WWF United Kingdom

Background In African populations, estimated glomerular filtration rate by cystatin C (eGFRcys) is better aligned with gold-standard GFR measurements than eGFR by creatinine (eGFRcr). Moreover, eGFRcys is unaffected by the effects of antiretroviral therapy (ART) on tubular secretion and may thus provide better estimates of GFR in people with HIV on ART. Setting Observational cohort study of people of African ancestry living with suppressed HIV RNA on ART in London, United Kingdom. Methods Cross-sectional analysis of 360 paired serum creatinine and cystatin C measurements. Participants whose eGFRcys substantially (>10%) exceeded eGFRcr were identified, and factors associated with this outcome were identified in logistic regression analysis. Results The median age of participants was 52 years, 56% were women, and 82% born in Africa or the Caribbean. The eGFRcys substantially exceeded eGFRcr in 42% of participants in the overall cohort, and in 68% of those with eGFRcr 45–75 mL/min/1.73 m². In multivariable analysis, a higher eGFRcr was associated with lower odds (0.59 [0.50, 0.68] per 10 mL/min/1.73 m² increase) of eGFRcys substantially exceeding eGFRcr; a higher BMI was also associated with this outcome, while ART regimens inhibiting tubular secretion of creatinine were not predictive. Of the 22 participants with eGFRcr 45–60 mL/min/1.73 m², 16 (73%) had eGFRcys >60 mL/min/1.73 m². Conclusions We report substantially higher eGFRcys than eGFRcr in a subset of people of African ancestry with suppressed HIV, particularly among those with eGFRcr 45–75 mL/min/1.73 m². In this population, eGFRcys provides clinically useful information irrespective of ART regimen.

Background and aims The COVID-19 pandemic led to changes in alcohol consumption in England. Evidence suggests that one-fifth to one-third of adults increased their alcohol consumption, while a similar proportion reported consuming less. Heavier drinkers increased their consumption the most and there was a 20% increase in alcohol-specific deaths in England in 2020 compared with 2019, a trend continuing through 2021 and 2022. This study aimed to quantify future health, healthcare, and economic impacts of changes in alcohol consumption observed during the COVID-19 pandemic. Methods This study used a validated microsimulation model of alcohol consumption and health outcomes. Inputted data were obtained from the Alcohol Toolkit Study, and demographic, health and cost data from published literature and publicly available datasets. Three scenarios were modelled: short, medium, and long-term, where 2020 drinking patterns continue until the end of 2022, 2024, and 2035, respectively. Disease incidence, mortality, and healthcare costs were modelled for nine alcohol-related health conditions. The model was run from 2020 to 2035 for the population of England and different occupational social grade groups. Results In all scenarios, the microsimulation projected significant increases in incident cases of disease, premature mortality, and healthcare costs, compared with the continuation of pre-COVID-19 trends. If COVID-19 drinking patterns continue to 2035, we projected 147,892 excess cases of diseases, 9,914 additional premature deaths, and £1.2 billion in excess healthcare costs in England. The projections show that the more disadvantaged (C2DE) occupational social grade groups will experience 36% more excess premature mortality than the least disadvantaged social group (ABC1) under the long-term scenario. Conclusions Alcohol harm is projected to worsen as an indirect result of the COVID-19 pandemic and inequalities are projected to widen. Early real-world data corroborate the findings of the modelling study. Increased rates of alcohol harm and healthcare costs are not inevitable but evidence-based policies and interventions are required to reverse the impacts of the pandemic on alcohol consumption in England.

The intriguing behavior of doped polyanilinine/graphene oxide (PANI/GO) offers a solution to the pivotal problem of device stability against moisture in perovskite solar cell (PSC). Tunable bandgap formation of doped PANI/GO with an absorber layer allows effective flexibility for charge carrier conduction and reduced series resistance further boosting the cell performance. Herein, the L9 Orthogonal Array (OA) Taguchi-based grey relational analysis (GRA) optimization was introduced to intensify the key output responses. Furthermore, this work also delved into incorporating a Pb-free absorber perovskite layer, formamidinium tin triiodide (FASnI3), and concomitantly eluding the environmentally hazardous substance. The numerical optimization supported by statistical analysis is based on experimental data to attain the utmost peak cell efficiency. Taguchi’s L9 OA-based GRA predictive modeling recorded over one-fold enhancement over experimental results, reaching as high as 20.28% power conversion efficiency (PCE). Despite that, the PCE of the structures is severely affected by interface defects at the electron transport layer/absorber (ETL/Abs) vicinity, which is almost zero at merely 1 × 10¹⁴ cm⁻², manifesting that control measures need to be taken into account. This work deduces the feasibility of ETL/Abs stack structure in replacing the conventional Pb-based perovskite absorber layer, while maximizing the potential use of doped PANI/GO as a hole transport layer (HTL).

Low-temperature atmospheric pressure plasma jets are generally small in scale (∼few mm) and often require high-breakdown voltages and high value gases to operate. This study investigates the advantageous properties of a novel multi-electrode jet-like source with separately powered (180° phase-shifted) live electrodes, namely significantly reduced breakdown voltage, increased operating voltage range and higher gas admixture capabilities. Gas breakdown voltage trends are demonstrated across multiple physical parameters, including tube diameter, electrode spacing and frequency. The potential uses of a safer, more practical discharge system are highlighted, as well as the conditions across the 3 kHz–30 kHz range under which plasma parameters are varied. An electrical analysis was also performed to provide a better understanding of the plasma characteristics beyond that of gas breakdown, specifically that of potential mode transitions that have not been taken into account in prior works.

Background Youth soccer players in the UK transition into the professional game at 16 years of age. Understanding the differences between youth and professional standards can help coaches and clubs to support player development during this transition. Objectives To (i) assess the differences in technical and possession statistics between different age groups (U16, U18, U23) and outfield positions (central defender [CD], wide defender [WD], central midfielder [CM], attacking midfielder [AM], wide midfielder [WM], striker [ST]), within an English academy soccer programme, during match-play. Methods All matches were monitored using foot-mounted inertial measurements units (F-IMU; Playermaker™) to quantify the technical (touches and releases from the feet) and individual possession statistics (Time on the ball, Time on the ball per possession) from each match. Teams were instructed to play a 1-4-3-3 formation as part of their clubs playing philosophy, with positions defined per this formation. Data were analysed using a multi-variate ANOVA Two-tailed statistical significance was accepted as p ≤ 0.05 and measures of effect size were calculated using partial eta-squared (η²). Magnitude of the effect sizes were small (0.2<ES<0.6), moderate (0.6<ES<1.2), large (1.2<ES<2) and very large (≥2). Results Trivial to small effect sizes were observed across age groups for both technical and possession-based statistics during match-play. Across all age groups and positions, CD`s had the highest number of technical actions (touches and releases), whereas ST`s & AM`s, had the highest amount of time in possession of the ball. Further, positional analysis showed ST`s and AM`s had moderate to large decreases in time on the ball per possession at the U23’s age group in comparison to the U16 and U18’s, with no technical differences observed within the same positional analysis. Conclusion Attacking players (AM & ST) are required to move the ball quicker as they progress from U16 to U23’s within the current English football academy. Further exploration is required to assess if these changes are context specific given requirements of those age groups.

Computational models are complex scientific constructs that have become essential for us to better understand the world. Many models are valuable for peers within and beyond disciplinary boundaries. However, there are no widely agreed-upon standards for sharing models. This paper suggests 10 simple rules for you to both (i) ensure you share models in a way that is at least “good enough,” and (ii) enable others to lead the change towards better model-sharing practices.

Background The progressive nature of dementia and the complex needs means that people living with dementia require tailored approaches to address their changing care needs over time. These include physical multimorbidity, psychological, behavioural, and cognitive symptoms and possible risks arising from these and helping family caregivers. However, provision of these interventions is highly variable between and within countries, partly due to uncertainty about their efficacy and scarce resources. In the 2024 update of the Lancet Commission we aimed to summarise published evidence about the effect of non‐pharmacological interventions for people with dementia and their carers on cognition, neuropsychiatric symptoms and other person‐centred outcomes. Method We reviewed and summarised evidence according to expert consensus opinion. Result There is moderate‐quality evidence from a Cochrane review of 25 studies for effect of cognitive stimulation therapy on cognition; 1.99 (1.24‐2.74) Mini‐Mental State Examination points higher compared to control groups, and clinically relevant improvements in communication and social interaction. Multicomponent interventions for family carers reduce family carer depression, burden, or stress and are cost‐effective but remote delivery of these interventions was not better than care as usual. A meta‐analysis of 7 studies of tailored activity programmes for people with dementia found a moderate effect on improving quality of life (standardised ES Cohen’s d 0.79, 0.39–1.18; 7 studies, n = 160), decreasing neuropsychiatric symptoms (0.62; 0.40–0.83) and decreasing carer burden (0.68, 0.29–1.07) but there is little evidence on cost‐effectiveness. Exercise interventions were not effective in improving neuropsychiatric symptoms, cognition or functioning. We discuss evidence for other treatments for specific neuropsychiatric symptoms. Conclusion There is developing evidence for benefit of psychological and social interventions on key outcomes including cognition, neuropsychiatric symptoms and quality of life, with sufficient strength of evidence and cost‐effectiveness to justify these being implemented and offered routinely to people with dementia. Interventions generally should be tailored to specific symptoms and individualised to patient preferences and goals. Most interventions have been tested in majority ethnic populations in high income countries: future interventions should be co‐designed with local communities to ensure that they are appropriate for the context, culture, beliefs and practices.

Background An estimated ∼40% of dementia cases are due to modifiable risk factors which can be targeted in lifestyle interventions. Effective interventions employ face‐to‐face delivery, making them resource‐intensive and burdensome. Digital interventions offer scalability, accessibility and cost‐effectiveness. Engagement and efficacy of digital interventions are unknown, as is whether the ‘human component’ of these interventions must be retained. Method The Five Lives app is a digital health solution that combines a CE‐marked dementia risk assessment with a digital coaching programme (DC) to facilitate behaviour changes which could lead to eventual reduced dementia risk. Three groups were compared: DC‐only, DC and access to brief 1‐to‐1 virtual clinician services (DC+VC) and no intervention (control). The study spanned 12 weeks and participants (n = 154) were aged 50‐69 with normal cognition. A lifestyle score was conducted at baseline and exit, which scores participants on behaviour relating to sleep, physical activity, diet, stress & mood and mental stimulation. Engagement was measured as the total number of app activities (brain games, articles, quizzes and lifestyle log) completed during the intervention period. Result Participant engagement was high (mean participant activities = 35/week). There was a significantly greater change in lifestyle score between intervention group (DC‐only and DC+VC pooled) and control (F(1,81) = 3.10, p = 0.049), and a trend for significance for a greater change in DC‐only versus control (F(1,24) = 3.96, p = 0.058). The change in lifestyle score between DC‐only and DC+VC was not significant, nor was the difference in app engagement. Total engagement was not predictive of lifestyle score change. Conclusion Participant engagement indicates the intervention is feasible in older adults. Results suggest the Five Lives app is a promising tool to facilitate behaviour change to potentially reduce dementia risk, and the VC does not provide significant additional benefits. This study provides initial data to warrant further development of DC interventions to reduce dementia risk. Future analyses should investigate which participants respond best to the intervention, barriers to change, and how engagement interplays with sustained dementia‐targeted lifestyle change.

Background We investigate perceptions of soft robotics in individuals with neurodegenerative diseases (NDD) from diverse communities. Soft robotics is made from soft, flexible materials to make it safer for users. It is a fast‐emerging medical field with applications ranging from diagnosis to rehabilitation practices. However, this area is underinvestigated in the older population with neurological disorders. Method We recruited individuals with NDD, e.g. dementia, Parkinson’s and mild cognitive impairment, via Bristol Brain Centre, charities, personal contacts, and social media advertisements. We aim to understand better user requirements and their views on such innovative technologies. In this ongoing study, we interviewed individuals with NDD, careers and clinicians to find the gap in designing soft robotics and conducted co‐design sessions with each group. To conclude the study, we will collect all the designs, create a prototype and gather iterative feedback. Result Preliminary results from the semi‐structured interviews have shown that interaction with soft robotics technologies, such as smart pillows, prosthetics, and others, needs further exploration but is challenging. Therefore, individuals found it difficult to think or acknowledge what could help them improve their quality of life. It also highlights the importance of technologies that can help carers facilitate patients' needs. Interviews with clinicians also emphasised carers' needs and technology that can promote independence and improve well‐being. Another interesting finding from the study is that previously, individuals were unaware of creating technologies personalised to them. Furthermore, co‐designing with this population showed that involving them in the ideation and designing process is critical for empowerment. Conclusion Do‐it‐yourself (DIY) practice offers a higher engagement in developing complex technologies, and the user‐centric design process using the Arduino prototyping platform improves the engagement rate. Cultural and ethnic diversity in the study population was another challenge, as it was challenging to get a clear view of their needs due to the language barrier. However, they overcame this by expressing their ideas by drawing. We aim to understand user requirements better and their views on such innovative technologies, present developments in soft robotics technology, and research challenges associated with our population to highlight research directions to understand this emerging field better.

Background Dementia rarely travels alone. People with dementia (PwD) often have multiple other physical diagnoses (multimorbidity) and experience poor quality, fragmented care. Over two thirds of carers of PwD are spouses, over half of which are 85 years old or above. Age is strongly associated with increased multimorbidity; therefore, carers are also likely to experience multimorbidity. Consequently, married or cohabiting couples are likely to experience the dementia journey together as well as live with multimorbidity. However, research has neglected to explore couples’ experiences of living with both dementia and multimorbidity, and the potential challenges they may face. Understanding couples’ experiences collectively will inform the development of appropriate, psychosocial interventions. Method Married couples aged 65 or above were asked to keep a photo diary for one month, taking photographs of their experiences of living with dementia and multimorbidity. Couples were given a choice to use either disposable cameras or their own digital device. This was followed by an audio‐recorded interview, using their printed photographs as a photo‐elicitation technique to aid discussion. Interpretative Phenomenological Analysis (IPA) was used to analyse the data. Results Six couples participated. IPA revealed couples have to ‘fight for help’, particularly in relation to dementia and stroke care; living with uncertainty was a significant theme. Couples discussed changes in their relationship, and behavioural and practical adaptations they have made in order to support each other. Some couples do not identify as being ‘ill’ or ‘disabled’ despite the multimorbidity they experience. Maintaining hobbies and interests that are important to them both as a couple and individually was vital for them to continue living a good quality of life. Conclusion Couples living with dementia and multimorbidity face significant challenges that can pose a threat to their relationship and quality of life. Challenges include inadequate support and healthcare, changes in the relationship and couple identity. However, despite this, couples maintain a positive outlook and ‘work as a team’ in order to adapt to each other’s health conditions and to continue leading a fulfilling life. These findings can be used to develop relationship‐centred interventions to support couples in the community.

The recent positive phase 3 clinical trials of new treatments and their licensing and roll‐out in the US and other countries represents a major turning point in Alzheimer’s disease research. As has been the case with many other diseases, e.g. multiple sclerosis and stroke, it is hoped that these successes will act as a catalyst, spurring the development not only of the next generation of amyloid immunotherapies but a range of other therapeutic approaches targeting different aspects of Alzheimer pathology, and different forms of dementia. How future trials are designed will likely have major impacts on their chances of success but also how they are deployed when licensed in clinical practice. It is of course vital that trials are designed to prioritise patient safety and use robust methodologies to produce valid results while maximising the possibility of gaining insights into mechanisms and any side‐effects. However, it is also imperative that protocols are acceptable to participants, and designed wherever possible to maximise compliance, improve accessibility, reduce cost and increase representativeness. Factors that need to be considered include those which may be dependent on the drug’s mode of action and likely effect, e.g. the length of the trial, the method of trial drug delivery, and any requirements for safety monitoring. Factors where there may be scope for change include, but are not limited to, the required number of trial visits, the length of assessments (e.g. including shorter MRI protocols for safety monitoring), the possibility of remote or at home as opposed to in‐hospital visits where possible, and simplifying methods for determining molecular pathology both as entry and potentially stopping criteria (e.g. if plasma can be used instead of CSF or molecular imaging). If we are to maximise the reach of our trials, ensure they are truly representative of all the people who might benefit, and increase recruitment rates, it is vital that we engage with study participants in the design of future studies, engage them as advocates for our research, and promote and actively involve individuals from diverse and under‐represented backgrounds.

Background The locus coeruleus (LC)‐norepinephrine (NE) system is one of the first systems affected in Alzheimer’s Disease (AD), prior to cortical involvement. LC‐NE system dysregulation has also been associated with neuropsychiatric and stress‐related symptoms, early non‐cognitive signals of AD. This study investigates whether structural and functional LC‐NE system metrics are associated with affective and stress‐related reports among predominantly cognitively healthy adults, and whether these associations are exacerbated by AD fluid biomarkers of tau, neurodegeneration and astrocyte reactivity. Method Cross‐sectional data from 116 life‐span study participants (cognitively healthy/MCI: N = 114/2; age range = 30‐87 years; female = 53%; Table 1) who completed affective (DASS–Stress, DASS–Anxiety, HDRS) and stress‐related (MIA–Anxiety, Perceived Stress Scale (PSS), NEO PI‐R–Neuroticism, DASS–Stress) questionnaires. Plasma 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG) and AD‐related markers (ptau217, ptau231, NfL, or GFAP), and 7T LC‐MRI scanning were obtained. MHPG was normalized against NE. LC MRI signal intensity was obtained using an MT‐TFL sequence, standardizing LC signal to the pontine tegmentum (reference), and creating a study‐specific LC template. Bootstrapped linear regression examined associations of affective and stress‐related questionnaires with LC MRI signal intensity alone, or interacted with AD markers. Linear regressions assessed equivalent associations with MHPG instead of LC MRI signal intensity. Analyses were based on complete cases, corrected for age and sex, and FDR‐adjusted. Results Lower LC MRI signal intensity related to higher DASS–Anxiety scores (pFDR = 0.008; Table 2/Fig. 1A). This relationship was more pronounced in individuals with higher ptau217 (pFDR = 0.002), ptau231 (p = 0.028), NfL (pFDR = 0.002) or GFAP (pFDR = 0.002; Table 2/Fig. 1B‐E). Higher MHPG was linked to higher PSS scores in individuals with elevated GFAP, while higher MHPG was associated with lower PSS in the context of lower GFAP (p = 0.029, Table 2/Fig. 1F). Conclusion This work suggests that structural and functional LC‐NE system metrics are distinctly related to stress and affective functioning. Lower structural LC integrity is associated with worse anxiety, particularly at elevated AD pathology levels. Among individuals with elevated astrocyte reactivity, higher LC metabolism is no longer protective against stress. These findings are consistent with previous autopsy and metabolite studies, and support the importance of the LC‐NE system in neuropsychiatric symptoms as the earliest AD manifestations.

Background In light of the poor fold change in the plasma amyloid‐β (Aβ) 42/amyloid‐β 40 ratio (Aβ42/40) between Alzheimer’s disease (AD) and control (CTRL) cases, novel Aβ biomarkers are needed which will require harnessing the increased sensitivity offered by a novel modification to the Quanterix Corporation Single molecule array (Simoa) technology. Method Simoa assays for the detection of Aβ43 and pyroglutamate‐modified Aβ 3‐40 (AβpE3‐40) have been developed on the standard HD‐X instrument. Aβ43 and AβpE3‐40 were measured in 8 CSF samples (1 AD, 4 mixed phenotype [MP] and 3 CTRL) on the HD‐X instrument, each of which were measured at four dilution levels – neat, 2x, 4x and 8x dilution. Result Out of a possible 32 measurements per analyte (four dilution levels per sample), Aβ43 was quantifiable in 68.8% of measurements, 72.7% of which fell below the concentration of calibrator B. In three samples, Aβ43 was measurable at all four dilution levels, and showed a strong but statistically non‐significant dilution linearity. In contrast, AβpE3‐40 was quantifiable in 93.8% samples, 96.6% of which fell below the concentrations of calibrator B. In six samples, AβpE3‐40 was measurable at all four dilution levels. One sample showed a strong but statistically non‐significant dilution linearity, with the remaining five samples showing a poor dilution linearity, suggesting the limits of HD‐X sensitivity had been reached. Conclusion The increased sensitivity provided by the modification to the Simoa SRx is needed to accurately quantify Aβ43 and AβpE3‐40 in CSF and subsequently plasma. Work is ongoing to transfer these novel assays from the HDx onto the modified SRx instrument.

Background The Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) Prognostic & Natural History Study (PNHS) is a prospective longitudinal PET cohort of over 1,500 non‐demented individuals from 10 parent cohorts across Europe. We provide an overview of ongoing efforts to curate and integrate magnetic resonance imaging (MRI) multimodal images across sites and to extract biologically meaningful information (i.e., image‐derived phenotypes; IDPs) in this early AD population. Data will be made available on the ADDI platform (fair.addi.ad‐datainitiative.org). Method Imaging protocols included core (T1w, T2w, T2*, FLAIR) and advanced (rs‐fMRI, SWI, DWI, and ASL) MRI sequences. Figure 1 provides an overview of the different acquisitions, their corresponding pipelines, and the obtained IDPs. For T1w images, we computed regional volumes and thickness values using FreeSurfer v7.1.1 (surfer.nmr.mgh.harvard.edu/). Morphometric similarity networks were computed using MIND (github.com/isebenius/MIND). White matter hyperintensity volumes were obtained from FLAIR images using Bayesian Model Selection (BaMoS). With rs‐fMRI, mean functional connectivity of canonical networks were extracted using FSL MELODIC and dual‐regression analyses after preprocessing with fMRIPrep v23.0.1 (fmriprep.org). Diffusion MRI scans were processed with QSIprep v0.16 (qsiprep.readthedocs.io) to compute tract‐based spatial statistics and tractograms to build structural connectivity matrices. Finally, cerebral blood flow and the spatial coefficient of variation were computed from ASL images using ExploreASL (github.com/ExploreASL). Statistical harmonization was performed using RELIEF (github.com/junjypark/RELIEF). Result Baseline and follow‐up characteristics of the 1537 subjects with available T1w are described in Table 1. Raw and statistically harmonized variants of 380 core and 298 advanced IDPs were calculated. Figure 2 shows the distribution of hippocampal volumes per site before and after statistical harmonization, and their relation with participants' age (R2raw=0.179, R2harmonized=0.422). Considering recent developments in the field, the AMYPAD PNHS aims to include additional IDPs associated with vascular health, such as perivascular spaces and other glymphatic system‐related markers. Conclusion We present the pipeline built for MRI harmonization and feature extraction of the AMYPAD PNHS dataset. The extracted IDPs can help identify novel imaging outcomes, support the development of disease progression models for the preclinical stages of AD, and provide a reference point for future studies to promote replicability and robustness of findings.

Background Tau‐PET imaging allows in‐vivo detection of neurofibrillary tangles. One tau‐PET tracer (i.e., [18F]flortaucipir) has received FDA‐approval for clinical use, and multiple other tau‐PET tracers have been implemented into clinical trials for participant selection and/or as a primary or secondary outcome measure. To optimize future use of tau‐PET, it is essential to understand how demographic, clinical and genetic factors affect tau‐PET‐positivity rates. Method This large‐scale multi‐center study includes 9713 participants from 35 cohorts worldwide who underwent tau‐PET with [18F]flortaucipir (n = 6420), [18F]RO948 (n = 1999), [18F]MK6240 (n = 878) or [18F]PI2620 (n = 416) (Table‐1). We analyzed individual‐level tau‐PET SUVR data using a cerebellar reference region that were processed either centrally (n = 3855) or by each cohort (n = 5858). We computed cohort‐specific SUVR thresholds based on the mean + 2 standard deviations in a temporal meta‐region of amyloid‐negative cognitively normal (CN) individuals aged >50. Logistic generalized estimating equations were used to estimate tau‐PET‐positivity probabilities, using an exchangeable correlation structure to account for within‐cohort correlations. Analyses were performed with (interactions between) age, amyloid‐status, and APOE‐e4 carriership as independent variables, stratified for syndrome diagnosis. Result The study included 5962 CN participants (7.5% tau‐PET‐positive), 1683 participants with mild cognitive impairment (MCI, 33.8% tau‐PET‐positive) and 2068 participants with a clinical diagnosis of dementia (62.1% tau‐PET‐positive) (Figure‐1). From age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 1.2% [95% CI: 0.9%‐1.5%] to 3.7% [2.3%‐5.1%] among CN amyloid‐negative participants; and from 16.4% [10.8%‐22.1%] to 20.5% [18.8%‐22.2%] among CN amyloid‐positive participants. Among amyloid‐negative participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 3.5% [1.6%‐5.3%] to 11.8% [7.1%‐16.5%] and from 12.6% [4.5%‐20.7%] to 15.9% [6.7%‐25.1%] respectively. In contrast, among amyloid‐positive participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity decreased from 66.5% [57.0%‐76.0%] to 48.3% [42.9%‐53.8%] and from 92.3% [88.7%‐95.9%] to 73.4% [67.5%‐79.3%] respectively. APOE‐e4 status primarily modulated the association of age with tau‐PET‐positivity estimates among CN and MCI amyloid‐positive participants (Figure‐2). Conclusion This large‐scale multi‐cohort study provides robust prevalence estimates of tau‐PET‐positivity, which can aid the interpretation of tau‐PET in the clinic and inform clinical trial designs.

Background A novel improvement to Quanterix Corporation Single molecule array (Simoa) SR‐X instrument has been shown to offer up to 100‐fold increased sensitivity compared with standard Simoa HD‐X and SR‐X instruments. We independently validated this increased sensitivity using the Simoa interleukin 17A (IL17A) assay. Method IL17A was measured in 32 paired Alzheimer’s disease (AD; n = 13) and control (CTRL; n = 19) serum and cerebrospinal fluid (CSF) samples. Mean IL17A concentrations were compared in both biofluids measured using four Simoa instruments ‐ one HD‐X instrument and three SR‐X instruments modified to improve the efficiency of reading beads. Result HD‐X quantified IL17A in 0% of CSF samples and 37.5% of serum samples, with mean serum IL17A concentrations of 0.126pg/mL in AD and 0.228pg/mL in CTRLs. In contrast, the modified SR‐X instruments A, B and C quantified CSF IL17A in 84.4%, 96.9% and 96.9% of CSF samples, respectively, with mean AD concentrations of 2.92fg/mL, 5.95fg/mL and 7.25fg/mL, respectively, and mean CTRL concentrations of 3.60fg/mL, 4.75fg/mL and 9.02fg/mL, respectively. Furthermore, the modified SR‐X instruments A, B and C all quantified IL17A in 100% of serum samples, with mean serum AD concentrations of 0.145pg/mL, 0.285pg/mL, and 0.249pg/mL, respectively, and mean CTRL concentrations of 0.300pg/mL, 0.406pg/mL and 0.362pg/mL, respectively. There were no statistically significant intra‐instrument differences between AD compared with CTRLs. All three modified SR‐X serum concentrations showed a strong positive statistically significant correlation with HD‐X serum concentrations. All three modified SR‐X serum concentrations also showed a strong positive statistically significant correlation with one another. Finally, all three modified SR‐X instruments showed no correlation between serum and CSF concentrations, in line with previous literature. Conclusion Increasing the bead reading efficiency of the SR‐X exhibits increased sensitivity compared with the standard Simoa HD‐X instrument, allowing the quantification of IL17A in CSF and a greater yield of serum samples.

Background There is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial. Method We included 269 amyloid‐ß‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐ß‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly. Result Tau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Fig.1). In line with this, tau epicenters were highly heterogeneous across variants (Fig.1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Fig.2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Fig.3). Conclusion This multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.

Background Cerebral Aβ accumulates decades before symptom onset in AD. Sampled iterative local approximation (SILA, Betthauser et al. 2022) is a technique for estimating time from Aβ positivity (Aβ+) using Aβ‐PET. Here we explore the influence of APOE‐ɛ4 carriership and sex on estimated age of Aβ+ (EAAβ) in primarily cognitively normal individuals from the longest‐running British birth cohort. Method Participants in Insight 46 were drawn from the 1946 British birth cohort and underwent combined PET/MR scanning with [18F]florbetapir at two timepoints. Centiloid (CL) values were calculated using a whole cerebellum reference region and partial volume correction. We used Gaussian mixture modelling (99th percentile of lower distribution) to define an Aβ+ threshold of 12 CL. We constructed a CL vs Aβ time curve with SILA from available longitudinal Aβ‐PET scans (n = 324, interval = 2.4±0.2yrs), which was applied to the whole sample (n = 463) to calculate EAAβ. Some scans were below the CL range that could be modelled, and the estimated EAAβ was truncated to the furthest time before onset on the CL vs time curve. Kaplan‐Meyer plots and Cox regression were used to investigate EAAβ and risk of estimated Aβ+ by APOE‐ɛ4 and sex, right censoring participants where EAAβ was truncated. Result Mean (SD) chronological age was 70.6±0.7yrs at baseline and 73.0±0.6yrs at follow‐up scan and 30.5% were Aβ+ve by follow‐up (n = 141, 55.3% APOE‐ɛ4, 51.8% female). SILA results and distribution of EAAβ are shown in figures 1 and 2. EAAβ were truncated due to low Aβ binding in 35.7% (n = 166, 15.7% APOE‐ɛ4, 50% female). APOE ɛ4 carriers reached median EAAβ 8.6 years earlier than non‐carriers (figure 3A). Median EAAβ for females was marginally earlier than males with overlapping CIs (figure 3B). APOE‐ɛ4 was strongly associated with risk of estimated Aβ+ (HR[95%CI] = 2.4[1.9,3.0]), adjusted for sex. Female sex (1.1[0.8,1.3]) and the interaction between APOE‐ɛ4 and sex (1.2[0.8,1.9]) were non‐significant. Conclusion Estimated Aβ positivity was reached on average 8.6 years earlier for APOE ɛ4 carriers. Consistent with results from other cohorts, APOE‐ɛ4, not sex, significantly heightened the risk of estimated Aβ positivity. Future research will explore life course and downstream events related to Aβ timing.

Background Recent advances in automatic face recognition have increased the risk that de‐identified research imaging data could be re‐identified from face imagery in brain scans. Method An ADNI committee of independent imaging experts evaluated 11 published techniques for face‐deidentification (“de‐facing”) and selected four algorithms (FSL‐UK Biobank, HCP/XNAT, mri_reface, and BIC) for formal testing using 183 longitudinal scans of 61 racially and ethnically diverse ADNI participants, evaluated by their facial feature removal on 3D rendered surfaces (confirming sufficient privacy protection) and by comparing measurements from ADNI routine image analyses on unmodified vs. de‐faced images (confirming negligible side effects on analyses). Result Effects of the de‐facing methods on FreeSurfer at UCSF (Figure 1‐top), ASHS at University of Pennsylvania (Figure 1 bottom‐left), and longitudinal atrophy at Mayo Clinic (Figure 1 bottom‐right) were comparable with each other and sufficiently small vs. unmodified scans to recommend de‐facing in ADNI‐4. The FSL and mri_reface methods were more thorough in removing facial features, partly because these also removed ears (Figure 2‐top). mri_reface was recommended for ADNI‐4 primarily because fewer (zero) images had modified brain (Figure 2‐bottom), and ADNI leadership approved de‐facing with mri_reface. ADNI performed a second validation of its latest version on another diverse sample of 100 ADNI‐3 participants. These analyses included: boundary shift interval at University College London, where average differences in measurements were all <0.05%; cortical white matter hyperintensities at UC Davis, where they found “minimum impact” (R>0.97); and others. Conclusion ADNI‐4 de‐faces all indicated image types (Table 1) before subsequent pre‐processing, analyses, and public release. Sites upload images to the central repository (LONI), where they are queued to the MRI Core at Mayo Clinic for de‐facing. Image types requiring de‐facing are de‐faced using mri_reface. Trained analysts inspect de‐faced images to confirm complete removal of the face and complete non‐modification of the brain, and any flagged images are re‐processed manually until issues are resolved. De‐faced images are converted back to DICOM and re‐uploaded for further distribution. Image types not requiring de‐facing are indicated to proceed directly to subsequent steps. In summary, ADNI‐4 has adopted mri_reface because it successfully de‐faces without substantially affecting brain measurements.