Plasma Total Tau Research Articles

Association of dementia with impaired kidney function and plasma biomarkers: A population-based study.

Emerging evidence has linked impaired kidney function with dementia in older adults, but the neuropathological pathways underlying their association remain poorly understood. We sought to examine the relationships of kidney function with dementia and plasma biomarkers in a Chinese rural population. This population-based study used data from the baseline examination of the Multimodal Interventions to Delay Dementia and Disability in rural China (MIND-China) cohort (March-September 2018; n = 5715). Kidney function was assessed using estimated glomerular filtration rate (eGFR) based on serum creatinine level. Dementia, Alzheimer's disease (AD) and vascular dementia (VaD) were diagnosed according to the international criteria. Plasma biomarkers were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, general linear, and mediation models. Of the 5715 participants, 306 were diagnosed with dementia, including 195 with AD and 100 with VaD. Impaired kidney function (eGFR <60 vs. ≥90 mL/min/1.73 m2) was associated with multivariable-adjusted odds ratios of 2.24 (95% confidence interval [CI] 1.44-3.46) for all-cause dementia, 1.85 (1.07-3.18) for AD, and 2.49 (1.16-5.22) for VaD. In the biomarker subsample, impaired kidney function was significantly associated with higher plasma amyloid-β (Aβ)40 (β-coefficient = 54.36, 95% CI 43.34-65.39), Aβ42 (β-coefficient = 3.14, 95% CI 2.42-3.86), neurofilament light chain (β-coefficient = 10.62, 95% CI 5.62-15.62), and total tau (β-coefficient = 0.68, 95% CI 0.44-0.91), and a lower Aβ42/Aβ40 ratio (β-coefficient = -4.11, 95% CI -8.08 to -0.14). The mediation analysis showed that plasma total tau significantly mediated 21.76% of the association between impaired kidney function and AD (p < 0.05). Impaired kidney function is associated with dementia and plasma biomarkers among rural-dwelling older Chinese adults, and the association with AD is partly mediated by plasma biomarkers for neurodegeneration.

Elevated C-Reactive Protein in Older Men With Chronic Pain: Association With Plasma Amyloid Levels and Hippocampal Volume.

Chronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with Alzheimer's disease (AD)-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation. Participants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aβ42, n = 871), Aβ40 (n = 887), total tau (t-tau, n = 841), and neurofilament light chain (NfL, n = 915), and serum high-sensitivity C-reactive protein (hs-CRP, n = 968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n = 385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use. Chronic pain was related to higher Aβ40 (β = 0.25, p = .009), but hs-CRP was unrelated to AD-related biomarkers (ps > .05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aβ42 (β = 0.36, p = .001) and Aβ40 (β = 0.29, p = .003). Chronic pain and hs-CRP did not interact to predict levels of Aβ42/Aβ40, t-tau, or NfL. Furthermore, there were significant interactions such that Aβ42 and Aβ40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP × Aβ42: β = -0.19, p = .002; hs-CRP × Aβ40: β = -0.21, p = .001), regardless of chronic pain status. Chronic pain was associated with higher plasma Aβ, especially when hs-CRP was also elevated. Higher hs-CRP and Aβ levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate the risk of neurodegeneration in AD-vulnerable regions.

Associations of Plasma Tau with Amyloid and Tau PET: Results from the Community-Based Framingham Heart Study.

Associations of plasma total tau levels with future risk of AD have been described. To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-β deposition in the precuneus region (β±SE, 0.11±0.05; p = 0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEɛ4 carriers. Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.

Cardiometabolic multimorbidity, peripheral biomarkers, and dementia in rural older adults: The MIND-China study.

Evidence has emerged that cardiometabolic multimorbidity (CMM) is associated with dementia, but the underlying mechanisms are poorly understood. This population-based study included 5704 older adults. Of these, data were available in 1439 persons for plasma amyloid-β (Aβ), total tau, and neurofilament light chain (NfL) and in 1809 persons for serum cytokines. We defined CMM following two common definitions used in previous studies. Data were analyzed using general linear, logistic, and mediation models. The presence of CMM was significantly associated with an increased likelihood of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) (p<0.05). CMM was significantly associated with increased plasma Aβ40, Aβ42, and NfL, whereas CMM that included visceral obesity was associated with increased serum cytokines. The mediation analysis suggested that plasma NfL significantly mediated the association of CMM with AD. CMM is associated with dementia, AD, and VaD in older adults. The neurodegenerative pathway is involved in the association of CMM with AD. The presence of CMM was associated with increased likelihoods of dementia, AD, and VaD in older adults. CMM was associated with increased AD-related plasma biomarkers and serum inflammatory cytokines. Neurodegenerative pathway was partly involved in the association of CMM with AD.

Sex-differences in the association of social health and marital status with blood-based immune and neurodegeneration markers in a cohort of community-dwelling older adults

BackgroundThe immune system has been proposed to play a role in the link between social health and all-cause dementia risk. We explored cross-sectional and longitudinal associations between social health, immune system balance and plasma neurodegeneration markers in community-dwelling older adults, and explored whether the balance between innate and adaptive immunity mediates associations between social health and both cognition and total brain volume. MethodsSocial health markers (social support, marital status, loneliness) were measured in the Rotterdam Study between 2002–2008. Immune system cell counts and balance were assessed repeatedly from 2002 to 2016 using white blood-cell-based indices and individual counts (granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)). Plasma neurodegeneration biomarkers (amyloid-β40, amyloid-β42, total tau and neurofilament light chain) were measured once from blood samples collected between 2002–2008. Global cognitive function and total brain volume (MRI) were measured at the follow-up visit between 2009–2014. We used linear mixed models to study longitudinal associations and performed causal mediation analyses. ResultsIn 8374 adults (mean age 65.7, 57 % female), never married participants (n = 394) had higher GLR, PLR and SII compared to married peers at baseline and during follow-up, indicating imbalance towards innate immunity. Being never married was associated with higher plasma amyloid-β40, and being widowed or divorced with higher plasma total tau levels at baseline. Widowed or divorced males, but not females, had higher GLR, PLR and SII at baseline. Higher social support was associated with lower PLR in females, but higher PLR in males. Loneliness was not associated with any of the immune system balance ratios. Never married males had higher levels of all plasma neurodegeneration markers at baseline. Immune system balance did not mediate associations between social health and cognition or total brain volume, but does interact with marital status. ConclusionThis study indicates that marital status is associated with blood-based immune system markers toward innate immunity and higher levels of plasma neurodegeneration markers. This is particularly evident for never married or previously married male older adults compared to married or female peers.

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

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

Novel Biomarkers for Alzheimer's Disease: Plasma Neurofilament Light and Cerebrospinal Fluid.

Neurodegenerative disorders such as Alzheimer's disease (AD) represent an increasingly significant public health concern. As clinical diagnosis faces challenges, biomarkers are becoming increasingly important in research, trials, and patient assessments. While biomarkers like amyloid-β peptide, tau proteins, CSF levels (Aβ, tau, and p-tau), and neuroimaging techniques are commonly used in AD diagnosis, they are often limited and invasive in monitoring and diagnosis. For this reason, blood-based biomarkers are the optimal choice for detecting neurodegeneration in brain diseases due to their noninvasiveness, affordability, reliability, and consistency. This literature review focuses on plasma neurofilament light (NfL) and CSF NfL as blood-based biomarkers used in recent AD diagnosis. The findings revealed that the core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aβ42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease, and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Elevated levels of plasma and cerebrospinal fluid NfL were linked to decreased [18F]FDG uptake in corresponding brain areas. In participants with Aβ positivity (Aβ+), NfL correlated with reduced metabolism in regions susceptible to Alzheimer's disease. In addition, CSF NfL levels correlate with brain atrophy and predict cognitive changes, while plasma total tau does not. Plasma P-tau, especially in combination with Aβ42/Aβ40, is promising for symptomatic AD stages. Though not AD-exclusive, blood NfL holds promise for neurodegeneration detection and assessing treatment efficacy. Given the consistent levels of T-tau, P-tau, Aβ42, and NFL in CSF, their incorporation into both clinical practice and research is highly recommended.

Cerebral Amyloidosis in Individuals with Subjective Cognitive Decline: From Genetic Predisposition to Actual Cerebrospinal Fluid Measurements.

The possible relationship between Subjective Cognitive Decline (SCD) and dementia needs further investigation. In the present study, we explored the association between specific biomarkers of Alzheimer's Disease (AD), amyloid-beta 42 (Aβ42) and Tau with the odds of SCD using data from two ongoing studies. In total, 849 cognitively normal (CN) individuals were included in our analyses. Among the participants, 107 had available results regarding cerebrospinal fluid (CSF) Aβ42 and Tau, while 742 had available genetic data to construct polygenic risk scores (PRSs) reflecting their genetic predisposition for CSF Aβ42 and plasma total Tau levels. The associations between AD biomarkers and SCD were tested using logistic regression models adjusted for possible confounders such as age, sex, education, depression, and baseline cognitive test scores. Abnormal values of CSF Aβ42 were related to 2.5-fold higher odds of SCD, while higher polygenic loading for Aβ42 was associated with 1.6-fold higher odds of SCD. CSF Tau, as well as polygenic loading for total Tau, were not associated with SCD. Thus, only cerebral amyloidosis appears to be related to SCD status, either in the form of polygenic risk or actual CSF measurements. The temporal sequence of amyloidosis being followed by tauopathy may partially explain our findings.

Association of objective sleep duration with cognition and brain aging biomarkers in older adults.

The neuropathological mechanisms underlying the association between sleep duration and mild cognitive impairment remain poorly understood. This population-based study included 2032 dementia-free people (age ≥ 60 years; 55.1% women) derived from participants in the Multimodal Interventions to Delay Dementia and Disability in Rural China; of these, data were available in 841 participants for Alzheimer's plasma biomarkers (e.g. amyloid-β, total tau and neurofilament light chain), 1044 for serum microvascular biomarkers (e.g. soluble adhesion molecules) and 834 for brain MRI biomarkers (e.g. whiter matter, grey matter, hippocampus, lacunes, enlarged perivascular spaces and white matter hyperintensity WMH). We used electrocardiogram-based cardiopulmonary coupling analysis to measure sleep duration, a neuropsychological test battery to assess cognitive function and the Petersen's criteria to define mild cognitive impairment. Data were analysed with multivariable logistic and general linear models. In the total sample (n = 2032), 510 participants were defined with mild cognitive impairment, including 438 with amnestic mild cognitive impairment and 72 with non-amnestic mild cognitive impairment. Long sleep duration (>8 versus 6-8 h) was significantly associated with increased likelihoods of mild cognitive impairment and non-amnestic mild cognitive impairment and lower scores in global cognition, verbal fluency, attention and executive function (Bonferroni-corrected P < 0.05). In the subsamples, long sleep duration was associated with higher plasma amyloid-β40 and total tau, a lower amyloid-β42/amyloid-β40 ratio and smaller grey matter volume (Bonferroni-corrected P < 0.05). Sleep duration was not significantly associated with serum-soluble adhesion molecules, white matter hyperintensity volume, global enlarged perivascular spaces and lacunes (P > 0.05). Alzheimer's and neurodegenerative pathologies may represent common pathways linking long sleep duration with mild cognitive impairment and low cognition in older adults.

Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aβ)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). In general linear models lower plasma Aβ42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Blood Pressure Variability and Plasma Alzheimer's Disease Biomarkers in the SPRINT Trial.

Recent observational studies suggest higher blood pressure (BP) variability (BPV) is associated with Alzheimer's disease (AD) biomarkers amyloid-beta (Aβ) and tau. Less is known about relationships in interventional cohorts with strictly controlled mean BP levels. Investigate the longitudinal relationship between BPV and change in plasma AD biomarkers under standard versus intensive BP treatment. In this post hoc analysis of the SPRINT trial, 457 participants (n = 206 in standard group, n = 251 in intensive group) underwent repeated BP measurement between baseline and 12-months follow-up, and venipuncture at baseline and median (IQR) 3.5 (3.0-4.0) years later to determine plasma AD biomarkers total tau and Aβ1-42:Aβ1-40 ratio. BPV was calculated as tertiles of variability independent of mean. Linear mixed models investigated the effect of BPV×time on AD biomarker levels. Higher BPV was associated with increased levels of total tau in the standard group (β [95% CI] 1st versus 3rd tertiles of BPV: 0.21 [0.02, 0.41], p = 0.035), but not in the intensive group (β [95% CI] 1st versus 3rd tertiles of BPV: -0.02 [-0.19, 0.16], p = 0.843). BPV was not associated with Aβ 1-42:Aβ 1-40 ratio in either group. Mean BP was not associated with biomarkers. Higher BPV was associated with increased plasma total tau under standard BP treatment. Findings add new evidence to prior observational work linking BPV to AD pathophysiology and suggest that, despite strict control of mean BP, BPV remains a risk for pathophysiological change underlying risk for AD.

Probable chronic pain, brain structure, and Alzheimer’s plasma biomarkers in older men

Chronic pain leads to tau accumulation and hippocampal atrophy in mice. In this study, we provide one of the first assessments in humans, examining the associations of probable chronic pain with hippocampal volume, integrity of the locus coeruleus (LC)—an upstream site of tau deposition—and Alzheimer’s Disease-related plasma biomarkers. Participants were mostly cognitively unimpaired men. Probable chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, 424 participants underwent structural magnestic resonance imaging (MRI) of hippocampal volume and LC-sensitive MRI providing an index of LC integrity (LC contrast-to-noise ratio). Analyses adjusted for confounders including major health conditions, depressive symptoms, and opioid use. Models showed that men with probable chronic pain had smaller hippocampal volume and lower rostral-middle—but not caudal—LC contrast-to-noise ratio compared to men without probable chronic pain. Men with probable chronic pain also had higher levels of plasma total tau, beta-amyloid-42, and beta-amyloid-40 compared to men without probable chronic pain. These findings suggest that probable chronic pain is associated with tau accumulation and reduced structural brain integrity in regions affected early in the development of Alzheimer’s Disease. PerspectiveProbable chronic pain was associated with plasma biomarkers and brain regions that are affected early in Alzheimer’s disease (AD). Reducing pain in midlife and elucidating biological mechanisms may help to reduce the risk of AD in older adults.

Body composition and plasma total-tau, neurofilament light chain, and amyloid-β: A population-based study.

A higher body mass at older age has been linked to a lower risk of dementia. This unexpected trend may be explained by age-related lean mass depletion, or methodological issues such as the long preclinical phase of dementia or competing risks. Focusing on preclinical markers of dementia may overcome these issues. Between 2002 and 2005, body composition and plasma total-tau, neurofilament light chain (NfL), amyloid-β40, and amyloid-β42 were measured in 3408 dementia-free participants from the population-based Rotterdam Study. The cross-sectional associations between body composition and plasma markers were determined using linear regression models. Whole body and fat mass, but not lean mass, were positively associated with total-tau, while all these measures were inversely associated with NfL. Apart from an inverse association between lean mass and amyloid-β40, body composition measures were not associated with plasma amyloid-β. Our findings suggest distinct effects of body composition on neurodegeneration.

Semorinemab Pharmacokinetics and The Effect on Plasma Total Tau Pharmacodynamics in Clinical Studies.

Semorinemab is a monoclonal antibody that targets the N-terminal domain of the tau protein that is in clinical development for the treatment of Alzheimer's disease. To perform model-based evaluations of the observed pharmacokinetics in serum and the total plasma tau target-engagement dynamics from clinical studies evaluating semorinemab. The observed semorinemab pharmacokinetics and plasma tau target engagement from phase 1 and 2 clinical studies were modeled using a non-linear mixed effect target-mediated drug disposition model. The model was simulated to understand target engagement at clinical dose levels. The clinical studies testing semorinemab were evaluated in healthy volunteers, subjects with prodromal-to-mild Alzheimer's disease, and subjects with mild-to-moderate Alzheimer's disease. The data included a total of 8430 semorinemab serum concentrations and 4772 total tau protein plasma concentrations from 463 subjects treated with a range of single and multiple doses of semorinemab. Serum concentrations of semorinemab and the total plasma tau concentrations were measured after administration of a range of doses of semorinemab to subjects with Alzheimer's disease. A sensitivity analysis was performed wherein key target-mediated drug disposition model parameters were estimated separately between healthy volunteers, subjects with prodromal-to-mild Alzheimer's disease, and subjects with mild-to-moderate Alzheimer's disease. Serum concentrations of semorinemab were consistent across studies and showed a dose-proportional increase across the evaluated dose range. The pharmacokinetic profile was comparable between healthy volunteers and subjects with Alzheimer's disease. Total plasma tau concentrations increased in a dose-dependent non-linear manner upon semorinemab administration. The target-mediated drug disposition model adequately described the serum pharmacokinetics and protein dynamics with an estimated antibody-ligand binding strength, Kss, of 42.7 nM. The estimated values of clearance and central volume of distribution were 0.109 L/day/70 kg and 2.95 L/70 kg, respectively, and were consistent with typical values for IgG mAbs. In the sensitivity analysis, Kss (32 nM) and baseline tau protein (0.30 µM) were estimated to be lower for healthy volunteers compared to subjects with Alzheimer's disease but were comparable between subjects with Alzheimer's disease of different severities (Kss: 52-57 nM, baseline tau: 0.44-0.47 µM). The models suggested that peripheral target engagement was over 90% at the clinical doses in each of the diagnostic subgroups. Our target-mediated drug disposition model adequately described the serum pharmacokinetics and the peripheral non-linear increase with dose of the total tau. The model confirmed that these dose-response relationships were consistent across populations of healthy volunteers and subjects with different severities of Alzheimer's disease.

Multimorbidity, cognitive phenotypes, and Alzheimer's disease plasma biomarkers in older adults: A population-based study.

To examine the burden and clusters of multimorbidity in association with mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD)-related plasma biomarkers among older adults. This population-based study included 5432 participants (age ≥60 years); of these, plasma amyloid beta (Aβ), total tau, and neurofilament light chain (NfL) were measured in a subsample (n=1412). We used hierarchical clustering to generate five multimorbidity clusters from 23 chronic diseases. We diagnosed dementia and MCI following international criteria. Data were analyzed using logistic and linear regression models. The number of chronic diseases was associated with dementia (multivariable-adjusted odds ratio= 1.22; 95% confidence interval [CI]= 1.11 to 1.33), AD (1.13; 1.01 to 1.26), vascular dementia (VaD) (1.44; 1.25 to 1.64), and non-amnestic MCI (1.25; 1.13 to 1.37). Metabolic cluster was associated with VaD and non-amnestic MCI, whereas degenerative ocular cluster was associated with AD (p<0.05). The number of chronic diseases was associated with increased plasma Aβ and NfL (p<0.05). Multimorbidity burden and clusters are differentially associated with subtypes of dementia and MCI and AD-related plasma biomarkers in older adults. We used hierarchical clustering to generate five clusters of multimorbidity. The presence and load of multimorbidity were associated with dementia and mild cognitive impairment. Multimorbidity clusters were differentially associated with subtypes of dementia and Alzheimer's disease plasma biomarkers.

Renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural older adults in China: a population‐based study

AbstractBackgroundEmerging evidence has linked impaired renal function with dementia, but the neuropathological mechanisms underlying the association remains poorly understood. We sought to examine the relationships of renal function, Alzheimer’s plasma biomarker, and cognitive phenotypes among rural Chinese older adults.MethodThis population‐based cross‐sectional study included 5715 participants (age ≥60 years; 57.15% women; 40.49% illiteracy) in the Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND‐China). We calculated the estimate glomerular filtration rate (eGFR) using serum creatinine and the simplified modification of diet in renal disease equation specifically for individuals from China, and impaired renal function was defined as eGFR &lt;60 mL/min/1.73 m2. Dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were diagnosed following the international criteria. Plasma amyloid‐β (Aβ) 40, Aβ42, total tau, and neurofilament light chain (NfL) concentrations were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, the general linear regression, and mediation models.ResultOf the 5715 participants, 283 (4.95%) were detected with renal function impairment, and 326 (5.70%) were diagnosed with dementia (195 with AD and 10 with VaD). The multivariable‐adjusted odds ratios of eGFR &lt;60 mL/min/1.73 m2 (vs. &gt;90mL/min/1.73 m2) were 2.43 (95% confidence interval [CI] 1.56‐3.72) for all‐cause dementia, 2.74 (1.64‐4.49) for AD, and 1.30 (0.50‐2.98) for VaD. In the plasma biomarkers subsample, controlling for demographic factors, impaired renal function was significantly associated with higher levels of plasma Aβ40 (demographic‐adjusted β‐coefficient = 59.06; 95%CI 46.93‐71.19), Aβ42 (3.41; 2.62‐4.20), NfL (14.57; 9.08‐20.05), and total tau (0.74; 0.48‐1.01), and the observed associations remained significant even in the multivariable‐adjusted model (P&lt;0.001). The mediation analysis showed that total tau mediated 12.77% of the association between impaired renal function and AD.ConclusionImpaired renal function is associated with an increased risk of dementia and AD. Plasma total tau may partly underlie the association of renal function with Alzheimer’s dementia.

Association of Cardiometabolic Multimorbidity with Dementia and Alzheimer’s Plasma Biomarkers in Older Adults: a population‐based study

AbstractBackgroundIndividual cardiometabolic disorders are associated with an increased dementia risk. However, the relationship of cardiometabolic multimorbidity (CMM) with dementia has not been studied in Chinese older adults and the underlying mechanisms are poorly understood.MethodThis population‐based study included 5665 rural‐dwelling adults (age ≥60 years, 57.3% women) in the baseline examination (March‐September 2018) of the Multimodal Interventions to Delay Dementia and Disability in Rural China study. Cardiometabolic diseases (CMDs), which included heart disease, stroke, type 2 diabetes, and obesity, were assessed through clinical and neurological examinations. CMM was defined as the concurrent presence of two or more CMDs. Amyloid‐β(Aβ), total tau, and neurofilament light chain (NfL) were measured using Simoa platform in a subsample (n = 1434). Dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were clinically diagnosed following international criteria. Data were analyzed using the general linear and logistic regression and mediation models.ResultOf the 5665 participants, 1091 (19.26%) were detected with CMM, and 302 (5.33%) were diagnosed with dementia (193 with AD and 98 with VaD). The multivariable‐adjusted odds ratios of CMM (vs. no CMD) were 3.00 (95% confidence interval [CI] 2.19‐4.11) for all‐cause dementia, 1.66 (1.11‐2.47) for AD, and 12.5 (6.47‐24.18) for VaD. There was a significant interaction between CMM and sex on the likelihood of dementia and subtypes (P for interaction&lt;0.05), such that the associations of CMM with dementia and subtypes were stronger in men than in women. In the biomarker subsample, CMM was significantly associated with higher plasma NfL (demographic‐adjusted β coefficient = 0.059; 95% CI 0.028‐0.091), Aβ40 (0.034; 0.018‐0.049), and Aβ42 (1.068; 0.636‐1.501); the observed association remained significant even in the multivariable‐adjusted model (P&lt;0.001). The mediation analysis showed that plasma NfL could mediate 19.46% of the association between CMM and AD (P&lt;0.05), whereas plasma Aβ and total tau showed no significant mediation (P&gt;0.05).ConclusionCMM is associated with increased likelihoods of dementia, AD, and VaD in older adults, especially in men. Neurodegenerative pathway might play a part in the association of CMM with AD.

AL002c‐mediated reduction in amyloid β pathology is reflected by changes in plasma Alzheimer’s disease biomarkers in 5XFAD mice

AbstractBackgroundThe R47H variant of the triggering receptor expressed on myeloid cells‐2 (TREM2) gene increases the risk for late‐onset Alzheimer’s disease (LOAD) and reduces TREM2 ligand binding in vitro, suggesting that enhancing TREM2 signaling has therapeutic potential in AD. AL002 is a novel humanized monoclonal Immunoglobulin G1 (IgG1) antibody that targets TREM2 and is currently being tested in a phase 2 trial in patients with early AD. Previously, AL002c, a variant of AL002, reduced filamentous amyloid β (Aβ) plaques and neurite dystrophy and increased inert plaques in a 5XFAD mouse model, while other Aβ pathology measures did not show treatment effects. Total Aβ42/40 ratio in plasma is inversely associated with amyloid burden independent of AD clinical diagnosis2 and is being used as a biomarker in AD clinical trials.3 To further evaluate the impact of AL002c on Aβ pathology, the present study assessed plasma AD biomarkers, including Aβ42/40 ratio, in residual samples from these 5XFAD mice.MethodFive‐month‐old 5XFAD mice (N = 32, n = 6‐13 per group) expressing either common variant (CV) or R47H variant human TREM2 (hTREM2), but lacking endogenous mouse Trem2, were injected intraperitoneally with 30 mg/kg AL002c or control mouse IgG1 weekly for 12 weeks (Figure 1). Levels of plasma Aβ42, Aβ40, and total tau (t‐tau) were quantified using Simoa® assay (Quanterix).ResultAL002c‐treated CV‐5XFAD and R47‐5XFAD mice had a higher plasma Aβ42/40 ratio (CV‐5XFAD p &lt;0.001; R47‐5XFAD p&lt;0.05; pooled CV and R47‐5XFAD p &lt; 0.01) and lower plasma t‐tau (CV‐5XFAD p &lt;0.05; R47‐5XFAD p&lt;0.001; pooled CV and R47‐5XFAD p &lt; 0.01) compared with their IgG1‐treated genotype counterparts (Figure 2). No differences were observed between R47H and CV genotypes in plasma Aβ42/40 ratio or t‐tau.ConclusionAL002c‐associated changes in plasma Aβ42/40 and tau were consistent with a concomitant reduction in filamentous plaques and neurite dystrophy.1 These results lend further support to the clinical utility of plasma Aβ42/40 as a marker for the reduction of neurotoxic amyloid plaques in clinical trials with AL002.

Genetic and Environmental Influences of Plasma Biomarkers and Their Relation to APOE status and Mild Cognitive Impairment

AbstractBackgroundBefore onset of Alzheimer’s dementia, aggregation of amyloid‐beta (Aβ) is thought to drive accumulation of Tau, followed by neurodegeneration (indexed here by neurofilament light chain [NFL]). Why or how Aβ increases Tau accumulation remains unclear. Using genetically informative twins aged 61.4 to 73.3 years, we sought to: (1) identify genetic and environmental influences on plasma Aβ (Aβ40, Aβ42, Aβ42/40), total Tau (t‐Tau), and NFL; (2) determine if their genetic and environmental influences are correlated with one another; (3) determine if Aβ40 and Aβ42 causally impact Tau levels; (4) measure associations between biomarkers and APOE‐ε4 status; and (5) measure associations between these biomarkers and mild cognitive impairment (MCI).MethodData were from 1,035 male twins in the Vietnam Era Twin Study of Aging. Average age was 67.1 years (SD = 2.6). Twin models were used to estimate heritability, genetic and environmental correlations, model the direction of causation between biomarkers, and associations with APOE‐ε4 status. Mixed effect linear regressions were applied to regress MCI on biomarkers.ResultHeritability for Aβ40, Aβ42, t‐Tau and NFL ranged from 43% to 51%, whereas Aβ42/40 heritability was not significantly different from zero. Phenotypic correlations between t‐Tau and Aβ40 (rP = 0.01) and Aβ42 (rP = 0.14) were small. Genetic correlations between t‐Tau and Aβ40 (rG = ‐0.05) and Aβ42 (rG = 0.05) were also very small. In contrast, genetic correlations between NFL and Aβ40 and Aβ42 were higher (rG ranging = 0.31‐0.37). We found no evidence to suggest that Aβ40 or Aβ42 causally impacts t‐Tau. APOE‐ε4 accounted for a significant, but very small amount of variance in Aβ40 and Aβ42. Finally, none of the biomarkers was significantly associated with MCI, which affected 15.1% of the sample.ConclusionBoth Aβ40 or Aβ42 appear heritable, but have very little phenotypic and genetic association with t‐Tau. The associations between the amyloid‐beta biomarkers and t‐Tau are mostly explained by non‐shared environmental factors, and the direction of causation is unclear. The small associations between APOE‐ε4 and the biomarkers, including their lack of association with MCI, may stem from the low sensitivity of plasma biomarkers, the relatively young age or the low proportion of MCI cases in this community‐dwelling sample.

Relationship between norepinephrine metabolism and plasma markers of tau pathology

AbstractBackgroundThe brainstem locus coeruleus (LC) constitutes the primary source of norepinephrine (NE) in the central nervous system and has been reported as one of the earliest accumulation sites of hyperphosphorylated tau protein in Alzheimer’s disease (AD). Autopsy and animal studies suggested that this aggregation of hyperphosphorylated tau in the LC is associated with hyperactivity in LC neurons and elevated concentrations of NE metabolites. Here, we investigated whether elevated concentrations of 3‐methoxy‐4‐hydrophenylglycol (MHPG), a NE metabolite measured in the plasma, is associated with plasma phosphorylated tau, a biomarker of AD pathology.MethodNinety‐eight cognitively unimpaired participants (age = 59.82 ± 13.13 [30‐84] y, 52 females, Table 1) underwent a blood draw. Plasma MHPG concentrations were measured and adjusted for NE. Levels of total tau, phosphorylated tau at threonine 181 (pTau181) and threonine 231 (pTau231) were quantified by single molecule array (Simoa), while phosphorylated tau at threonine 217 (pTau217) was quantified by the Meso Scale Discovery (MSD) platform. Multiple linear regression models tested for the relationship between MHPG concentrations and plasma levels of tau‐related measures, while controlling for age and sex.ResultPTau231 and MHPG concentrations were positively correlated (t = 2.26, p = .03, Figure 1). No significant relationships were found between MHPG and other phosphorylated tau biomarkers (all p &gt; .23), but we observed a trend for a positive association with plasma total tau levels (t = 1.88, p = .06).ConclusionConsistent with previous CSF studies as well as animal studies, we found that elevated NE metabolism co‐occurs with the earliest events in the phosphorylation cascade of tau proteins, suggesting an important role of a dysregulated NE system early in the AD pathophysiologic cascade. Future work will need to determine the evolution of theses associations as the disease progresses, potential effect modifications by beta‐amyloid and the downstream effects of these processes on cognition and behavior.