Cerebrospinal Fluid P-tau Research Articles

Identification of an APOE ε4-specific blood-based molecular pathway for Alzheimer's disease risk.

The precise apolipoprotein E (APOE) ε4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by APOE genotype. The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C-reactive protein (CRP), complement C3, and complement factor H (CFH), had dose-dependent associations with CSF p-tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. The study identifies the APOE ε4-specific CRP-C3-CFH inflammation pathway for AD, suggesting potential drug targets for the disease.Highlights: Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD.CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes.Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.

Association of APOE-ε4 and GAP-43-related presynaptic loss with β-amyloid, tau, neurodegeneration, and cognitive decline

Apolipoprotein E-ε4 (APOE-ε4) carriers had elevated cerebrospinal fluid (CSF) presynaptic protein growth-associated protein-43 (GAP-43), but the underlying mechanism is not fully understood. We investigated how the APOE-ε4 genotype affects the baseline and longitudinal changes in CSF GAP-43 and their associations with β-amyloid positron emission tomography (Aβ PET), CSF phosphorylated tau 181 (p-Tau181), neurodegeneration, and cognitive decline. Compared to APOE-ε4 non-carriers, APOE-ε4 carriers had higher baseline levels and faster rates of increases in Aβ PET, CSF p-Tau181, and CSF GAP-43. Both higher baseline levels and faster rates of increase in CSF GAP-43 were associated with greater baseline Aβ PET and CSF p-Tau181, which fully mediated the APOE-ε4 effect on CSF GAP-43 elevations. Independent of Aβ PET and CSF p-Tau181, APOE-ε4 carriage was associated with exacerbated GAP-43-related longitudinal hippocampal atrophy and cognitive decline, especially in Aβ+ participants (GAP-43 × time × APOE-ε4). These findings suggest that the APOE-ε4 effect on GAP-43-related presynaptic dysfunction is mediated by primary Alzheimer’s pathologies and independently correlates to hippocampal atrophy and cognitive decline in the future.

Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression.

We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages. We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade. Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/40 was associated with Aβ aggregation on positron emission tomography (PET) and with CSF p-tau181 , which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aβ42/40 and Aβ-PET, and CSF YKL-40 partly explained the association between Aβ-PET, p-tau181 , and NfL. Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aβ, CSF YKL-40 mediates the latter association between Aβ and downstream Aβ-induced tau pathology and tau-induced neuronal injury. Lower CSF Aβ42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aβ and insoluble Aβ. CSF YKL-40 mediated Aβ-induced tau phosphorylation and tau-induced neuronal injury.

Cross-sectional associations of CSF tau levels with Rey's AVLT: A recency ratio study.

The preeminent in vivo cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are amyloid β 1-42 (Aβ42), phosphorylated Tau (p-tau), and total Tau (t-tau). The goal of this study was to examine how well traditional (total and delayed recall) and process-based (recency ratio [Rr]) measures derived from Rey's Auditory Verbal Learning test (AVLT) were associated with these biomarkers. Data from 235 participants (Mage = 65.5, SD = 6.9), who ranged from cognitively unimpaired to mild cognitive impairment, and for whom CSF values were available, were extracted from the Wisconsin Registry for Alzheimer's Prevention. Bayesian regression analyses were carried out using CSF scores as outcomes, AVLT scores as predictors, and controlling for demographic data and diagnosis. We found moderate evidence that Rr was associated with both CSF p-tau (Bayesian factor [BFM] = 5.55) and t-tau (BFM = 7.28), above and beyond the control variables, while it did not correlate with CSF Aβ42 levels. In contrast, total and delayed recall scores were not linked with any of the AD biomarkers, in separate analyses. When comparing all memory predictors in a single regression, Rr remained the strongest predictor of CSF t-tau levels (BFM = 3.57). Our findings suggest that Rr may be a better cognitive measure than commonly used AVLT scores to assess CSF levels of p-tau and t-tau in nondemented individuals. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study

BackgroundDespite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer’s disease (AD). However, whether Aβ42 and amyR have different meanings and whether Aβ40 represents more than an Aβ42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ42 and amyR to detect AD pathology in terms of p-tau/Aβ42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET).MethodsCSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ42 and normal p-tau (A + T − = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A − T −). A + T − patients were further stratified into those with normal (CSFAβ42 + /amyR − = 46) and pathological amyR (CSFAβ42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls.ResultsCSF Aβ40 levels were the lowest in A − T − and in CSFAβ42 + /amyR − , higher in CSFAβ42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ40 and p-tau in A − T − (β = 0.58; p < 0.001), CSFAβ42 + /amyR − (β = 0.47; p < 0.001), and CSFAβ42 + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ40: + 4.5 z-score). CSFAβ42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ42 than CSFAβ42 + /amyR − (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A − T − . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ42 + /amyR − compared to controls, and further reduction in frontal areas in CSFAβ42 + /amyR + , like in A + T + .ConclusionsPathological p-tau/Aβ42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ42 levels alone. AmyR positivity, associated with higher Aβ40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.

Plasma MMP-9/TIMP-1 ratio serves as a novel potential biomarker in Alzheimer's disease.

This study aimed to explore the diagnostic potential of plasma MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for Alzheimer's disease (AD). This retrospective study was performed in a cohort consisting of patients with AD (AD group) and cognitive normal subjects (HC group). Cerebrospinal fluid (CSF) classic biomarkers including Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) levels, and plasma MMP-9 and TIMP-1 levels were measured by commercially available ELISA kits, respectively. The differential diagnostic potential of plasma MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio was evaluated using the receiver operating characteristic curve analysis. It was observed that significantly elevated levels of plasma MMP-9 and MMP-9/TIMP-1 ratio in patients with AD than HC. Both MMP-9 and MMP-9/TIMP-1 ratios were negatively correlated with CSF Aβ42/Aβ40 ratio and positively correlated with CSF p-tau in AD group. ROC curve analysis showed better diagnostic accuracy of MMP-9/TIMP-1 ratio than MMP-9 for AD at a cutoff value of 1.35 with an area under the curve of 0.906 and sensitivity and specificity of 95.8% and 75%, respectively. Our findings encourage the use of plasma MMP-9/TIMP-1 ratio as a biomarker in the diagnosis of AD.

Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy.

To examine the extent to which positron emission tomography (PET)-, cerebrospinal fluid (CSF)-, and plasma-related amyloid-β/tau/neurodegeneration (A/T/N) biomarkers are associated with Alzheimer's disease (AD) neuropathology at autopsy. A total of 100 participants who respectively underwent antemortem biomarker measurements and postmortem neuropathology were included in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined the associations of PET-, CSF-, and plasma-related A/T/N biomarkers in combinations or alone with AD neuropathological changes (ADNC). PET- and CSF-related A/T/N biomarkers in combination showed high concordance with the ADNC stage and alone showed high accuracy in discriminating autopsy-confirmed AD. However, the plasma-related A/T/N biomarkers alone showed better discriminative performance only when combined with apolipoprotein E (APO)E ε4 genotype. This study supports that PET- and CSF-related A/T/N profiles can be used to predict accurately the stages of AD neuropathology. For diagnostic settings, PET-, CSF-, and plasma-related A/T/N biomarkers are all useful diagnostic tools to detect the presence of AD neuropathology. PET- and CSF-related A/T/N biomarkers in combination can accurately predict the specific stages of AD neuropathology. PET- and CSF-related A/T/N biomarkers alone may serve as a precise diagnostic tool for detecting AD neuropathology at autopsy. Plasma-related A/T/N biomarkers may need combined risk factors when used as a diagnostic tool. Aβ PET and CSF p-tau181/Aβ42 were most consistent with Aβ pathology, while tau PET and CSF p-tau181/Aβ42 were most consistent with tau pathology.

Biomarkers of Alzheimer’s disease in Black and/or African American Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants

Majority of dementia research is conducted in non-Hispanic White participants despite a greater prevalence of dementia in other racial groups. To obtain a better understanding of biomarker presentation of Alzheimer’s disease (AD) in the non-Hispanic White population, this study exclusively examined AD biomarker abnormalities in 85 Black and/or African American participants within the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were classified by the ADNI into 3 clinical groups: cognitively normal, mild cognitive impairment, or dementia. Data examined included demographics, apolipoprotein E (APOE) ε4, cerebrospinal fluid (CSF) Aβ1-42, CSF total tau (t-tau), CSF phosphorylated tau (p-tau), 3T magnetic resonance imaging (MRI), and measures of cognition and function. Analyses of variance and covariance showed lower cortical thickness in 5 of 7 selected MRI regions, lower hippocampal volume, greater volume of white matter hyperintensities, lower measures of cognition and function, lower measures of CSF Aβ1-42, and greater measures of CSF t-tau and p-tau between clinical groups. Our findings confirmed greater AD biomarker abnormalities between clinical groups in this sample.

CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease

Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R2 ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R2 ≤ 0.48) approached that of tau-PET (0.44 ≤ R2 ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates (‘T’).

Associations of neuroinflammatory IL-6 and IL-8 with brain atrophy, memory decline, and core AD biomarkers – in cognitively unimpaired older adults

Concentrations of pro-inflammatory cytokines –interleukin-6 (IL-6) and interleukin-8 (IL-8) – are increased with age and in Alzheimer’s disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62–91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time – up to 9 years – with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-β (Aβ-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aβ-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology.

Increased Cerebrospinal Fluid Levels of Soluble Triggering Receptor Expressed on Myeloid Cells 2 and Chitinase-3-Like Protein 1 in Idiopathic Normal-Pressure Hydrocephalus.

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. 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)). 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. 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). 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.

Influence of kidney function and CSF/serum albumin ratio on plasma Aβ42 and Aβ40 levels measured on a fully automated platform in patients with Alzheimer's disease.

Alzheimer's disease (AD) is characterized by decreased cerebrospinal fluid (CSF) Aβ42 and Aβ42/Aβ40 ratio. Aβ peptides can now be measured also in plasma and are promising peripheral biomarkers for AD. We evaluated the relationships of plasma Aβ species with their CSF counterparts, kidney function, and serum/CSF albumin ratio (Q-Alb) in AD patients. We measured plasma Aβ42 and Aβ40, as well as CSF AD biomarkers, with the fully automated Lumipulse platform in a cohort of N = 30 patients with clinical and neurochemical diagnosis of AD. The two plasma Aβ peptides correlated strongly with each other (r = 0.7449), as did the corresponding CSF biomarkers (r = 0.7670). On the contrary, the positive correlations of plasma Aβ42, Aβ40, and Aβ42/Aβ40 ratio with their CSF counterparts and the negative correlation of plasma Aβ42/Aβ40 ratio with CSF P-tau181 were not statistically significant. Plasma levels of both Aβ species negatively correlated with estimated glomerular filtration rate (eGFR) (Aβ42: r = -0.4138; Aβ40: r = -0.6015), but plasma Aβ42/Aβ40 ratio did not. Q-Alb did not correlate with any plasma Aβ parameter. Plasma Aβ42 and Aβ40 are critically influenced by kidney function; however, their ratio is advantageously spared from this effect. The lack of significant correlations between plasma Aβ species and their CSF counterparts is probably mainly due to small sample size and inclusion of only Aβ + individuals. Q-Alb is not a major determinant of plasma Aβ concentrations, highlighting the uncertainties about mechanisms of Aβ transfer between CNS and periphery.

Improving statistical modeling with a neuropathology‐based APOE genetic risk score

AbstractBackgroundThe apolipoprotein E gene (APOE) is the predominant genetic risk factor for late‐onset Alzheimer disease (AD), with three alleles contributing to disease risk and strongly associated with many AD endophenotypes: ε2 (reduced risk), ε3 (reference), and ε4 (increased risk). Researchers often include APOE ε4 carrier status (ε4+/‐) in analyses to account for the genetic effect; however, this does not adequately account for the protective effects of APOE ε2 or the heterogeneous effect of different APOE genotypes (ε2ε2, ε2ε3, ε2ε4, ε3ε3, ε3ε4, and ε4ε4). We hypothesized that accounting for the effect of the full APOE genotype would better recapitulate the influence of APOE in statistical analyses than APOE ε4 status.MethodTo generate a weighted risk score for APOE genotype (APOE‐npscore), we log‐transformed the odds ratios from a recent study reporting APOE genetic risk for neuropathology‐confirmed AD. We regressed cerebrospinal fluid (CSF) AD endophenotypes on the APOE‐npscore using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP: 233 cognitively unimpaired (CU), 3 mild cognitive impairment (MCI‐AD)) and Wisconsin Alzheimer’s Disease Research Center (WADRC: 287 CU, 42 MCI‐AD, 48 dementia‐AD). In preliminary analyses, APOE‐npscores were tested against CSF amyloid‐beta1‐42 (Aβ42) and phosphorylated tau 181 (pTau181) measured using Elecsys® immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland).ResultAfter adjusting for sex and age at lumbar puncture, the APOE‐npscore was associated with CSF Aβ42 (β = ‐115.9, p = 5.7e‐17) and pTau181 (β = 2.05, p = 4.7e‐8). APOE ε4 carrier status also associated with CSF Aβ42 (β = ‐238.0, p = 1.9e‐13) and pTau181 (β = 4.25, p = 1.1e‐6); however, models using APOE‐npscore explained 2.4% more variation in CSF Aβ42 and 0.8% more variation in CSF pTau181 than APOE ε4 status. These findings were similar in the subset of cognitively unimpaired participants.ConclusionOur preliminary results demonstrate the benefit of using a pseudo‐continuous variable like the neuropathology‐based APOE risk score instead of binary APOE ε4 status. The APOE‐npscore allows researchers to use a continuous measure to account for APOE genetic risk for AD that does not collapse important genotype categories. This increases statistical power, avoids modeling issues that result from small cell sizes, and allows for a more nuanced interpretation of the genetic effect in analyses.

Genome‐Wide Association Study for CSF Aβ42, Tau, and pTau in a Large Multi‐cohort Study to Identify Novel AD Genetic Variants

AbstractBackgroundPrevious studies have identified more than 20 genetic loci to be associated with AD risk. These reported loci do not account for all the estimated heritability nor report enough information on the undelaying biological mechanism. Genome‐wide association studies of endophenotypes have identified new loci associated with Alzheimer’s disease. To better understand AD pathology and identify new variants implicated in AD much larger samples size is needed. We conducted a GWAS of Amyloid‐beta (Aβ42) tau, and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) to detect novel variants associated with AD.MethodsAD CSF biomarkers were measured in 7282 individuals from 24 different cohorts. Samples were genotyped using different array technology with stringent quality control standards to each dataset before combining datasets. Minimum call rate for single nucleotide polymorphism (SNP) and individuals was 99.85%. SNPs not in Hardy–Weinberg equilibrium were excluded. X‐chromosome SNPs were analyzed to verify sex identification. Duplicates and cryptic relatedness among samples were tested by pairwise genome‐wide estimates of proportion identity‐by‐descent. PLINK was used to calculate principal component analysis. CSF biomarker levels were log10‐transformed to approximate a normal distribution with the mean standardized to zero for each dataset to account for the variability on the different platforms used to measure proteins levels. One‐stage joint‐GWAS to maximize the power in our analysis. Post‐GWAS analyses Colocalization, Madelian Randomization, LD Score Regression, were implemented to detect colocalization of two potential related signals to detect common causal variant and to evaluate the overlap in genetic architecture of CSF Biomarkers and risk factor for ADResultsThis study represents one of the largest multi‐cohort GWAS analyses on CSF AD biomarkers. Several genome‐wide significant hits were found including APOE. Additional analyses are underway.ConclusionsCSF Aβ42, tau, and ptau are well established AD endophenotypes with a clear genetic association with APOE genotype and AD risk. Genetic studies on endophenotypes provide enough power to detect association with a smaller sample size than case‐control studies helping us to better understand the biological mechanism of the disease. With this study we aim to identify novel variants implicated in AD.

Changes of basal forebrain volume along the Alzheimer’s disease continuum in Down syndrome

AbstractBackgroundAtrophy of basal forebrain (BF) cholinergic neurons is an early event in Alzheimer’s disease (AD) and is associated with cognitive impairment. Down syndrome (DS) is now recognized as a genetically determined form of AD. Therefore, people with DS represent a priority population to study biomarkers of AD pathology and neurodegeneration. Degeneration of BF neurons occurs both in sporadic AD and in DS brains with advanced AD pathology. However, the dynamics of BF atrophy and its changes with age and AT(N) biomarkers have not been studied in DS.MethodWe included 246 adults with DS (mean age 43.2 ±11.0 years; 43% female). Volumes of antero‐medial and posterior areas of the BF (amBF and pBF, respectively) were extracted from T1‐weighted 3T MR images using voxel‐based morphometry in SPM12 in combination with a stereotactic atlas of BF functional subdivisions (Figure 1). Differences in amBF and pBF volume in each AD clinical stage (Asymptomatic, Prodromal and Demented) were assessed with Kruskall‐Wallis and pairwise Wilcoxon tests. The relationship of BF volumes with age and AT(N) biomarkers in the cerebrospinal fluid (CSF) (amyloid‐β 42/40 ratio [aβ ratio], phosphorylated Tau 181 [pTau], total Tau [tTau] and neurofilament light [NFL]) was assessed in a subset of subjects (n = 161 [aβ ratio, pTau and tTau] and n = 95 [NFL]) with locally estimated scatterplot smoothing (LOESS) and linear regression in R, respectively.ResultVolumes of amBF and pBF decreased significantly with age (Figure 2), with a steeper decline during the fifth decade of life. BF volumes also declined with AD clinical stage (Figure 3), and had significant correlations with CSF aβ ratio (p&lt;0.001 r2 = 0.22), pTau (p&lt;0.001 r2 = 0.20), tTau (p&lt;0.001 r2 = 0.20) and NFL (p&lt;0.001 r2 = 0.33) (Figure 4).ConclusionIn DS, BF volume decreases with age, AT(N) biomarkers and along the cognitive stages of the AD continuum.

Estimated glomerular filtration rate is a biomarker of cognitive impairment in Parkinson's disease.

The relationship between kidney function and cognitive impairment in Parkinson's disease (PD) is poorly understood and underexplored. This study aims to explore whether renal indices can serve as indicators to monitor the cognitive impairment of PD. A total of 508 PD patients and 168 healthy controls from the Parkinson's Progression Markers Initiative (PPMI) were recruited, and 486 (95.7%) PD patients underwent longitudinal measurements. The renal indicators including serum creatinine (Scr), uric acid (UA), and urea nitrogen, as well as UA/Scr ratio and estimated glomerular filtration rate (eGFR), were measured. Cross-sectional and longitudinal associations between kidney function and cognitive impairment were evaluated using multivariable-adjusted models. eGFR was associated with lower levels of cerebrospinal fluid (CSF) Aβ1-42 (p = 0.0156) and α-synuclein (p = 0.0151) and higher serum NfL (p = 0.0215) in PD patients at baseline. Longitudinal results showed that decreased eGFR predicted a higher risk of cognitive impairment (HR = 0.7382, 95% CI = 0.6329-0.8610). Additionally, eGFR decline was significantly associated with higher rates of increase in CSF T-tau (p = 0.0096), P-tau (p = 0.0250), and serum NfL (p = 0.0189), as well as global cognition and various cognitive domains (p < 0.0500). The reduced UA/Scr ratio was also linked to higher NfL levels (p = 0.0282) and greater accumulation of T-tau (p = 0.0282) and P-tau (p = 0.0317). However, no significant associations were found between other renal indices and cognition. eGFR is altered in PD subjects with cognitive impairment, and predict larger progression of cognitive decline. It may assist identifying patients with PD at risk of rapid cognitive decline and have the potential to monitoring responses to therapy in future clinical practice.

CSF Aβ42 and tau biomarkers in cognitively unimpaired Aβ- middle-aged and older APOE ε4 carriers

This study aimed to determine the relationship between the apolipoprotein E (APOE) ε4 allele and cerebrospinal fluid (CSF) and neuroimaging biomarkers of Alzheimer’s disease, and cognition in cognitively unimpaired (CU) middle-aged adults (n = 82; Mage = 58.2), and in Aβ- CU older adults (n = 71; Mage = 71.8). Aβ- CU middle-aged ε4 carriers showed lower CSF Aβ42 levels, higher levels of CSF total tau (t-tau) and neurofilament light (NfL), and poorer cognitive performance compared to noncarriers (Cohen’s d: 0.30–0.56). In Aβ- CU older adults, ε4 carriers also had lower CSF Aβ42 levels and higher levels of CSF t-tau and p-tau181, compared to noncarriers (Cohen’s d: 0.65–0.74). In both Aβ- middle-aged and older adults, hippocampal and total brain volume were equivalent between ε4 carriers and noncarriers. In Aβ- CU middle-aged adults, APOE ε4 is associated with decreased levels of Aβ, increased tau and NfL, and poorer cognition. Similar relationships were observed in Aβ- CU older adults. These results have implications for understanding clinicopathological relationships between APOE ε4 and the emergence of cognitive and biomarker abnormalities in Aβ- adults.

Comparing Tau PET Visual Interpretation with Tau PET Quantification, Cerebrospinal Fluid Biomarkers, and Longitudinal Clinical Assessment.

18F-flortaucipir PET received FDA approval to visualize aggregated neurofibrillary tangles (NFTs) in brains of adult patients with cognitive impairment being evaluated for Alzheimer's disease (AD). However, manufacturer's guidelines for visual interpretation of 18F-flortaucipir PET differ from how 18F-flortaucipir PET has been measured in research settings using standardized uptake value ratios (SUVRs). How visual interpretation relates to 18F-flortaucipir PET SUVR, cerebrospinal fluid (CSF) biomarkers, or longitudinal clinical assessment is not well understood. We compare various diagnostic methods in participants enrolled in longitudinal observational studies of aging and memory (n = 189, 23 were cognitively impaired). Participants had tau PET, Aβ PET, MRI, and clinical and cognitive evaluation within 18 months (n = 189); the majority (n = 144) also underwent lumbar puncture. Two radiologists followed manufacturer's guidelines for 18F-flortaucipir PET visual interpretation. Visual interpretation had high agreement with SUVR (98.4%)and moderate agreement with CSF p-tau181 (86.1%). Two participants demonstrated 18F-flortaucipir uptake from meningiomas. Visual interpretation could not predict follow-up clinical assessment in 9.52% of cases. Visual interpretation was highly consistent with SUVR (discordant participants had hemorrhagic infarcts or occipital-predominant AD NFT deposition) and moderately consistent with CSF p-tau181 (discordant participants had AD pathophysiology not detectable on tau PET). However, close association between AD NFT deposition and clinical onset in group-level studies does not necessarily hold at the individual level, with discrepancies arising from atypical AD, vascular dementia, or frontotemporal dementia. A better understanding of relationships across imaging, CSF biomarkers, and clinical assessment is needed to provide appropriate diagnoses for these individuals.

Neuroinflammatory CSF biomarkers MIF, sTREM1, and sTREM2 show dynamic expression profiles in Alzheimer’s disease

BackgroundThere is a need for novel fluid biomarkers tracking neuroinflammatory responses in Alzheimer’s disease (AD). Our recent cerebrospinal fluid (CSF) proteomics study revealed that migration inhibitory factor (MIF) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1) increased along the AD continuum. We aimed to assess the potential use of these proteins, in addition to sTREM2, as CSF biomarkers to monitor inflammatory processes in AD.MethodsWe included cognitively unimpaired controls (n = 67, 63 ± 9 years, 24% females, all amyloid negative), patients with mild cognitive impairment (MCI; n = 92, 65 ± 7 years, 47% females, 65% amyloid positive), AD (n = 38, 67 ± 6 years, 8% females, all amyloid positive), and DLB (n = 50, 67 ± 6 years, 5% females, 54% amyloid positive). MIF, sTREM1, and sTREM2 levels were measured by validated immunoassays. Differences in protein levels between groups were tested with analysis of covariance (corrected for age and sex). Spearman correlation analysis was performed to evaluate the association between these neuroinflammatory markers with AD-CSF biomarkers (Aβ42, tTau, pTau) and mini-mental state examination (MMSE) scores.ResultsMIF levels were increased in MCI (p < 0.01), AD (p < 0.05), and DLB (p > 0.05) compared to controls. Levels of sTREM1 were specifically increased in AD compared to controls (p < 0.01), MCI (p < 0.05), and DLB patients (p > 0.05), while sTREM2 levels were increased specifically in MCI compared to all other groups (all p < 0.001). Neuroinflammatory proteins were highly correlated with CSF pTau levels (MIF: all groups; sTREM1: MCI, AD and DLB; sTREM2: controls, MCI and DLB). Correlations with MMSE scores were observed in specific clinical groups (MIF in controls, sTREM1 in AD, and sTREM2 in DLB).ConclusionInflammatory-related proteins show diverse expression profiles along different AD stages, with increased protein levels in the MCI stage (MIF and sTREM2) and AD stage (MIF and sTREM1). The associations of these inflammatory markers primarily with CSF pTau levels indicate an intertwined relationship between tau pathology and inflammation. These neuroinflammatory markers might be useful in clinical trials to capture dynamics in inflammatory responses or monitor drug–target engagement of inflammatory modulators.

Plasma p-tau181 as a promising non-invasive biomarker of Alzheimer’s Disease pathology in Subjective Cognitive Decline. (P7-6.001)

<h3>Objective:</h3> To explore plasma phosphorylated tau (p-tau) 181 levels in Subjective Cognitive Decline and to investigate its role as a potential biomarker for Alzheimer’s Disease (AD) in Subjective Cognitive Decline (SCD). <h3>Background:</h3> One of the greatest challenges in AD is the discovery of new non-invasive, sensitive and specific biomarkers, which might be useful in the early stages such as SCD. Plasma p-tau181 is becoming increasingly notable in prodromal stages of AD, as a valuable marker for tauopathy, one of the core features of AD. <h3>Design/Methods:</h3> We included 27 SCD patients, who underwent clinical evaluation, neuropsychological assessment, Apolipoprotein E (APOE) genotyping, plasma p-tau181 analysis with SiMoA assay and cerebrospinal fluid (CSF) biomarkers analysis (Aβ1–42, Aβ1–42/1–40, p-tau, t-tau).Patients were rated according to A/T(N) system and classified as carrier of AD pathology (AP+) when A+ was associated with either T+ or N+, or non-carriers (AP−) when they were classified as A− (regardless of T and N classification), or A+/T−/N−. <h3>Results:</h3> Plasma p-tau181 levels were correlated with CSF p-tau (ϱ=0.819, <i>p</i>&lt;0.001) and also with age (ϱ=0.605, <i>p</i>=0.001), CSF Aβ1–42 (ϱ= −0.461, <i>p</i>=0.012), CSF Aβ1–42/1–40 (ϱ= −0.770, <i>p</i>&lt;0.001) and CSF t-tau (ϱ=0.535, <i>p</i>=0.009). A multivariate linear regression analysis showed that plasma p-tau181 were significantly associated only with CSF p-tau levels (<i>p</i>=0.027). When comparing AP+ and AP− subgroups, we found that plasma p-tau181 levels were significantly higher in the former group (2.85±0.53 vs 1.75±.66, <i>p</i>&lt;0.001). A ROC curve analysis demonstrated that plasma p-tau181 was highly accurate for discriminating between AP+ and AP− SCD patients (AUC = 0.908). <h3>Conclusions:</h3> Plasma p-tau181 levels strongly correlated with CSF p-tau. Plasma p-tau showed a high accuracy in differentiating SCD patients who were carriers from SCD patients who were non-carriers of AD pathology. Our preliminary results suggest that plasma p-tau181 might be a promising noninvasive biomarker of AD pathology which might be useful in preclinical stage of AD. <b>Disclosure:</b> Ms. Giacomucci has nothing to disclose. Mr. Mazzeo has nothing to disclose. Dr. Bagnoli has nothing to disclose. Dr. Ingannato has nothing to disclose. Sonia Padiglioni has nothing to disclose. Sandro Sorbi has nothing to disclose. Valentina Bessi has nothing to disclose. Benedetta Nacmias has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier.