Gauthier, Serge

Abstract BACKGROUND Tau‐derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid‐beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long‐term anti‐Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them. METHODS A post‐hoc analysis of the DIAN‐TU‐001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab ( n = 50), gantenerumab ( n = 52), or placebo ( n = 40). High‐resolution mass spectrometry quantified CSF tau species over four years. RESULTS Phosphorylated tau (p‐tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab‐mediated Aβ plaque reduction. Nearly a decade later, MTBR‐tau243 and p‐tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression. DISCUSSION Initially changing soluble p‐tau species track Aβ plaque reduction, while ptau205 and MTBR‐243 reflect tau tangle pathology, informing different pathways of therapeutic strategies. Highlights p‐tau217 and p‐tau231 correlate with Aβ‐PET and respond to Aβ‐plaque lowering therapies. Aβ immunotherapy trials support a direct link between p‐tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT‐related biomarkers. Blood‐based p‐tau217 assays may provide a non‐invasive tool to monitor Aβ therapies. MTBR‐tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT‐targeting therapies.

Abstract INTRODUCTION Monoclonal anti‐amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS In the DIAN‐TU‐001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [ 11 C]‐Pittsburgh compound‐B (PiB) positron emission tomography (PET), [ 18 F]‐fluoro‐2‐deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS Gantenerumab significantly reduced PiB‐PET uptake overall and in most regions and showed no changes in FDG‐PET or MRI measures. Drug effects were associated with baseline PiB‐PET uptake, and the largest effects occurred in medial regions. DISCUSSION Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB‐PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. Highlights Gantenerumab unevenly decreased Aβ burden as measured by PiB‐PET across brain regions. The strongest decrease in PiB‐PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG‐PET metabolism or MRI volumetrics after 4 years.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

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] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 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

ObjectiveTo determine the characteristics of participants with amyloid‐related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD).Methods142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β‐amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross‐sectional and longitudinal analyses evaluated potential ARIA‐related risk factors.ResultsEleven participants developed ARIA‐E, including 3 with mild symptoms. No ARIA‐E was reported under solanezumab while gantenerumab was associated with ARIA‐E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE‐ɛ4 carriers were more likely to develop ARIA‐E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA‐E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA‐E occurrence, all ARIA‐E participants were amyloid‐PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA‐H. Most ARIA‐E radiologically resolved after dose adjustment and developing ARIA‐E did not significantly increase odds of trial discontinuation. ARIA‐E was more frequently observed in the occipital lobe (90%). ARIA‐E severity was associated with age at time of ARIA‐E.InterpretationIn DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA‐E risk, with additional risk for individuals APOE‐ɛ4(+) or with microhemorrhage. ARIA‐E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729–744

AbstractBackgroundAs the only optically accessible part of the central nervous system, the retina represents an intriguing opportunity for the detection of biomarkers for Alzheimer’s disease (AD). This study evaluated the performance of the Retinal Deep PhenotypingTM platform, a digital biomarker platform comprising a hyperspectral retinal camera and image analysis algorithms, for the detection of likely positron‐emission tomography (PET) amyloid status (negative or positive) in older adults. A set of phenotypic features that correlates with the cerebral amyloid status as determined by amyloid PET scan were identified and used to train a classifying algorithm.MethodHyperspectral retinal images acquired with a Mydriatic Hyperspectral Retinal Camera from 194 participants (age ≥ 50 years), including cognitively normal and cognitively impaired (mild cognitive impairment and dementia) across 5 imaging sites were processed in order to train the model. Of these 194 participants, 73 individuals (38%) were amyloid‐positive, as confirmed by unanimous readings of PET scans by a panel of 3 expert reviewers. The pre‐processed hyperspectral images were segmented into various anatomical sites, and a texture‐based approach was used to extract several thousands of spatial‐spectral features. The most relevant features for the classification task were selected using a minimum redundancy maximum relevance (MRMR) algorithm and used to train a linear support vector machine (SVM) classifier. A nested, cross‐validation technique was used to evaluate the performance of the classifier.ResultThe resulting model based on the 17 most significant features showed high performance to discriminate between amyloid positive and negative subjects with an area under the receiver operating curve (AUCROC) of 0.87 (95% CI: 0.83 – 0.92).ConclusionThe Retinal Deep PhenotypingTM platform shows promise for detecting the likely cerebral amyloid PET status in adults 50 years and older from a simple, non‐invasive retinal scan and could provide an accessible means to identify individuals with abnormal cerebral amyloid in a clinical or drug development context. This phenotyping platform provides a flexible approach that could also be used for the detection of multiple biomarkers involved in cognitive decline from the same hyperspectral images of the retina.

AbstractBackgroundBlood phosphorylated tau (p‐tau) has proven to be the primary candidate as an accessible and scalable biomarker for Alzheimer’s disease (AD). Both p‐tau181 and p‐tau217 are highly accurate to detect AD within dementia cases. Our recent work in cerebrospinal fluid, however, indicates p‐tau231 to be associated to incipient AD pathology. In light of this, we developed a Single molecule array (Simoa) to detect plasma p‐tau231 and assessed its performance in multiple domains, specifically, its ability to detect preclinical AD.MethodIn all cohorts, plasma p‐tau231 was quantified using an in‐house Simoa method developed at the Clinical Neurochemistry Laboratory, Gothenburg University, Sweden. Data presented in this study are samples acquired from Translational Biomarkers of Aging and Dementia (TRIAD, n=503), King’s College London (n=55), Mayo Clinic Study of Aging (n=145), KARVIAH (n=140), Baltimore Longitudinal Study of Aging (n=430), University College London (n=70), Paris University (n=213), PREVENT‐AD (n=257), University of California (n=309) and ALFA+ (n=385).ResultIn the TRIAD cohort, plasma p‐tau231 demonstrated high accuracy in determining AD from young individuals (AUC=0.95), Aβ‐ elderly (AUC=0.92), Aβ‐ MCI (AUC=0.88) and other neurodegenerative disorders (AUC=0.92). In an autopsy study, plasma p‐tau231 could detect neuropathologically confirmed AD amongst dementia cases (AUC=0.99). In comparing healthy elderly Aβ‐ and Aβ+ individuals, p‐tau231 predicted preclinical Aβ pathology (AUC=0.83). Furthermore, inflection points of the weighted regression curves demonstrate that increases in plasma p‐tau231 occur before plasma p‐tau181 as a function of Aβ deposition load. Plasma p‐tau231 data from additional cohorts will focus on cross‐sectional and longitudinal preclinical datasets. In addition, further data will show the performance of p‐tau231 in symptomatic and presymptomatic PSEN1/APP mutation carriers, memory clinic cohorts, longitudinal neuropathology confirmed and acute neurological injury.ConclusionPlasma p‐tau231 is a new biomarker specific for AD pathology and at higher concentrations relative to p‐tau181 and p‐tau217. Our initial results indicate that plasma p‐tau231 is equivalent to p‐tau181 in diagnostic utility but has greater potential as a biomarker to monitor emerging Aβ pathology. This presentation will give an overview of novel cross‐sectional and longitudinal plasma p‐tau231 data, in more than 3000 individuals, that encompasses the AD continuum, familial AD and other neurological conditions.

AbstractBackgroundAmyloid‐related imaging abnormalities (ARIA), edema (E) or hemorrhagic (H) type, have been reported in trials of anti‐β‐amyloid passive immunotherapies in sporadic and dominantly inherited Alzheimer Disease (DIAD). However, beyond APOE‐ɛ4 the risk factors and clinical implications of ARIA are not well understood, especially in DIAD populations. Here we characterize ARIA, focusing on ARIA‐E in the DIAN‐TU‐001 trial evaluating gantenerumab and solanezumab in DIAD.MethodThe DIAN‐TU‐001 trial enrolled 194 participants, including 144 DIAD mutation‐carriers receiving gantenerumab (n=52), solanezumab (n=52), or a placebo (n=40). Clinical assessments included the Clinical Dementia Rating (CDR). Imaging assessments included PiB‐PET and safety MR, including T2‐FLAIR and T2*‐GRE. Treatment dosage and APOE‐ɛ4 status were also reported.ResultEleven participants developed a total of 14 ARIA‐E episodes (discovered on scheduled safety MR) and three had associated mild symptoms reported in retrospect (e.g. headache, imbalance disorder). Though one ARIA‐E case was observed in the solanezumab arm, the following results focus on the gantenerumab arm to prevent unblinding. Recipients of gantenerumab were more likely to develop ARIA‐E compared to placebo (odds ratio (OR)=9.29, 95% confidence interval (CI)=[1.1,75.9], p‐value<0.05). ARIA‐E participants were PiB‐PET+ and 60% were CDR>0. APOE‐ɛ4 tends to be associated with risk for developing ARIA‐E (OR=5.0, 95%CI=[1.0,30.4], p‐value=0.055). ARIA‐E were not observed at initial 225mg dose and were first observed after a titration step (within 4‐24 weeks, after 1‐6 injections, Table 1). Time‐to‐resolution of ARIA‐E was 10.4±6.2weeks. Seven of ten ARIA‐E patients paused/reduced dose escalation and three discontinued treatment. Overall, developing ARIA‐E did not increase the odds of trial discontinuation (OR=1.57, 95%CI=[0.34,7.33], p‐value=0.57). ARIA‐E occurred primarily in the occipital lobe (71%) with associated incident ARIA‐H (microhemorrhages or superficial siderosis) in 60% of ARIA‐E participants. ARIA‐E size was associated with microhemorrhage count (Spearman’s rho=0.72, p‐value<0.05), rate of change (rho=0.78, p‐value<0.01), and baseline PiB‐PET (rho=0.68, p‐value<0.05). Normalizing by baseline, PiB‐PET decreased similarly in ARIA‐E+ (‐0.21±0.20) and ARIA‐E‐ (‐0.16±0.20) participants.ConclusionIn DIAD, gantenerumab dose over 225mg increased ARIA‐E risk, possibly more for APOE‐ɛ4 carriers. ARIA‐E was reversible, generally asymptomatic, and without increased odds of trial discontinuation. These aspects of drug response give insights for managing ARIA‐E occurrence in future trials.

AbstractBackgroundTranslating recent advances in the diagnosis of Alzheimer’s disease (AD) and other dementias to clinical practice using biomarker‐based approaches requires accessible, affordable biomarkers. This protocol tested the performance of a Retinal Deep Phenotyping platform for the detection of likely positron‐emission tomography (PET) amyloid status (negative or positive) in human subjects. This platform generates data rich retinal reflectance images captured non‐invasively with a Metabolic Hyperspectral Retinal Camera (MHRC) yielding specific spatial‐spectral features which are analyzed by a machine learning algorithm relatively to a recognized gold standard biomarker (in this case PET amyloid imaging).Methods134 subjects (50 years and older) from 3 clinical sites were included, 94 with normal, 40 with abnormal cognition, imaged with the MHRC and amyloid PET (unanimous visual reads from a panel of 3 expert reviewers; 42 amyloid positive, 92 negative). Over 600 spatial‐spectral features were extracted from hyperspectral retinal images obtained at 450‐900 nm. After a feature selection based on F‐score ranking, a classifier was trained on the datasets from 87 patients (2/3 of the cohort) using the most discriminating features. The classification performance was then evaluated with the datasets from the remaining 47 patients.ResultsResubstituting the training set of 87 patients into the classifier yielded sensitivity and specificity values of 88% and 91%, respectively. The training misclassification rate was predicted using the k‐fold loss metric, with a predicted error rate of 19%. To verify this performance, the test set of 47 patients was classified by the model resulting in sensitivity and specificity values of 80% and 81%, respectively.ConclusionsThe Retinal Deep Phenotyping platform shows promise for detecting the likely cerebral amyloid PET status in human subjects and could serve as a screening tool to identify subjects in the AD continuum, for instance in a clinical or drug development context. The platform could also be used for the detection of other biomarkers involved in cognitive decline.

AbstractBackgroundAlzheimer’s disease (AD) prevention trials aim to intervene prior to significant neuronal loss, brain damage, and symptom onset to delay or slow cognitive decline. In dominantly inherited AD (DIAD), mutation carriers develop symptomatic AD at predictable ages with near 100% penetrance. In 2012, the Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial (DIAN‐TU APT) platform launched a double‐blind, randomized, placebo‐controlled, parallel group trial of two anti‐amyloid‐beta monoclonal antibodies with two different antigenic targets, gantenerumab and solanezumab (NCT01760005). The DIAN‐TU scientific development, implementation of the first AD prevention trial, trial challenges and opportunities, including dose escalation, and top‐line results will be presented.MethodDIAN was established in 2008 in response to a call from the National Institute of Aging to establish a network to study DIAD and enable future clinical trials. Successive breakthroughs in understanding disease processes enabled the launch of the DIAN‐TU adaptive prevention trial, a global adaptive platform trial supporting testing multiple drugs in parallel. The DIAN‐TU partners include patients and families at risk for DIAD, global academic researchers, the NIH, Alzheimer’s Association, philanthropic supporters, the DIAN‐TU Pharma Consortium, and pharmaceutical companies with drugs being tested. Important milestones include developing a platform to enable a comprehensive efficient treatment trial for this rare population, adding tau PET as part of AMP AD, adapting dosing mid‐trial and extending the original biomarker trial to continue randomized dosing to test a cognitive endpoint until the last patient reaches 4 years, developing a disease progression statistical model and inclusion of DIAN observational data to increase the power to determine drug effects.ResultThe primary and key secondary outcomes of the DIAN‐TU trial will be presented for each therapy in the context of targeting amyloid‐beta at pre‐clinical and clinically symptomatic stages of disease.ConclusionThese results inform about AD hypotheses, timing of treatment and the prospect of slowing, or preventing AD in DIAD and sporadic AD.