Novel non-linear models for clinical trial analysis with longitudinal data: A tutorial using SAS for both frequentist and Bayesian methods.

Longitudinal data from clinical trials are commonly analyzed using mixed models for repeated measures (MMRM) when the time variable is categorical or linear mixed-effects models (ie, random effects model) when the time variable is continuous. In these models, statistical inference is typically based on the absolute difference in the adjusted mean change (for categorical time) or the rate of change (for continuous time). Previously, we proposed a novel approach: modeling the percentage reduction in disease progression associated with the treatment relative to the placebo decline using proportional models. This concept of proportionality provides an innovative and flexible method for simultaneously modeling different cohorts, multivariate endpoints, and jointly modeling continuous and survival endpoints. Through simulated data, we demonstrate the implementation of these models using SAS procedures in both frequentist and Bayesian approaches. Additionally, we introduce a novel method for implementing MMRM models (ie, analysis of response profile) using the nlmixed procedure.

Molecular neuroimaging in dominantly inherited versus sporadic early-onset Alzheimer's disease.

Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-ß accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-ß plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial.

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] ß = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] ß = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] ß = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] ß = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] ß = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] ß = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] ß = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aß42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aß42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aß42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. METHODS: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. FINDINGS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. INTERPRETATION: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. FUNDING: None.

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

Comparison of cerebrospinal fluid, plasma and neuroimaging biomarker utility in Alzheimer's disease.

Alzheimer's disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer's disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning. Data were obtained from 527 community-dwelling volunteers enrolled in studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University in St Louis. We used hierarchical clustering to group 27 imaging, CSF and plasma measures of amyloid beta, tau [phosphorylated tau (p-tau), total tau t-tau)], neuronal injury and inflammation drawn from MRI, PET, mass-spectrometry assays and immunoassays. Neuropsychological and genetic measures were also included. Random forest-based feature selection identified the strongest predictors of amyloid PET positivity across the entire cohort. Models also predicted cognitive impairment across the entire cohort and in amyloid PET-positive individuals. Four clusters emerged reflecting: core Alzheimer's disease pathology (amyloid and tau), neurodegeneration, AT8 antibody-associated phosphorylated tau sites and neuronal dysfunction. In the entire cohort, CSF p-tau181/Aß40lumi and Aß42/Aß40lumi and mass spectrometry measurements for CSF pT217/T217, pT111/T111, pT231/T231 were the strongest predictors of amyloid PET status. Given their ability to denote individuals on an Alzheimer's disease pathological trajectory, these same markers (CSF pT217/T217, pT111/T111, p-tau/Aß40lumi and t-tau/Aß40lumi) were largely the best predictors of worse cognition in the entire cohort. When restricting analyses to amyloid-positive individuals, the strongest predictors of impaired cognition were tau PET, CSF t-tau/Aß40lumi, p-tau181/Aß40lumi, CSF pT217/217 and pT205/T205. Non-specific CSF measures of neuronal dysfunction and inflammation were poor predictors of amyloid PET and cognitive status. The current work utilized machine learning to understand the interrelationship structure and utility of a large number of biomarkers. The results demonstrate that, although the number of biomarkers has rapidly expanded, many are interrelated and few strongly predict clinical outcomes. Examining the entire corpus of available biomarkers simultaneously provides a meaningful framework to understand Alzheimer's disease pathobiological change as well as insight into which biomarkers may be most useful in Alzheimer's disease clinical practice and trials.

Oriented Graphene Oxide Scaffold Promotes Nerve Regeneration in vitro and in vivo.

Background: Treating peripheral nerve injuries (PNI) with defects remains challenging in clinical practice. The commercial conduits have shown suboptimal nerve regeneration and functional recovery due to their basic tubular design without electroactive and oriented topographical cues. Purpose: To develop a new scaffold with oriented microstructure and electroactive Graphene oxide (GO) and investigate its' therapeutic effect on nerve regeneration in vitro and in vivo. Methods: This study employed a straightforward approach to co-spin PCL and GO, yielding an oriented hybrid nanofibrous scaffold known as the O-GO/PCL scaffold. The physical and chemical properties of nanofibrous scaffold were tested by scanning electron microscopy (SEM), transmission electron microscope (TEM), tensile test and so on. Primary Schwann cells (SCs) and dorsal root ganglia (DRG) were used to investigate the impact of the newly developed scaffolds on the biological behavior of neural cells in vitro. Transcriptome sequencing (mRNA-seq) was employed to probe the underlying mechanisms of the synergistic effect of electroactive GO and longitudinal topographic guidance on nerve regeneration. Furthermore, the developed O-GO/PCL scaffold was utilized to bridge a 10-mm sciatic nerve defect in rat, aiming to investigate its therapeutic potential for peripheral nerve regeneration in vivo. Results and discussion: The SEM and TEM revealed that the newly developed O-GO/PCL scaffold showed longitudinally oriented microstructure and GO particles were homogenously and uniformly distributed inside the nanofibers. Primary SCs were utilized to assess the biocompatibility of the GO-based scaffold, revealing that negligible cytotoxicity when GO concentration does not exceed 0.5%. In vitro analysis of nerve regeneration demonstrated that axons in the O-GO/PCL group exhibited an average length of 1054.88 ± 161.32 µm, significant longer than those in the other groups (P < 0.05). Moreover, mRNA sequencing results suggested that the O-GO/PCL scaffold could enhance nerve regeneration by upregulating genes associated with neural regeneration, encompassing ion transport, axon guidance and cell-cell interactions. Most importantly, we employed the O-GO/PCL scaffold to repair a 10-mm sciatic nerve defect in rat, resulting in augmented nerve regeneration, myelination, and functional recovery. Conclusion: The O-GO/PCL scaffold with oriented microstructure and electroactive GO represents a promising heral nerve reconstruction.

Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging.

BACKGROUND: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. METHODS: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. FINDINGS: We found both tau metrics significantly elevated across increasing disease stages (p < 0.0001) and as a function of increasing amyloid burden for participants with preclinical (p < 0.0001, p = 0.0056) and symptomatic (p = 0.010, p = 0.0021) AD. An interaction was found between tau burden and tau spatial spread when predicting amyloid burden (p = 0.00013). Analyses of slope between tau metrics demonstrated more spread than burden in preclinical AD (ß = 0.59), but then tau burden elevated relative to spread (ß = 0.42) once participants had symptomatic AD, when the tau metrics became highly correlated (R = 0.83). INTERPRETATION: Tau burden and tau spatial spread are both strong biomarkers for early AD but provide unique information, particularly at the preclinical stage. Tau spatial spread may demonstrate earlier changes than tau burden which could have broad impact in clinical trial design. FUNDING: This research was supported by the Knight Alzheimer Disease Research Center (Knight ADRC, NIH grants P30AG066444, P01AG026276, P01AG003991), Dominantly Inherited Alzheimer Network (DIAN, NIH grants U01AG042791, U19AG03243808, R01AG052550-01A1, R01AG05255003), and the Barnes-Jewish Hospital Foundation Willman Scholar Fund.

Examining amyloid reduction as a surrogate endpoint through latent class analysis using clinical trial data for dominantly inherited Alzheimer's disease.

INTRODUCTION: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab. METHODS: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker. RESULTS: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid-no-change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid-reduction class exhibited reductions in the annual decline rates compared to the amyloid-growth class across multiple biomarker, clinical, and cognitive outcomes. DISCUSSION: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials. HIGHLIGHTS: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid-reduction class exhibited remarkably better outcomes compared to the amyloid-growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects.

An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an HLA-DP5+ nasopharyngeal cancer mouse model.

Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135-transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen-presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients.

Timing of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset.

OBJECTIVE: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). METHODS: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. RESULTS: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15-19 years before estimated symptom onset for CSF Aß42/Aß40, plasma Aß42/Aß40, CSF pT217/T217, and amyloid PET; 12-14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7-9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. INTERPRETATION: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951-965.

Baseline levels and longitudinal rates of change in plasma Aß42/40 among self-identified Black/African American and White individuals.

Objective: The use of blood-based biomarkers of Alzheimer disease (AD) may facilitate access to biomarker testing of groups that have been historically under-represented in research. We evaluated whether plasma Aß42/40 has similar or different baseline levels and longitudinal rates of change in participants racialized as Black or White. Methods: The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to evaluate for potential differences in AD biomarkers between individuals racialized as Black or White. Plasma samples collected at three AD Research Centers (Washington University, University of Pennsylvania, and University of Alabama-Birmingham) underwent analysis with C2N Diagnostics' PrecivityAD™ blood test for Aß42 and Aß40. General linear mixed effects models were used to estimate the baseline levels and rates of longitudinal change for plasma Aß measures in both racial groups. Analyses also examined whether dementia status, age, sex, education, APOE ε4 carrier status, medical comorbidities, or fasting status modified potential racial differences. Results: Of the 324 Black and 1,547 White participants, there were 158 Black and 759 White participants with plasma Aß measures from at least two longitudinal samples over a mean interval of 6.62 years. At baseline, the group of Black participants had lower levels of plasma Aß40 but similar levels of plasma Aß42 as compared to the group of White participants. As a result, baseline plasma Aß42/40 levels were higher in the Black group than the White group, consistent with the Black group having lower levels of amyloid pathology. Racial differences in plasma Aß42/40 were not modified by age, sex, education, APOE ε4 carrier status, medical conditions (hypertension and diabetes), or fasting status. Despite differences in baseline levels, the Black and White groups had a similar longitudinal rate of change in plasma Aß42/40. Interpretation: Black individuals participating in AD research studies had a higher mean level of plasma Aß42/40, consistent with a lower level of amyloid pathology, which, if confirmed, may imply a lower proportion of Black individuals being eligible for AD clinical trials in which the presence of amyloid is a prerequisite. However, there was no significant racial difference in the rate of change in plasma Aß42/40, suggesting that amyloid pathology accumulates similarly across racialized groups.

Naturalistic assessment of reaction time variability in older adults at risk for Alzheimer's disease.

OBJECTIVE: Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer's disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD. METHOD: Three hundred and seventy older adults (aged 75.8 +/- 5.8 years) completed a week of remote daily testing on the Ambulatory Research in Cognition (ARC) smartphone platform and also completed clinical, genetic, and conventional in-clinic cognitive assessments. RT variability was assessed in a brief (20-40 seconds) processing speed task using two different measures of variability, the Coefficient of Variation (CoV) and the Root Mean Squared Successive Difference (RMSSD) of RTs on correct trials. RESULTS: Symptomatic participants showed greater variability compared to cognitively normal participants. When restricted to cognitively normal participants, APOE ε4 carriers exhibited greater variability than noncarriers. Both CoV and RMSSD showed significant, and similar, correlations with several in-clinic cognitive composites. Finally, both RT variability measures significantly mediated the relationship between APOE ε4 status and several in-clinic cognition composites. CONCLUSIONS: Attentional fluctuations over 20-40 seconds assessed in daily life, are sensitive to clinical status and genetic risk for AD. RT variability appears to be an important predictor of cognitive deficits during the preclinical disease stage.

Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network.

INTRODUCTION: Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD). METHODS: Three hundred twenty-five mutation carriers (55% female) and one hundred eighty-six non-carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross-sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography (11 C-PiB PET) and structural magnetic resonance imaging (MRI). RESULTS: Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences. DISCUSSION: Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD.

Relationships of Cognitive Measures with Cerebrospinal Fluid but Not Imaging Biomarkers of Alzheimer Disease Vary between Black and White Individuals.

OBJECTIVE: Biomarkers of Alzheimer disease vary between groups of self-identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups. METHODS: Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z-transformations. RESULTS: The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aß42/40, total tau, p-tau181, and neurofilament light. CSF Aß42/40 was negatively correlated with total tau and p-tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aß42/40, total tau, and p-tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aß42/40, Aß42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures. INTERPRETATION: Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495-506.

Correlational analyses of biomarkers that are harmonized through a bridging study due to measurement errors.

Evaluating correlations between disease biomarkers and clinical outcomes is crucial in biomedical research. During the early stages of many chronic diseases, changes in biomarkers and clinical outcomes are often subtle. A major challenge to detecting subtle correlations is that studies with large sample sizes are usually needed to achieve sufficient statistical power. This challenge is even greater when biofluid and imaging biomarker data are used because the required procedures are burdensome, perceived as invasive, and/or expensive, limiting sample sizes in individual studies. Combining data across multiple studies may increase statistical power, but biomarker data may be generated using different assay platforms, scanner types, or processing protocols, which may affect measured biomarker values. Therefore, harmonizing biomarker data is essential to combining data across studies. Bridging studies involve re-processing of a subset of samples or imaging scans to evaluate how biomarker values vary by studies. This presents an analytic challenge on how to best harmonize biomarker data across studies to allow unbiased and optimal estimates of their correlations with standardized clinical outcomes. We conceptualize that a latent biomarker underlies the observed biomarkers across studies, and propose a novel approach that integrates the data in the bridging study with the study-specific biomarker data for estimating the biological correlations between biomarkers and clinical outcomes. Through extensive simulations, we compare our method to several alternative methods/algorithms often used to estimate the correlations. Finally, we demonstrate the application of this methodology to a real-world multi-center Alzheimer's disease biomarker study to correlate cerebrospinal fluid biomarker concentrations with cognitive outcomes.

Predicting cognitive decline: Which is more useful, baseline amyloid levels or longitudinal change?

The use of biomarkers for the early detection of Alzheimer's disease (AD) is crucial for developing potential therapeutic treatments. Positron Emission Tomography (PET) is a well-established tool used to detect ß-amyloid (Aß) plaques in the brain. Previous studies have shown that cross-sectional biomarkers can predict cognitive decline (Schindler et al.,2021). However, it is still unclear whether longitudinal Aß-PET may have additional value for predicting time to cognitive impairment in AD. The current study aims to evaluate the ability of baseline- versus longitudinal rate of change in-11C-Pittsburgh compound B (PiB) Aß-PET to predict cognitive decline. A cohort of 153 participants who previously underwent PiB-PET scans and comprehensive clinical assessments were used in this study. Our analyses revealed that baseline Aß is significantly associated with the rate of change in cognitive composite scores, with cognition declining more rapidly when baseline PiB Aß levels were higher. In contrast, no signification association was identified between the rate of change in PiB-PET Aß and cognitive decline. Additionally, the ability of the rate of change in the PiB-PET measures to predict cognitive decline was significantly influenced by APOE ε4 carrier status. These results suggest that a single PiB-PET scan is sufficient to predict cognitive decline and that longitudinal measures of Aß accumulation do not improve the prediction of cognitive decline once someone is amyloid positive.

Assessing the structure and diversity of fungal community in plant soil under different climatic and vegetation conditions.

Introduction: Understanding microbial communities in diverse ecosystems is crucial for unraveling the intricate relationships among microorganisms, their environment, and ecosystem processes. In this study, we investigated differences in the fungal community structure and diversity in soils from two contrasting climatic and vegetation conditions: the Xinjiang western China plateau and the Fujian southeastern coastal province. Methods: A total of 36 soil samples collected from two climatic regions were subjected to high-throughput ITS gene sequencing for fungal community analysis. In conjunction soil physicochemical properties were assessed and compared. Analyses included an examination of the relationship of fungal community structure to environmental factors and functional profiling of the community structure was using the FUNGuild pipeline. Results: Our data revealed rich fungal diversity, with a total of 11 fungal phyla, 31 classes, 86 orders, 200 families, 388 genera, and 515 species identified in the soil samples. Distinct variations in the physicochemical properties of the soil and fungal community structure were seen in relation to climate and surface vegetation. Notably, despite a colder climate, the rhizosphere soil of Xinjiang exhibited higher fungal (α-)diversity compared to the rhizosphere soil of Fujian. ß-diversity analyses indicated that soil heterogeneity and differences in fungal community structure were primarily influenced by spatial distance limitations and vegetation type. Furthermore, we identified dominant fungal phyla with significant roles in energy cycling and organic matter degradation, including members of the Sordariomycetes, Leotiomycetes, Archaeosporomycetes, and Agaricomycetes. Functional analyses of soil fungal communities highlighted distinct microbial ecological functions in Xinjiang and Fujian soils. Xinjiang soil was characterized by a focus on wood and plant saprotrophy, and endophytes, whereas in Fujian soil the fungal community was mainly associated with ectomycorrhizal interactions, fungal parasitism, and wood saprotrophy. Discussion: Our findings suggest fungal communities in different climatic conditions adapt along distinct patterns with, plants to cope with environmental stress and contribute significantly to energy metabolism and material cycling within soil-plant systems. This study provides valuable insights into the ecological diversity of fungal communities driven by geological and environmental factors.

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease.

BACKGROUND: "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. METHODS: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-ß-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE Îµ4 carrier status, sex, and education. RESULTS: Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. CONCLUSIONS: We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.