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Abstract Background Plasma p-tau217 has emerged as the most promising blood-based marker (BBM) for the detection of Alzheimer Disease (AD) pathology, yet few studies have evaluated plasma p-tau217 performance in memory clinic settings. We examined the performance of plasma p-tau217 for the detection of AD using a high-sensitivity immunoassay in individuals undergoing diagnostic lumbar puncture (LP). Methods Paired plasma and cerebrospinal fluid (CSF) samples were analysed from the TIMC-BRAiN cohort. Amyloid (Aβ) and Tau (T) pathology were classified based on established cut-offs for CSF Aβ42 and CSF p-tau181 respectively. High-sensitivity electrochemiluminescence (ECL) immunoassays were performed on paired plasma/CSF samples for p-tau217, p-tau181, Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light (NfL) and total tau (t-tau). Biomarker performance was evaluated using Receiver-Operating Curve (ROC) and Area-Under-the-Curve (AUC) analysis. Results Of 108 participants (age: 69 ± 6.5 years; 54.6% female) with paired samples obtained at time of LP, 64.8% (n = 70/108) had Aβ pathology detected (35 with Mild Cognitive Impairment and 35 with mild dementia). Plasma p-tau217 was over three-fold higher in Aβ + (12.4 pg/mL; 7.3—19.2 pg/mL) vs. Aβ- participants (3.7 pg/mL; 2.8—4.1 pg/mL; Mann–Whitney U = 230, p

Summary: Autosomal dominant Alzheimer's disease (ADAD) and Down syndrome (DS) constitute genetic forms of Alzheimer's disease (AD). The study of these forms has been crucial in understanding the biomarker changes and disease progression, notably in advancing our knowledge of the natural history of AD. However, some specific characteristics of biomarkers in genetically determined forms and, most importantly, the near full penetrance and predictability of disease onset lead to a very different context of use for biomarkers in these populations. This article delves into the similarities and differences in biomarker profiles between genetically determined AD and sporadic cases, discussing the implications for research and clinical practice. It also emphasizes the need to account for factors that may affect biomarker reliability differently in genetically determined AD. Enhancing our understanding of the disease will pave the way for more personalized therapeutic approaches for affected individuals.

We report the generation of a gene-edited human induced pluripotent stem cell (iPSC) line from an Alzheimer’s disease patient-derived iPSC line harbouring the PSEN1 H163R mutation. This line demonstrates pluripotent stem cell morphology, expression of pluripotency markers, and maintains a normal karyotype.

Abstract Cortical tau accumulation is a key pathological event that partly defines Alzheimer’s disease (AD) onset and is associated with cognitive decline and future disease progression. However, an improved understanding of the timing and pattern of early tau deposition in AD and how this may be tracked in vivo is needed. Data from 59 participants involved in two longitudinal cohort studies of autosomal dominant AD (ADAD) were used to investigate whether tau PET can detect and track presymptomatic change; seven participants were symptomatic, and 52 were asymptomatic but at a 50% risk of carrying a pathogenic mutation. All had baseline flortaucipir (FTP) PET, MRI and clinical assessments; 26 individuals had more than one FTP PET scan. Standardised uptake value ratios (SUVRs) in prespecified regions of interest (ROIs) were obtained using inferior cerebellar grey matter as the reference region. We compared the changes in FTP SUVRs between presymptomatic carriers, symptomatic carriers and non-carriers, adjusting for age, sex and study site. We also investigated the relationship between regional FTP SUVRs and estimated years to/from symptom onset (EYO). Compared to both non-carriers and presymptomatic carriers, FTP SUVRs were significantly higher in symptomatic carriers in all ROIs tested (p 0.05), although increased FTP signal uptake was seen posteriorly in some individuals around the time of expected symptom onset. When we examined the relationship of FTP SUVR with respect to EYO, the earliest significant regional difference between mutation carriers and non-carriers was detected within the precuneus prior to estimated symptom onset in some cases. This study supports preliminary studies suggesting that presymptomatic tau tracer uptake is rare in ADAD. In cases where early uptake was seen, there was often a predilection for posterior regions (the precuneus and post-cingulate) as opposed to the medial temporal lobe, highlighting the importance of examining in vivo tau uptake beyond the confines of traditional Braak staging.

Introduction Alzheimer’s disease and other dementias affect >50 million individuals globally and are characterised by broad clinical and biological heterogeneity. Cohort and biobank studies have played a critical role in advancing the understanding of disease pathophysiology and in identifying novel diagnostic and treatment approaches. However, further discovery and validation cohorts are required to clarify the real-world utility of new biomarkers, facilitate research into the development of novel therapies and advance our understanding of the clinical heterogeneity and pathobiology of neurodegenerative diseases.Methods and analysis The Tallaght University Hospital Institute for Memory and Cognition Biobank for Research in Ageing and Neurodegeneration (TIMC-BRAiN) will recruit 1000 individuals over 5 years. Participants, who are undergoing diagnostic workup in the TIMC Memory Assessment and Support Service (TIMC-MASS), will opt to donate clinical data and biological samples to a biobank. All participants will complete a detailed clinical, neuropsychological and dementia severity assessment (including Addenbrooke’s Cognitive Assessment, Repeatable Battery for Assessment of Neuropsychological Status, Clinical Dementia Rating Scale). Participants undergoing venepuncture/lumbar puncture as part of the clinical workup will be offered the opportunity to donate additional blood (serum/plasma/whole blood) and cerebrospinal fluid samples for longitudinal storage in the TIMC-BRAiN biobank. Participants are followed at 18-month intervals for repeat clinical and cognitive assessments. Anonymised clinical data and biological samples will be stored securely in a central repository and used to facilitate future studies concerned with advancing the diagnosis and treatment of neurodegenerative diseases.Ethics and dissemination Ethical approval has been granted by the St. James’s Hospital/Tallaght University Hospital Joint Research Ethics Committee (Project ID: 2159), which operates in compliance with the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004 and ICH Good Clinical Practice Guidelines. Findings using TIMC-BRAiN will be published in a timely and open-access fashion.

“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18–89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.

Abstract The basis of visual short-term memory (VSTM) impairments in preclinical Alzheimer’s disease (AD) remains unclear. Research suggests that eye movements may serve as indirect surrogates to investigate VSTM. Yet, investigations in preclinical populations are lacking. Fifty-two individuals from a familial Alzheimer’s disease (FAD) cohort (9 symptomatic carriers, 17 presymptomatic carriers and 26 controls) completed the “Object-localisation” VSTM task while an eye-tracker recorded eye movements during the stimulus presentation. VSTM function and oculomotor performance were compared between groups and their association during encoding investigated. Compared to controls, symptomatic FAD carriers showed eye movement patterns suggestive of an ineffective encoding and presymptomatic FAD carriers within 6 years of their expected age at symptom onset, were more reliant on the stimuli fixation time to achieve accuracy in the localisation of the target. Consequently, for shorter fixation times on the stimuli, presymptomatic carriers were less accurate at localising the target than controls. By contrast, the only deficits detected on behavioural VSTM function was in symptomatic individuals. Our findings provide novel evidence that encoding processes may be vulnerable and weakened in presymptomatic FAD carriers, most prominently for spatial memory, suggesting a possible explanation for the subtle VSTM impairments observed in the preclinical stages of AD.

Abstract Background Understanding the earliest manifestations of Alzheimer’s disease (AD) is key to realising disease-modifying treatments. Advances in neuroimaging and fluid biomarkers have improved our ability to identify AD pathology in vivo. The critical next step is improved detection and staging of early cognitive change. We studied an asymptomatic familial Alzheimer’s disease (FAD) cohort to characterise preclinical cognitive change. Methods Data included 35 asymptomatic participants at 50% risk of carrying a pathogenic FAD mutation. Participants completed a multi-domain neuropsychology battery. After accounting for sex, age and education, we used event-based modelling to estimate the sequence of cognitive decline in presymptomatic FAD, and uncertainty in the sequence. We assigned individuals to their most likely model stage of cumulative cognitive decline, given their data. Linear regression of estimated years to symptom onset against model stage was used to estimate the timing of preclinical cognitive decline. Results Cognitive change in mutation carriers was first detected in measures of accelerated long-term forgetting, up to 10 years before estimated symptom onset. Measures of subjective cognitive decline also revealed early abnormalities. Our data-driven model demonstrated subtle cognitive impairment across multiple cognitive domains in clinically normal individuals on the AD continuum. Conclusions Data-driven modelling of neuropsychological test scores has potential to differentiate cognitive decline from cognitive stability and to estimate a fine-grained sequence of decline across cognitive domains and functions, in the preclinical phase of Alzheimer’s disease. This can improve the design of future presymptomatic trials by informing enrichment strategies and guiding the selection of outcome measures.

Abstract There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course “Biomarkers in neurodegenerative diseases”. In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.

Abstract Background To investigate how serum neurofilament light (NfL) concentration changes through the course of disease in familial Alzheimer’s disease (FAD) and to assess when NfL concentration first increases. Methods NfL was measured using an ultrasensitive immunoassay in 117 serum samples from 61 individuals from families with PSEN1 or APP mutations in a longitudinal study (mean ± SD = 1.9 ± 1.1 visits/patient; inter-visit interval = 1.8 ± 1.1 years). The relationship between NfL concentration and estimated years to/from symptom onset (EYO) was modelled using linear regression, including all time points and robust standard errors to allow for repeated measurements, adjusting for age at visit and sex. Also, for the 27 participants who became symptomatic (during or before the study), NfL concentration was also modelled against known actual years to/from onset (AYO). Results There were 15 non-carriers and 46 mutation carriers (21 symptomatic; 25 presymptomatic). NfL concentration was increased (p = 0.045) in mutation carriers compared with non-carriers 15 years prior to expected symptom onset, increasing progressively thereafter. There was a significant inter- and intra-individual variability in the longitudinal pattern of change. Modelling NfL for the 27 mutation carriers with known AYO also showed a progressive increase over time. Conclusions There is evidence that serum NfL is increased more than a decade before the onset of clinical symptoms in FAD and rises thereafter. While there is variability in change over time, both within and between individuals, and more work is needed to understand the sources of this variability, serum NfL remains a promising, accessible biomarker of early neurodegeneration in presymptomatic Alzheimer’s disease.

The discovery of unique autoantibodies has informed and altered our approach to the diagnosis and management of the inflammatory myopathies. This study reports the initial clinical experience of use of the Extended Myositis Antibody (EMA) panel in the largest university teaching hospital in Ireland. We conducted a retrospective review of all patients who had serum samples tested for myositis specific antibodies and myositis associated antibodies from April 2014 to March 2015. A positive EMA panel was of significant clinical utility in facilitating decisions on appropriate investigations, and need for onward referral to other physicians. Furthermore, this paper highlights the diversity of possible presentations of idiopathic inflammatory myopathy with subsequent need for multi-speciality involvement, and serves to heighten awareness among clinicians of the diagnostic use of extended myositis antibody testing in these cases.