Alzheimer's Disease Biomarkers Research Articles

Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer's disease.

Recent expansion of proteomic coverage opens unparalleled avenues to unveil new biomarkers of Alzheimer's disease (AD). Among 6,361 cerebrospinal fluid (CSF) proteins analysed from the ADNI database, YWHAG performed best in diagnosing both biologically (AUC = 0.969) and clinically (AUC = 0.857) defined AD. Four- (YWHAG, SMOC1, PIGR and TMOD2) and five- (ACHE, YWHAG, PCSK1, MMP10 and IRF1) protein panels greatly improved the accuracy to 0.987 and 0.975, respectively. Their superior performance was validated in an independent external cohort and in discriminating autopsy-confirmed AD versus non-AD, rivalling even canonical CSF ATN biomarkers. Moreover, they effectively predicted the clinical progression to AD dementia and were strongly associated with AD core biomarkers and cognitive decline. Synaptic, neurogenic and infectious pathways were enriched in distinct AD stages. Mendelian randomization did not support the significant genetic link between CSF proteins and AD. Our findings revealed promising high-performance biomarkers for AD diagnosis and prediction, with implications for clinical trials targeting different pathomechanisms.

Associations of endogenous estrogens, plasma Alzheimer's disease biomarkers, and APOE4 carrier status on regional brain volumes in postmenopausal women.

Women carrying the APOE4 allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by APOE4 carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes in a sample of late midlife postmenopausal women. Participants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, APOE4 carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography-tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aβ42/Aβ40, Aβ42/p-tau181), and APOE4 carrier status predict regional brain volume (21 regions per hemisphere, selected a priori); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by APOE4 carrier status. There was no main effect of APOE4 carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and APOE4 carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aβ42/40, lower Aβ42/p-tau181 ratios). In APOE4-stratified analyses, these interactions were driven by non-APOE4 carriers. We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non-APOE4 carriers, suggesting that APOE4 carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause.

Investigation of the Circular Transcriptome in Alzheimer’s Disease Brain

Circular RNAs (circRNAs) are a subclass of non-coding RNAs which have demonstrated potential as biomarkers for Alzheimer’s disease (AD). In this study, we conducted a comprehensive exploration of the circRNA transcriptome within AD brain tissues. Specifically, we assessed circRNA expression patterns in the dorsolateral prefrontal cortex collected from nine AD-afflicted individuals and eight healthy controls. Utilising two circRNA detection tools, CIRI2 and CIRCexplorer2, we detected thousands of circRNAs and performed a differential expression analysis. CircRNAs which exhibited statistically significantly differential expression were identified as AD-specific differentially expressed circRNAs. Notably, our investigation revealed 120 circRNAs with significant upregulation and 1325 circRNAs displaying significant downregulation in AD brains when compared to healthy brain tissue. Additionally, we explored the expression profiles of the linear RNA counterparts corresponding to differentially expressed circRNAs in AD-afflicted brains and discovered that the linear RNA counterparts exhibited no significant changes in the levels of expression. We used CRAFT tool to predict that circUBE4B had potential to target miRNA named as hsa-miR-325-5p, ultimately regulated CD44 gene. This study provides a comprehensive overview of differentially expressed circRNAs in the context of AD brains, underscoring their potential as molecular biomarkers for AD. These findings significantly enhance our comprehension of AD’s underlying pathophysiological mechanisms, offering promising avenues for future diagnostic and therapeutic developments.

Associations between Microglia and Astrocytic Proteins and Tau Biomarkers across the Continuum of Alzheimer's Disease.

Recent investigations implicate neuroinflammatory changes, including astrocyte and microglia activation, as crucial in the progression of Alzheimer's disease (AD) Thus, we compared selected proteins reflecting neuroinflammatory processes to establish their connection to AD pathologies. Our study, encompassing 80 subjects with (n = 42) AD, (n = 18) mild cognitive impairment (MCI) and (n = 20) non-demented controls compares the clinical potential of tested molecules. Using antibody-based methods, we assessed concentrations of NGAL, CXCL-11, sTREM1, and sTREM2 in cerebrospinal fluid (CSF). Proinflammatory proteins, NGAL, and CXCL-11 reached a peak in the early stage of the disease and allowed for the identification of patients with MCI. Furthermore, the concentration of the anti-inflammatory molecule sTREM2 was highest in the more advanced stage of the disease and permitted differentiation between AD and non-demented controls. Additionally, sTREM2 was biochemically linked to tau and pTau in the AD group. Notably, NGAL demonstrated superior diagnostic performance compared to classical AD biomarkers in discriminating MCI patients from controls. These findings suggest that proteins secreted mainly through microglia dysfunction might play not only a detrimental but also a protective role in the development of AD pathology.

The memory binding test in a longitudinal study of cognitive aging and preclinical disease.

The Memory Binding Test (MBT) shows promise in detecting early cognitive changes associated with Alzheimer's disease (AD). This study assesses the psychometric properties (i.e., construct and criterion validity, test-retest reliability) of the MBT and its sensitivity to incipient disease and incident cognitive impairment. One hundred forty-nine cognitively unimpaired adults ages 45-85 completed the MBT and neuropsychological tests at baseline; 132 returned for 2-year follow-up. Based on neuroradiological ratings of amyloid positron emission tomography and MRI markers at baseline, they were categorized as healthy (n = 94) or having preclinical disease (n = 55, either on the AD continuum or having non-AD pathologic change). Construct validity was assessed by the associations between MBT scores, demographics, and neuropsychological scores within the healthy group. Criterion validity was assessed by testing how MBT scores correlate with AD biomarkers, differ and discriminate between groups at baseline, and predict incident cognitive impairment. MBT scores decreased with age and were strongly associated with memory and global cognition. MBT scores were largely not associated with amyloid, hippocampal volume, or AD signature cortical volume but related to white matter lesion volume in those with preclinical disease. The preclinical groups performed worse on MBT immediate free recall at baseline than the healthy group, but no scores predicted incident cognitive impairment at follow-up. Most scores demonstrated modest test-retest reliability. This study demonstrates that the MBT has adequate construct validity in cognitively unimpaired adults, moderate sensitivity to preclinical disease cross-sectionally, and limited prognostic utility. Careful consideration of demographic influences on score interpretation remains necessary. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Adenosine A2A Receptor Antagonist Sch58261 Improves the Cognitive Function in Alzheimer's Disease Model Mice Through Activation of Nrf2 via an Autophagy-Dependent Pathway.

Aims: Adenosine, an important endogenous neuromodulator, contributes to a broad set of several neurodegenerative diseases. The adenosine A2A receptor (A2AR) is the most involved in neuropathological effects and plays an important role in the pathogenesis of Alzheimer's disease (AD). However, the effect of A2AR antagonist and the underlying mechanism in AD model mice remains unclear. Results: The amyloid beta (Aβ)1-42-induced mice AD models were used in this study. Several behavioral experiments were performed to evaluate the improvement of AD mice treated with A2AR antagonist. For mechanism analysis, autophagy-related proteins, Kelch-like ECH-associated protein1 (Keap1)-nuclear factor erythroid-derived factor 2-related factor (Nrf2) pathway activation, and synaptic function were studied using Western blot, immunofluorescence, immunohistochemistry, transmission electron microscope, real-time quantitative PCR, and patch clamp. Pharmacological blockade of adenosine A2AR by SCH58261 (SCH) ameliorated cognitive deficits and decreased expression levels of several AD biomarkers, including Aβ and hyperphosphorylation of Tau. Moreover, SCH activated the Nrf2 pathway through autophagy mediated Keap1 degradation, resulting in the improvement of neuron autophagy dysfunction, synaptic plasticity, and synaptic transmission. Innovation: Our data clarified that the SCH (an antagonist of A2AR) could increase the level of autophagy, promote the ability of antioxidative stress by the activation of Keap1-Nrf2 pathway, and improve the synaptic function in Aβ1-42-induced AD mice or cell model, which provided a potential therapeutic strategy for AD. Conclusion: A2AR antagonism represents a promising strategy for the anti-AD agent development through autophagy-dependent pathway.

18F]-D3FSP β-amyloid PET imaging in older adults and alzheimer's disease.

[18F]-D3FSP is a new β-amyloid (Aβ) PET imaging tracer designed to decrease nonspecific signals in the brain by reducing the formation of the N-demethylated product. However, its optimal reference region for calculating the standardized uptake value ratio (SUVR) and its relation to the well-established biomarkers of Alzheimer's disease (AD) are still unclear. We recruited 203 participants from the Greater Bay Area Healthy Aging Brain Study (GHABS) to undergo [18F]-D3FSP Aβ PET imaging. We analyzed plasma Aβ42/Aβ40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. We compared the standardized uptake value (SUV) of five reference regions (cerebellum, cerebellum cortex, brainstem/PONs, white matter, composite of the four regions above) and AD typical cortical region (COMPOSITE) SUVR among different clinical groups. The association of D3FSP SUVR with plasma biomarkers, imaging biomarkers, and cognition was also investigated. Brainstem/PONs SUV showed the lowest fluctuation across diagnostic groups, and COMPOSITE D3FSP SUVR had an enormous effect distinguishing cognitively impaired (CI) individuals from cognitively unimpaired (CU) individuals. COMPOSITE SUVR (Referred to brainstem/PONs) was positively correlated with p-Tau181 (p < 0.001), GFAP (p < 0.001), NfL (p = 0.014) in plasma and temporal-metaROI tau deposition (p < 0.001), and negatively related to plasma Aβ42/Aβ40 (p < 0.001), temporal-metaROI cortical thickness (p < 0.01), residual hippocampal volume (p < 0.001) and cognition (p < 0.001). The voxel-wise analysis replicated these findings. This study suggests brainstem/PONs as an optimal reference region for calculating D3FSP SUVR to quantify cortical Aβ plaques in the brain. [18F]-D3FSP could distinguish CI from CU and strongly correlates with well-established plasma biomarkers, tau PET, neurodegeneration, and cognitive decline. However, future head-to-head comparisons of [18F]-D3FSP PET images with other validated Aβ PET tracers or postmortem results are crucial.

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression

While immune function is known to play a mechanistic role in Alzheimer’s disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression – a central feature of AD – remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aβ accumulation, including causal relationships with Aβ PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.

Longitudinal plasma phosphorylated-tau217 and other related biomarkers in a non-demented Alzheimer's risk-enhanced sample.

Understanding longitudinal change in key plasma biomarkers will aid in detecting presymptomatic Alzheimer's disease (AD). Serial plasma samples from 424 Wisconsin Registry for Alzheimer's Prevention participants were analyzed for phosphorylated-tau217 (p-tau217; ALZpath) and other AD biomarkers, to study longitudinal trajectories in relation to disease, health factors, and cognitive decline. Of the participants, 18.6% with known amyloid status were amyloid positive (A+); 97.2% were cognitively unimpaired (CU). In the CU, amyloid-negative (A-) subset, plasma p-tau217 levels increased modestly with age but were unaffected by body mass index and kidney function. In the whole sample, average p-tau217 change rates were higher in those who were A+ (e.g., simple slopes(se) for A+ and A- at age 60 were 0.232(0.028) and 0.038(0.013))). High baseline p-tau217 levels predicted faster preclinical cognitive decline. p-tau217 stands out among markers for its strong association with disease and cognitive decline, indicating its potential for early AD detection and monitoring progression. Phosphorylated-tau217 (p-tau217) trajectories were significantly different in people who were known to be amyloid positive. Subtle age-related trajectories were seen for all the plasma markers in amyloid-negative cognitively unimpaired. Kidney function and body mass index were not associated with plasma p-tau217 trajectories. Higher plasma p-tau217 was associated with faster preclinical cognitive decline.

Novel measures of cognition and function for the AD spectrum in the Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD) project: Psychometric properties, convergent validation, and contrasts with established measures.

This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early-stage Alzheimer's disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well-established measures. For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers. Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test-retest reliability) and stronger associations with AD-related demographic, genetic, and brain risk markers than well-established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early-stage AD clinical trials. Well-established cognitive tests may not accurately detect subtle cognitive changes. No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties. NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains. Novel measures had better psychometric properties compared to established measures. Significant associations with Alzheimer's disease biomarkers were found with novel measures.

Time-encoded ASL reveals lower cerebral blood flow in the early AD continuum.

Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time-encoded arterial spin labeling (te-ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals. We compared te-ASL with single-postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aβ) negative (-), CU Aβ positive (+), and CI Aβ+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants. te-ASL was more sensitive at detecting CBF reduction in the CU Aβ+ and CI Aβ+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aβ, tau, synaptic dysfunction, and neurodegeneration. CBF reduction occurs early in the AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF changes in AD. Lower CBF can be detected in CU subjects in the early AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF alterations in AD. CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration.

Neuroimaging biomarkers and CSF sTREM2 levels in Alzheimer’s disease: a longitudinal study

Understanding the exact pathophysiological mechanisms underlying the involvement of triggering receptor expressed on myeloid cells 2 (TREM2) related microglia activation is crucial for the development of clinical trials targeting microglia activation at different stages of Alzheimer’s disease (AD). Given the contradictory findings in the literature, it is imperative to investigate the longitudinal alterations in cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels as a marker for microglia activation, and its potential association with AD biomarkers, in order to address the current knowledge gap. In this study, we aimed to assess the longitudinal changes in CSF sTREM2 levels within the framework of the A/T/N classification system for AD biomarkers and to explore potential associations with AD pathological features, including the presence of amyloid-beta (Aβ) plaques and tau aggregates. The baseline and longitudinal (any available follow-up visit) CSF sTREM2 levels and processed tau-PET and Aβ-PET data of 1001 subjects were recruited from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A+ /TN+ , A+ /TN− , A− /TN+ , and A− /TN− . Linear regression analyses were conducted to assess the relationship between CSF sTREM2 with cognitive performance, tau and Aβ-PET adjusting for age, gender, education, and APOE ε4 status. Based on our analysis there was a significant difference in baseline and rate of change of CSF sTREM2 between ATN groups. While there was no association between baseline CSF sTREM2 and cognitive performance (ADNI-mem), we found that the rate of change of CSF sTREM2 is significantly associated with cognitive performance in the entire cohort but not the ATN groups. We found that the baseline CSF sTREM2 is significantly associated with baseline tau-PET and Aβ-PET rate of change only in the A+ /TN+ group. A significant association was found between the rate of change of CSF sTREM2 and the tau- and Aβ-PET rate of change only in the A+ /TN− group. Our study suggests that the TREM2-related microglia activation and their relations with AD markers and cognitive performance vary the in presence or absence of Aβ and tau pathology. Furthermore, our findings revealed that a faster increase in the level of CSF sTREM2 might attenuate future Aβ plaque formation and tau aggregate accumulation only in the presence of Aβ pathology.

The role of the Alzheimer's Disease Neuroimaging Initiative in establishing the Dominantly Inherited Alzheimer Network.

The Dominantly Inherited Alzheimer Network (DIAN) initially was funded by the National Institute on Aging (NIA) in 2008 and thus was able to adopt and incorporate the protocols developed by the Alzheimer's Disease Neuroimaging Initiative (ADNI) that had been established by the NIA in 2004. The use of ADNI protocols for DIAN neuroimaging studies and assays of biological fluids for Alzheimer disease (AD) biomarkers permitted examination of the hypothesis that autosomal dominant AD (ADAD), studied by DIAN, and "sporadic" late-onset AD (LOAD), studied by ADNI, shared the same pathobiological construct. In a collaborative effort, the longitudinal DIAN and ADNI databases were compared and the findings supported the conclusion that ADAD and LOAD share a similar pathophysiology. The importance of the DIAN study thus is amplified by its relevance to LOAD, as characterized by the "parent" ADNI program.

Nanoscale flow cytometry-based quantification of blood-based extracellular vesicle biomarkers distinguishes MCI and Alzheimer's disease.

Accurate testing for Alzheimer's disease (AD) represents a crucial step for therapeutic advancement. Currently, tests are expensive and require invasive sampling or radiation exposure. We developed a nanoscale flow cytometry (nFC)-based assay of extracellular vesicles (EVs) to screen biomarkers in plasma from mild cognitive impairment (MCI), AD, or controls. Circulating amyloid beta (Aβ), tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, p-tauS235, ubiquitin, and lysosomal-associated membrane protein 1-positive EVs distinguished AD samples. p-tau181, p-tau217, p-tauS235, and ubiquitin-positive EVs distinguished MCI samples. The most sensitive marker for AD distinction was p-tau231, with an area under the receiver operating characteristic curve (AUC) of 0.96 (sensitivity 0.95/specificity 1.0) improving to an AUC of 0.989 when combined with p-tauS235. This nFC-based assay accurately distinguishes MCI and AD plasma without EV isolation, offering a rapid approach requiring minute sample volumes. Incorporating nFC-based measurements in larger populations and comparison to "gold standard" biomarkers is an exciting next step for developing AD diagnostic tools. Extracellular vesicles represent promising biomarkers of Alzheimer's disease (AD) that can be measured in the peripheral circulation. This study demonstrates the utility of nanoscale flow cytometry for the measurement of circulating extracellular vesicles (EVs) in AD blood samples. Multiple markers including amyloid beta, tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, and p-tauS235 accurately distinguished AD samples from healthy controls. Future studies should expand blood and cerebrospinal fluid-based EV biomarker development using nanoflow cytometry approaches.

Diffusion model enables quantitative CBF analysis of Alzheimer's Disease.

Cerebral blood flow (CBF) measured by arterial spin labeling (ASL) is a promising biomarker for Alzheimer's Disease (AD). ASL data from multiple vendors were included in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. However, the M0 images were missing in Siemens ASL data, prohibiting CBF quantification. Here, we utilized a generative diffusion model to impute the missing M0 and validated generated CBF data with acquired data from GE. A conditional latent diffusion model was trained to generate the M0 image and validate it on an in-house dataset (N=55) based on image similarity metrics, accuracy of CBF quantification, and consistency with the physical model. This model was then applied to the ADNI dataset (Siemens: N=211) to impute the missing M0 for CBF calculation. We further compared the imputed data (Siemens) and acquired data (GE) regarding regional CBF differences by AD stages, their classification accuracy for AD prediction, and CBF trajectory slopes estimated by a mixed effect model. The trained diffusion model generated the M0 image with high fidelity (Structural similarity index, SSIM=0.924±0.019; peak signal-to-noise ratio, PSNR=33.348±1.831) and caused minimal bias in CBF values (mean difference in whole brain is 1.07±2.12ml/100g/min). Both generated and acquired CBF data showed similar differentiation patterns by AD stages, similar classification performance, and decreasing slopes with AD progression in specific AD-related regions. Generated CBF data also improved accuracy in classifying AD stages compared to qualitative perfusion data. This study shows the potential of diffusion models for imputing missing modalities for large-scale studies of CBF variation with AD.

Data-driven retrieval of population-level EEG features and their role in neurodegenerative diseases.

Electrophysiologic disturbances due to neurodegenerative disorders such as Alzheimer's disease and Lewy Body disease are detectable by scalp EEG and can serve as a functional measure of disease severity. Traditional quantitative methods of EEG analysis often require an a-priori selection of clinically meaningful EEG features and are susceptible to bias, limiting the clinical utility of routine EEGs in the diagnosis and management of neurodegenerative disorders. We present a data-driven tensor decomposition approach to extract the top 6 spectral and spatial features representing commonly known sources of EEG activity during eyes-closed wakefulness. As part of their neurologic evaluation at Mayo Clinic, 11 001 patients underwent 12 176 routine, standard 10-20 scalp EEG studies. From these raw EEGs, we developed an algorithm based on posterior alpha activity and eye movement to automatically select awake-eyes-closed epochs and estimated average spectral power density (SPD) between 1 and 45 Hz for each channel. We then created a three-dimensional (3D) tensor (record × channel × frequency) and applied a canonical polyadic decomposition to extract the top six factors. We further identified an independent cohort of patients meeting consensus criteria for mild cognitive impairment (30) or dementia (39) due to Alzheimer's disease and dementia with Lewy Bodies (31) and similarly aged cognitively normal controls (36). We evaluated the ability of the six factors in differentiating these subgroups using a Naïve Bayes classification approach and assessed for linear associations between factor loadings and Kokmen short test of mental status scores, fluorodeoxyglucose (FDG) PET uptake ratios and CSF Alzheimer's Disease biomarker measures. Factors represented biologically meaningful brain activities including posterior alpha rhythm, anterior delta/theta rhythms and centroparietal beta, which correlated with patient age and EEG dysrhythmia grade. These factors were also able to distinguish patients from controls with a moderate to high degree of accuracy (Area Under the Curve (AUC) 0.59-0.91) and Alzheimer's disease dementia from dementia with Lewy Bodies (AUC 0.61). Furthermore, relevant EEG features correlated with cognitive test performance, PET metabolism and CSF AB42 measures in the Alzheimer's subgroup. This study demonstrates that data-driven approaches can extract biologically meaningful features from population-level clinical EEGs without artefact rejection or a-priori selection of channels or frequency bands. With continued development, such data-driven methods may improve the clinical utility of EEG in memory care by assisting in early identification of mild cognitive impairment and differentiating between different neurodegenerative causes of cognitive impairment.

Free Recall Outperforms Story Recall in Associations with Plasma Biomarkers in Preclinical Alzheimer Disease

BackgroundA decline in episodic memory is one of the earliest cognitive characteristics of Alzheimer disease and memory tests are heavily featured in cognitive composite endpoints that are used to demonstrate treatment efficacy. Assessments of episodic memory can take many forms including free recall, associate learning, and paragraph or story recall. Plasma biomarkers of Alzheimer disease are now widely available and will likely form the backbone of cohort enrichment strategies for future clinical trials. Thus, it is critical to evaluate which episodic memory measures are most sensitive to plasma markers of Alzheimer disease pathology.ObjectivesTo compare the associations of common episodic memory tests with plasma biomarkers of Alzheimer disease.DesignLongitudinal cohort study.SettingAcademic medical center in the midwestern United States.ParticipantsA total of 161 cognitively normal older adults with at least one plasma biomarker assessment and two or more annual clinical and cognitive assessments which included up to three different tests of episodic memory.MeasurementsEpisodic memory performance using free recall, paired associates recall or paragraph recall. Plasma Aβ42, Aβ40, ptau217, and neurofilament light chain were measured.ResultsFree recall on the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) was substantially more sensitive to longitudinal cognitive change associated with abnormal baseline plasma Aβ42/Aβ40 and ptau217 compared to other measures of episodic memory. A cognitive composite that included only free recall showed larger decline associated with baseline Aβ42/Aβ40 when compared to those that included paragraph recall. Differences in decline across composites were minimal when considering baseline ptau217 or NfL.ConclusionEpisodic memory is a critical domain to assess in preclinical Alzheimer disease. Methods of assessing memory are not equal and longitudinal change in free recall substantially outperformed both paired associates and paragraph recall. Clinical trial results will depend critically on the episodic memory test(s) that are chosen for a composite endpoint and free recall from the FCSRT + IR is an optimal memory measure to include rather than paired associates or paragraph recall.

Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C2N Diagnostics’ PrecivityAD test for Aβ42 and Aβ40. Compared to white individuals, Black individuals had higher average plasma Aβ42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aβ40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aβ42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups.

Changes in Alzheimer's disease blood biomarkers in kidney failure before and after kidney transplant.

Alzheimer's disease (AD) blood biomarkers show promise for clinical diagnosis but their reliability in chronic kidney disease (CKD) is debated. This study investigates the impact of kidney transplant (KT) on AD biomarkers in CKD. We assessed AD biomarkers in 46 CKD patients pre-KT, at 12weeks and 12 months post-KT, with baseline measures from 13 non-CKD controls. Using linear mixed models, we examined associations with participant groups, estimated glomerular filtration rate (eGFR) and cognition. CKD patients showed elevated levels of neurofilament light (117±72vs. 11±5 pg/mL), phosphorylated tau 181 (75±42vs. 13±8 pg/mL), glial fibrillary acidic protein (193±127vs. 94±39 pg/mL), amyloid β 42 (17±5vs. 5±1 pg/mL), and amyloid β 40 (259±96vs. 72±17 pg/mL) compared to controls. Post-KT, biomarker levels approached normal with improved eGFR, paralleled by enhanced cognitive function. AD blood biomarker elevations in CKD are reversible with improved kidney function through KT. AD biomarker levels are extremely high in severe CKD.AD biomarker levels are higher in patients with kidney failure on dialysis when compared to CKD patients not on dialysis.These elevations in AD biomarker levels in kidney failure are reversable and decrease dramatically after kidney transplantation.The change in biomarker levels after transplantation align with changes in kidney function.The change in biomarker levels after transplantation align with changes in cognitive function.

Advances in Blood Biomarkers for Alzheimer's Disease: Ultra-Sensitive Detection Technologies and Impact on Clinical Diagnosis.

Alzheimer's disease has escalated into a critical public health concern, marked by its neurodegenerative nature that progressively diminishes cognitive abilities. Recognized as a continuously advancing and presently incurable condition, AD underscores the necessity for early-stage diagnosis and interventions aimed at delaying the decline in mental function. Despite the proven efficacy of cerebrospinal fluid and positron emission tomography in diagnosing AD, their broader utility is constrained by significant costs and the invasive nature of these procedures. Consequently, the innovation of blood biomarkers such as Amyloid-beta, phosphorylated-tau, total-tau et al, distinguished by their high sensitivity, minimal invasiveness, accessibility, and cost-efficiency, emerges as a promising avenue for AD diagnosis. The advent of ultra-sensitive detection methodologies, including single-molecule enzyme-linked immunosorbent assay and immunoprecipitation-mass spectrometry, has revolutionized the detection of AD plasma biomarkers, supplanting previous low-sensitivity techniques. This rapid advancement in detection technology facilitates the more accurate quantification of pathological brain proteins and AD-associated biomarkers in the bloodstream. This manuscript meticulously reviews the landscape of current research on immunological markers for AD, anchored in the National Institute on Aging-Alzheimer's Association AT(N) research framework. It highlights a selection of forefront ultra-sensitive detection technologies now integral to assessing AD blood immunological markers. Additionally, this review examines the crucial pre-analytical processing steps for AD blood samples that significantly impact research outcomes and addresses the practical challenges faced during clinical testing. These discussions are crucial for enhancing our comprehension and refining the diagnostic precision of AD using blood-based biomarkers. The review aims to shed light on potential avenues for innovation and improvement in the techniques employed for detecting and investigating AD, thereby contributing to the broader field of neurodegenerative disease research.