DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain.

BACKGROUND: Plasma growth differentiation factor 15 (GDF15) and N-terminal proB-type natriuretic peptide (NT-proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. RESULTS: In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36-1.41, PFDR < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R2 range of 5.7-12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population. CONCLUSIONS: EpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.

A prediction model of dementia conversion for mild cognitive impairment by combining plasma pTau181 and structural imaging features.

AIMS: The early stages of Alzheimer's disease (AD) are no longer insurmountable. Therefore, identifying at-risk individuals is of great importance for precise treatment. We developed a model to predict cognitive deterioration in patients with mild cognitive impairment (MCI). METHODS: Based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we constructed models in a derivation cohort of 761 participants with MCI (138 of whom developed dementia at the 36th month) and verified them in a validation cohort of 353 cognitively normal controls (54 developed MCI and 19 developed dementia at the 36th month). In addition, 1303 participants with available AD cerebrospinal fluid core biomarkers were selected to clarify the ability of the model to predict AD core features. We assessed 32 parameters as candidate predictors, including clinical information, blood biomarkers, and structural imaging features, and used multivariable logistic regression analysis to develop our prediction model. RESULTS: Six independent variables of MCI deterioration were identified: apolipoprotein E ε4 allele status, lower Mini-Mental State Examination scores, higher levels of plasma pTau181, smaller volumes of the left hippocampus and right amygdala, and a thinner right inferior temporal cortex. We established an easy-to-use risk heat map and risk score based on these risk factors. The area under the curve (AUC) for both internal and external validations was close to 0.850. Furthermore, the AUC was above 0.800 in identifying participants with high brain amyloid-ß loads. Calibration plots demonstrated good agreement between the predicted probability and actual observations in the internal and external validations. CONCLUSION: We developed and validated an accurate prediction model for dementia conversion in patients with MCI. Simultaneously, the model predicts AD-specific pathological changes. We hope that this model will contribute to more precise clinical treatment and better healthcare resource allocation.

P-tau217 and other blood biomarkers of dementia: variation with time of day.

Plasma biomarkers of dementia, including phosphorylated tau (p-tau217), offer promise as tools for diagnosis, stratification for clinical trials, monitoring disease progression, and assessing the success of interventions in those living with Alzheimer's disease. However, currently, it is unknown whether these dementia biomarker levels vary with the time of day, which could have implications for their clinical value. In two protocols, we studied 38 participants (70.8 ± 7.6 years; mean ± SD) in a 27-h laboratory protocol with either two samples taken 12 h apart or 3-hourly blood sampling for 24 h in the presence of a sleep-wake cycle. The study population comprised people living with mild Alzheimer's disease (PLWA, n = 8), partners/caregivers of PLWA (n = 6) and cognitively intact older adults (n = 24). Single-molecule array technology was used to measure phosphorylated tau (p-tau217) (ALZpath), amyloid-beta 40 (Aß40), amyloid-beta 42 (Aß42), glial fibrillary acidic protein, and neurofilament light (NfL) (Neuro 4-Plex E). Analysis with a linear mixed model (SAS, PROC MIXED) revealed a significant effect of time of day for p-tau217, Aß40, Aß42, and NfL, and a significant effect of participant group for p-tau217. For p-tau217, the lowest levels were observed in the morning upon waking and the highest values in the afternoon/early evening. The magnitude of the diurnal variation for p-tau217 was similar to the reported increase in p-tau217 over one year in amyloid-ß-positive mild cognitively impaired people. Currently, the factors driving this diurnal variation are unknown and could be related to sleep, circadian mechanisms, activity, posture, or meals. Overall, this work implies that the time of day of sample collection may be relevant in the implementation and interpretation of plasma biomarkers in dementia research and care.

Causal Association between Circulating Metabolites and Dementia: A Mendelian Randomization Study.

The causal association of circulating metabolites with dementia remains uncertain. We assessed the causal association of circulating metabolites with dementia utilizing Mendelian randomization (MR) methods. We performed univariable MR analysis to evaluate the associations of 486 metabolites with dementia, Alzheimer's disease (AD), and vascular dementia (VaD) risk. For secondary validation, we replicated the analyses using an additional dataset with 123 metabolites. We observed 118 metabolites relevant to the risk of dementia, 59 of which were lipids, supporting the crucial role of lipids in dementia pathogenesis. After Bonferroni adjustment, we identified nine traits of HDL particles as potential causal mediators of dementia. Regarding dementia subtypes, protective effects were observed for epiandrosterone sulfate on AD (OR = 0.60, 95% CI: 0.48-0.75) and glycoproteins on VaD (OR = 0.89, 95% CI: 0.83-0.95). Bayesian model averaging MR (MR-BMA) analysis was further conducted to prioritize the predominant metabolites for dementia risk, which highlighted the mean diameter of HDL particles and the concentration of very large HDL particles as the predominant protective factors against dementia. Moreover, pathway analysis identified 17 significant and 2 shared metabolic pathways. These findings provide support for the identification of promising predictive biomarkers and therapeutic targets for dementia.

Serum Uric Acid Levels Associated with Outcomes of Neurodegenerative Disorders and Brain Health: Findings from the UK Biobank.

BACKGROUND: The relationship between serum uric acid (SUA) levels and brain-related health remains uncertain. OBJECTIVES: This study aimed to investigate the relationship between SUA levels and some neurodegenerative disorders and brain structure. DESIGN: A longitudinal study. SETTING AND PARTICIPANTS: 384,517 participants who did not have stroke, dementia, and Parkinsonism, with complete urate testes and covariates were included. MEASUREMENTS: Cox proportional hazards models, competing risk models, and restricted cubic spine models were applied. RESULTS: During the median follow-up time of 12.7 years (interquartile range [IQR]:12.0, 13.5), 7821 (2.0%) participants developed stroke, 5103 (1.3%) participants developed dementia, and 2341 (0.6%) participants developed Parkinsonism. Nonlinear relationships were identified between SUA levels and stroke (J-shaped), dementia, and Parkinsonism (U-shaped). SUA levels of 4.2 mg/dl, 6.4 mg/dl, and 6.6 mg/dl yielded the lowest risk of stroke, dementia, and Parkinsonism, respectively. Besides, we found high SUA levels reduced the volumes of total brain, grey matter, white matter, grey matter in the hippocampus, and hippocampus, but increased lateral-ventricle volume. Inflammation accounted for 9.1% and 10.0% in the association of SUA with stroke and lateral-ventricle volume. CONCLUSIONS: Lower SUA levels increased the risk of Parkinsonism, while both lower and higher SUA levels were positively associated with increased risk of stroke and dementia. Moreover, high SUA levels reduced brain structure volumes. Our findings suggest the association between SUA levels and brain-related disorders and highlight the importance of SUA management.

Association between glycemic status and all-cause mortality among individuals with dementia: a nationwide cohort study.

BACKGROUND: To examine the association between glycemic status and all-cause mortality risk among individuals with dementia. METHODS: We enrolled 146,832 individuals aged 40 and older with dementia as identified through the Korean National Health Insurance Service health screening test between 2008 and 2016. Mortality status was evaluated at the end of 2019. Participants were classified into normoglycemia, prediabetes, or diabetes mellitus (DM) categories. The duration of diabetes was noted in those with DM. This study focused on the association between glycemic status and all-cause mortality. RESULTS: The cohort, which was predominantly elderly (average age 75.1 years; 35.5% male), had a 35.2% mortality rate over an average 3.7-year follow-up. DM was linked with increased all-cause mortality risk (hazard ratio [HR] 1.34; 95% confidence interval [CI]: 1.32-1.37) compared to non-DM counterparts. The highest mortality risk was observed in long-term DM patients (≥ 5 years) (HR 1.43; 95% CI: 1.40-1.47), followed by newly diagnosed DM (HR 1.35; 95% CI: 1.30-1.40), shorter-term DM (< 5 years) (HR 1.17; 95% CI: 1.13-1.21), and prediabetes (HR 1.03; 95% CI: 1.01-1.05). These patterns persisted across Alzheimer's disease and vascular dementia, with more pronounced effects observed in younger patients. CONCLUSIONS: Glucose dysregulation in dementia significantly increased mortality risk, particularly in newly diagnosed or long-standing DM. These findings suggest the potential benefits of maintaining normal glycemic levels in improving the survival of patients with dementia.

Glycated Hemoglobin A1c Time in Range and Dementia in Older Adults With Diabetes.

Importance: Individuals with diabetes commonly experience Alzheimer disease and related dementias (ADRD). Factors such as hypoglycemia, hyperglycemia, and glycemic variability have been associated with increased risk of ADRD. Traditional glycemic measures, such as mean glycated hemoglobin A1c (HbA1c), may not identify the dynamic and complex pathophysiologic factors in the association between diabetes and ADRD. The HbA1c time in range (TIR) is a previously developed measure of glycemic control that expresses HbA1c stability over time within specific ranges. This measure may inform the current understanding of the association between glucose levels over time and ADRD incidence. Objective: To examine the association between HbA1c TIR and incidence of ADRD in older veterans with diabetes. Design, Setting, and Participants: The study sample for this cohort study was obtained from administrative and health care utilization data from the Veterans Health Administration and Medicare from January 1, 2004, to December 31, 2018. Veterans 65 years or older with diabetes were assessed. Participants were required to have at least 4 HbA1c tests during the 3-year baseline period, which could start between January 1, 2005, and December 31, 2014. Data analysis was conducted between July and December 2023. Main Outcomes and Measures: Hemoglobin A1c TIR was calculated as the percentage of days during baseline in which HbA1c was in individualized target ranges based on clinical characteristics and life expectancy, with higher HbA1c TIR viewed as more favorable. The association between HbA1c TIR and ADRD incidence was estimated. Additional models considered ADRD incidence in participants who were above or below HbA1c target ranges most of the time. Results: The study included 374 021 veterans with diabetes (mean [SD] age, 73.2 [5.8] years; 369 059 [99%] male). During follow-up of up to 10 years, 41 424 (11%) developed ADRD. Adjusted Cox proportional hazards regression models showed that lower HbA1c TIR was associated with increased risk of incident ADRD (HbA1c TIR of 0 to <20% compared with ≥80%: hazard ratio, 1.19; 95% CI, 1.16-1.23). Furthermore, the direction of out-of-range HbA1c levels was associated with incident ADRD. Having greater time below range (≥60%, compared with ≥60% TIR) was associated with significantly increased risk (hazard ratio, 1.23; 95% CI, 1.19-1.27). Findings remained significant after excluding individuals with baseline use of medications associated with hypoglycemia risk (ie, insulin and sulfonylureas) or with hypoglycemia events. Conclusions and Relevance: In this study of older adults with diabetes, increased HbA1c stability within patient-specific target ranges was associated with a lower risk of ADRD. Lower HbA1c TIR may identify patients at increased risk of ADRD.

Novel diagnostic and prognostic approach for rapidly progressive dementias: Indicators based on amyloid/tau/neurodegeneration (ATN) framework.

AIMS: Apply established cerebrospinal fluid (CSF) and serum biomarkers and novel combined indicators based on the amyloid/tau/neurodegeneration (ATN) framework to improve diagnostic and prognostic power in patients with rapidly progressive dementias (RPDs). METHODS: CSF and serum biomarkers of Alzheimer's disease (AD) common neuropathology including Aß42, Aß40, p-Tau, and t-Tau were measured in cognitively normal (CN) controls (n = 33) and three RPD groups with rapidly progressive AD (rpAD, n = 23), autoimmune encephalitis (AE, n = 25), and Creutzfeldt-Jakob disease (CJD, n = 28). Logistic regression and multiple linear regression were used for producing combined indicators and prognostic assessment, respectively, including A&T, A&N, T&N, A&T&N, etc. RESULTS: Combined diagnostic indicator with A&T&N had the potential for differentiating AE from other types of RPDs, identifying 62.51% and 75% of AE subjects based on CSF and serum samples, respectively, compared to 39.13% and 37.5% when using autoantibodies. CSF t-Tau was associated with survival in the CJD group (adjusted R-Square = 0.16, p = 0.02), and its prognosis value improved when using combined predictors based on the ATN framework (adjusted R-Square = 0.273, p = 0.014). CONCLUSION: Combined indicators based on the ATN framework provide a novel perspective for establishing biomarkers for early recognition of RPDs due to treatment-responsive causes.

HbA1c variability associated with dementia risk in people with type 2 diabetes.

INTRODUCTION: Although poor glycemic control is associated with dementia, it is unknown if variability in glycemic control, even in those with optimal glycosylated hemoglobin A1c (HbA1c) levels, increases dementia risk. METHODS: Among 171,964 people with type 2 diabetes, we evaluated the hazard of dementia association with long-term HbA1c variability using five operationalizations, including standard deviation (SD), adjusting for demographics and comorbidities. RESULTS: The mean baseline age was 61 years (48% women). Greater HbA1c SD was associated with greater dementia hazard (adjusted hazard ratio = 1.15 [95% confidence interval: 1.12, 1.17]). In stratified analyses, higher HbA1c SD quintiles were associated with greater dementia hazard among those with a mean HbA1c < 6% (P = 0.0004) or 6% to 8% (P < 0.0001) but not among those with mean HbA1c ≥ 8% (P = 0.42). DISCUSSION: Greater HbA1c variability is associated with greater dementia risk, even among those with HbA1c concentrations at ideal clinical targets. These findings add to the importance and clinical impact of recommendations to minimize glycemic variability. HIGHLIGHTS: We observed a cohort of 171,964 people with type 2 diabetes (mean age 61 years). This cohort was based in Northern California between 1996 and 2018. We examined the association between glycosylated hemoglobin A1c (HbA1c) variability and dementia risk. Greater HbA1c variability was associated with greater dementia hazard. This was most evident among those with normal-low mean HbA1c concentrations.

High-Sensitivity Troponin T, NT-proBNP, and Cognitive Outcomes in SPRINT.

BACKGROUND: Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who derive greater cognitive benefits from lower systolic blood pressure targets. METHODS: In the SPRINT (Systolic Blood Pressure Intervention Trial) MIND study, participants were categorized as having both hs-cTnT and NT-proBNP in the lower 2 tertiles (n=4226), one in the highest tertile (n=2379), and both in the highest tertile (n=1506). We assessed the effect of intensive versus standard treatment on the composite of mild cognitive impairment (MCI) or probable dementia (PD) across biomarker categories. RESULTS: Over a median follow-up of 5.1 years, 830 of 8111 participants (10.2%) developed MCI or PD. Participants in the highest biomarker category were at higher risk of MCI or PD compared with those in the lowest category (hazard ratio, 1.34 [95% CI, 1.00-1.56]). The effect of intensive treatment on reducing the risk of MCI or PD was greater among participants in the lowest biomarker category (hazard ratio, 0.64 [95% CI, 0.50-0.81]) than those in the intermediate (hazard ratio, 1.01 [95% CI, 0.80-1.28]) or highest categories (hazard ratio, 0.90 [95% CI, 0.72-1.13]; Pinteraction=0.02). The 5-year absolute risk differences in MCI or PD with intensive treatment were -2.9% (-4.4%, -1.3%), -0.2% (-3.0%, 2.6%), and -1.9% (-6.2%, 2.4%) in the lowest, intermediate, and highest biomarker categories, respectively. CONCLUSIONS: In SPRINT, the relative effect of intensive systolic blood pressure lowering on preventing cognitive impairment appears to be stronger among participants with lower compared with higher cardiac biomarker levels, though the absolute risk reductions were similar.

Malignant left ventricular hypertrophy and risk of cognitive impairment in SPRINT MIND trial.

BACKGROUND: The association of malignant left ventricular hypertrophy (LVH), a specific subphenotype of LVH characterized by elevated levels of high-sensitivity cardiac troponin (hs-cTnT) or N-terminal pro-B-type natriuretic peptide (NT-proBNP), with cognitive decline remains understudied. METHODS: This post-hoc analysis included a total of 8,027 (67.9 ± 9.3 years) SPRINT MIND trial participants who had with at least 1 follow-up cognitive assessment. Participants were classified into 6 groups on the basis of LVH status on electrocardiogram (ECG), and elevations in levels of hs-cTnT ≥14 ng/L or NT-proBNP ≥125 pg/mL at baseline visit. Multivariate Cox proportional hazard models were used to examine the association of LVH/biomarker groups with incident probable dementia, mild cognitive impairment (MCI) and a composite of MCI/probable dementia. RESULTS: Over a median follow-up period of 5 years, there were 306, 597, and 818 incidents of MCI, probable dementia and a composite of MCI/probable dementia, respectively. Compared with participants without LVH and normal biomarker levels, those with concomitant LVH and elevated levels of both biomarkers were associated with a higher risk of probable dementia (HR, 2.50; 95% CI (1.26-4.95), MCI (HR, 1.78; 95% CI (0.99-3.23) and the composite of MCI/ probable dementia (HR, 1.89; 95% CI, 1.16-3.10). CONCLUSIONS: Among SPRINT participants, malignant LVH is associated with incident probable dementia and mild cognitive impairment. These findings underscore the potential utility of measuring hs-cTnT and NT-proBNP levels when LVH is detected on ECG, aiding in the differentiation of individuals with a favorable risk for cognitive impairment from those with a higher risk.

Association of remnant cholesterol with risk of dementia: a nationwide population-based cohort study in South Korea.

BACKGROUND: The association between remnant cholesterol (remnant-C) and cardiovascular disease risk is well established, but its association with dementia remains unclear. We aimed to examine this association using a large-scale population dataset. METHODS: We did a nationwide, population-based cohort study in which we identified participants aged 40 years and older who underwent the national health examination in 2009 from South Korea's National Health Insurance Service. We excluded people who were younger than 40 years and those with a triglyceride concentration of 400 mg/dL or higher due to concerns regarding the accuracy of calculated low-density lipoprotein cholesterol concentration in individuals with extremely high triglyceride concentrations. People who were previously diagnosed with dementia before the index date, and those who had any missing variables were also excluded. To minimise the influence of possible reverse causation, we excluded individuals who had developed any type of dementia within 1 year of the baseline measurements. We calculated hazard ratios (HRs) for all-cause dementia, Alzheimer's disease, and vascular dementia in each quartile of remnant-C using the Cox proportional hazards model adjusted for age, sex, body-mass index, estimated glomerular filtration rate, income level, smoking status, alcohol consumption, regular exercise, diabetes, hypertension, statin and fibrate use, and total cholesterol concentrations. We also did subgroup analyses to investigate the association between remnant-C and the risk of dementia stratified by age, sex, obesity, glycaemic status (normoglycaemia, impaired fasting glucose, new-onset type 2 diabetes, type 2 diabetes with a duration of less than 5 years, and type 2 diabetes with a duration of 5 years or more), hypertension, chronic kidney disease, and dyslipidaemia, using likelihood ratio tests. FINDINGS: 4 234 415 individuals who underwent the national health examination in 2009 were deemed eligible for inclusion. We excluded 1 612 819 individuals on the basis of age, triglyceride concentration, missing variables, or having dementia at baseline. We identified 2 621 596 participants aged 40 years and older (1 305 556 men and 1 316 040 women) who underwent the national health examination and followed them up until the date of any incident of dementia or the end of the study period of Dec 31, 2020. During a median follow-up of 10·3 years (IQR 10·1-10·6), 146 991 (5·6%) participants developed all-cause dementia, 117 739 (4·5%) developed Alzheimer's disease, and 14 536 (0·6%) developed vascular dementia. The risk of dementia increased progressively with higher remnant-C concentrations. Compared with the lowest quartile of remnant-C (quartile 1), HRs in the highest quartile (quartile 4) were 1·11 (95% CI 1·09-1·13) for all-cause dementia, 1·11 (1·08-1·13) for Alzheimer's disease, and 1·15 (1·09-1·21) for vascular dementia. Subgroup analyses revealed that the risk of dementia associated with high remnant-C concentrations was higher in middle-aged people aged 40-59 years than in older people. The risk of dementia associated with high concentrations of remnant-C was notably more pronounced in individuals with diabetes compared with those without diabetes, and the risk increased steeply with a longer duration of diabetes. INTERPRETATION: Results showed that higher remnant-C concentrations were independently associated with increased risks of all-cause dementia, Alzheimer's disease, and vascular dementia. More research is needed to determine the mechanisms underlying this finding. Monitoring and managing higher concentrations of remnant-C might have important implications for reducing the risk of dementia. FUNDING: None.

Potential Biomarkers in Cerebrospinal Fluid and Plasma for Dementia.

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.

Shared plasma metabolomic profiles of cognitive and mobility decline predict future dementia.

Experiencing decline in both cognition and mobility is associated with a substantially higher dementia risk than cognitive decline only. Metabolites associated with both cognitive and mobility declines may be early predictors of dementia and reveal specific pathways to dementia. We analyzed data from 2450 participants initially free of dementia who had 613 metabolites measured in plasma in 1998-1999 (mean age = 75.2 ± 2.9 years old, 37.8% Black, 50% women) from the Health, Aging and Body Composition study. Dementia diagnosis was determined by race-specific decline in 3MS scores, medication use, and hospital records through 2014. Cognition and mobility were repeatedly measured using 3MS and a 20-m walking test up to 10 years, respectively. We examined metabolite associations with changes in 3MS (n = 2046) and gait speed (n = 2019) using multivariable linear regression adjusted for age, sex, race, and baseline performance and examined metabolite associations with dementia risk using Cox regression. During a mean follow-up of 9.3 years, 534 (21.8%) participants developed dementia. On average, 3MS declined 0.47/year and gait declined 0.04 m/sec/year. After covariate adjustment, 75 metabolites were associated with cognitive decline, and 111 metabolites were associated with gait decline (FDR-adjusted p < 0.05). Twenty-six metabolites were associated with both cognitive and gait declines. Eighteen of 26 metabolites were associated with dementia risk (p < 0.05), notably amino acids, glycerophospholipids (lysoPCs, PCs, PEs), and sphingolipids. Results remained similar after adjusting for cardiovascular disease or apolipoprotein E ɛ4 carrier status. During aging, metabolomic profiles of cognitive decline and mobility decline show distinct and shared signatures. Shared metabolomic profiles suggest that inflammation and deficits in mitochondria and the urea cycle in addition to the central nervous system may play key roles in both cognitive and mobility declines and predict dementia. Future studies are warranted to investigate longitudinal metabolite changes and metabolomic markers with dementia pathologies.

Plasma IL-6 levels and their association with brain health and dementia risk: A population-based cohort study.

BACKGROUND: Recent studies have associated immune abnormalities with dementia. IL-6 is a crucial cytokine in inflammatory responses, and recent evidence has linked elevated IL-6 levels to changes in brain structure and cognitive decline. However, the connection between IL-6 levels, cognition, brain volumes, and dementia risk requires exploration in large prospective cohorts. METHODS: This study utilized a longitudinal cohort from the UK Biobank to analyze the correlation between IL-6 expression levels, cognitive performance, and cortical and subcortical brain volumes through linear regression. Additionally, we assessed the association between IL-6 levels and long-term dementia risk using Cox regression analysis. We also used one-sample Mendelian randomization to analyze the impact of genetic predisposition of dementia on elevated IL-6 levels. RESULTS: A total of 50,864 participants were included in this study, with 1,391 new cases of all-cause dementia identified. Higher plasma IL-6 levels are associated with cortical and subcortical atrophy in regions such as the fusiform, thalamus proper, hippocampus, and larger ventricle volumes. IL-6 levels are negatively associated with cognitive performance in pair matching, numeric memory, prospective memory, and reaction time tests. Furthermore, elevated IL-6 levels are linked to a 23-35 % increased risk of all-cause dementia over an average follow-up period of 13.2 years. The one-sample Mendelian randomization analysis did not show associations between the genetic predisposition of dementia and elevated IL-6 levels. CONCLUSIONS: Increased IL-6 levels are associated with worse cognition, brain atrophy, and a heightened risk of all-cause dementia. Our study highlights the need to focus on the role of peripheral IL-6 levels in managing brain health and dementia risk.

Non-linear relationship between serum cholesterol levels and cognitive change among older people in the preclinical and prodromal stages of dementia: a retrospective longitudinal study in Taiwan.

BACKGROUND: Adverse effects of rigorously lowering low-density lipoprotein cholesterol on cognition have been reported; therefore, we aimed to study the contribution of serum cholesterol in cognitive decline in older people with or without dementia. METHODS: Cognitive function was assessed by the Cognitive Abilities Screening Instrument (CASI). We investigated associations between serum cholesterol with cognitive decline using multiple regressions controlling for the effects of demographics, vascular risk factors, and treatments. RESULTS: Most associations between cholesterol and CASI scores could be explained by non-linear and inverted U-shaped relationships (R2 = 0.003-0.006, p < 0.016, Sidákcorrection). The relationships were most evident between changes in cholesterol and CASI scores in older people at the preclinical or prodromal stages of dementia (R2 = 0.02-0.064, p values < 0.016). There were no differences in level of changes in CASI scores between individuals in 1st decile and 10th decile groups of changes in cholesterol (p = 0.266-0.972). However, individuals in the 1st decile of triglyceride changes and with stable and normal cognitive functions showed significant improvement in CASI scores compared to those in the 10th decile (t(202) = 2.275, p values < 0.05). CONCLUSION: These findings could implicate that rigorously lowering cholesterol may not be suitable for the prevention of cognitive decline among older people, especially among individuals in preclinical or prodromal stages of dementia.

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

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

Diagnostic and Prognostic Value of Plasma GFAP in Sporadic Creutzfeldt-Jakob Disease in the Clinical Setting of Rapidly Progressive Dementia.

The diagnostic and prognostic value of plasma glial fibrillary acidic protein (pl-GFAP) in sporadic Creutzfeldt-Jakob disease (sCJD) has never been assessed in the clinical setting of rapidly progressive dementia (RPD). Using commercially available immunoassays, we assayed the plasma levels of GFAP, tau (pl-tau), and neurofilament light chain (pl-NfL) and the CSF total tau (t-tau), 14-3-3, NfL, phospho-tau181 (p-tau), and amyloid-beta isoforms 42 (Aß42) and 40 (Aß40) in sCJD (n = 132) and non-prion RPD (np-RPD) (n = 94) patients, and healthy controls (HC) (n = 54). We also measured the CSF GFAP in 67 sCJD patients. Pl-GFAP was significantly elevated in the sCJD compared to the np-RPD and HC groups and affected by the sCJD subtype. Its diagnostic accuracy (area under the curve (AUC) 0.760) in discriminating sCJD from np-RPD was higher than the plasma and CSF NfL (AUCs of 0.596 and 0.663) but inferior to the 14-3-3, t-tau, and pl-tau (AUCs of 0.875, 0.918, and 0.805). Pl-GFAP showed no association with sCJD survival after adjusting for known prognostic factors. Additionally, pl-GFAP levels were associated with 14-3-3, pl-tau, and pl-NfL but not with CSF GFAP, Aß42/Aß40, and p-tau. The diagnostic and prognostic value of pl-GFAP is inferior to established neurodegeneration biomarkers. Nonetheless, pl-GFAP noninvasively detects neuroinflammation and neurodegeneration in sCJD, warranting potential applications in disease monitoring.

High plasma homocysteine levels predict the progression from mild cognitive impairment to dementia.

High levels of blood homocysteine (HCy), a well-known cardiovascular risk factor and promoter of oxidative stress, have been associated with the incidence of cognitive impairment and dementia. Nonetheless, contrasting data are still present on its involvement in the progression from Mild Cognitive Impairment (MCI) to overt dementia. In this study we aimed to observe whether blood HCy level are associated with the evolution from MCI, divided into amnestic MCI (aMCI) and non-amnestic MCI (naMCI), to dementia. Blood HCy was measured in 311 MCI subjects (aMCI: 64%, naMCI: 36%) followed-up for a median of 33 months (range 10-155 months). At follow-up, 137 individuals converted to dementia (naMCI, n = 34; aMCI, n = 103). Based on HCy distribution, subjects in the highest tertile had a greater risk to convert to dementia compared to tertile I (Hazard Ratio (95% confidence interval): 2.25 (1.05-4.86); p = 0.04). aMCI subjects did not show increased risk to convert to dementia with increasing HCy concentration, but was significant in naMCI (p = 0.04). We observed a non-significant increase in the risk of progression to dementia from naMCI/low HCy (reference group, HCy cutoff value = 16 µmol/L) to naMCI/high HCy, but it was significant from aMCI/low HCy (HR: 2.73; 95%CI: 1.06-7.0; p:0.03), to aMCI/high HCy (HR: 3.24; 95%CI: 1.17-8.47; p:0.02). Our results suggest that HCy levels are associated with the progression from MCI to dementia. This association seems significant only for the naMCI group, indirectly supporting the notion that hyperhomocysteinemia damages the nervous system through its role as a vascular risk factor.

Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank.

BACKGROUND: Peripheral glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are sensitive markers of neuroinflammation and neuronal damage. Previous studies with highly selected participants have shown that peripheral GFAP and NfL levels are elevated in the pre-clinical phase of Alzheimer's disease (AD) and dementia. However, the predictive value of GFAP and NfL for dementia requires more evidence from population-based cohorts. METHODS: This was a prospective cohort study to evaluate UK Biobank participants enrolled from 2006 to 2010 using plasma GFAP and NfL measurements measured by Olink Target Platform and prospectively followed up for dementia diagnosis. Primary outcome was the risk of clinical diagnosed dementia. Secondary outcomes were cognition. Linear regression was used to assess the associations between peripheral GFAP and NfL with cognition. Cox proportional hazard models with cross-validations were used to estimate associations between elevated GFAP and NfL with risk of dementia. All models were adjusted for covariates. RESULTS: A subsample of 48,542 participants in the UK Biobank with peripheral GFAP and NfL measurements were evaluated. With an average follow-up of 13.18 ± 2.42 years, 1312 new all-cause dementia cases were identified. Peripheral GFAP and NfL increased up to 15 years before dementia diagnosis was made. After strictly adjusting for confounders, increment in NfL was found to be associated with decreased numeric memory and prolonged reaction time. A greater annualized rate of change in GFAP was significantly associated with faster global cognitive decline. Elevation of GFAP (hazard ratio (HR) ranges from 2.25 to 3.15) and NfL (HR ranges from 1.98 to 4.23) increased the risk for several types of dementia. GFAP and NfL significantly improved the predictive values for dementia using previous models (area under the curve (AUC) ranges from 0.80 to 0.89, C-index ranges from 0.86 to 0.91). The AD genetic risk score and number of APOE*E4 alleles strongly correlated with GFAP and NfL levels. CONCLUSIONS: These results suggest that peripheral GFAP and NfL are potential biomarkers for the early diagnosis of dementia. In addition, anti-inflammatory therapies in the initial stages of dementia may have potential benefits.