first study to integrate plasma and CSF proteins to identify potential biomarkers for different dementias. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) may confer risk for Alzheimer's disease (AD) through amyloid-β (Aβ) overproduction. However, the relationship between TBI and Aβ levels in cerebrospinal fluid (CSF) remains unclear. Objective: To explore whether Aβ overproduction is implicated in the relationship between TBI and AD, we compared CSF levels of Aβ in individuals with a TBI history versus controls (CTRLs) and related CSF Aβ levels to cognitive markers associated with preclinical AD. Methods: Participants were 112 non-impaired Veterans (TBI = 56, CTRL = 56) from the Alzheimer's Disease Neuroimaging Initiative-Department of Defense database with available cognitive data (Boston Naming Test [BNT], Rey Auditory Verbal Learning Test [AVLT]) and CSF measures of Aβ42, Aβ40, and Aβ38. Mediation models explored relationships between TBI history and BNT scores with Aβ peptides as mediators. Results: The TBI group had higher CSF Aβ40 (t = –2.43, p = 0.017) and Aβ38 (t = –2.10, p = 0.038) levels than the CTRL group, but groups did not differ in CSF Aβ42 levels or Aβ42/Aβ40 ratios (p > 0.05). Both Aβ peptides negatively correlated with BNT (Aβ40: rho = –0.20, p = 0.032; Aβ38: rho = –0.19, p = 0.048) but not AVLT (p > 0.05). Aβ40 had a significant indirect effect on the relationship between TBI and BNT performance (β= –0.16, 95% CI [–0.393, –0.004], PM = 0.54). Conclusions: TBI may increase AD risk and cognitive vulnerability through Aβ overproduction. Biomarker models incorporating multiple Aβ peptides may help identify AD risk among those with TBI. [ABSTRACT FROM AUTHOR]

Background: The Free and Cued Selective Reminding Test (FCSRT), assessing verbal episodic memory with controlled learning and semantic cueing, has been recommended for detecting the genuine encoding and storage deficits characterizing AD-related memory disorders. Objective: The present study aims at investigating the ability of FCSRT in predicting cerebrospinal fluid (CSF) evidence of amyloid-β positivity in subjects with amnestic mild cognitive impairment (aMCI) and exploring its associations with amyloidopathy, tauopathy and neurodegeneration biomarkers. Methods: 120 aMCI subjects underwent comprehensive neurological and neuropsychological examinations, including the FCSRT assessment, and CSF collection; CSF Aβ42/40 ratio, p-tau181, and total-tau quantification were conducted by an automated CLEIA method on Lumipulse G1200. Based on the Aβ42/40 ratio value, subjects were classified as either A+ or A–. Results: All FCSRT subitem scores were significantly lower in A+ group and significantly predicted the amyloid-β status, with Immediate Total Recall (ITR) being the best predictor. No significant correlations were found between FCSRT and CSF biomarkers in the A– aMCI group, while in the A+ aMCI group, all FCSRT subitem scores were negatively correlated with CSF p-tau181 and total-tau, but not with the Aβ42/40 ratio. Conclusions: FCSRT confirms its validity as a tool for the diagnosis of AD, being able to predict the presence of amyloid-β deposition with high specificity. The associations between FCSRT subitem scores and CSF p-tau-181 and total-tau levels in aMCI due to AD could further encourage the clinical use of this simple and cost-effective test in the evaluation of individuals with aMCI. [ABSTRACT FROM AUTHOR]

Background: The association between carotid plaque and cognitive decline has recently been reported. However, the current research evidence is insufficient, and the possible causes of cognitive changes are unknown. Objective: This study aims to explore the relationships between carotid plaque and cognition functions, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cognitively intact adults, and try to study the underlying mechanisms. Methods: We enrolled 165 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, who had CSF AD biomarker measurements and carotid ultrasound. Linear modeling was used to assess the association of carotid plaque with CSF biomarkers and cognition. Additionally, mediation analysis was conducted through 10,000 bootstrapped iterations to explore potential links between carotid plaque, AD pathology, and cognition. Results: We found that carotid plaque exhibited significant correlations with Aβ42 (β = –1.173, p = 0.022), Aβ42/Aβ40 (β = –0.092, p < 0.001), P-tau/Aβ42 (β = 0.110, p = 0.045), and T-tau/Aβ42 (β = 0.451, p = 0.010). A significant correlation between carotid plaque and cognition decline was also found in men (β = –0.129, p = 0.021), and mediation analyses revealed that the effect of carotid plaque on cognitive function could be mediated by Aβ42/Aβ40 (proportion of mediation = 55.8%), P-tau/Aβ42 (proportion of mediation = 51.6%, p = 0.015) and T-tau/Aβ42 (proportion of mediation = 43.8%, p = 0.015) mediated. Conclusions: This study demonstrated the link between carotid plaque and CSF AD biomarkers in cognitively intact adults, and the important role that AD pathology may play in the correlation between carotid plaque and cognitive changes. [ABSTRACT FROM AUTHOR]

Background: Amnestic syndrome of the hippocampal type (ASHT) in Memory Clinics is a presentation common to Alzheimer's disease (AD). However, ASHT can be found in other neurodegenerative disorders. Objective: To compare brain morphometry including hippocampal volumes between amnestic older adults with and without AD pathology and investigate their relationship with memory performance and cerebrospinal fluid (CSF) biomarkers. Methods: Brain morphometry of 92 consecutive patients (72.5±6.8 years old; 39% female) with Free and Cued Selective Recall Reminding Test (FCSRT) total recall < 40/48 was assessed with an automated algorithm and compared between AD and non-AD patients, as defined by CSF biomarkers. Results: AD and non-AD patients presented comparable brain morphology. Total recall was associated to hippocampal volume irrespectively from AD pathology. Conclusions: Brain morphometry, including hippocampal volumes, is similar between AD and non-AD older adults with ASHT evaluated in a Memory Clinic, underlying the importance of using molecular biomarkers for the diagnosis of AD. [ABSTRACT FROM AUTHOR]

Background: Early-onset Alzheimer's disease (EOAD) exhibits a notable degree of heterogeneity as compared to late-onset Alzheimer's disease (LOAD). The proteins and pathways contributing to the pathophysiology of EOAD still need to be completed and elucidated. Objective: Using correlation network analysis and machine learning to analyze cerebrospinal fluid (CSF) proteomics data to identify potential biomarkers and pathways associated with EOAD. Methods: We employed mass spectrometry to conduct CSF proteomic analysis using the data-independent acquisition method in a Chinese cohort of 139 CSF samples, including 40 individuals with normal cognition (CN), 61 patients with EOAD, and 38 patients with LOAD. Correlation network analysis of differentially expressed proteins was performed to identify EOAD-associated pathways. Machine learning assisted in identifying crucial proteins differentiating EOAD. We validated the results in an Western cohort and examined the proteins expression by enzyme-linked immunosorbent assay (ELISA) in additional 9 EOAD, 9 LOAD, and 9 CN samples from our cohort. Results: We quantified 2,168 CSF proteins. Following adjustment for age and sex, EOAD exhibited a significantly greater number of differentially expressed proteins than LOAD compared to CN. Additionally, our data indicates that EOAD may exhibit more pronounced synaptic dysfunction than LOAD. Three potential biomarkers for EOAD were identified: SH3BGRL3, LRP8, and LY6 H, of which SH3BGRL3 also accurately classified EOAD in the Western cohort. LY6 H reduction was confirmed via ELISA, which was consistent with our proteomic results Conclusions: This study provides a comprehensive profile of the CSF proteome in EOAD and identifies three potential EOAD biomarker proteins. [ABSTRACT FROM AUTHOR]

Background: Blood biomarkers are proposed as a diagnostic alternative to amyloid PET or cerebrospinal fluid (CSF) analyses for the diagnosis of Alzheimer's disease (AD). Relatively little is known of the natural history of patients identified by different blood biomarkers. Objective: To identify patients with elevated plasma phosphorylated tau (pTau)181 from a prior Phase 2a trial, and explore the natural histories of their clinical progression, and potential efficacy of Xanamem, a selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in these patients. Methods: A prespecified, double-blind analysis was conducted in 72 participants with clinically diagnosed AD and available plasma samples from baseline and Week 12 of the "XanADu" Phase 2a trial of Xanamem versus placebo. The analysis prespecified plasma pTau181 > median to identify patients more likely to have AD ("H", > 6.74 pg/mL, n = 34). Cohen's d (d) of≥0.2 defined potential clinical significance. Results: In the placebo group, H patients showed greater clinical progression compared to L patients (pTau181≤median) on ADCOMS (d = 0.55, p < 0.001), CDR-SB (d = 0.63, p < 0.001), MMSE (d = 0.52, p = 0.12), and ADAS-Cog14 (d = 0.53, p = 0.19). In H patients, a potentially clinically meaningful Xanamem treatment effect compared to placebo was seen in the CDR-SB (LS mean difference 0.6 units, d = 0.41, p = 0.09) and Neuropsychological Test Battery (NTB; LS mean difference 1.8 units, d = 0.26, p = 0.48) but not ADCOMS or ADAS-Cog14. Conclusions: This trial demonstrates that elevated plasma pTau181 identifies participants more likely to have progressive AD and is a suitable method for enrichment in AD clinical trials. Xanamem treatment showed evidence of potential clinically meaningful benefits. [ABSTRACT FROM AUTHOR]

Background: The NIA-AA Research Framework on Alzheimer's disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS). Objective: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals. Methods: We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed. Results: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42/ptau181 ratio compared to those with neither SCD nor OBJ. Conclusions: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology. [ABSTRACT FROM AUTHOR]

Background: Although Lumipulse assays and conventional ELISA are strongly correlated, the precise relationship between their measured values remains undetermined. Objective: To determine the relationship between Lumipulse and ELISA measurement values. Methods: Patients who underwent cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker measurements and consented to biobanking between December 2021 and June 2023 were included. The relationship between values measured via Lumipulse assays and conventional ELISA were evaluated by Passing-Bablok analyses for amyloid-β 1-42 (Aβ42), total tau (t-tau), and phospho-tau 181 (p-tau 181). Studies using both assays were systematically searched for in PubMed and summarized after quality assessment. Results: Regression line slopes and intercepts were 1.41 (1.23 to 1.60) and –77.8 (–198.4 to 44.5) for Aβ42, 0.94 (0.88 to 1.01) and 98.2 (76.9 to 114.4) for t-tau, and 1.60 (1.43 to 1.75) and –21.1 (–26.9 to –15.6) for p-tau181. Spearman's correlation coefficients were 0.90, 0.95, and 0.95 for Aβ42, t-tau, and p-tau181, respectively. We identified 13 other studies that included 2,117 patients in total. Aβ42 slope varied among studies, suggesting inter-lab difference of ELISA. The slope and intercept of t-tau were approximately 1 and 0, respectively, suggesting small proportional and systematic differences. Conversely, the p-tau181 slope was significantly higher than 1, distributed between 1.5–2 in most studies, with intercepts significantly lower than 0, suggesting proportional and systematic differences. Conclusions: We characterized different relationship between measurement values for each biomarker, which may be useful for understanding the differences in CSF biomarker measurement values on different platforms and for future global harmonization. [ABSTRACT FROM AUTHOR]

Three recent anti-amyloid-β antibody trials for Alzheimer's disease reported similar effect sizes, used non-reactive saline as placebo, and showed large numbers of adverse events including imaging anomalies (ARIA) that correlate with cognitive changes. Conversely, all previous antibody trials were less reactive and pronounced ineffective. We argue that these observations point to unblinding bias, inflating apparent efficacy and thus altering the risk-benefit balance. Further, we highlight data demonstrating that beyond reducing amyloid, monoclonal antibodies increase monomeric amyloid-β42 in cerebrospinal fluid, which may explain potential benefits. We should recalibrate the efficacy of these antibodies and devote more resources into strategies beyond removing amyloid. [ABSTRACT FROM AUTHOR]

Three recent anti-amyloid-β antibody trials for Alzheimer's disease reported similar effect sizes, used non-reactive saline as placebo, and showed large numbers of adverse events including imaging anomalies (ARIA) that correlate with cognitive changes. Conversely, all previous antibody trials were less reactive and pronounced ineffective. We argue that these observations point to unblinding bias, inflating apparent efficacy and thus altering the risk-benefit balance. Further, we highlight data demonstrating that beyond reducing amyloid, monoclonal antibodies increase monomeric amyloid-β42 in cerebrospinal fluid, which may explain potential benefits. We should recalibrate the efficacy of these antibodies and devote more resources into strategies beyond removing amyloid. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a complicated condition involving multiple metabolic and immunologic pathophysiological processes that can occur with the hallmark pathologies of amyloid-β, tau, and neurodegeneration. Metformin, an anti-diabetes drug, targets several of these disease processes in in vitro and animal studies. However, the effects of metformin on human cerebrospinal fluid (CSF) and plasma proteins as potential biomarkers of treatment remain unexplored. Objective: Using proteomics data from a metformin clinical trial, identify the impact of metformin on plasma and CSF proteins. Methods: We analyzed plasma and CSF proteomics data collected previously (ClinicalTrials.gov identifier: NCT01965756, conducted between 2013 and 2015), and conduced bioinformatics analyses to compare the plasma and CSF protein levels after 8 weeks of metformin or placebo use to their baseline levels in 20 non-diabetic patients with mild cognitive impairment (MCI) and positive AD biomarkers participants. Results: 50 proteins were significantly (unadjusted p < 0.05) altered in plasma and 26 in CSF after 8 weeks of metformin use, with 7 proteins in common (AZU1, CASP-3, CCL11, CCL20, IL32, PRTN3, and REG1A). The correlation between changes in plasma and CSF levels of these 7 proteins after metformin use relative to baseline levels was high (r = 0.98). The proteins also demonstrated temporal stability. Conclusions: Our pilot study is the first to investigate the effect of metformin on plasma and CSF proteins in non-diabetic patients with MCI and positive AD biomarkers and identifies several candidate plasma biomarkers for future clinical trials after confirmatory studies. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common type of dementia, causing a huge socioeconomic burden. In parallel with the widespread uptake of single-cell RNA sequencing (scRNA-seq) technology, there has been a rapid accumulation of data produced by researching AD at single-cell resolution, which is more conductive to explore the neuroimmune-related mechanism of AD. Objective: To explore the potential features of T cells in the peripheral blood and cerebrospinal fluid of AD patients. Methods: Two datasets, GSE181279 and GSE134578, were integrated from GEO database. Seurat, Monocle, CellChat, scRepertoire, and singleR packages were mainly employed for data analysis. Results: Our analysis demonstrated that in peripheral blood, T cells were significantly expanded, and these expanded T cells were possessed effector function, such as CD8+TEMRA, CD4+TEMRA, and CD8+TEM. Interestingly, CD8+TEMRA and CD4+TEMRA cells positioned adjacently after dimensions reduction and clustering. Notably, we identified that the expanded T cells were developed from Naïve T cells and TCM cells, and TEM cells was in the intermediate state of this developing process. Additionally, in cerebrospinal fluid of AD patients, the amplified T cells were mainly CD8+TEMRA cells, and the number and strength of communication between CD4+TEM, CD8+TEM, and CD8+TEMRA were decreased in AD patients. Conclusions: Our comprehensive analyses identified the cells in cerebrospinal fluid from AD patients are expanded TEMRA or TEM cells and the TEMRA cells communicating with other immune cells is weakened, which may be an important immune feature that leads to AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disease that imposes economic and societal burden. Biomarkers have played a crucial role in the recent approval of aducanumab and lecanemab as disease-modifying therapies which marked a significant milestone for the treatment of AD. The inclusion of biomarkers in AD trials facilitates precise diagnosis, monitors safety, demonstrates target engagement, and supports disease modification. Objective: This study analyzed the utilization state and trends of biomarkers as endpoints in AD trials. Methods: In this retrospective study, trials were collected by searching clinicaltrials.gov using the term "Alzheimer". Primary and secondary outcomes were analyzed separately for each phase. Results: Among the 1,048 analyzed trials, 313 (29.87%) adopted biomarkers as primary endpoints and 364 (34.73%) as secondary endpoints, mainly in phases 1 and 2. The top three biomarkers adopted as primary endpoints in phases 1, 2, and 3 were amyloid-PET, tau-PET, and MRI. The top three biomarkers adopted as secondary endpoints, in phase 1, were cerebrospinal fluid (CSF) amyloid-β (Aβ), blood Aβ and amyloid-PET; in phase 2, they were MRI, CSF Aβ, and CSF phospho-tau; and in phase 3, they were amyloid PET, MRI, and blood Aβ. There was a statistically significant increase in the adoption of biomarkers as primary endpoints in phase 2 trials (p = 0.001) and secondary endpoints in phase 3 trials (p = 0.001). Conclusions: The growing recognition of the importance of biomarkers in AD trial' design and drug development is evident by the significant steady increase in biomarkers' utilization in phases 2 and 3. [ABSTRACT FROM AUTHOR]

Background: Longitudinal magnetic resonance imaging (MRI) has been proposed for tracking the progression of Alzheimer's disease (AD) through the assessment of brain atrophy. Objective: Detection of brain atrophy patterns in patients with AD as the longitudinal disease tracker. Methods: We used a refined version of orthonormal projective non-negative matrix factorization (OPNMF) to identify six distinct spatial components of voxel-wise volume loss in the brains of 83 subjects with AD from the ADNI3 cohort relative to healthy young controls from the ABIDE study. We extracted non-negative coefficients representing subject-specific quantitative measures of regional atrophy. Coefficients of brain atrophy were compared to subjects with mild cognitive impairment and controls, to investigate the cross-sectional and longitudinal associations between AD biomarkers and regional atrophy severity in different groups. We further validated our results in an independent dataset from ADNI2. Results: The six non-overlapping atrophy components represent symmetric gray matter volume loss primarily in frontal, temporal, parietal and cerebellar regions. Atrophy in these regions was highly correlated with cognition both cross-sectionally and longitudinally, with medial temporal atrophy showing the strongest correlations. Subjects with elevated CSF levels of TAU and PTAU and lower baseline CSF Aβ42 values, demonstrated a tendency toward a more rapid increase of atrophy. Conclusions: The present study has applied a transferable method to characterize the imaging changes associated with AD through six spatially distinct atrophy components and correlated these atrophy patterns with cognitive changes and CSF biomarkers cross-sectionally and longitudinally, which may help us better understand the underlying pathology of AD. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) or blood biomarkers like phosphorylated tau proteins (p-tau) are used to detect Alzheimer's disease (AD) early. Increasing studies on cognitive function and blood or CSF p-tau levels are controversial. Objective: Our study examined the potential of p-tau as a biomarker of cognitive status in normal control (NC), mild cognitive impairment (MCI), and AD patients. Methods: We searched PubMed, Cochrane, Embase, and Web of Science for relevant material through 12 January 2023. 5,017 participants from 20 studies—1,033 AD, 2,077 MCI, and 1,907 NC—were evaluated. Quantitative analysis provided continuous outcomes as SMDs with 95% CIs. Begg tested publication bias. Results: MCI patients had lower CSF p-tau181 levels than AD patients (SMD =−0.60, 95% CI (−0.85, −0.36)) but higher than healthy controls (SMD = 0.67). AD/MCI patients had greater plasma p-tau181 levels than healthy people (SMD =−0.73, 95% CI (−1.04, −0.43)). MCI patients had significantly lower p-tau231 levels than AD patients in plasma and CSF (SMD =−0.90, 95% CI (−0.82, −0.45)). MCI patients showed greater CSF and plasma p-tau231 than healthy controls (SMD = 1.34, 95% CI (0.89, 1.79) and 0.43, (0.23, 0.64)). Plasma p-tau181/231 levels also distinguished the three categories. MCI patients had higher levels than healthy people, while AD patients had higher levels than MCI patients. Conclusions: CSF p-tau181 and p-tau231 biomarkers distinguished AD, MCI, and healthy populations. Plasma-based p-tau181 and p-tau231 biomarkers for AD and MCI need further study. [ABSTRACT FROM AUTHOR]

Background: Cerebral microbleeds (CMB) play an important role in neurodegenerative pathology. Objective: The present study aims to test whether cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) level is linked to CMBs in elderly people. Methods: A total of 750 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had measurements of GAP-43 and CMBs were included in the study. According to the presence and extent of CMBs, participants were stratified into different groups. Regression analyses were used to assess cross-sectional and longitudinal associations between GAP-43 and CMBs. Results: Participants with CMB were slightly older and had higher concentrations of CSF GAP43. In multivariable adjusted analyses for age, gender, APOEɛ4 status, and cognitive diagnoses, higher CSF GAP-43 concentrations were modestly associated with CMB presence (OR = 1.169, 95% CI = 1.001–1.365) and number (β= 0.020, SE = 0.009, p = 0.027). Similarly, higher CSF GAP43 concentrations were accrual of CMB lesions, associated with higher CMB progression (OR = 1.231, 95% CI = 1.044–1.448) and number (β= 0.017, SE = 0.005, p = 0.001) in the follow up scan. In stratified analyses, slightly stronger associations were noted in male participants, those 65 years and older, carriers of APOEɛ4 alleles, and with more advanced cognitive disorders. Conclusions: CSF GAP-43 was cross-sectionally associated with the presence and extent of CMBs. GAP-43 might be used as a biomarker to track the dynamic changes of CMBs in elderly persons. [ABSTRACT FROM AUTHOR]

We analyzed Lewy body (LB) pathology in 18 autosomal dominant Alzheimer's disease (ADAD) brains via immunohistochemistry. Real-time quaking induced conversion was used to detect misfolded α-synuclein (α-syn) in 18 living ADAD cerebrospinal fluid (CSF) samples. Concomitant LB pathology was present in 44% ADAD brains. Only 6% CSF samples were positive for misfolded α-syn. In an additional AD sample, all patients with confirmed LB presented misfolded α-syn in postmortem CSF regardless of the LB staging. In conclusion, misfolded α-syn in CSF was scarce in symptomatic living ADAD individuals, in contrast to postmortem brain tissue. These results suggest late appearance of LB pathology in ADAD. [ABSTRACT FROM AUTHOR]

Background: Although cerebrospinal fluid (CSF) amyloid-β42 peptide (Aβ42) and phosphorylated tau (p-tau) and blood p-tau are valuable for differential diagnosis of Alzheimer's disease (AD) from cognitively normal (CN) there is a lack of validated biomarkers for mild cognitive impairment (MCI). Objective: This study sought to determine how plasma and CSF protein markers compared in the characterization of MCI and AD status. Methods: This cohort study included Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 75 proteins measured commonly in plasma and CSF (257 total, 46 CN, 143 MCI, and 68 AD). Logistic regression, least absolute shrinkage and selection operator (LASSO) and Random Forest (RF) methods were used to identify the protein candidates for the disease classification. Results: We observed that six plasma proteins panel (APOE, AMBP, C3, IL16, IGFBP2, APOD) outperformed the seven CSF proteins panel (VEGFA, HGF, PRL, FABP3, FGF4, CD40, RETN) as well as AD markers (CSF p-tau and Aβ42) to distinguish the MCI from AD [area under the curve (AUC) = 0.75 (plasma proteins), AUC = 0.60 (CSF proteins) and AUC = 0.56 (CSF p-tau and Aβ42)]. Also, these six plasma proteins performed better than the CSF proteins and were in line with CSF p-tau and Aβ42 in differentiating CN versus MCI subjects [AUC = 0.89 (plasma proteins), AUC = 0.85 (CSF proteins) and AUC = 0.89 (CSF p-tau and Aβ42)]. These results were adjusted for age, sex, education, and APOEϵ4 genotype. Conclusions: This study suggests that the combination of 6 plasma proteins can serve as an effective marker for differentiating MCI from AD and CN. [ABSTRACT FROM AUTHOR]

Background: Blood-brain barrier (BBB) dysfunction could favor the pathogenesis and progression of Alzheimer's disease (AD). Vascular risk factors (VRF) could worsen BBB integrity, thus promoting neurode generation. Objective: To investigate BBB permeability and its relation with VRF along the AD continuum (ADc). Cerebrospinal fluid (CSF) Amyloid (A) and p-tau (T) levels were used to stratify patients. Methods: We compared CSF/plasma albumin ratio (QAlb) of 131 AD patients and 24 healthy controls (HC). APOE genotype and VRF were evaluated for each patient. Spearman's Rho correlation was used to investigate the associations between Qalb and CSF AD biomarkers. Multivariate regression analyses were conducted to explore the relationship between Qalb and AD biomarkers, sex, age, cognitive status, and VRF. Results: QAlb levels did not show significant difference between ADc patients and HC (p = 0.984). However, QAlb was significantly higher in A + T–compared to A + T+ (p = 0.021). In ADc, CSF p-tau demonstrated an inverse correlation with QAlb, a finding confirmed in APOE4 carriers (p = 0.002), but not in APOE3. Furthermore, in APOE4 carriers, sex, hypertension, and hypercholesterolemia were associated with QAlb (p = 0.004, p = 0.038, p = 0.038, respectively), whereas only sex showed an association in APOE3 carriers (p = 0.026). Conclusions: BBB integrity is preserved in ADc. Among AT categories, A + T–have a more permeable BBB than A + T+. In APOE4 carriers, CSF p-tau levels display an inverse association with BBB permeability, which in turn, seems to be affected by VRF. These data suggest a possible relationship between BBB efficiency, VRF and CSF p-tau levels depending on APOE genotype. [ABSTRACT FROM AUTHOR]

Background: The associations between neuropsychiatric symptoms (NPSs) and Alzheimer's disease (AD) have been well-studied, yet gaps remain. Objective: We aimed to examine the associations of four subsyndromes (hyperactivity, psychosis, affective symptoms, and apathy) of NPSs with cognition, neurodegeneration, and AD pathologies. Methods: Totally 1,040 non-demented elderly (48.07% males) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. We assessed the relationships between NPSs and AD neuropathologies, cognition, neurodegeneration, and clinical correlates in cross-sectional and longitudinal via multiple linear regression, linear mixed effects, and Cox proportional hazard models. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition and neurodegeneration. Results: We found that individuals with hyperactivity, psychosis, affective symptoms, or apathy displayed a poorer cognitive status, a lower CSF amyloid-β (Aβ) level and a higher risk of clinical conversion (p < 0.05). Hyperactivity and affective symptoms were associated with increasing cerebral Aβ deposition (p < 0.05). Except psychosis, the other three subsyndromes accompanied with faster atrophy of hippocampal volume (p < 0.05). Specific NPSs were predominantly associated with different cognitive domains decline through an 8-year follow-up (p < 0.05). Moreover, the relationships between NPSs and cognitive decline, neurodegeneration might be associated with Aβ, the mediation percentage varied from 6.05% to 17.51% (p < 0.05). Conclusions: NPSs could be strongly associated with AD. The influences of NPSs on cognitive impairments, neurodegeneration might be partially associated with Aβ. [ABSTRACT FROM AUTHOR]

Background: Although the concordance between cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers and amyloid-PET findings is well known, there are no data regarding the concordance of amyloid-PET with inconclusive CSF values of amyloid-β (Aβ)1 - 42 and p-tau for the diagnosis of AD. Objective: To investigate the relationship between the amyloid-PET results with discordant AD biomarkers values in CSF (Aβ1 - 42+/p-tau–or Aβ1 - 42–/p-tau+). Methods: An observational retrospective study, including 62 patients with mild cognitive impairment (32/62) or dementia (30/62), suspicious of AD who had undergone a lumbar puncture to determine CSF AD biomarkers, and presented discordant values in CSF between Aβ1 - 42 and p-tau (Aβ1 - 42+/p-tau–or Aβ1 - 42–/p-tau+). All of them, underwent an amyloid-PET with 18F-Florbetaben. An extensive neuropsychological testing as part of their diagnostic process (MMSE and TMA-93), was performed, and it was also obtained the Global Deterioration Scale. Results: Comparing the discordant CSF results of each patient with the cerebral amyloid-PET results, we found that in the group with Aβ1 - 42+ and p-tau–CSF values, the amyloid-PET was positive in 51.2% and negative in 48.8% of patients, while in the group with Aβ1 - 42–and p-Tau+ CSF values, the amyloid-PET was positive in 52.6% of patients and negative in 47.4% of them. No significant association was found (p = 0.951) between the results of amyloid-PET and the two divergent groups in CSF. Conclusions: No significant relationship was observed between the results of discordant AD biomarkers in CSF and the result of amyloid-PET. No trend in amyloid-PET results was observed in relation to CSF biomarker values. [ABSTRACT FROM AUTHOR]

Background: Recent genetic research identified a protective factor against late-onset Alzheimer's disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. Objective: We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer's Disease Neuroimaging Initiative database (ADNI). Methods: A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ɛ4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. Results: We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aβ levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. Conclusion: Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments. [ABSTRACT FROM AUTHOR]

Background: The APOE genotype has emerged as the major genetic factor for AD but differs among different alleles. Objective: To investigate the discrepant effects of APOE genotype on AD cerebrospinal fluid (CSF) biomarkers. Methods: A total of 989 non-demented ADNI participants were included. The associations of APOEɛ2 and APOEɛ4 with CSF biomarkers were investigated using linear regression models. Interaction and subgroup analyses were used to investigate the effects of sex and age on these associations. Furthermore, we used mediation analyses to assess whether Aβ mediated the associations between APOE genotypes and tau. Results: APOEɛ2 carriers only showed higher Aβ levels (β [95% CI] = 0.07 [0.01, 0.13], p = 0.026). Conversely, APOEɛ4 carriers exhibited lower Aβ concentration (β [95% CI] = –0.27 [–0.31, –0.24], p < 0.001), higher t-Tau (β [95% CI] = 0.25 [0.08, 0.18], p < 0.001) and higher p-Tau (β [95% CI] = 0.31 [0.25, 0.37], p < 0.001). Subgroup analysis showed that APOE ɛ2 was significantly positively associated with Aβ only in females (β [95% CI] = 0.12 [0.04, 0.21], p = 0.005) and older people (β [95% CI] = 0.06 [0.001, 0.12], p = 0.048). But the effects of APOE ɛ4 were independent of gender and age. Besides, the associations of APOE ɛ4 with t-Tau and p-Tau were both mediated by baseline Aβ. Conclusions: Our data suggested that APOEɛ2 could promote Aβ clearance, while the process could be modified by sex and age. However, APOEɛ4 might cause the accumulation of Aβ and tau pathology independent of sex and age. [ABSTRACT FROM AUTHOR]

Background: The subcortical small vessel type of dementia (SSVD) is a common subtype of vascular dementia, but there is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers. Objective: We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid-β protein precursor α (sAβPPα), sAβPPβ, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer's disease (AD), and mixed dementia (combined AD and SSVD). Methods: This was a mono-center study of patients with SSVD (n = 38), AD (n = 121), mixed dementia (n = 62), and controls (n = 96). The CSF biomarkers were measured using immunoassays, and their independent contribution to the separation between groups were evaluated using the Wald test. Then, the area under the receiver operating characteristics curve (AUROC) and 95% confidence intervals (CIs) were calculated. Results: Elevated neurofilament light chain (NFL) and decreased sAβPPβ independently separated SSVD from controls, and sAβPPβ also distinguished SSVD from AD and mixed dementia. The combination of NFL and sAβPPβ discriminated SSVD from controls with high accuracy (AUROC 0.903, 95% CI: 0.834–0.972). Additionally, sAβPPβ combined with the core AD biomarkers (amyloid-β42, total tau, and phosphorylated tau181) had a high ability to separate SSVD from AD (AUROC 0.886, 95% CI: 0.830–0.942) and mixed dementia (AUROC 0.903, 95% CI: 0.838–0.968). Conclusions: The high accuracy of NFL and sAβPPβ to separate SSVD from controls supports that SSVD is a specific diagnostic entity. Moreover, SSVD was distinguished from AD and mixed dementia using sAβPPβ in combination with the core AD biomarkers. [ABSTRACT FROM AUTHOR]

Background: Accumulation of amyloid-β (Aβ) plaques is one of the main features of Alzheimer's disease (AD). Physical performance has been related to dementia risk and Aβ, and it has been hypothesized as one of the mechanisms leading to greater accumulation of Aβ. Yet, no evidence synthesis has been performed in humans. Objective: To investigate the association of physical performance with Aβ in humans, including Aβ accumulation on brain, and Aβ abnormalities measured in cerebrospinal fluid (CSF) and blood. Methods: A systematic review with multilevel meta-analysis was performed from inception to June 16th, 2022. Studies were eligible if they examined the association of physical performance with Aβ levels, including the measure of physical performance as a predictor and the measure of Aβ as an outcome in humans. Results: 7 articles including 2,619 participants were included in the meta-analysis. The results showed that physical performance was not associated with accumulation of Aβ in the brain (ES = 0.01; 95% CI –0.21 to 0.24; I2 = 69.9%), in the CSF (ES = –0.28; 95% CI –0.98 to 0.41; I2 = 91.0%) or in the blood (ES = –0.19; 95% CI –0.61 to 0.24; I2 = 99.75%). Significant heterogeneity was found across the results , which posed challenges in arriving at consistent conclusions; and the limited number of studies hindered the opportunity to conduct a moderation analysis. Conclusions: The association between physical performance and Aβ is inconclusive. This uncertainly arises from the limited number of studies, study design limitations, and heterogeneity of measurement approaches. More studies are needed to determine whether physical performance is related to Aβ levels in humans. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) carry an increased risk of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). There is a need to understand how to integrate NPS into the paradigm outlined in the 2018 NIA-AA Research Framework. Objective: To evaluate a prediction model of MCI-AD progression using a collection of variables, including NPS, cognitive testing, apolipoprotein E4 status (APOE4), imaging and laboratory AD biomarkers. Methods: Of 300 elderly subjects, 219 had stable MCI and 81 MCI-AD progression over a 5-year follow-up. NPS were measured using the Neuropsychiatric Inventory (NPI). A multivariate Cox Proportional Hazards Regression Analysis assessed the effects of APOE4, baseline NPI, baseline CSF amyloid-β, phosphorylated and total tau, baseline AD-signature MRI biomarker, baseline memory and executive function on MCI-AD progression. Results: 27% progressed to dementia (median follow-up = 43 months). NPS were found in stable MCI (62.6%) and MCI-AD converters (70.3%). The Cox model exhibited a good fit (p < 0.001), and NPS (HR = 1.033, p = 0.027), phosphorylated tau (HR = 1.011, p = 0.025), total tau (HR = 1.005, p = 0.024), AD-signature MRI biomarker (HR = 0.111, p = 0.002), executive function (HR = 0.727, p = 0.045), and memory performance (HR = 0.387, p < 0.001) were significantly associated with dementia. Conclusions: NPS may inform dementia risk assessment in conjunction with cognitive testing and imaging and laboratory AD biomarkers. NPS is independently associated with the risk of MCI-dementia progression, over and beyond the contributions of CSF biomarkers. [ABSTRACT FROM AUTHOR]

Background: The cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 217 (p217tau) or 181 (p181tau), and neurofilament light chain (NfL) are definite biomarkers of tauopathy and neurodegeneration in Alzheimer's disease (AD). Objective: To validate their utility in excluding other neurological diseases and age-related changes in clinical settings. Methods: We developed monoclonal antibodies against p217tau and NfL, established novel ELISAs, and analyzed 170 CSF samples from patients with AD or other neurological diseases. Results: In AD, p217tau is a more specific and abundant CSF component than p181tau. However, CSF NfL levels increase age-dependently and to a greater extent in central and peripheral nervous diseases than in AD. Conclusions: CSF p217tau correlates better with AD neurodegeneration than other tau-related biomarkers and the major phosphorylated tau species. The clinical usage of NfL as a neurodegeneration biomarker in AD requires exclusion of various central and peripheral neurological diseases. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is considered a prodromal state of dementia. Abnormal values of cerebrospinal fluid Alzheimer's disease biomarkers (CSF-AD-b) have been associated with a higher risk of conversion to dementia (due to Alzheimer's disease), but studies evaluating the ability of Montreal Cognitive Assessment (MoCA) in this task are lacking. Objective: This study aims to investigate the relationship between MoCA and CSF-AD-b, as well as the ability of those tools to predict conversion to dementia. Methods: Taking advantage of our MCI cohort with biological characterization on longitudinal follow-up (180 patients followed for 62.6 months during which 41.3% converted), we computed MoCA and MMSE z-scores, using Portuguese normative data. The performance in MoCA z-score was correlated with CSF-AD-b and the relative time to conversion and risk according to baseline characteristics were analyzed using Kaplan-Meier analysis and Cox regression models. Results: MoCA z-scores were correlated with Aβ42 (p = 0.026), t-tau (p = 0.033), and p-tau (p = 0.01). Impaired MMSE (p < 0.001) and MoCA z-scores (p = 0.019), decreased Aβ42 (p < 0.001) and increased t-tau (p < 0.001) and p-tau (p < 0.001) were associated with shorter estimated time of conversion. Aβ42 (p < 0.001) and MMSE z-scores (p = 0.029) were independent predictors of conversion. For those with at least 9 years of education, MoCA z-score (p = 0.004) (but not MMSE) was an independent predictor of conversion as well as Aβ42. Conclusions: This study confirms the role of CSF-AD-b, namely Aβ42, in predicting conversion from MCI to dementia and suggests the utility of MoCA in predicting conversion in highly educated subjects, supporting its use in the evaluation of MCI patients. [ABSTRACT FROM AUTHOR]

Background: Single photon emission tomography (SPECT) can detect early changes in brain perfusion to support the diagnosis of dementia. Inflammation is a driver for dementia progression and measures of inflammation may further support dementia diagnosis. Objective: In this study, we assessed whether combining imaging with markers of inflammation improves prediction of the likelihood of Alzheimer's disease (AD). Methods: We analyzed 91 participants datasets (Institutional Ethics Approval 20/NW/0222). AD biomarkers and markers of inflammation were measured in cerebrospinal fluid. Statistical parametric mapping was used to quantify brain perfusion differences in perfusion SPECT images. Logistic regression models were trained to evaluate the ability of imaging and inflammation markers, both individually and combined, to predict AD. Results: Regional perfusion reduction in the precuneus and medial temporal regions predicted Aβ42 status. Increase in inflammation markers predicted tau and neurodegeneration. Matrix metalloproteneinase-10, a marker of blood-brain barrier regulation, was associated with perfusion reduction in the right temporal lobe. Adenosine deaminase, an enzyme involved in sleep homeostasis and inflammation, was the strongest predictor of neurodegeneration with an odds ratio of 10.3. The area under the receiver operator characteristic curve for the logistic regression model was 0.76 for imaging and 0.76 for inflammation. Combining inflammation and imaging markers yielded an area under the curve of 0.85. Conclusions: Study results showed that markers of brain perfusion imaging and markers of inflammation provide complementary information in AD evaluation. Inflammation markers better predict tau status while perfusion imaging measures represent amyloid status. Combining imaging and inflammation improves AD prediction. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common type of dementia, affecting individuals over 65. AD is also a multifactorial disease, with disease mechanisms incompletely characterized, and disease-modifying therapies are marginally effective. Biomarker signatures may shed light on the diagnosis, disease mechanisms, and the development of therapeutic targets. tRNA-derived RNA fragments (tRFs), a family of recently discovered small non-coding RNAs, have been found to be significantly enhanced in human AD hippocampus tissues. However, whether tRFs change in body fluids is unknown. Objective: To investigate whether tRFs in body fluids are impacted by AD. Methods: We first used T4 polynucleotide kinase-RNA-seq, a modified next-generation sequencing technique, to identify detectable tRFs in human cerebrospinal fluid and serum samples. The detectable tRFs were then compared in these fluids from control, AD, and mild cognitive impairment patients using tRF qRT-PCR. The stability of tRFs in serum was also investigated by checking the change in tRFs in response to protein digestion or exosome lysis. Results: Among various tRFs, tRF5-ProAGG seemed to be impacted by AD in both cerebrospinal fluid and serum. AD-impacted serum tRF5-ProAGG showed a correlation with the AD stage. Putative targets of tRF5-ProAGG in the hippocampus were also predicted by a computational algorithm, with some targets being validated experimentally and one of them being in a negative correlation with tRF5-ProAGG even using a small size of samples. Conclusions: tRF5-ProAGG showed the potential as an AD biomarker and may play a role in disease progression. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have shown that the complement system plays an important role in Alzheimer's disease (AD). However, whether complement 4 (C4) protein in cerebrospinal fluid (CSF) was associated with AD pathology, especially in the early stage of AD, is still unclear. Objective: We aimed to explore the association of CSF C4 with AD pathology and cognition in the preclinical AD. Methods: The study included a total of 287 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Based on the A/T scheme, they were divided into four groups to access the changes of CSF C4 in the preclinical AD. Linear regression models were used to test the associations between CSF C4 and AD core biomarkers, namely Aβ42, P-tau, and T-tau. Results: The level of CSF C4 decreased in the A + T- group compared with the A-T- group (p = 0.04) and it increased in the A-T+ group compared to the A + T- group (p = 0.01). In pooled samples, C4 was significantly associated with AD core biomarkers (all p < 0.05), but only in the A + group after stratification according to the A/T scheme. Furthermore, CSF C4 levels at baseline were associated with longitudinal cognitive changes. Conclusions: Our results showed that CSF C4 levels changed dynamically in the preclinical AD, and that the responses of CSF C4 to brain Aβ pathology, tau pathology and neurodegeneration were found only in the presence of amyloid plaques, both of which indicates the complex link between C4 and AD. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are altered many years before the onset of clinical symptoms of mild cognitive impairment (MCI). Incorporating clinical symptom onset time into biomarker modeling may enhance our understanding of changes preceding MCI. Objective: Using a new analytical approach, we examined patterns of biomarker change prior to MCI symptom onset among individuals who progressed from normal cognition to MCI, stratified based on the age of symptom onset. We also analyzed biomarker patterns of change among participants who remained cognitively normal, and examined potential modifiers of biomarker trajectories, including demographics and apolipoprotein E (APOE) status. Methods: Analyses included 93 participants who progressed from normal cognition to MCI and 186 participants who remained cognitively normal, over an average follow-up period of 16.2 years. CSF biomarkers, including Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau181 (p-tau181), were measured using the fully automated Lumipulse assays. Results: Among participants who progressed to MCI, Aβ42/Aβ40 decreased, and t-tau and p-tau181 increased. For participants who did not progress to MCI, CSF biomarkers showed relatively stable patterns. In both progressors and non-progressors, APOE4 carriers showed lower Aβ 42/Aβ40 levels (compared to non-carriers) at each point of the mean curves. Among non-progressors, APOE4 carriers had higher levels of p-tau181, p-tau181/(Aβ 42/Aβ40), and t-tau/(Aβ 42/Aβ 40). Additionally, among those who did not progress, female sex was associated with higher levels of t-tau, p-tau181, t-tau/(Aβ 42/Aβ 40), and p-tau181/(Aβ 42/Aβ 40). Conclusions: These findings suggest that this analytic approach may provide additional insights into biomarker changes during early phases of AD. [ABSTRACT FROM AUTHOR]

Background: The established Erlangen Score (ES) for the interpretation of cerebrospinal fluid (CSF) biomarkers in the diagnostics of Alzheimer's disease (AD) uses markers of amyloidopathy and tauopathy, equally weighted to form an easy-interpretable ordinal scale. However, these biomarkers are not equally predictive for AD. Objective: The higher weighting of the Aβ42/Aβ40 ratio, as a reconceptualized ERlangen Score (ERS), was tested for advantages in diagnostic performance. Methods: Non-demented subjects (N = 154) with a mean follow up of 5 years were assigned to a group ranging from 0 to 4 in ES or ERS. Psychometric trajectories and dementia risk were assessed. Results: The distribution of subjects between ES and ERS among the groups differed considerably, as grouping allocated 32 subjects to ES group 2, but only 2 to ERS group 2. The discriminative accuracy between the ES (AUC 73.2%, 95% CI [64.2, 82.2]) and ERS (AUC 72.0%, 95% CI [63.1, 81.0]) for dementia risk showed no significant difference. Without consideration of the Aβ42/Aβ40 ratio in ES grouping, the optimal cut-off of the ES shifted to ≥2. Conclusions: The ERS showed advantages over the ES in test interpretation with comparable overall test performance, as fewer cases were allocated to the intermediate risk group. The established cut-off of ≥2 can be maintained for the ERS, whereas it must be adjusted for the ES when determining the Aβ42/Aβ40 ratio. [ABSTRACT FROM AUTHOR]

Concomitant Alzheimer's disease (AD) pathology can be observed in approximately 10–15% of cases with amyotrophic lateral sclerosis (ALS). ALS-AD patients have a higher prevalence of amnestic cognitive disturbances, which may often precede motor symptoms. Cerebrospinal fluid (CSF) AD core biomarkers usually show no or slightly significant changes in ALS, whereas blood phosphorylated tau protein might be increased independently from AD copathology. Neurofilament proteins are consistently elevated in CSF and blood of ALS, but have been poorly investigated in ALS-AD. All these issues should be taken into account when using fluid biomarkers as inclusion criteria or secondary endpoints in clinical trials. [ABSTRACT FROM AUTHOR]

Dementia is a chronic syndrome which is common among the elderly and is associated with significant morbidity and mortality for patients and their caregivers. Alzheimer's disease (AD), the most common form of clinical dementia, is biologically characterized by the deposition of amyloid-β plaques and neurofibrillary tangles in the brain. The onset of AD begins decades before manifestation of symptoms and clinical diagnosis, underlining the need to shift from clinical diagnosis of AD to a more objective diagnosis using biomarkers. Having performed a literature search of original articles and reviews on PubMed and Google Scholar, we present this review detailing the existing biomarkers and risk assessment tools for AD. The prevalence of dementia in low- and middle-income countries (LMICs) is predicted to increase over the next couple of years. Thus, we aimed to identify potential biomarkers that may be appropriate for use in LMICs, considering the following factors: sensitivity, specificity, invasiveness, and affordability of the biomarkers. We also explored risk assessment tools and the potential use of artificial intelligence/machine learning solutions for diagnosing, assessing risks, and monitoring the progression of AD in low-resource settings. Routine use of AD biomarkers has yet to gain sufficient ground in clinical settings. Therefore, clinical diagnosis of AD will remain the mainstay in LMICs for the foreseeable future. Efforts should be made towards the development of low-cost, easily administered risk assessment tools to identify individuals who are at risk of AD in the population. We recommend that stakeholders invest in education, research and development targeted towards effective risk assessment and management. [ABSTRACT FROM AUTHOR]

BackgroundKlotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease.ObjectiveTest whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer's disease risk factors.MethodsCirculating klotho was measured in serum (n = 1,116) and CSF (n = 183) of cognitively intact participants (aged 62.4 ± 6.5 years; 69.5% female). KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics.ResultsSerum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF.ConclusionIn a cohort enriched for risk for Alzheimer's disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health.

Serum light-chain neurofilaments (sNfL) have been investigated as a potential minimally invasive biomarker that could help in the diagnosis of patients with cognitive symptoms. We assessed the correlation between sNfL and cerebrospinal fluid (CSF) biomarkers (sNfL versus CSF NfL, ρ= 0.70, p < 0.001), the performance of sNfL in distinguishing controls from patients (controls versus frontotemporal dementia, area under curve 0.86), and sNfL differences in mild cognitive impairment according to amyloid-β (Aβ) deposition (Aβ versus non-Aβ, p = 0.017). Our results support the role of this biomarker in the screening and risk stratification of patients followed in a neurological consultation of a tertiary center. [ABSTRACT FROM AUTHOR]

Background: Conventional neuropsychological norms likely include cognitively unimpaired (CU) individuals with preclinical Alzheimer's disease (AD) pathology (amyloid-β, tau, and neurodegeneration) since they are based on cohorts without AD biomarkers data. Due to this limitation, population-based norms would lack sensitivity for detecting subtle cognitive decline due to AD, the transitional stage between healthy cognition and mild cognitive impairment. We have recently published norms for memory tests in individuals with normal cerebrospinal fluid (CSF) AD biomarker levels. Objective: The aim of the present study was to provide further AD biomarker-based cognitive references covering attentional, executive function, linguistic, and visual processing tests. Methods: We analyzed 248 CU individuals aged between 50–70 years old with normal CSF Aβ, p-tau, and neurodegeneration (t-tau) biomarker levels. The tests included were the Trail Making Test (TMT), Semantic Fluency Test, Digit and Symbol Span, Coding, Matrix Reasoning, Judgement of Line Orientation and Visual Puzzles. Normative data were developed based on regression models adjusted for age, education, and sex when needed. We present equations to calculate z-scores, the corresponding normative percentile tables, and online calculators. Results: Age, education, and sex were associated with performance in all tests, except education for the TMT-A, and sex for the TMT-B, Coding, and Semantic Fluency. Cut-offs derived from the current biomarker-based reference data were higher and more sensitive than standard norms. Conclusion: We developed reference data obtained from individuals with evidence of non-pathologic AD biomarker levels that may improve the objective characterization of subtle cognitive decline in preclinical AD. [ABSTRACT FROM AUTHOR]

Background: The medium term outcome (over more than one year) of epileptic prodromal AD (epAD) patients treated with antiseizure medications (ASMs) is unknown in terms of seizure response, treatment tolerability, and cognitive and functional progression. Objective: To describe such medium term outcome over a mean of 5.1±2.1 years. Methods: We retrospectively compared 19 epAD patients with 16 non-epileptic prodromal AD (nepAD) patients: 1) at baseline for demographics, medical history, cognitive fluctuations (CFs), psychotropic medications, MMSE scores, visually rated hippocampal atrophy, CSF neurodegenerative biomarkers, and standard EEG recordings; 2) during follow-up (FU) for psychotropic medications, MMSE progression, and conversion to dementia. In the epAD group, we analyzed baseline and FU types of seizures as well as each line of ASM with the corresponding efficacy and tolerability. Results: At baseline, the epAD group had more CFs than the nepAD group (58% versus 20%, p = 0.03); focal impaired awareness seizures were the most common type (n = 12, 63.1%), occurring at a monthly to quarterly frequency (89.5%), and were well controlled with monotherapy in 89.5% of cases (including 63.1% seizure-free individuals). During FU, treated epAD patients did not differ significantly from nepAD patients in MMSE progression or in conversion to dementia. Conclusion: Epilepsy is commonly controlled with ASMs over the medium term in epAD patients, with similar functional and cognitive outcomes to nepAD patients. Pathophysiologically, epilepsy is likely to be an ASM-modifiable cognitive aggravating factor at this stage of AD. [ABSTRACT FROM AUTHOR]

Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer's disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide and a frequent comorbidity in idiopathic normal pressure hydrocephalus (iNPH). The presence of AD pathology is associated with worse outcomes after a shunt procedure in iNPH. Preoperative diagnosis of AD is challenging in patients with iNPH, which involves reduced concentrations of the cerebrospinal fluid (CSF) AD biomarkers. Objective: Our aim was to estimate the effect size of iNPH as a factor in CSF levels of AD biomarkers and to test if correction could be used to improve diagnostic value. Methods: Our cohort included 222 iNPH patients with data in the Kuopio NPH registry and brain biopsy and CSF samples available. We divided the patients into groups according to AD pathology per brain biopsy. For control cohorts, we had CSF samples from cognitively healthy individuals (n = 33) and patients with diagnosed AD and no iNPH (n = 39). *-31pt Results: Levels of all investigated biomarkers differed significantly between groups, with the exception of t-Tau levels between healthy individuals and iNPH patients with AD pathology. Applying a correction factor for each biomarker (0.842*Aβ1 - 42, 0.779*t-Tau, and 0.610*P-Tau181) for the effect of iNPH yielded a sensitivity of 2.4% and specificity of 100%. The ratio of P-Tau181 to Aβ1 - 42 was moderately effective in aiding recognition of AD pathology in iNPH patients (sensitivity 0.79, specificity 0.76, area under the curve 0.824). Conclusion: Correcting for iNPH as a factor failed to improve diagnostic effectiveness, but the P-Tau181/Aβ1 - 42 ratio showed some utility in the diagnosis of AD in iNPH patients. [ABSTRACT FROM AUTHOR]

BackgroundAge-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer's disease (AD), although their interactive effects have yet to be fully examined.ObjectiveThe current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI).MethodsThis study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1-42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified.ResultsMultiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aβ42 (B = -1.01, p = 0.02); greater inflammation was associated with higher levels of Aβ42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s

Numerous studies have demonstrated defects in multiple metabolic pathways in Alzheimer's disease (AD), detected in autopsy brains and in the cerebrospinal fluid in vivo. However, until the advent of techniques capable of measuring thousands of metabolites in a single sample, it has not been possible to rank the relative magnitude of these abnormalities. A recent study provides evidence that the abnormal turnover of the brain's most abundant phospholipids: phosphatidylcholine and phosphatidylethanolamine, constitutes a major metabolic pathology in AD. We place this observation in a historical context and discuss the implications of a central role for phospholipid metabolism in AD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Differentiating dementia due to small vessel disease (SVD) from dementia due to Alzheimer's disease (AD) with concomitant SVD is challenging in clinical practice. Accurate and early diagnosis of AD is critical to delivering stratified patient care. Objective: We characterized the results of Elecsys® cerebrospinal fluid (CSF) immunoassays (Roche Diagnostics International Ltd) in patients with early AD, diagnosed using core clinical criteria, with varying extent of SVD. Methods: Frozen CSF samples (n = 84) were measured using Elecsys β-Amyloid(1–42) (Aβ42), Phospho-Tau (181P) (pTau181), and Total-Tau (tTau) CSF immunoassays, adapted for use on the cobas® e 411 analyzer (Roche Diagnostics International Ltd), and a robust prototype β-Amyloid(1–40) (Aβ40) CSF immunoassay. SVD was assessed by extent of white matter hyperintensities (WMH) using the lesion segmentation tool. Interrelations between WMH, biomarkers, fluorodeoxyglucose F18-positron emission tomography (FDG-PET), and other parameters (including age and Mini-Mental State examinations [MMSE]) were assessed using Spearman's correlation, sensitivity/specificity, and logistic/linear regression analyses. Results: The extent of WMH showed significant correlation with Aβ42/Aβ40 ratio (Rho=-0.250; p = 0.040), tTau (Rho = 0.292; p = 0.016), tTau/Aβ42 ratio (Rho = 0.247; p = 0.042), age (Rho = 0.373; p = 0.002), and MMSE (Rho=-0.410; p = 0.001). Sensitivity/specificity point estimates for Elecsys CSF immunoassays versus FDG-PET positivity for underlying AD pathophysiology were mostly comparable or greater in patients with high versus low WMH. WMH were not a significant predictor and did not interact with CSF biomarker positivity but modified the association between pTau181 and tTau. Conclusion: Elecsys CSF immunoassays detect AD pathophysiology regardless of concomitant SVD and may help to identify patients with early dementia with underlying AD pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative disease pathology is associated with neuroinflammation, but evidence on idiopathic normal pressure hydrocephalus (iNPH) remains limited and cerebrospinal fluid (CSF) biomarker profiles need to be elucidated. Objective: To investigate whether iNPH pathological mechanisms are associated with greater CSF markers of core Alzheimer's disease pathology (amyloid-β42 (Aβ42), phosphorylated tau (P-tau)), neurodegeneration (total tau (T-tau)), and neuroinflammation (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40)). Methods: The study analyzed lumbar CSF samples from 63 patients with iNPH and 20 age-matched orthopedic surgery patients who had no preoperative gait or cognitive impairment (control group). Aβ42, T-tau, P-tau, sTREM2, and YKL-40 in different subgroups were investigated. Results: CSF sTREM2 levels were significantly higher in the iNPH group than in the control group, but no significant between-group difference was noted in YKL-40. Moreover, YKL-40 levels were significantly higher in the tap test non-responders than in the tap test responders (p = 0.021). At the 1-year follow-up after shunt surgery, the CSF P-tau levels were significantly lower (p = 0.020) in those with gait improvement and the CSF sTREM2 levels were significantly lower (p = 0.041) in those with cognitive improvement. In subgroup analysis, CSF sTREM2 levels were strongly correlated with CSF YKL-40 in the iNPH group (r = 0.443, p < 0.001), especially in the tap test non-responders (r = 0.653, p = 0.002). Conclusion: YKL-40 and sTREM2 are disease-specific markers of neuroinflammation, showing higher CSF levels in iNPH. In addition, sTREM2 is positively associated with YKL-40, indicating that interactions of glial cells play an important role in iNPH pathogenesis. [ABSTRACT FROM AUTHOR]