Search

Background: 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‐β [Aβ] pathology) being much higher than previously estimated. However, the extent to which Aβ 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. Method: 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‐ε4 were used as independent variables. Clinical follow‐up was 3.4 ± 1.8 years (up to ±10 years) on average. Result: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Method: 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. Result: Participants had a median age of 65 years, 57% were females, 41% were APOE‐ε4 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Method: We selected 330 cognitively unimpaired individuals from 6 cohorts of the AMYPAD study. All had available baseline data on CSF aß1‐42 (A), p‐tau181 (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. Result: 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+. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Method: 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. Result: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Method: 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. Result: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: BIIB080 (formerly IONIS MAPT‐RX) is an antisense oligonucleotide (ASO) designed to bind to MAPT pre‐mRNA, promote its degradation, and prevent translation of all forms of tau protein. BIIB080 is, to our knowledge, the first tau targeting ASO to enter human clinical trials in Alzheimer's disease (AD). BIIB080 was evaluated in Study ISIS 814907‐CS1 (NCT03186989) a Phase 1b, placebo‐controlled, double blind, multiple ascending dose clinical trial with 13‐week treatment period and 23‐week follow‐up period followed by an open‐label long term extension in patients with mild Alzheimer's disease. BIIB080 was generally well tolerated. Importantly, robust, time‐dependent and dose‐dependent decreases in CSF total and phosphorylated tau were observed. Additionally, BIIB080 impacted aggregated tau pathology as measured by tau PET as early as 25 weeks. Based on the Phase 1b results, Biogen is conducting a Phase 2 study, Study 247AD201 (NCT05399888) that will evaluate the efficacy, safety, and tolerability of BIIB080 in participants with mild cognitive impairment (MCI) due to Alzheimer's disease or mild Alzheimer's disease dementia. Method: Randomized, double‐blind, placebo‐controlled, parallel‐group Phase 2 study (CELIA), is enrolling approximately 735 individuals aged 50‐80 years, with MCI due to Alzheimer's disease or mild Alzheimer's disease dementia, Clinical Dementia Rating (CDR) global score 0.5‐1, Mini Mental State Examination (MMSE) score 22‐30, objective evidence of cognitive impairment at Screening, and evidence of amyloid pathology as measured by PET or cerebrospinal fluid (CSF) sampling. The Phase 2 study will randomize participants to receive 1 of 3 different dose regimens of intrathecal (IT) BIIB080 or placebo every 12 or 24 weeks during the 76‐week placebo‐controlled period. The primary endpoint will assess the dose‐response in change from Baseline to Week 76 on the CDR‐SB. The study includes a tau PET substudy to assess the effect of BIIB080 on tau aggregates with 18F‐MK6240. Result: The Ph2 CELIA study is currently recruiting participants. Conclusion: The ongoing Ph2 CELIA trial will assess the efficacy, safety and tolerability of BIIB080, compared to placebo in subjects with MCI due to Alzheimer's disease or mild Alzheimer's disease dementia. [ABSTRACT FROM AUTHOR]

Background: Plasma biomarkers have proven to indicate developing cerebral pathologies and injury that underpin neurodegenerative disorders in a non‐invasive manner. However, the measurement of certain blood biomarkers requires on‐site sampling with strict, time‐limited and temperature dependant processing protocols. To further facilitate the usefulness of blood biomarkers, methods for remote and/or unsupervised sample collection would greatly increase the utility as a screening and monitoring tool in secondary care and therapeutic trials. This pilot study investigated a novel method to quantify neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated tau (p‐tau) in capillary dry blood spots (DBScapillary) and venous dry blood spots (DBSvenous). Methods: We included 77 memory clinic participants from ACE Alzheimer Center Barcelona. DBScapillary, DBSvenous, and EDTA plasma as well as neuropsychological measures were obtained from each participant. A subset (n = 23) had cerebrospinal fluid (CSF) biomarkers. Capillary whole blood was obtained by a macro lancet needle from the left index finger. A total of 65µL of capillary and venous blood were spotted and dried on Noviplex DBS cards, which were shipped overnight without temperature control or cooling to Gothenburg, Sweden. Samples were extracted from DBScapillary and DBSvenous cards, and NfL, GFAP, p‐tau181, and, in a subset (n = 11), p‐tau217 were measured by single molecular array (Simoa). Statistical analysis included Pearson correlation between DBS and EDTA plasma. Results: DBScapillary GFAP (r = 0.7180, p<0.0001), and NfL (r = 0.6967, p<0.0001) correlated highly with their counterparts in EDTA plasma. We also demonstrated that DBScapillary p‐tau217 (r = 0.8955, p = 0.0002), but not DBScapillary p‐tau181 (r = 0.0132, p = 0.9447) correlated with the same measures in EDTA plasma, likewise DBSvenous GFAP (r = 0.7614, p<0.0001), NfL (r = 0.7701, p<0.0001), p‐tau217 (r = 0.9625, p<0.0001) and p‐tau181 (r = 0.6619, p<0.0001). Moreover, DBScapillary GFAP and DBSvenous GFAP, NfL and p‐tau181 correlated with MMSE, CDR and amyloid status (all p<0.05). Conclusion: This pilot study demonstrates the potential of remote collection and quantification of GFAP, NfL, p‐tau217 and p‐tau181 without low‐temperature storage/transportation or centrifugation (DBSvenous). Our data also suggests that this may be possible from a simple finger prick collection, including p‐tau217. We speculate that this simple, self‐executable method of blood collection would facilitate regular monitoring of patients with suspected neurological conditions. [ABSTRACT FROM AUTHOR]