There is a need for automated, high-throughput assays to quantify immune response after SARS-CoV-2 vaccination. This study assessed the combined utility of the Elecsys® Anti-SARS-CoV-2 S (ACOV2S) and the Elecsys Anti-SARS-CoV-2 (ACOV2N) assays using samples from the mRNA-1273 (Spikevax™) phase 2 trial (NCT04405076). Samples from 593 healthy participants in two age cohorts (18–54 and ≥ 55 years), who received two injections with placebo (n = 198) or mRNA-1273 (50 μg [n = 197] or 100 μg [n = 198]), were collected at days 1 (first vaccination), 15, 29 (second vaccination), 43, and 57. ACOV2S results were used to assess humoral response to vaccination in different subgroups and were compared to live virus microneutralization assay. Samples from patients with either previous or concomitant infection (identified per ACOV2N) were analyzed separately. Receptor-binding domain-specific antibodies were readily detectable by ACOV2S for the vast majority of participants (174/189, 92.1

IMPORTANCE Alzheimer disease (AD), a neurodegenerative disease characterized by beta-amyloid plaques and tau tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression. OBJECTIVE To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting beta-amyloid oligomers, in participants with prodromal to mild (early) AD. DESIGN, SETTING, AND PARTICIPANTS Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively. INTERVENTIONS Participants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was change from baseline to week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. RESULTS There were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was -0.17 (95% CI, -0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point. CONCLUSIONS AND RELEVANCE Crenezumab was well tolerated but did not reduce clinical decline in participants with early AD.

INTRODUCTION:There is a great need for fully automated plasma assays that can measure amyloid beta (Aβ) pathology and predict future Alzheimer's disease (AD) dementia. METHODS:Two cohorts (n = 920) were examined: Panel A+ (n = 32 cognitively unimpaired [CU], n = 106 mild cognitive impairment [MCI], and n = 89 AD) and BioFINDER-1 (n = 461 CU, n = 232 MCI). Plasma Aβ42/Aβ40, phosphorylated tau (p-tau)181, two p-tau217 variants, ApoE4 protein, neurofilament light, and GFAP were measured using Elecsys prototype immunoassays. RESULTS:The best biomarker for discriminating Aβ-positive versus Aβ-negative participants was Aβ42/Aβ40 (are under the curve [AUC] 0.83-0.87). Combining Aβ42/Aβ40, p-tau181, and ApoE4 improved the AUCs significantly (0.90 to 0.93; P< 0.01). Adding additional biomarkers had marginal effects (ΔAUC ≤0.01). In BioFINDER, p-tau181, p-tau217, and ApoE4 predicted AD dementia within 6 years in CU (AUC 0.88) and p-tau181, p-tau217, and Aβ42/Aβ40 in MCI (AUC 0.87). DISCUSSION:The high accuracies for Aβ pathology and future AD dementia using fully automated instruments are promising for implementing plasma biomarkers in clinical trials and clinical routine.

Background and Objectives To determine how fully automated Elecsys CSF immunoassays for beta-amyloid (A beta) and tau biomarkers and an ultrasensitive Simoa assay for neurofilament light chain (NFL) correlate with neuropathologic changes of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). Methods We studied 101 patients with antemortem CSF and neuropathology data. CSF samples were collected a mean of 2.9 years before death (range 0.2-7.5 years). CSF was analyzed for A beta(40), A beta(42), total tau (T-tau), tau phosphorylated at amino acid residue 181 (P-tau), P-tau/A beta(42) and A beta(42)/A beta(40) ratios, and NFL. Neuropathology measures included Thal phases, Braak stages, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores, AD neuropathologic change (ADNC), and primary and contributory pathologic diagnoses. Associations between CSF biomarkers and neuropathologic features were tested in regression models adjusted for age, sex, and time from sampling to death. Results CSF biomarkers were associated with neuropathologic measures of A beta (Thal, CERAD score), tau (Braak stage), and overall ADNC. The CSF P-tau/A beta(42) and A beta(42)/A beta(40) ratios had high sensitivity, specificity, and overall diagnostic performance for intermediate-high ADNC (area under the curve range 0.95-0.96). Distinct biomarker patterns were seen in different FTLD subtypes, with increased NFL and reduced P-tau/T-tau in FTLD-TAR DNA-binding protein 43 and reduced T-tau in progressive supranuclear palsy compared to other FTLD variants. Discussion CSF biomarkers, including P-tau, T-tau, A beta(42), A beta(40), and NFL, support in vivo identification of AD neuropathology and correlate with FTLD neuropathology. Classification of Evidence This study provides Class II evidence that distinct CSF biomarker patterns, including for P-tau, T-tau, A beta(42), A beta(40), and NFL, are associated with AD and FTLD neuropathology.

Background Cerebrospinal fluid (CSF) analysis for detecting amyloid positivity may be as reliable as positron emission tomography (PET). We evaluated the performance of the amyloid beta (Aβ)42/40 ratio for predicting amyloid positivity by PET, compared with Aβ42 alone, and phosphorylated tau 181 (pTau181)/Aβ42 and total tau (tTau)/Aβ42 ratios, using fully automated CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) in a heterogeneous cohort of patients with a range of cognitive disorders reflecting the typical population of a memory clinic. Methods CSF samples from 103 patients with known amyloid PET status (PET positive = 54; PET negative = 49) were retrospectively selected from one site in Germany; 71 patients were undergoing treatment for mild cognitive impairment ( n = 44) or mild-to-moderate dementia ( n = 27) due to Alzheimer’s disease (AD), and 32 patients were undergoing treatment for non-AD-related cognitive disorders. Aβ42, pTau181, and tTau concentrations were measured in CSF samples using the respective Elecsys ® CSF immunoassays modified for use on the cobas e 411 analyzer; Aβ40 concentrations were measured using a non-commercially available robust prototype assay. Sensitivities/specificities for amyloid positivity cut-offs (Youden-derived and pre-defined) were calculated, and receiver operating characteristic analyses determined area under the curve (AUC) versus amyloid PET status. Limitations include a small sample size, use of a pre-analytical protocol not in accordance with the Elecsys CSF immunoassay method sheets, and the lack of a pre-defined cut-off for Aβ42/40. Results Point estimates for sensitivity and specificity of CSF biomarkers and biomarker ratios versus amyloid PET were 0.93 and 0.57 for Aβ42, 0.96 and 0.69 for pTau181/Aβ42, 0.92 and 0.69 for tTau/Aβ42, and 0.94 and 0.82 for Aβ42/40. For AUCs, point estimates (95% confidence intervals) versus amyloid PET were 0.78 (0.68−0.88) for Aβ42, 0.88 (0.81−0.95) for pTau181/Aβ42, 0.87 (0.80−0.95) for tTau/Aβ42, and 0.90 (0.83−0.97) for Aβ42/40. Conclusions CSF Aβ42/40 ratio can predict PET amyloid positivity with high accuracy in patients with a range of cognitive disorders when evaluating Aβ pathology independent of tau and neurodegeneration for research purposes. The performance of Aβ42/40 was comparable with pTau181/Aβ42 and tTau/Aβ42 used in clinical practice and better than Aβ42 alone.

Background The ability to quantify an immune response after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential. This study assessed the clinical utility of the quantitative Roche Elecsys® Anti-SARS-CoV-2 S assay (ACOV2S) using samples from the 2019-nCoV vaccine (mRNA-1273) phase 1 trial (NCT04283461). Methods Samples from 30 healthy participants, aged 18–55 years, who received two injections with mRNA-1273 at a dose of 25 μg (n=15) or 100 μg (n=15), were collected at Days 1 (first vaccination), 15, 29 (second vaccination), 43 and 57. ACOV2S results (shown in U/mL – equivalent to BAU/mL per the first WHO international standard) were compared with results from ELISAs specific to antibodies against the Spike protein (S-2P) and the receptor binding domain (RBD) as well as neutralization tests including nanoluciferase (nLUC80), live-virus (PRNT80), and a pseudovirus neutralizing antibody assay (PsVNA50). Results RBD-specific antibodies were already detectable by ACOV2S at the first time point of assessment (d15 after first vaccination), with seroconversion before in all but two participants (25 μg dose group); all had seroconverted by Day 29. Across all post-baseline visits, geometric mean concentration of antibody levels was 3.27–7.48-fold higher in the 100 μg compared with the 25 μg dose group. ACOV2S measurements were highly correlated with those from RBD ELISA (Pearson’s r=0.938; p<0.0001) and S-2P ELISA (r=0.918; p<0.0001). For both ELISAs, heterogeneous baseline results and smaller increases in antibody levels following the second vs first vaccination compared with ACOV2S were observed. ACOV2S showed absence of any baseline noise indicating high specificity detecting vaccine-induced antibody response. Moderate–strong correlations were observed between ACOV2S and neutralization tests (nLUC80 r=0.933; PsVNA50, r=0.771; PRNT80, r=0.672; all p ≤ 0.0001). Conclusion The Elecsys Anti-SARS-CoV-2 S assay (ACOV2S) can be regarded as a highly valuable method to assess and quantify the presence of RBD-directed antibodies against SARS-CoV-2 following vaccination and may indicate the presence of neutralizing antibodies. As a fully automated and standardized method, ACOV2S could qualify as the method of choice for consistent quantification of vaccine-induced humoral response.

We aimed to provide cut points for the automated Elecsys Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers.

INTRODUCTION:The prognostic utility of cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) and p-tau181 is not understood.METHODS:Analyses included 753 Mayo Clinic Study on Aging participants (median age = 71.6; 57% male). CSF amyloid beta (Aβ)42 and p-tau181 were measured with Elecsys immunoassays. CSF p-tau181 and p-tau217 were also measured with Meso Scale Discovery (MSD). We used Cox proportional hazards models for risk of mild cognitive impairment (MCI) and linear mixed models for risk of global and domain-specific cognitive decline and cortical thickness. Analyses were stratified by elevated brain amyloid based on CSF Aβ42 or amyloid positron emission tomography for those with imaging.RESULTS:CSF p-tau217 was superior to p-tau181 for the diagnosis of Alzheimer's disease (AD) pathology. CSF MSD p-tau181 and p-tau217 were associated with risk of MCI among amyloid-positive individuals. Differences between CSF p-tau measures predicting cortical thickness were subtle.DISCUSSION:There are subtle differences for CSF p-tau217 and p-tau181 as prognostic AD markers.

To compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer’s Disease (AD) Research Framework derived from [18F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181). We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/mL). FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181. The choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.

Key Points Question How well does plasma amyloid-β 42/40 (Aβ42/40), measured using 8 different assays, detect brain Aβ pathology in the early stages of Alzheimer disease? Findings In this study, including 408 participants from 2 independent cohorts (BioFINDER and Alzheimer Disease Neuroimaging Initiative), plasma Aβ42/40 quantified using certain mass spectrometry–based methods showed better discriminative accuracy than immunoassays when identifying individuals with abnormal intracerebral Aβ status according to cerebrospinal fluid Aβ42/40 levels and Aβ positron emission tomography. Meaning Certain mass spectrometry–based plasma tests might have sufficient performance to detect brain Aβ pathology in Alzheimer disease.

Objective We studied interrelationships between CSF biomarkers and associations withAPOE epsilon 4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota. Methods We included 774 Mayo Clinic Study of Aging participants (693 cognitively unimpaired [CU]; 71 with mild cognitive impairment [MCI]). CSF beta-amyloid 42 (A beta 42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using A beta 42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations ofAPOE epsilon 4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population. Results Interrelationships between CSF A beta 42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 [71%]), we found a strong positive correlation between A beta 42 and p-tau (rho = 0.81), while the correlation was much smaller in group 2 (rho = 0.26, n = 227 [29%]). Group 2 was associated with older age,APOE epsilon 4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall,APOE epsilon 4 genotype and MCI were associated with A beta 42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk. Conclusion We hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF A beta 42 and p-tau/t-tau (represented also by the p-tau/t-tau/A beta 42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF A beta 42 and p-tau/t-tau, while AD leads to dissociation of these proteins.

AbstractBackgroundPrevious studies comparing white matter (WM) integrity and biomarkers of Alzheimer’s disease (AD) at early stages have yielded inconsistent results and findings have remained inconclusive. In this work, we used diffusion‐weighted imaging (DWI) and cerebrospinal fluid (CSF) biomarkers to study the relationship between neuropathological burden and neural injury in the WM in a middle‐aged cognitively unimpaired population: the ALFA+ study.MethodsN=318 cognitively unimpaired individuals from the ALFA+ study, aged from 45 to 74 (mean: 60.79∓4.66) underwent DWI and lumbar puncture. Biomarkers were measured with Elecsys® and NeuroToolKit robust prototype assays (Roche Diagnostics). Using tract‐based spatial statistics, we assessed their association with DWI metrics using individuals models including CSF markers of core AD pathology (A𝛃42, A𝛃42/40 ratio, p‐tau), neuronal injury (neurofilament light [NfL], t‐tau), synaptic dysfunction (neurogranin [NGR], 𝛂Synuclein), and inflammation (sTREM2, YKL40, GFAP, IL6, S100b). Age, sex and APOE e4 carriership were included as covariates. Supplementary analyses were performed including levels of AD core biomarkers as additional covariates and stratifying the sample into A/T groups.ResultsDWI metrics showed significant associations with A𝛃42, YKL40, IL6, NFL, NGR, pTau, tTau, S100, 𝛂Synuclein; none with GFAP, sTREM2, nor A𝛃42/40 ratio (Figures 1 and 2). Positive associations in fractional anisotropy (FA) (and negative with diffusivity) were found with A𝛃42, YKL40, NFL, NGR, S100, p‐tau and t‐tau. Negative association in FA (positive in diffusivity) was found for IL6 only. p‐tau showed the only association to be significant in both directions with FA, positive in cingular/callosal and negative in corticospinal tracts. Post‐hoc analyses on p‐tau showed significant interaction with A/T stage (Figure 3) with positive association with FA in A‐T‐ and negative in A+T+ subjects (inversely with diffusivity).ConclusionWM microstructural properties correlate in extensive regions with CSF AD core biomarkers, inflammation and axonal degeneration markers. Such associations illustrate the interplay of multiple pathways in early stages of Alzheimer’s continuum such as deleterious effects of amyloid deposition or the involvement of glial activation/inflammatory processes, resulting in observed reduced diffusivity. Furthermore, interaction with A/T stage suggest the presence of non‐monotonic dynamics occurring along the Alzheimer’s continuum.

AbstractBackgroundAPI Generation Program evaluated the effectiveness of the BACE1 inhibitor umibecestat and the active immunotherapy CAD106 in delaying the onset of AD symptoms in APOE4 carriers. Data from imaging (vMRI and PET scans), and fluid biomarkers (blood and CSF) were collected during the 12‐week Screening phase. In this presentation, we will summarize results across the two studies and investigate the relationships between the various biomarkers and key baseline characteristics.MethodAmyloid levels were assessed via CSF and/or Amyloid PET scan in both studies for the APOE4 carriers. Generation Study 2 enrolled heterozygotes based on the following elevated amyloid inclusion criteria: Roche Elecsys® CSF p‐Tau/Abeta42 ratio > 0.024 and/or PET scans with any of the 3 amyloid F18 tracers (florbetapir, flutemetamol or florbetaben). If the centralized visual read of PET scan was negative, the SUVr was calculated (cortical composite in reference to whole cerebellum) for the three tracers in order to assess borderline cases. Thresholds for amyloid positivity equivalent to SUVR of 1.1 with florbetapir were used for the final decision on inclusion.ResultAcross both studies, over 500 lumbar punctures, 2700 amyloid PET scans and about 150 tau PET scans (conducted using flortaucipir) were performed. In Generation Study 1, over 200 FDG PET scans were also performed. Participants underwent amyloid testing during screening, blood sampling (plasma and serum) and underwent MRI scans for safety and to measure brain volumes. All baseline biomarker data will be presented, including available concentrations from CSF Tau/p‐Tau/Aβ42/Aβ40 along with the eligibility ratio for pTau/ab42. In about 150 participants, concordance between elevated/non elevated amyloid status by CSF and PET (using centiloids) will be shown. Baseline brain volume (whole brain and hippocampus) will be summarized for the different co‐variates (age, sex, cognition, genotype and amyloid status). Correlations among the various fluid biomarkers and imaging will be discussed.ConclusionThese data describe the biomarker signature of the world’s largest cohort of cognitively unimpaired APOE4 carriers with and without elevated amyloid. The anonymized study data, biomarker samples as well as images collected will be shared with the scientific community after study completion and reporting. ELECSYS is a registered trademark of Roche.

pTau181/Aβ42 (A+/T+ as per A/T/(N) classification) and tTau/Aβ42 (A+/(N)+) ratios using fully automated Elecsys® cerebrospinal‐fluid (CSF) immunoassays have been shown to perform well in distinguishing amyloid‐positivity (A+) by positron emission tomography (PET) among patients with subjective and mild to severe cognitive impairment. Higher performance has also been demonstrated for the CSF Aβ42/40 ratio compared to CSF amyloid 42 (Aβ42) alone. We aimed to further evaluate the performance of the Elecsys® Aβ42/40 ratio in a clinical cohort.

AbstractBackgroundThe pathophysiological events that occur early in the preclinical Alzheimer’s disease (AD) continuum are not fully understood. Here, we sought for associations, in cognitively unimpaired individuals, between cerebrospinal (CSF) biomarkers of the main pathophysiological events described in AD vs. patterns of gray matter volume (GMv) and cerebral glucose metabolism (rCMRGlu).MethodThe first consecutive 381 participants of the ALFA+ study with valid T1w MRI, [18F]FDG‐PET scans and CSF samples were included. CSF biomarkers were measured with the NeuroToolKit robust prototype assays and Elecsys® immunoassays (Roche Diagnostics) and related to amyloid (Aβ42, Aβ40) and tau (pTau) metabolism, neuronal and axonal damage (NfL), synaptic dysfunction (neurogranin), neuroinflammation (sTREM2, YKL40, GFAP, S100, IL6), and α‐synuclein. Individuals were staged using the A/T system and pre‐established cut‐offs for the Aβ42/40 ratio and pTau concentrations. Modulated GMv maps were obtained from T1w scans. [18F]FDG uptake was normalized to the pons. Exploratory voxelwise associations between maps of GMv and rCMRGlu vs. CSF biomarkers (and differences between A/T groups in the AD continuum) were assessed with SPM12 (p<0.005, k>50 voxels) after accounting for the effect of age, sex, education, and APOE‐ε4 carriership, as well as for the Total Intracranial Volume (TIV) in the GMv analysis.ResultDemographics are shown in Table 1. Figure 1 shows regional differences in GMv and rCMRGlu between A/T groups and Figure 2 associations with biomarkers. Compared to the A‐T‐ group, A+T‐ individuals presented a widespread pattern of higher GMv. Higher pTau levels were associated with an extensive pattern of higher GMv and rCMRGlu. Higher sTREM2 values were associated with higher GMv in the temporoparietal junction and posterior cingulate cortex overlapping pTau GMv effects (Figure 3). Lower Aβ42/40 values were also associated to lower rCMRGlu in bilateral hippocampus and anterior cingulate. Higher NfL levels were coupled with lower GMv in bilateral parietotemporal cortices.ConclusionResults suggest that pathogenic events in very early stages of the Alzheimer’s continuum are unexpectedly associated with higher GMv and rCMRGlu. The overlap of pTau and sTREM2 effects in GMv may point towards a TREM2‐mediated microglial reaction to initial tau pathology. Interactions between biomarkers and A/T groups will be presented.

AbstractBackgroundAmyloid pathology can be detected using cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET) imaging, even though they measure two distinct beta‐amyloid (Aβ) pools. While CSF Aβ concentrations reflect the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques in the brain tissue. Many studies have shown the concordance between the two measures in individuals along the Alzheimer’s continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for Alzheimer’s disease (AD), affects the pattern of cerebral Aβ load as a function of CSF Aβ levels.MethodThe first consecutive 276 cognitively unimpaired (CDR = 0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ40 and Aβ42 concentrations were determined with the Roche NeuroToolKit (Roche Diagnostics) and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxel‐wise regression was performed to predict FTM uptake, with the following independent variables: age, sex, APOE‐ε4, and CSF Aβ42/40 ratio. Statistical threshold was set to p < 0.001 with a cluster extent correction of 100 voxels.ResultAs expected, CSF Aβ42/40 ratio was negatively associated with cerebral FTM uptake (Figure 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM‐binding across the whole sample (Figure 2b‐2c). Importantly, we found a significant interaction between CSF Aβ42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Figure 3).ConclusionCompared to non‐carriers, APOE‐ε4 carriers showed higher cerebral Ab load for any given level of CSF Aβ42/40 in areas that are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the Alzheimer’s continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.

AbstractBackgroundTau‐PET is included in the AT(N) research framework to define T‐status. However, no consensus exists as to how to classify patients as T+ or T‐ with this modality. We aim to compare T‐status derived from 18F‐Flortaucipir (FTP) PET visual assessment, 18F‐FTP SUVR quantification, and CSF pTau.Methods278 subjects who underwent 18F‐FTP PET and CSF analysis within 1 year were included from UCSF and ADNI. The cohort consisted of a continuum from cognitively normal controls (CN) to Alzheimer’s disease dementia (AD), and non‐Alzheimer’s disorders (clinical diagnoses, Table 1). T‐status was derived from: (1) 18F‐FTP consensus between two readers performing blinded visual assessment based on a priori criteria (Figure 1, inter‐rater k=0.68, 95%CI 0.59‐0.76; Provost et al, HAI Conference, 2020); (2) 18F‐FTP SUVR quantification of from a temporal meta‐ROI using a previously validated threshold (SUVR >1.27, Ossenkoppele et al. 2018); (3) Elecsys® Phospho‐Tau (181P) CSF (Roche Diagnostics) applying a ROC‐based threshold derived from an external ADNI cohort comparing amyloid‐positive AD vs. healthy controls (pTau >24.5 pg/mL).ResultsT+ was assigned in a higher proportion of AD, MCI and amyloid‐positive CN with 18F‐FTP visual assessment compared to 18F‐FTP SUVR and CSF pTau (Table 2). However, visual ratings also yielded the highest proportion of T+ in amyloid‐negative CN and MCI. Contrasting amyloid‐positive AD/MCI with other groups, sensitivity was highest for 18F‐FTP visual assessment, while specificity was highest for 18F‐FTP SUVR (Table 3). In a subset of patients with autopsy (n=11), T‐status derived from 18F‐FTP visual assessment had an accuracy of 100%, compared to 82% for SUVR quantification and 64% for CSF pTau. Overall agreement between the 3 classification criteria ranged from 68% to 76% in the whole cohort (Figure 2) and was highest in patients with AD (94%). Patients with concordant T‐status across all three modalities were significantly younger, had higher CSF pTau, higher 18F‐FTP SUVR (Figure 3), and were more likely to be amyloid positive.ConclusionsConcordance of T‐status derived from 18F‐FTP visual assessment, SUVR quantification and CSF pTau varies across disease stage, being highest in AD. 18F‐FTP visual assessment offers highest sensitivity, while SUVR threshold maximizes specificity.

We studied interrelationships between CSF biomarkers and associations with APOE ε4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota.We included 774 Mayo Clinic Study of Aging participants (693 cognitively unimpaired [CU]; 71 with mild cognitive impairment [MCI]). CSF β-amyloid 42 (Aβ42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using Aβ42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations of APOE ε4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population.Interrelationships between CSF Aβ42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 [71%]), we found a strong positive correlation between Aβ42 and p-tau (ρ = 0.81), while the correlation was much smaller in group 2 (ρ = 0.26, n = 227 [29%]). Group 2 was associated with older age, APOE ε4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall, APOE ε4 genotype and MCI were associated with Aβ42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk.We hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF Aβ42 and p-tau/t-tau (represented also by the p-tau/t-tau/Aβ42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF Aβ42 and p-tau/t-tau, while AD leads to dissociation of these proteins.

AbstractBackgroundWeight loss is common in Alzheimer’s disease (AD) and may start before cognitive impairment, but little is known about the relationship between weight change and AD biomarkers in the preclinical Alzheimer’s continuum. We aimed to assess the association between weight change and AD biomarkers and cognitive performance in cognitively unimpaired (CU) adults from the ALFA+ study.MethodWe analyzed data from 295 CU middle‐aged adults with two consecutive (mean interval 3.7 years) weight measures and neuropsychological assessments (n=267). Preclinical Alzheimer's Cognitive Composite (PACC) was computed as an average of z‐scores of episodic memory, semantic fluency and processing speed measures. We measured cerebrospinal fluid (CSF) levels of Aβ42, Aβ40, p‐tau, t‐tau, neurofilament light (NfL) and neurogranin using the Roche NeuroToolKit and Elecsys® immunoassays (n=280), and performed a [18F]flutemetamol PET scan in the follow‐up visit (n=252). PET results were dichotomized (Aβ positive or negative) based on visual read. Using established CSF cutoffs, we grouped participants in three biomarker categories: A‐T‐ (both Aβ and tau negative), A+T‐ (Aβ positive only) and A+T+ (both Aβ and tau positive). Linear and logistic regression and Kernel‐weighted local polynomial smoothing were used for analyses, which were adjusted by age, sex, body mass index, APOE genotype and years of education, as appropriate.ResultWeight loss predicted amyloid PET positivity (odds ratio 1.1, p=0.028) and was associated with significantly higher CSF levels of p‐tau (p=0.005), t‐tau (p=0.005) and neurogranin (p=0.002) (Table 1). Weight loss ≥5% (a standard cutoff for clinically relevant weight change) yielded 87% specificity and 30% sensitivity for amyloid PET positivity. Participants from the A+T+ group experienced significantly higher weight loss compared to A+T‐ (p=0.0029) and A‐T‐ (p=0.0005) groups (Figure 1). Weight loss was not associated with longitudinal changes in cognitive performance and preceded cognitive decline when using Aβ42/40 as a proxy of AD change progression (Table 1, Figure 2).ConclusionWeight loss predicts amyloid PET positivity in CU middle‐aged adults. Our results suggest that weight loss is mainly related with changes in tau‐related and synaptic dysfunction biomarkers and may precede cognitive decline in the preclinical stage of the Alzheimer’s continuum.