Alzheimer's & Dementia

IntroductionComprehensive treatment of Alzheimers disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. The Coaching for Cognition in Alzheimers (COCOA) trial was a prospective randomized controlled trial (RCT) to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage Alzheimers disease (AD). AD results from the interplay of multiple interacting dysfunctional biological systems. Specific causes of AD differ between individuals. Personalized, multimodal therapies are needed to best prevent and treat AD. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic and microbiome data at multiple timepoints across two years for each participant. These data enable systems-biology analyses. We report analyses of the first COCOA data freeze. This analysis includes an evaluation of the effect of the intervention on outcome measures. It also includes systems analyses to identify molecular mediators that convey the effect of personalized multimodal lifestyle interventions on amelioration of cognitive trajectory. MethodsA total of 55 participants with early-stage AD from Southern California were randomized into two parallel arms. Arm 1 (control; N=24) received standard of care. Arm 2 (intervention; N=31) also received telephonic personalized coaching for multiple lifestyle interventions including diet, exercise, and cognitive training. COCOAs overarching aim was to gather dense molecular data from an AD cohort to improve understanding of pathophysiology and advance treatment. For the RCT, COCOAs objective was to test the hypothesis that the Memory Performance Index (MPI) trajectory would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test (FAST) was assessed for a secondary outcome. Assessments were blinded. The nature of the intervention precluded participant blinding. ResultsThe intervention arm ameliorated 2.6 {+/-} 0.8 MPI points (p = 0.0007; N = 48) compared to the control arm over the two-year intervention. Top-ranked candidate mediators included: albumin, propionylcarnitine, sphingomyelin, hexadecanedioate, acetylkynurenine, tiglylcarnitine, IL18R1, palmitoyl-sphingosine-phosphoethanolamine, acetyltryptophan, and IL17D. These individual molecules implicated inflammatory and nitrogen/tryptophan metabolism pathways. No important adverse events or side effects were observed. ConclusionsClinical trials should include frequent assessment of dense data to maximize knowledge gained. Such knowledge is useful not only in testing a primary hypothesis, but also in advancing basic biological and pathophysiological knowledge, understanding mechanisms explaining trial results, generating synergistic knowledge tangential to preconceived hypotheses, and refining interventions for clinical translation. Data from every trial should allow an intervention to be refined and then tested in future trials, driving iterative improvement. Multimodal lifestyle interventions are effective for ameliorating cognitive decline and may have an effect size larger than pharmacological interventions. Effects may be molecularly idiosyncratic; personalization of interventions is important. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.

We examined whether a 24-week resistance training program influenced brain amyloid-{beta} (A{beta}) and Alzheimers Disease (AD)-related blood-based biomarkers. Ninety cognitively normal, physically inactive older adults aged 65-80 years were randomly allocated to a 24-week resistance training program (three [~]60-min supervised sessions/week) or a wait-list control group. Primary analyses assessed exercise-induced changes in brain A{beta} (Centiloid values) and plasma ptau217/A{beta}1-42 IPMS ratio. Secondary analyses examined ptau217/A{beta}42 SIMOA ratio, ptau217, ptau181 and A{beta}42/40, as well as potential interactions with sex, age, education, apolipoprotein {varepsilon}4 (APOE4) status, amyloid PET-positivity, and comorbidities. The intervention produced no significant differences on brain A{beta} or AD-related blood-based biomarkers (p>0.05) compared to the control group. However, the ptau217/A{beta}1-42 IPMS ratio showed a small, non-significant increase in the control group (SMD = 0.162; 95% CI: -0.159 to 0.483) while remaining stable in the exercise group (SMD = 0.01; 95% CI: -0.291 to 0.310) with a similar trend for ptau217/A{beta}42 SIMOA. Moderator analyses indicated differential responses by amyloid PET-positivity and APOE4 status on brain A{beta} (p for interaction<0.05), with increases observed in APOE4 carriers and amyloid PET-positive individuals in the control group, whereas those allocated to the exercise intervention reduced their levels. The specificity observed within our subgroups suggests that resistance exercise may serve as a targeted intervention to modulate AD pathophysiology, raising new questions regarding its broader role in the delay of the disease in vulnerable populations.

INTRODUCTIONWe validated plasma p-tau217 cut-points for Alzheimers disease (AD) diagnosis using two commercial assays in two biomarker-defined cohorts and examined influences of pre-analytical factors and chronic kidney disease (CKD) on p-tau217 concentrations. METHODSLumipulse (Fujirebio) and ALZpath (Quanterix) assays quantified plasma p-tau217 in symptomatic patients (AD status definition CSF n=257; amyloid PET n=76). ROC analyses established [&ge;]95% sensitivity/specificity cut-points. In separate cohorts we evaluated the impact of pre-analytical handling/transport variations (n=40/10) and cognitively normal (CN)-CKD individuals (n=58). RESULTSDiagnostic accuracy was similar (AUROC Lumipulse 0.947; ALZpath 0.940). Lumipulse p-tau217 achieved 95% sensitivity and 97% specificity using dual cut-points (0.153/0.422 pg/mL), producing indeterminate results in 19.4% (CSF-defined) and 34.2% (PET-defined). P-tau217 concentrations were stable across handling conditions and kit lots, and mostly in the low-to-intermediate range in CN-CKD. DISCUSSIONLumipulse plasma p-tau217, now available in our UKAS-accredited clinical NHS laboratory, will be used in a randomized trial of p-tau217 result disclosure in memory services.

BackgroundPathological brain changes such as white matter hyperintensities (WMHs) occur with increased age and contribute to cognitive decline. Current research is still unclear regarding the association of amyloid positivity with WMH burden and progression to dementia in people with mild cognitive impairment (MCI). MethodsThis study examined whether WMH burden increases differently in both amyloid-negative (A{beta}-) and amyloid-positive (A{beta}+) people with MCI who either remain stable or progress to dementia. We also examined regional WMHs differences in all groups: amyloid positive (A{beta}+) progressor, amyloid negative (A{beta}-) progressor, amyloid positive (A{beta}+) stable, and amyloid negative (A{beta}-) stable. MCI participants from the Alzheimers Disease Neuroimaging Initiative were included if they had APOE {varepsilon}4 status and if they had amyloid measures to determine amyloid status (i.e., positive, or negative). A total of 820 MCI participants that had APOE {varepsilon}4 status and amyloid measures were included in the study with 5054 follow-up time points over a maximum period of 13 years with an average of 5.7 follow-up timepoints per participant. Linear mixed-effects models were used to examine group differences in global and regional WMHs. ResultsPeople who were A{beta}- stable had lower baseline WMHs compared to both A{beta}+ progressors and A{beta}+ stable across all regions. When examining change over time, compared to A{beta}- stable, all groups had steeper change in WMH burden with A{beta}+ progressors having the largest change (largest increase in WMH burden over time). ConclusionThese findings suggest that WMH progression is a contributing factor to conversion to dementia both in amyloid-positive and negative people with MCI.

Older individuals frequently harbor multiple brain pathologies, including Alzheimers disease (AD) related amyloid-{beta} (A{beta}) and tau alongside -synucleinopathy and vascular pathology. Proteomic profiling offers a strategy to better understand common as well as unique features of these different brain pathologies. We analyzed cerebrospinal fluid (CSF) (n=1,658) and plasma (n=749) samples from participants in the BioFINDER cohorts using the automated NULISAseq CNS Disease panel of 125 proteins. Differentially abundant proteins (DAPs) related to AD pathology (based on A{beta}- and tau-PET positivity), -synuclein (based on synuclein amplification assay [SAA] positivity) and vascular pathology (based on white matter lesion [WML] load) were identified with linear models simultaneously including a binary measure for the three pathologies. In the BioFINDER-2 subcohorts, DAPs were further evaluated for associations with continuous baseline (n=1,137) and longitudinal (n=656) A{beta}-PET, tau-PET, and WML measures in models accounting for all pathologies. Associations with AD-signature cortical atrophy (n=915) and cognitive decline by the MMSE (n=1054) were also examined. We identified 84 CSF DAPs, with largely distinct protein signatures for each pathology (AD, n=66 DAPs; vascular pathology, n=55; -synuclein pathology, n=16). 10 DAPs (e.g., FABP3, UCHL1, NPTXR, NPTX2) were altered across all three pathologies, reflecting general neurodegeneration. AD-associated DAPs included glial/inflammatory markers (CHIT1, CX3CL1, CD63) linked to A{beta} pathology, and synaptic/neuronal injury markers (VSNL1, NRGN, NEFL) and metabolic enzymes (FABP3, MDH1) linked to tau pathology. A{beta}-associated proteomic differences were most evident in CU individuals, while tau-associated differences predominated in MCI. More proteins, particularly neurodegeneration and synaptic markers, were associated with tau change than with A{beta} change. Vascular pathology exhibited a distinct profile, enriched for inflammatory, angiogenic and extracellular matrix proteins (PGF, POSTN, TREM1, VCAM1). DDC was the main protein associated with -synucleinopathy. Only a few proteins, including UCHL1, NPTX2, and NEFL, predicted cognitive decline and cortical atrophy after accounting for all brain pathologies. In plasma, although fewer DAPs were identified (n=20), findings included established AD biomarkers. Only plasma VCAM1 and NEFL were associated with -synuclein and vascular pathology. NULISA identified stage-dependent, disease-specific CSF biomarker signatures with limited overlap, alongside shared neurodegenerative markers, supporting improved biological interpretation and more refined classification of neurodegenerative pathology.

BackgroundMultianalyte plasma proteomic panels that can accurately detect initial AD pathology in preclinical populations and simultaneously measure related biological processes relevant for disease risk are critical for advancing early detection and prognosis. MethodsUsing the NULISAseq CNS panel, we measured plasma from 193 clinically unimpaired (CU) older adults enrolled in the Stanford Aging and Memory Study (SAMS). We evaluated correspondence of core AD-relevant biomarkers A{beta}42, A{beta}40, pTau217, pTau181, GFAP, NfL, A{beta}42/A{beta}40, and pTau217/A{beta}42 measured using NULISAseq and established Lumipulse immunoassays. ROC curve analyses compared the accuracy of these biomarkers for detecting Lumipulse CSF A{beta}-positivity across platforms. Linear models were applied across 124 NULISAseq proteins to examine associations with common AD risk factors, including age, female sex, and APOE-{varepsilon}4, as well as with biomarkers CSF A{beta}42/A{beta}40 and pTau181, 18F-PI2620 Tau PET, and memory. Fold change differences in NULISAseq proteins as a function of CSF A{beta} (A+) and pTau181 (T+) status were examined using Wilcoxon rank-sum tests. ResultsModerate to high correlations were observed between NULISAseq and Lumipulse AD plasma biomarkers. Across platforms, plasma pTau217/A{beta}42 exhibited the highest performance in discriminating CSF A+ (NULISAseq AUC: 0.940, 95%CI: 0.885-0.995; Lumipulse AUC: 0.907, 95%CI: 0.849-0.966). Age and sex were associated with differential expression of NULISAseq targets linked to neurodegeneration, microglial activation, and inflammation. CSF A+ was associated with fold change differences in A{beta}42, pTau217, pTau231, pTau181, and GFAP, while CSF T+ was additionally associated with increases in TREM1, TIMP3, SAA1, and S100A12. When stratified by AT groups, A+T-exhibited lower A{beta}42 and elevated pTau217 compared to A-T-, whereas A+T+ exhibited elevated pTau231 and pTau181 compared to A+T-. Temporal cortex tau was positively associated with NULISAseq pTau217, pTau231, pTau181, and pTau217/A{beta}42. Memory function was negatively associated with pTau isoforms and PRDX6, YWHAZ, ENO2, ARSA, CHI3L1, CXCL8, and FCN2. These associations remained when controlling for pTau217 and restricting to A-CU, suggesting these targets may represent AD-independent biological pathways relevant for memory function. ConclusionsNULISAseq immunoassay-based multiplexing accurately detects AD pathology among CU older adults and identifies multiple biological pathways related to early biomarker abnormality and memory function that may become dysregulated in preclinical AD.

BackgroundPlasma p-tau217 is a promising biomarker for detecting incipient AD pathology, but direct comparison of different p-tau217 assays in community-based cohorts are limited. MethodsWe evaluated two cohorts from southwestern Pennsylvania, USA; the MYHAT-NI sub-study, which included two-year longitudinal follow-up neuroimaging assessments of A{beta}, tau, and cortical thickness; and the Human Connectome Project/CoBRA, targeting a 50:50 split of self-identified Black and non-Hispanic White individuals. Plasma p-tau217 was measured using four different assays: Lumipulse, Johnson&Johnson, ALZpath, and NULISA. A{beta} and tau pathologies were assessed with [11C]PiB PET and [18F]Flortaucipir PET, respectively. Clinical Dementia Rating (CDR) and Montreal Cognitive Assessment were used to assess cognitive performance. ResultsWe included 344 participants (MYHAT-NI: n=111, median age 76 [IQR: 72-80], 54% female; HCP/CoBRA: n=234, median age 62 [IQR: 52-70], 65% female). All four p-tau217 assays exhibited moderate to strong cross-platform correlations (Spearman correlations of 0.40 - 0.86), and statistically equivalent AUCs (of 0.84-0.90) for determining A{beta} positivity. ConclusionsOur findings showed strong equivalent performances of plasma p-tau217 assays to identify amyloid positivity across two highly diverse cohorts of community-dwelling older adults.

BackgroundBlood-based biomarkers are gaining grounds for Alzheimers disease (AD) detection. However, two key obstacles need to be addressed: the lack of methods for multi-analyte assessments and the need for markers of neuroinflammation, vascular, and synaptic dysfunction. Here, we evaluated a novel multi-analyte biomarker platform, NULISAseq CNS disease panel, a multiplex NUcleic acid-linked Immuno-Sandwich Assay (NULISA) targeting [~]120 analytes, including classical AD biomarkers and key proteins defining various disease hallmarks. MethodsThe NULISAseq panel was applied to 176 plasma samples from the MYHAT-NI cohort of cognitively normal participants from an economically underserved region in Western Pennsylvania. Classical AD biomarkers, including p-tau181, p-tau217, p-tau231, GFAP, NEFL, A{beta}40, and A{beta}42, were also measured using Single Molecule Array (Simoa). Amyloid pathology, tau pathology, and neurodegeneration were evaluated with [11C] PiB PET, [18F]AV-1451 PET, and MRI, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA biomarkers and AD pathologies. Spearman correlations were used to compare NULISA and Simoa. ResultsNULISA concurrently measured 116 plasma biomarkers with good technical performance, and good correlation with Simoa measures. Cross-sectionally, p-tau217 was the top hit to identify A{beta} pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in A{beta}-PET+ participants, including TIMP3, which regulates brain A{beta} production, the neurotrophic factor BDNF, the energy metabolism marker MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited A{beta} PET-dependent yearly increases in A{beta}-PET+ participants. Markers with tau PET-dependent longitudinal changes included the microglial activation marker CHIT1, the reactive astrogliosis marker CHI3L1, the synaptic protein NPTX1, and the cerebrovascular markers PGF, PDGFRB, and VEFGA; all previously linked to AD but only reliably measured in cerebrospinal fluid. SQSTM1, the autophagosome cargo protein, exhibited a significant association with neurodegeneration status after adjusting age, sex, and APOE {varepsilon}4 genotype. ConclusionsTogether, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD.

INTRODUCTIONThis study uses longitudinal amyloid biomarker and cognitive data to generate sample size estimates for two-armed, pre-clinical amyloid clearance clinical trials. METHODSPET PiB DVR ranges defined three amyloid groups (positive, "A+"; sub threshold/low positive, "subA+"; and negative, "A-") in cognitively unimpaired Wisconsin Registry for Alzheimers Prevention participants. Amyloid group trajectories estimated from mixed effects models informed per-treatment-arm sample size estimates to detect plausible treatment effects over 3-year (biomarker) or 6-year (cognition) study windows (80% power). RESULTSTo detect [&ge;]60% slowing in PiB accumulation, [&le;]40 may be needed per arm for both SubA+ and A+; to detect the same effect sizes in plasma p-tau217 trajectories, [~]50-1700 are needed, depending on assay and amyloid subgroup. Among cognitive outcomes, Digit Symbol Substitution and a 5-test Preclinical Alzheimers Cognitive Composite consistently required fewest (<2000) per arm. DISCUSSIONEarly intervention study planning will benefit from selection of outcomes that are most sensitive to AD biomarker-related preclinical change.

ImportancePhosphorylated tau (pTau) is a specific blood biomarker for Alzheimers disease (AD) pathology, with pTau217 considered to have the most utility. However, availability of pTau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. ObjectiveTo determine the utility of a novel and commercially available Single molecule array (Simoa) for plasma pTau217 (ALZpath) to detect AD pathology. To evaluate references ranges for abnormal A{beta} across three selected cohorts. Design, Setting, ParticipantsThree single-centre observational cohorts were involved in the study: Translational Biomarkers in Aging and Dementia (TRIAD), Wisconsin Registry for Alzheimers Prevention (WRAP), and Sant Pau Initiative on Neurodegeneration (SPIN). MRI, A{beta}-PET, and tau-PET data were available for TRIAD and WRAP, while CSF biomarkers were additionally measured in a subset of TRIAD and SPIN. Plasma measurements of pTau181, pTau217 (ALZpath), pTau231, A{beta}42/40, GFAP, and NfL, were available for all cohorts. Longitudinal blood biomarker data spanning 3 years for TRIAD and 8 years for WRAP were included. ExposuresMRI, A{beta}-PET, tau-PET, CSF biomarkers (A{beta}42/40 and pTau immunoassays) and plasma pTau217 (ALZpath Simoa). Main Outcomes and MeasuresThe accuracy of plasma pTau217 for detecting abnormal amyloid and tau pathology. Longitudinal pTau217 change according to baseline pathology status. ResultsThe study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%]) were included in the study. High accuracy was observed in identifying elevated A{beta} (AUC, 0.92-0.96; 95%CI 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95%CI 0.84-0.99) across all cohorts. These accuracies were significantly higher than other plasma biomarker combinations and comparable to CSF biomarkers. The detection of abnormal A{beta} pathology using binary or three-range references yielded reproducible results. Longitudinally, plasma pTau217 showed an annual increase only in A{beta}-positive individuals, with the highest increase observed in those with tau-positivity. Conclusions and RelevanceThe ALZpath plasma pTau217 Simoa assay accurately identifies biological AD, comparable to CSF biomarkers, with reproducible cut-offs across cohorts. It detects longitudinal changes, including at the preclinical stage, and is the first widely available, accessible, and scalable blood test for pTau217 detection. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the capabilities of the ALZpath plasma pTau217 Single molecule array (Simoa) to identify Alzheimers disease (AD) pathophysiology? FindingsALZpath pTau217 showed similar accuracies to cerebrospinal fluid biomarkers in identifying abnormal A{beta} and tau pathologies. Calculated reference ranges for detecting abnormal A{beta} were consistent across three cohorts. Over 8 years, the largest change of pTau217 was in individuals positive for both A{beta} and tau. MeaningThese results demonstrate the high-performance of the ALZpath plasma pTau217 Simoa in identifying AD-type pathophysiology. The wider availability of high-performing assays will expedite the use of blood biomarkers in clinical settings and benefit the research community.

Identification of genetic alleles associated with both Alzheimers disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) and APOE genotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset. We assessed six outcomes in 931 total participants. The outcomes were two concussion recovery measures (number of days to asymptomatic status, number of days to return to play (RTP)) and four concussion severity measures (scores on SAC and BESS, SCAT symptom severity, and total number of symptoms). We calculated PRS using a published score [1] and performed multiple linear regression (MLR) to assess the relationship of PRS with the outcomes. We also used t-tests and chi-square tests to examine outcomes by APOE genotype, and MLR to analyze outcomes in European and African genetic ancestry subgroups. Higher PRS was associated with longer injury to RTP in the normal RTP (<24 days) subgroup (p = 0.024), and one standard deviation increase in PRS resulted in a 9.89 hour increase to the RTP interval. There were no other consistently significant effects, suggesting that high AD genetic risk is not strongly associated with more severe concussions or poor recovery in young adults. Future studies should attempt to replicate these findings in larger samples with longer follow-up using PRS calculated from diverse populations.

BackgroundAccurate prediction of which patients with mild cognitive impairment (MCI) will progress to Alzheimers disease (AD) remains a major unmet clinical need. Current biomarkers detect amyloid pathology with high accuracy but offer limited prognostic value for disease progression. MethodsWe conducted a prospective analysis in the multicentre BALTAZAR cohort (NCT01315639), all diagnosed with MCI at baseline and followed clinically for 3 years. Paired cerebrospinal fluid (CSF) and plasma samples were collected on the same day and analysed with the NULISA ultrasensitive multimarker platform quantifying 120 central nervous system biomarkers. Prognostic performance for conversion to AD dementia was assessed using area under the receiver operating characteristic curve (AUC) and hazard ratios (HRs), both for individual markers and for elastic-net-derived biomarker combinations validated by bootstrap and survival analyses. FindingsDuring the 3-year follow-up, 63% of participants converted to AD. Plasma p-tau biomarkers showed strong accuracy for detecting amyloid positivity (AUC > 0{middle dot}90) but limited prognostic value for conversion (AUC < 0{middle dot}75). In CSF, markers of neurodegeneration (tau, p-tau181, NfL) and synaptic dysfunction (NPTX2) predicted conversion with higher accuracy, matching or exceeding p-tau217 performance. The best-performing CSF combination (IL-16, tau, NPTX2) achieved an AUC of 0{middle dot}86 (95% CI 0{middle dot}80-0{middle dot}91) and an HR of 39{middle dot}8 (95% CI 9{middle dot}6-165{middle dot}2). Plasma combinations (e.g., p-tau181 or p-tau217 with YWHAG) provided only modest improvement, likely reflecting the absence of robust synaptic markers in blood. InterpretationPrognostic assessment of MCI progression to AD is best achieved through CSF biomarker combinations reflecting neurodegeneration and synaptic dysfunction, complemented by inflammatory markers. These findings emphasise the clinical and pathophysiological relevance of downstream processes beyond amyloid and tau, and support the implementation of multimarker panels for prognosis and therapeutic monitoring.

INTRODUCTIONWe evaluated clinical performance of the fully-automated, high-throughput, prototype Elecsys(R) Phospho-Tau (217P) plasma immunoassay (Roche Diagnostics) for detecting amyloid pathology. METHODSPlasma pTau217 levels were determined in samples from cognitively impaired and unimpaired individuals from five cohorts (N=7252) using the pTau217 plasma immunoassay. Clinical performance was evaluated against amyloid positron emission tomography. RESULTSFor cognitively impaired, mean plasma pTau217 levels for amyloid-positive (A+) were higher (n=394; 0.835 pg/mL) than amyloid-negative (A-) individuals (n=144; 0.361 pg/mL); similarly, for cognitively unimpaired, A+ (n=224; 0.516 pg/mL) and A- individuals (n=1386; 0.220 pg/mL). Area under curve was 0.878 (95% confidence interval [CI] 0.840, 0.915) (impaired) and 0.907 (95% CI 0.885, 0.929) (unimpaired). Cutoff < 0.189 pg/mL reliably ruled-out individuals without amyloid pathology. High negative predictive values [92.51% (impaired); 98.60% (unimpaired)] were observed with sensitivity/specificity of 98.98%/29.17% and 95.54%/50.72%, respectively. DISCUSSIONThe pTau217 plasma immunoassay accurately detects amyloid pathology, irrespective of cognitive status. RESEARCH IN CONTEXTO_ST_ABS1. Systematic reviewC_ST_ABSPrior literature on blood-based biomarkers, particularly pTau217, was reviewed using PubMed and recent conference proceedings. Several studies support plasma pTau217 as a promising biomarker to aid Alzheimers disease (AD) diagnosis, showing high concordance with amyloid positron emission tomography (PET) and cerebrospinal fluid biomarkers. 2. InterpretationThe high-throughput, fully automated Elecsys(R) prototype pTau217 plasma immunoassay (Roche Diagnostics Ltd) accurately detected amyloid pathology across cognitively diverse populations in a large multi-cohort study (N=7252). The assay achieved a high area under curve ([&ge;] 0.878) with respect to amyloid PET. A low-risk cutoff (< 0.189 pg/mL) showed good negative predictive value, supporting utility as a rule out tool. 3. Future directionsThese results confirm the pTau217 plasma immunoassay as a reliable, scalable, and clinically useful biomarker for detection of amyloid pathology. Prospective validation in diverse populations and evaluation of outcomes in early AD care pathways are essential. HighlightsO_LIEvaluated Elecsys(R) pTau217 plasma immunoassay (Roche Diagnostics) in five cohorts. C_LIO_LIHigh performance detecting amyloid pathology in cognitively impaired/unimpaired. C_LIO_LIHigh negative predictive value supported utility as a pre-screener in AD. C_LIO_LIIdentified cutoffs suitable as rule out pre-screener tools in clinical trials. C_LIO_LIReinforced use of high-throughput pTau217 plasma measurements to aid AD diagnosis. C_LI Trial registration number: A4, NCT02008357; SKYLINE, NCT05256134; AIBL, SAGE Project ID Number: 2022/PID06188; SVHM Local Ref ID: HREC 028/06; CREAD, NCT02670083; CREAD2, NCT03114657

INTRODUCTIONPlasma biomarkers offer promise for improving diagnosis of Alzheimers disease (AD) and differentiating AD and other neurodegenerative disorders (ND) like frontotemporal dementia (FTD) from primary psychiatric disorders (PPD), particularly in younger patients. METHODSIn this prospective study, we investigated plasma phosphorylated tau 217 (ptau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in 341 unselected participants from a neuropsychiatry memory clinic, including AD (n=40), bvFTD (n=15), PPD (n=69), other ND, and controls. RESULTSPlasma ptau217 showed strong diagnostic performance for distinguishing AD from bvFTD (96% accuracy) and PPD (93% accuracy). NfL best distinguished all ND from PPD, while GFAP showed limited diagnostic utility. Biomarker profiles using predefined cut-offs and age-adjusted z-scores further clarified group differences. DISCUSSIONPlasma ptau217 and NfL have strong diagnostic utility in real-world, diagnostically complex cohorts. These findings support implementation of scalable blood-based biomarkers to improve early and accurate diagnosis in memory clinic settings.

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSThe NULISASeq CNS Disease Panel has high potential for AD diagnosis, but the comparability of serum vs. plasma remains unclear. METHODSWe compared its performance on 43 matched serum-plasma pairs from a memory clinic cohort. RESULTSThe panel reproducibly quantified 124 targets (mean CV=4.9%) with high detectability (mean=95.7%). Serum-plasma correlations were strong ({rho}>0.7) for 79 targets. 48 targets had significant NPQ differences, with 32 higher in plasma. Plasma had more erythrocyte-enriched proteins (HBA1, PGK1, SOD1, PRDX6), while serum had more platelet-derived proteins (CD40LG, BDNF, VEGFA, A{beta}40). For classical AD biomarkers, serum-plasma correlations were stronger for p-tau, GFAP, and NfL ({rho}>0.9) than for A{beta} targets ({rho}=0.594- 0.785). Tau levels were higher in plasma; GFAP and NfL were similar, and A{beta} peptides were mixed. Twelve targets, along with p-tau217/A{beta}42, were linked to AD diagnosis, with plasma generally showing stronger effects. DISCUSSIONOur results support serum use but suggest plasma performs better for AD using this panel.

BackgroundBlood-based biomarkers offer a scalable alternative to cerebrospinal fluid and PET imaging for Alzheimers disease (AD) detection, yet traditional venipuncture limits participation among rural and socioeconomically disadvantaged populations. Self-collection using the Tasso+ capillary device could reduce access barriers, but its feasibility and validity for AD plasma biomarkers remain uncertain, particularly with real-world delays prior to processing. MethodsAdults aged 45-90 years from the Wisconsin SHOW cohort who were underrepresented in AD research (Black or Hispanic race/ethnicity, rural residence, or <bachelors degree) were recruited (n=28). At community "pop-up" clinics participants completed: (1) self-collection of capillary blood via Tasso+; (2) experience surveys; (3) Montreal Cognitive Assessment; and (4) standard venipuncture. To simulate home-based collection and mail return, Tasso+ samples were held at room temperature for 24 hours before centrifugation, whereas venous samples were processed within 30 minutes. Plasma A{beta}40, A{beta}42, A{beta}42/40, GFAP, NfL, and pTau217 were measured on the Quanterix Simoa platform. Between-method agreement was evaluated using Pearson/Spearman correlations, Lins concordance correlation coefficients (CCC), Bland-Altman analyses, and relative bias. Predictors of percent difference were explored with univariate regression. ResultsTasso+ collection was successful for 96% of participants; 64% rated it very easy and 86% reported comfort/no pain, yet 57% preferred future venipuncture--particularly Black, lower-income, and lower-education participants. Agreement varied markedly by biomarker. GFAP and NfL demonstrated excellent concordance (CCC 0.97-0.98) with minimal bias (-6% to -8%). A{beta}40 and A{beta}42 showed modest correlations (r=0.40-0.47) and substantial underestimation (-60% to -70%). A{beta}42/40 and pTau217 exhibited poor correlation and extreme positive bias for pTau217 ([~]+2600%). Hemolysis was more frequent in Tasso+ samples and contributed to disagreement for several markers; processing lag and sample volume were not strong predictors. ConclusionsRemote capillary self-collection with a 24-hour delay is suitable for measuring GFAP and NfL but not currently reliable for A{beta} or pTau217 without improved handling (e.g., temperature control, hemolysis reduction). Although user experience was favorable, trust and logistical concerns limited preference among underrepresented groups. Community-informed strategies and optimized pre-analytics are essential before deploying Tasso+ in large AD studies.

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSThe interpretation of plasma phosphorylated tau (pTau) levels may be influenced by metabolic conditions, such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), obesity, and kidney function. We examined the extent to which metabolic factors are associated with plasma pTau concentrations (pTau181, pTau217, pTau231) and the contribution of these factors on analytical outcomes. METHODSWe analyzed data from 287 participants using partial Spearmans rho, Mann Whitney U, ROC analysis, and linear mixed models. RESULTSConcordance between plasma pTau217 and amyloid PET was not influenced by IR or estimated-glomerular-filtration-rate (eGFR). Accounting for eGFR improved concordance of pTau181 and pTau231 with amyloid PET. Age, binarized waist-to-hip ratio, and amyloid status were associated with all longitudinal pTau concentrations, and eGFR associated with longitudinal pTau231. DISCUSSIONMetabolic health may influence the interpretation of some plasma pTau biomarkers, potentially necessitating adjustments for metabolic factors in research and clinical settings.

IntroductionWe compared associations between phosphorylated tau biomarkers (p-tau217, p-tau181, p-tau231) and vascular risk factors with clinical progression and cognitive decline along the AD continuum. MethodsBaseline plasma p-tau concentrations and vascular risk factors were assessed in 280 CIMA-Q participants. Associations between these markers, cognition and clinical progression over 8 years were examined. ResultsElevated p-tau217 predicted progression from mild cognitive impairment (MCI) to AD dementia (p<.01), while hypertension predicted progression from cognitively unimpaired (CU) to MCI (p<.02). Higher p-tau levels, particularly p-tau217, and hypertension were linked to cognitive decline in MCI individuals. In the CU group, few associations were seen between p-tau levels and cognitive decline, with minimal effect of vascular risk factors. DiscussionPlasma p-tau217 was the most sensitive marker of AD-related decline, but hypertension was particularly relevant at earlier stages. The results highlight the need for multimodal profiling to optimize prediction and intervention along the AD continuum.

INTRODUCTIONPlasma A{beta}42/40 ratio can be used to help predict amyloid PET status, but its clinical utility in Alzheimers disease (AD) assessment is unclear. METHODSA{beta}42/40 ratio was measured by LC-MS/MS in 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and 6,192 consecutive clinical specimens submitted for A{beta}42/40 testing. RESULTSHigh diagnostic sensitivity and negative predictive value (NPV) for A{beta}-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between A{beta}42/40 values for individuals with positive vs negative A{beta}-PET results. Assuming a moderate prevalence of A{beta}-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients cognitive impairment and help reduce PET evaluation by about 40%. DISCUSSIONUsing high-throughput plasma A{beta}42/40 LC-MS/MS assays can help reduce PET evaluations in patients with low likelihood of AD pathology, allowing for cost savings. HighlightsO_LIA new plasma LC-MS/MS assay for the A{beta}42/A{beta}40 ratio has clinical utility in AD assessment. C_LIO_LIPerformance was assessed using specimens with a moderate prevalence of A{beta}-PET positivity. C_LIO_LIAnalysis was extrapolated to 6,192 consecutive clinical specimens submitted for ratio testing. C_LIO_LIAssay cutpoints were proposed to help suggest clinical management decisions. C_LIO_LIBased on the assays high NPV, costly PET evaluations may be avoided for many individuals. C_LI Research in ContextO_ST_ABSSystematic ReviewC_ST_ABSA{beta}42/A{beta}40 ratio data were analyzed from 250 ADRC cohort participants and 6,192 plasma specimens submitted for A{beta}42/40 ratio testing by LC-MS/MS at Quest Diagnostics. InterpretationBased on its high NPV, the assay identifies individuals likely to have negative amyloid PET results. Higher discriminatory power and larger fold-changes between PET-positive and negative individuals were observed compared with previous studies. Our "real-world" data set, combined with known performance characteristics, allows us to suggest cutpoints and clinical decisions based on plasma A{beta}42/40 ratios. Future DirectionsLongitudinal plasma specimens from individuals who convert from PET-negative to positive, or that transition from cognitively normal to MCI and AD, will improve understanding of the prognostic utility of the A{beta}42/40 ratio. Using A{beta}42/40 ratio alone or combined with other biomarkers, to follow patients with cognitive impairment may yield insights regarding their disease conditions and progression and who may benefit from disease-modifying therapeutics.

STRUCTURED ABSTRACTO_ST_ABSIntroductionC_ST_ABSMetabolic disorders are risk factors for Alzheimers disease (AD), although underlying mechanisms remain unclear. We investigated the relationship between peripheral metabolic markers - adiponectin, FGF-21 and IGFBP-2 - and AD. MethodsParticipants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD and cognitively healthy controls (CH) were from the CIMA-Q cohort (n=287). Serum adiponectin, FGF-21, and IGFBP-2 concentrations were measured, compared between groups, and assessed for associations with clinical, cognitive, biochemical and MRI data. ResultsMetabolic dysfunction was linked to lower adiponectin and IGFBP-2, but higher FGF-21. Both FGF-21 and IGFBP-2 increased with age and were inversely associated with cognitive performance. IGFBP-2 was elevated at SCD stage and correlated with plasma pTau181 and amygdala atrophy. Adiponectin was unrelated to cognition. DiscussionThese findings suggest that IGFBP-2, and FGF-21 to a lesser extent, may serve as early biomarkers of cognitive impairment, reflecting intricate links between peripheral dysmetabolism and AD.