JNJ-42165279 is a potent, selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid N-arachidonoylethanolamide (anandamide), which plays a role in regulation of fear and anxiety responses. This double-blind, randomised, placebo-controlled, phase 2a study assessed the efficacy, safety and pharmacodynamics of adjunctive treatment with JNJ-42165279 in participants with major depressive disorder (MDD) with anxious distress and inadequate response to selective serotonin reuptake inhibitors (SSRI) or serotonergic/noradrenergic reuptake inhibitors (SNRI). Eligible participants (18-64 years; N = 153) were randomised (1:1) to receive JNJ-42165279 (25 mg) or placebo orally once daily and were maintained on their current SSRI/SNRI treatment. The primary endpoint was the change from baseline at week 6 in the 17-item Hamilton Depression Rating Scale (HDRS17). The study results did not show a significant treatment effect of adjunctive JNJ-42165279 on the primary endpoint versus placebo (least square mean difference [standard error]:-0.2 [1.04]; one-sided p=0.416) in the enriched intent-to-treat population. Findings for the key secondary efficacy endpoints also did not demonstrate an additional benefit of adjunctive JNJ-42165279 treatment over placebo. Treatment with JNJ-42165279 produced substantial increases in the mean concentrations of fatty acid amides in plasma, and the plasma JNJ-42165279 and anandamide levels were strongly correlated. The safety results were consistent with the known safety profile of JNJ-42165279. Overall, adjunctive treatment with JNJ-42165279 at the dose tested did not provide significant benefit in reducing depression/ anxiety symptoms versus placebo but showed no new safety signals in participants with MDD and anxious distress.

Poor self-reported sleep quality is associated with cognitive impairment. Alzheimer’s disease (AD) patients present sleep disruptions decades before they start to decline clinically. Similarly, amyloid-β (Aβ) starts accumulating during the preclinical phase of the disease. This study investigated associations between self-reported sleep quality and Aβ burden longitudinally in clinically unimpaired (CU) adults. Four hundred seventeen CU adults from the AMYPAD PNHS cohort were included, with baseline self-reported sleep quality assessments (Pittsburgh Sleep Quality Index, PSQI) and longitudinal Aβ PET scans. Participants were categorized by baseline Aβ levels as negative (A-), grey-zone (GZ), or positive (A+). Linear mixed-effects (LME) models tested the association between baseline sleep quality and Aβ burden over time, including interaction effects with baseline Aβ status. Global PSQI score was not associated with Aβ burden over time in the entire group. However, a significant interaction with baseline Aβ status was found, whereby poorer subjective sleep quality was linked to accelerated Aβ accumulation in GZ participants. Poorer subjective sleep quality is associated with faster Aβ accumulation in CU individuals with intermediate Aβ levels, highlighting sleep as a potential target for early AD prevention and identifying an optimal intervention window.

Background:This double-blind, placebo-controlled, phase 2a clinical trial evaluated the efficacy and safety of JNJ-55308942 (zanvipixant), a selective, brain-penetrant P2X7 receptor antagonist, in bipolar depression. Methods:Outpatients ages 18 to 64 years with bipolar I/II disorder, who were experiencing a major depressive episode and carried a specific gain-of-function P2RX7 mutation without either of 2 specific loss-of-function P2RX7 mutations, were randomized at a 1:1 ratio to receive 50 mg JNJ-55308942 or placebo once daily. The primary end point was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Results:The mean (SD) change in the MADRS total score from baseline to 6 weeks was -16.0 (10.43) for the JNJ-55308942 group (n = 42) and -15.4 (9.81) for the placebo group (n = 50), with a nonstatistically significant least squares (LS) mean difference of -0.3 (95% CI, -4.21 to 3.59). However, the ability to detect an effect was obscured by a high placebo response, rendering this study inconclusive. Notably, the week-6 LS mean difference between treatment groups in MADRS total score among participants homozygous for a P2RX7 gain-of-function allele (JNJ-55308942, n = 11; placebo, n = 16) was -3.5 (95% CI, -11.32 to 4.26), and the week-6 LS mean difference between treatment groups in Patient-Reported Outcomes Measurement Information System Ability to Participate in Social Roles and Activities T score (JNJ-55308942, n = 42; placebo, n = 50) was 3.32 (95% CI, 0.12 to 6.52). Adverse events were generally mild or moderate, with no clear differences between treatment groups. Conclusions:While the primary end point was not achieved, clinically meaningful findings in secondary outcomes and a tolerable safety profile warrant further investigation into P2X7 receptor antagonism in bipolar depression.

The emergence of disease-modifying drug therapies is expected to revolutionize the field of Alzheimer's disease (AD). Recent results from anti-amyloid clinical trials highlight the importance of early identification and accurate risk-stratification of individuals in early stages of the disease. In this context, the Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) Prognostic and Natural History Study (PNHS) was established, leveraging existing cohorts to alleviate the burden of recruiting de novo participants. Here, we describe the harmonization and integration efforts of brain imaging, clinical, cognitive, and fluid biomarker data. Access to the data is available through the Alzheimer’s Disease Data Initiative, with additional details provided at https://amypad.eu/data/ The AMYPAD PNHS integrates prospective and historical data from 32 European sites across 10 countries. These sites contribute data from 10 Parent Cohorts (PC), predominantly comprising non-demented at-risk subjects, including EPAD LCS, EMIF-AD (60++ and 90+), ALFA+, FACEHBI, FPACK, UCL-2010-412, Microbiota, DELCODE, and the AMYPAD Diagnostic and Patient Management Study. A meticulous data curation process was implemented, harmonizing metrics and questionnaires through strategies such as recoding into categories, Percentage of Maximum Possible Scores, and z-scores. Expert reviewers at each site conducted PET visual reads. Centralized quantification of static PET images, employing site-specific Gaussian smoothing, yielded harmonized Centiloid values. Parametric modelling of dynamic PET scans was also performed providing metrics such as the distribution volume ratio. The initial data set includes 3366 participants (55% females, 67±8 years), with 2629 having at least one follow-up visit (2.6±1.9 years). Of those, 1618 underwent baseline amyloid PET, 888 with follow-up. The dataset incorporates clinical outcomes, biomarkers, risk factors, and other relevant variables (Figure 1). Distribution of participants based on amyloid PET status at baseline yielded 60% negative (<12CL), 24% grey-zone (12-50CL), and 16% positive (>50CL) cases. The AMYPAD PNHS represents the largest European longitudinal dataset phenotyping individuals at risk of AD-related progression. The consortium is currently evolving into its new phase, namely the Euro-PAD collaborative framework, and the dataset will be expanded in terms of variables (e.g., currently integrating GWAS and advanced MRI data) and number of cohorts. Interested to join, please contact us at https://amypad.eu/

Post-traumatic stress disorder (PTSD) is a severe mental health disorder with limited treatment options. Gold standard treatment includes cognitive behavioral therapies (CBT) that incorporate exposure to traumatic memories to facilitate extinction. CBT can be effective in PTSD, but effects are incomplete and symptoms are prone to spontaneous return. Pharmacologically facilitating fear extinction could potentiate the effects of exposure-based therapy. Here, we explored whether targeting the endocannabinoid (eCB) system, a neuromodulatory system critically involved in fear extinction, would promote the efficacy of exposure-based CBT. Specifically, we tested the effects of elevating the eCB ligand anandamide (AEA) via inhibition of its main degradative enzyme, fatty acid amide hydrolase (FAAH). In this double-blind, placebo-controlled study, patients with PTSD (N = 100; 85 women) were randomized to the FAAH inhibitor (FAAHi) JNJ-42165279 (25 mg b.i.d.) or placebo for 12 weeks. In weeks 5–12, all participants completed an internet-delivered CBT that included exposure-based modules. The primary outcome was clinician-assessed PTSD symptom severity (CAPS-5). Secondary outcomes included self-reported symptoms of PTSD, depression, anxiety, and sleep quality. Blood samples were taken to measure levels of drug and eCBs. Overall, PTSD symptoms improved over time. While FAAHi increased AEA levels, there was no effect of FAAHi on PTSD symptoms or any secondary measure. FAAHi combined with internet-delivered CBT did not improve PTSD symptoms to a greater extent than internet-delivered CBT alone. Thus, FAAH inhibition does not appear to be a suitable adjunct treatment for enhancing CBT in PTSD. This study was registered as Eudra-CT 2020-001965-36.

The selective orexin-1 receptor antagonist JNJ-61393215 (tebideutorexant) has shown anti-panic properties in rodent and human panic-anxiety models. This double-blind, placebo-controlled, randomized, parallel-group, multicenter, phase 2a study evaluated the efficacy, safety, and tolerability of JNJ-61393215 in 222 patients (18-64 years) with major depressive disorder (MDD) with anxious distress who had experienced a suboptimal response to standard antidepressants. Eligible patients were randomized (1:1) to receive either adjunctive JNJ61393215 (135 mg) or placebo, once daily. The primary objective was to evaluate the efficacy of JNJ-61393215 versus placebo, as assessed by the change from baseline to week 6 on the 17-item Hamilton Depression Rating Scale (HDRS17). The key secondary objective was to evaluate the impact of JNJ-61393215 versus placebo on the severity of anxiety as measured by the change in the Hamilton Anxiety Rating Scale (HAM-A) from baseline to week 6. The study results for the full intent-to-treat analysis dataset did not show significant treatment effects of adjunctive treatment with JNJ-61393215 on either the primary endpoint (the least squares mean difference [standard error]:-0.67 [0.893]; p=0.2227) or the key secondary endpoint (0.23 [1.007]; p=0.5889). The safety results were consistent with the known safety profile of JNJ-61393215 with no serious adverse events reported during the study. Overall, adjunctive treatment with an orexin-1 antagonist did not provide significant benefit relative to adjunctive placebo to patients with MDD and anxious distress. Trial registration number: ClinicalTrials.gov Identifier: NCT04080752

We investigated spatial variation in the apparent affinity of the D2 antagonist drug, JNJ-37822681, for dopamine receptors across single-dose (SD) and repeat-dose (RD) PET occupancy studies. Traditional whole-brain EC 50 estimates overlook potential spatial variation in drug affinity. We reanalyzed PET occupancy data from two published studies in healthy male volunteers (SD: administering 1 dose between 2–20 mg; RD: administering 13 doses of 10 mg over 7 days). Voxel-level occupancy images were generated from binding potential maps using Lassen Plot Filter (LPF), clustered via SLIC-Occ, and fitted to one- and two-parameter E max models to generate EC 50 images, revealing regional variation in apparent affinity within the striatum. The two-parameter model incorporated receptor upregulation in a joint analysis of SD and RD data. EC 50 images demonstrated reproducible spatial variation in drug affinity across striatal subregions; caudate and ventral striatum showed lower EC 50 values than putamen. Additionally, left-right asymmetries in EC 50 were detected, once the effects of upregulation were addressed. Our findings validate EC 50 images for capturing spatial variation in drug affinity and highlights the importance of accurate modeling in chronic dosing studies. LPF and SLIC-Occ provide a robust framework for analyzing occupancy data, aiding dose optimization for drug trials.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R) are the primary determinants of synaptic strength in most glutamatergic neurons. Inhibition or negative modulation of AMPA-Rs is an attractive strategy for therapeutic intervention in central nervous system (CNS) disorders characterized by excessive neuronal activity. We report the clinical qualification of a AMPA-R associated TARP-γ8 specific PET ligand [18F]JNJ-64511070 in healthy volunteers including biodistribution, dosimetry and kinetic modelling. Whole body dosimetry was performed in 3 healthy male subjects (22-41y). Upon estimation of the normalized cumulated activity (NCA), the effective dose (ED) was calculated using OLINDA v1.1. In a second part, 120-minute dynamic brain scanning with arterial blood sampling was done in five healthy males (25-53y) to determine the appropriate kinetic model and evaluate time stability of total distribution volume (VT). Both 1- and 2-tissue compartment models (1-2TCM) as well as Logan graphical analysis (LGA) were considered to assess regional VT. The average ED (± SD) was 15.6 ± 1.0 µSv/MBq. Brain uptake of [18F]JNJ-64511070 was fast and showed slow clearance from brain. The intact parent tracer fraction was 80

This was a double-blind, randomized, phase 2 study of adults (18-64 years) with DSM-5 diagnosis of major depressive disorder (MDD), with moderate-to-severe episode severity (Montgomery-& Aring;sberg Depression Rating Scale [MADRS] >= 25) despite an adequate course with ongoing antidepressant for >= 6 weeks to <= 12 months. Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10 mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant n = 85, placebo n = 84) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (<30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: -2.1 [-1.09], 1-sided p = 0.044; effect size (ES) 0.23; fITT -3.1 [2.21], 1-sided p = 0.002; ES 0.36). The between-group difference was larger among participants with Snaith-Hamilton Pleasure Scale (SHAPS) score greater/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials.

JNJ-42165279, a highly selective and orally bioavailable fatty acid amide (FAA) hydrolase inhibitor, was evaluated for efficacy and safety in adolescents and adults with autism spectrum disorder (ASD) in this phase 2, double-blind, placebo-controlled, multicenter study (NCT03664232). Participants aged 13–35 years, with a diagnosis of ASD (Diagnostic and Statistical Manual of Mental Disorders, 5th edition; Autism Diagnostic Observation Schedule, 2nd edition) were randomized (1:1) to 12 weeks of treatment with JNJ-42165279 (25 mg, twice-daily) or placebo. Primary endpoints were the change in the Autism Behavior Inventory (ABI) Core Domain (ABI-CD), ABI-Social Communication (ABI-SC), and ABI-Repetitive/Restrictive Behavior (ABI-RB) scores from baseline to day 85. Of the 61 participants (16 female, 45 male) included in the efficacy analyses, 53 (87

The relationship between cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD), APOE -ε4 and longitudinal cortical amyloid deposition in preclinical AD is relevant for AD trial design but remains unclear. Thus, we aimed to investigate longitudinal cortical amyloid accumulation on PET as predicted by baseline CSF AD biomarker profiles and APOE -ε4 carriership in cognitively unimpaired individuals. We selected 330 cognitively unimpaired individuals from 6 cohorts of the AMYPAD study. All had available baseline data on CSF aß 1-42 (A), p-tau 181 (T), APOE -ε4 carriership (yes/no), and baseline and follow-up amyloid PET data. To evaluate different AD stages, individuals were classified as A-T-, A-T+, A+T-, or A+T+ based on CSF biomarker abnormality using center-specific cut-offs. We used a continuous outcome measure of global cortical amyloid deposition on PET expressed in centiloids. Analyses were performed in the total sample and stratified for APOE -ε4, using generalized linear mixed models with random intercepts and slopes, adjusted for age and sex. 58% were female, 49% APOE -ε4 carriers, and mean age was 64+-6.1 years, with an average follow-up of 3 years. 170 individuals were A-T-, 70 A-T+, 59 A+T-, and 31 A+T+. Baseline cortical amyloid deposition was different between all groups, with A+T+ having the highest deposition, followed by A+T-, A-T+ and A-T- (Figure 1, Table 1). Longitudinally, all groups showed increased amyloid deposition, except A-T-. Moreover, A+ groups showed greater increases in longitudinal amyloid deposition than A- groups. In APOE -ε4 carriers, all AT groups showed increased longitudinal amyloid deposition, while in non-carriers, A-T+ and A-T- did not (Figure 2, Table 1). Only in APOE -ε4 carriers, A+T+ showed greater increases in longitudinal amyloid deposition than A+T-, with A+T- showing a similar longitudinal deposition as A-T+. APOE -ε4 impacts the association between CSF AD biomarkers and longitudinal amyloid PET deposition in cognitively unimpaired persons. Amyloid-negative APOE -ε4 carriers could be at an early AD stage, as they showed increased cortical amyloid longitudinally, independent of baseline p-tau status. In amyloid-positive persons, p-tau abnormality related to higher baseline cortical amyloid, but only in APOE -ε4 carriers to steeper increases in cortical amyloid longitudinally. This has important implications for AD trial design.

Discordance between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid-ß (Aß) occurs in up to 20% of individuals. Generally, Aß discordance is defined using binary cut-offs. Given the methodological limitations of this approach, we propose a continuous Aß CSF/PET imbalance model. We investigated biological and methodological factors underlying discrepancy in these amyloid biomarkers and associations with longitudinal cognition. We included 383 non-demented subjects (Nunimpaired = 326, Nmildly-impaired = 57) from the AMYPAD-PNHS cohort. Z-scored CSF Aß42 and amyloid-PET (Centiloids [CL]) units were fitted to a hyperbolic regression model by minimizing the Euclidian distance of the observed datapoints to the fitted line. Subject-specific standardized residuals were derived as a measure of continuous imbalance (Zimbalance), with Zimbalance<0 reflecting greater Aß abnormality in CSF relative to PET and Zimbalance>0 greater Aß abnormality in PET relative to CSF (Figure-1). Linear models adjusted for relevant covariates (Figure-2) were run between Zimbalance and (1) methodological factors (CSF-PET interval, CSF kit, PET tracer, and PET injected dose); (2) demographics (age, sex, education, APOE genotype) and CSF p-tau biomarker; (3) vascular burden (white matter hyperintensities measured as Fazekas scores). Linear mixed models were used to investigate the predictive value of Zimbalance on longitudinal cognition in several domains. Sample characteristics are shown in Table-1. Methodological factors were not significantly associated with Zimbalance. Increased CSF p-tau levels were significantly associated with a higher Zimbalance (i.e. greater Aß abnormality in PET relative to CSF) (ß = 0.06±0.03, p = .033) (Figure-2). In addition, a lower Zimbalance (i.e. greater Aß abnormality in CSF relative to PET) was associated with a higher Fazekas score (n = 189, ß = -0.55±0.26, p = .038) and predictive of faster cognitive decline on a language categorical fluency test (ß = -0.03±0.02, p = .038) (Figure-2). We found that methodological factors did not contribute to a continuous model of Aß CSF/PET imbalance, suggesting that this imbalance reflects distinct biological profiles. Indeed, continuous CSF/PET imbalance showed differential associations, with greater pathological levels of aggregated Aß relative to soluble Aß being related to increased CSF p-tau levels and excess pathological levels of soluble Aß relative to aggregated Aß to increased white matter hyperintensities and steeper cognitive decline.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non-profit organizations that have until recently been managed by the Foundation for the National Institutes of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer's disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond.

Longitudinal amyloid-PET-based imaging endpoints are often included in clinical trials, where they provide critical evidence of treatment efficacy. We assessed the longitudinal variability of the Centiloid (CL) scale and its ability to predict early amyloid accumulation. Longitudinal amyloid-PET with 18F-flutemetamol and 18F-florbetaben (N = 711 at follow-up 1, time interval: 3.0±1.3years; N = 98 at follow-up 2, 5.1±0.7years) was conducted in predominantly cognitively unimpaired participants of the AMYPAD Prognostic and Natural History Study (PNHS). Quantification of scans was performed using the MR-based CL pipeline and visually read (VR) by local certified assessors. Longitudinal change in CL was modelled using linear mixed effects models corrected for age, sex, and education. Subjects were classified based on VR status over time (i.e., Stable VR-, VR-Converters or Stable VR+) and based on amyloid accumulation over time (i.e., Accumulator or Non-accumulator; Accumulator if annualised rate of change [ARC]>95th percentile of a subset of 110 subjects for whom no amyloid accumulation was expected, selection criteria in Table-1). Finally, a baseline CL cut-off to identify future Accumulators was derived from a receiver operating characteristic (ROC) curve analysis. Participants had a median age of 65 years, 57% were females, 41% were APOE-e4 carriers, and 18% had baseline VR+ scan (Table-1). The 95th percentile of ARC in the stable 110 subjects was 2.7 CL/year. Baseline CL was higher in Accumulators compared to Non-accumulators (24.8 versus 8.7 CL, p<.001). Based on the ROC analysis, the optimal baseline CL threshold to predict Accumulators was 12.1 CL (sensitivity = 67% and specificity = 74%, Figure B-C-D), in line with the baseline CL threshold that best predicts VR conversion (11.6 CL). Baseline CL values and ARC were also higher in Stable VR+ and VR-Converters compared to Stable VR- (p<.001), but no significant difference in ARC was found between VR-Converters and Stable VR+ (Table-1, Figure A). Results were robust across tracers. Increases over 2.7 CL/year can be indicative of reliable amyloid accumulation. A CL cut-off of ∼12CL can help identify subjects more likely to accumulate amyloid in the short future. Annualised rates of change in amyloid deposition where highly comparable across tracers.

Amyloid-ß (Aß) PET is commonly used for studying the earliest phases of Alzheimer’s disease (AD) in cognitively unimpaired (CU) individuals. In this group, the expected changes in Aß pathology are small, which emphasizes the importance of selecting a method with the highest possible precision for measuring these changes. This study compared several methods for quantifying Aß pathology longitudinally in mostly CU individuals from the AMYPAD-PNHS cohort. Participants were scanned with either [18F]flutemetamol (baseline N = 360, follow-up N = 243) or [18F]florbetaben (N = 66 baseline, N = 49 follow-up), according to a dual-time window protocol(Table 1). A subset of participants had = 2 timepoints available (N = 206, N = 43, respectively). SUVRs were calculated, and parametric modelling was performed using RPM, SRTM2, RLogan, MRTM0, MRTM and MRTM2 using PPET software to generate parametric BPND or DVR images for a global cortical region, all with cerebellar cortex as reference tissue. Annual percentage change (APC) was calculated and compared between methods using an ANOVA. To check for changes in Aß pathology over time, a linear mixed effects model was used. Bland-Altman analyses were used to explore agreement between SUVR, and the outcome parameter from the parametric methods. All analyses were run per tracer, separately for visual Aß-positive and Aß-negative individuals, with a p-value threshold of p<0.05. For both tracers, there were no differences in APC between methods. However, method-dependent differences in interquartile range of the APC were observed(Figure 1,2). For [18F]flutemetamol, only the Aß-negative group showed a significant change in Aß pathology for SUVR and SRTM2 (both -0.004/year). For [18F]florbetaben, only the Aß-positive group showed a significant change in Aß pathology for all methods except MRTM2 (range: +0.020-0.032/year). No significant bias was observed between APC in SUVR and the other methods for either tracer or Aß-group. There were no significant differences in APC between methods, despite method-dependent variability. In the [18F]flutemetamol-cohort, two methods showed a minimal decrease in Aß pathology in the Aß-negative-group, possibly related to measurement variability, which requires further investigation. In the [18F]florbetaben-cohort, which included more participants with a very mild cognitive impairment, a significant increase in Aß pathology was observed in the Aß-positive-group, except for MRTM2.

The prevention of symptomatic Alzheimer’s disease (AD) is a major endeavor currently in the field, with the prevalence of subjects on the AD continuum (i.e. presence of amyloid-ß [Aß] pathology) being much higher than previously estimated. However, the extent to which Aß pathology and its interaction with common risk factors in the aging population relates to disease progression is still limited. The AMYPAD Prognostic and Natural History Study (PNHS) aims to evaluate the value of amyloid-PET for predicting AD-related disease progression. A total of 1423 non-demented subjects were included from the AMYPAD-PNHS pan-European cohort (17 sites across 10 Parent Cohorts), for who a baseline [18F]flutemetamol or [18F]florbetaben amyloid-PET scans that passed quality control was available (Table-1). Amyloid burden was assessed using the Centiloid (CL) method (whole cerebellum reference region). Independent linear mixed-effect models were used to assess the predictive value of continuous CL, and its interaction with time, across cognitive domains: mini-mental state examination (MMSE), memory, attention, language fluency, visuospatial, and executive functions. Years from baseline, age, sex, years of education, cognitive dementia rating (CDR), and APOE-e4 were used as independent variables. Clinical follow-up was 3.4 ± 1.8 years (up to ±10 years) on average. At baseline, 90% of the subjects were classified as cognitively unimpaired (CDR = 0). Based on CL, most subjects were categorized as amyloid-negative (59%, 0±9CL), followed by grey-zone (24%, 25±11CL), and amyloid-positive (17%, 82±21CL). Baseline CL and its interaction with time were predictive of MMSE scores, memory, attention, and language fluency. Baseline CL, but not its interaction with time, was predictive of executive function. Finally, the interaction of baseline CL with time, but not its main effect, was predictive of visuospatial functioning (Figure-1). Age and sex were significant contributors to nearly all models. Higher baseline CL was associated with lower cognitive performance in all explored domains, suggesting that emerging cerebral amyloid accumulation in non-demented individuals is predictive of overall cognitive function. Also, higher CL values were predictive of decline across cognitive domains, except for executive function. Further analysis is ongoing, including different confounding factors, longitudinal PET outcomes, and other biomarkers of the disease.

BackgroundAmyloid-β (Aβ) accumulation is considered the earliest pathological change in Alzheimer's disease (AD). The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and ‘Small and Medium-sized enterprises’ (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population.The AMYPAD studiesIn the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with [18F]flutemetamol or [18F]florbetaben radiotracers was performed and quantified using the Centiloid (CL) method.ResultsAMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BPND), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging Aβ burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine.Future stepsThe AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.

We previously described three spatio-temporal subtypes of amyloid accumulation trajectories, measured with PET (Collij et al., 2022). APOE4 carriers tended to have initial amyloid deposition in frontal regions compared to those showing initial deposition in parietal and occipital regions, suggesting different underlying disease mechanisms. Here, we investigated the relationship between global and regional amyloid burden and Alzheimer’s disease polygenic risk scores (AD-PRS). AD-PRS were calculated for 458 non-demented individuals participating in EPAD and AMYPAD, based on 85 identified risk loci, including and excluding the two major APOE variants (Bellenguez et al., 2022). After exclusion of APOE , the remaining 83 risk loci were functionally annotated and classified into six pathway sets (annotation tool as defined in Tesi et al., (2020)): path-PRSimmune-activation, path-PRSsignal-transduction, path-PRSinflammatory-response, path-PRSmigration, path-PRSamyloid-production, path-PRSclearance. 18F-Florbetaben or 18F-Flutemetamol PET were acquired and quantified using the Centiloid pipeline to obtain global and regional (frontal, precuneus, lateral parietal, lateral temporal, occipital) amyloid burden (Klunk et al., 2015). Linear models assessed the association between amyloid burden and each (path-)PRS, corrected for age, sex, and PET-tracer. Participants were 67.5±7.03 years of age, 57.6% female, and 109 were considered amyloid-positive (CL>21). Global amyloid burden was highly associated with AD-PRS APOE and, to a lesser extent, AD-PRS noAPOE (β = 14.75, p <5.9e-15 and β = 7.99, p = 0.03, respectively, Figure 1 ). Similar results were obtained for regional burden ( Table 1 ). After exclusion of APOE , both path-PRSmigration (β = 51.92, p = 0.02) and path-PRSclearance (β = 39.87, p = 0.02) were significantly associated with global amyloid burden, where path-PRSclearance showed the strongest association with amyloid burden across all regions (frontal: β = 38.96, p = 0.009; precuneus: β = 50.11, p = 0.006; lateral parietal: β = 44.10, p = 0.003; lateral temporal: β = 26.59, p = 0.04; occipital: β = 17.17, p = 0.049). Path-PRSmigration and Path-PRSamyloid-production were significantly associated with only the precuneus (β = 58.15, p = 0.02; β = 19.03, p = 0.04, respectively) and lateral parietal cortex (β = 47.12, p = 0.02; β = 16.41, p = 0.03, respectively). Results illustrate that genetic predisposition beyond APOE is associated with global and regional amyloid burden. Path-PRS results implicate clearance mechanisms in early disease pathogenesis, though strongest with the precuneus and lateral parietal cortex, which are early amyloid-accumulating regions. Since AD-PRS were associated with longitudinal changes in amyloid (Luckett et al., 2022), we aim to further investigate the association of path-PRS with longitudinal amyloid within EPAD and AMYPAD.