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.

Comparative gene regulatory networks modulating APOE expression in microglia and astrocytes.

Background: Single-cell technologies have unveiled various transcriptional states in different brain cell types. Transcription factors (TFs) regulate the expression of related gene sets, thereby controlling these diverse expression states. Apolipoprotein E (APOE), a pivotal risk-modifying gene in Alzheimer's disease (AD), is expressed in specific glial transcriptional states associated with AD. However, it is still unknown whether the upstream regulatory programs that modulate its expression are shared across brain cell types or specific to microglia and astrocytes. Methods: We used pySCENIC to construct state-specific gene regulatory networks (GRNs) for resting and activated cell states within microglia and astrocytes based on single-nucleus RNA sequencing data from AD patients' cortices from the Knight ADRC-DIAN cohort. We then identified replicating TF using data from the ROSMAP cohort. We identified sets of genes co-regulated with APOE by clustering the GRN target genes and identifying genes differentially expressed after the virtual knockout of TFs regulating APOE. We performed enrichment analyses on these gene sets and evaluated their overlap with genes found in AD GWAS loci. Results: We identified an average of 96 replicating regulators for each microglial and astrocyte cell state. Our analysis identified the CEBP, JUN, FOS, and FOXO TF families as key regulators of microglial APOE expression. The steroid/thyroid hormone receptor families, including the THR TF family, consistently regulated APOE across astrocyte states, while CEBP and JUN TF families were also involved in resting astrocytes. AD GWAS-associated genes (PGRN, FCGR3A, CTSH, ABCA1, MARCKS, CTSB, SQSTM1, TSC22D4, FCER1G, and HLA genes) are co-regulated with APOE. We also uncovered that APOE-regulating TFs were linked to circadian rhythm (BHLHE40, DBP, XBP1, CREM, SREBF1, FOXO3, and NR2F1). Conclusions: Our findings reveal a novel perspective on the transcriptional regulation of APOE in the human brain. We found a comprehensive and cell-type-specific regulatory landscape for APOE, revealing distinct and shared regulatory mechanisms across microglia and astrocytes, underscoring the complexity of APOE regulation. APOE-co-regulated genes might also affect AD risk. Furthermore, our study uncovers a potential link between circadian rhythm disruption and APOE regulation, shedding new light on the pathogenesis of AD.

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.

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.

Adapting prescribing criteria for amyloid-targeted antibodies for adults with Down syndrome.

Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti-amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late-onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease-modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness-raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti-amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease-modifying therapeutics for Alzheimer's disease.

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.

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.

Systematic proteomics in Autosomal dominant Alzheimer's disease reveals decades-early changes of CSF proteins in neuronal death, and immune pathways.

Background: To date, there is no high throughput proteomic study in the context of Autosomal Dominant Alzheimer's disease (ADAD). Here, we aimed to characterize early CSF proteome changes in ADAD and leverage them as potential biomarkers for disease monitoring and therapeutic strategies. Methods: We utilized Somascan® 7K assay to quantify protein levels in the CSF from 291 mutation carriers (MCs) and 185 non-carriers (NCs). We employed a multi-layer regression model to identify proteins with different pseudo-trajectories between MCs and NCs. We replicated the results using publicly available ADAD datasets as well as proteomic data from sporadic Alzheimer's disease (sAD). To biologically contextualize the results, we performed network and pathway enrichment analyses. Machine learning was applied to create and validate predictive models. Findings: We identified 125 proteins with significantly different pseudo-trajectories between MCs and NCs. Twelve proteins showed changes even before the traditional AD biomarkers (Aß42, tau, ptau). These 125 proteins belong to three different modules that are associated with age at onset: 1) early stage module associated with stress response, glutamate metabolism, and mitochondria damage; 2) the middle stage module, enriched in neuronal death and apoptosis; and 3) the presymptomatic stage module was characterized by changes in microglia, and cell-to-cell communication processes, indicating an attempt of rebuilding and establishing new connections to maintain functionality. Machine learning identified a subset of nine proteins that can differentiate MCs from NCs better than traditional AD biomarkers (AUC>0.89). Interpretation: Our findings comprehensively described early proteomic changes associated with ADAD and captured specific biological processes that happen in the early phases of the disease, fifteen to five years before clinical onset. We identified a small subset of proteins with the potentials to become therapy-monitoring biomarkers of ADAD MCs. Funding: Proteomic data generation was supported by NIH: RF1AG044546.

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.

"And Does That Necessarily Mean Absolutely Alzheimer's?" An Analysis of Questions Raised Following Amyloid PET Results Disclosure.

INTRODUCTION: Amyloid PET scans provide individuals with mild cognitive impairment (MCI) information about their risk of progressing to Alzheimer's dementia (AD). Given the wide-ranging implications of this information, best practice guidelines are needed to support researchers and clinicians disclosing these high-stakes test results. To inform the development of such guidelines, this analysis aims to describe questions and concerns raised during the disclosure of amyloid PET results in the context of MCI. METHODS: Qualitative description was performed to analyze (n = 34) transcripts of audio-recorded amyloid PET results disclosure sessions involving MCI care dyads. The analysis focused on characterizing the frequency and nature of questions raised during an open question-and-answer (Q&A) period following the return of scan results using a standardized protocol. RESULTS: Nearly all (n = 32/34) dyads posed questions during Q&A. Questions fell within six main categories with the most common being requests for clarification regarding AD/MCI, and next steps given the result. Questions were interspersed with comments reflecting the need for emotional support. Independently administered assessments of comprehension of results showed that, following the disclosure and Q&A, 31/32 participants with MCI and 31/31 care partners scored ≥4 on a 5-point scale. The number of questions asked by care partners during Q&A positively correlated with their level of comprehension (n = 31, Spearman's r = 0.370, p = 0.040). DISCUSSION: This analysis highlights the value of providing opportunities for patients and their family members to ask questions upon learning patients' brain amyloid status. Disclosing clinicians should be prepared to provide clarification, resources, and support to patients and families during the return of amyloid PET results.

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.

Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer's disease.

Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P < 0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.

Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer disease.

Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer Disease (AD). Given their essential role in neural communication, disruptions to these hubs have profound implications for overall brain network integrity and functionality. Hub disruption, or targeted impairment of functional connectivity at the hubs, is recognized in AD patients. Computational models paired with evidence from animal experiments hint at a mechanistic explanation, suggesting that these hubs may be preferentially targeted in neurodegeneration, due to their high neuronal activity levels-a phenomenon termed "activity-dependent degeneration". Yet, two critical issues were unresolved. First, past research hasn't definitively shown whether hub regions face a higher likelihood of impairment (targeted attack) compared to other regions or if impairment likelihood is uniformly distributed (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We applied a refined hub disruption index to determine the presence of targeted attacks in AD. Furthermore, we explored potential evidence for activity-dependent degeneration by evaluating if hub vulnerability is better explained by global connectivity or connectivity variations across functional systems, as well as comparing its timing relative to amyloid beta deposition in the brain. Our unique cohort of participants with autosomal dominant Alzheimer Disease (ADAD) allowed us to probe into the preclinical stages of AD to determine the hub disruption timeline in relation to expected symptom emergence. Our findings reveal a hub disruption pattern in ADAD aligned with targeted attacks, detectable even in pre-clinical stages. Notably, the disruption's severity amplified alongside symptomatic progression. Moreover, since excessive local neuronal activity has been shown to increase amyloid deposition and high connectivity regions show high level of neuronal activity, our observation that hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in Aß PET cortical markers is consistent with the activity-dependent degeneration model. Intriguingly, these disruptions were discernible 8 years before the expected age of symptom onset. Taken together, our findings not only align with the targeted attack on hubs model but also suggest that activity-dependent degeneration might be the cause of hub vulnerability. This deepened understanding could be instrumental in refining diagnostic techniques and developing targeted therapeutic strategies for AD in the future.

T1 and FLAIR signal intensities are related to tau pathology in dominantly inherited Alzheimer disease.

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (µ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-µ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1-σ and FLAIR-σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR-µ decreased and T1-σ and FLAIR-σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity-based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease.

Importance: Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective: To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants: This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). Main Outcome and Measures: The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results: Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = -3.1 [P = .002]; ADNI: t = -5.6 [P < .001]; HABS: t = -2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001). Conclusions and Relevance: The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease.

Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-ß (Aß) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aß plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aß plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aß and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aß and tau.

Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease.

Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aß compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic ß-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.