REM Sleep Behaviour Disorder (RBD) is a hallmark of the prodromal phase of α-synucleinopathies. We aimed to describe the prevalence of probable RBD and to assess its associations with demographics, cognition, and location in a large sample of older adults in Luxembourg, as a first step toward identifying individuals with RBD symptoms for future prodromal-marker assessment. In 2021, residents of Luxembourg aged 55–75 were invited to complete an online survey including the RBD Screening Questionnaire (RBDSQ); with a threshold of ≥ 7 defining screen-positive probable RBD (sppRBD). Screen-positive participants underwent a telephone interview, and those confirmed were categorised as telephone-assessed probable RBD (pRBD). Bayesian spatial mapping assessed the geographical distribution of pRBD, and logistic regression identified determinants of sppRBD and pRBD. Among 15,915 participants (54% male; median age 62 [IQR 58–67]), 12.4% had sppRBD. The telephone interview confirmed only 34.8% of these as pRBD, yielding a projected prevalence of 4.3%. Self-reported cognitive impairment, male sex, and Portuguese as questionnaire language were associated with pRBD, which showed heterogeneous geographical distribution. Online questionnaires may yield false positives, potentially reflecting e-health literacy issues; therefore, a confirmation step is essential. This analysis identifies individuals with RBD symptoms warranting further prodromal-marker assessment, a candidate group for, rather than a validated instance of, an at-risk-for-α-synucleinopathy cohort.

Background Neuropsychiatric symptoms are common in later life, and can be as problematic as cognitive impairment for individuals with memory concerns, yet they are seldom assessed systematically in memory clinics. Early identification of NPS and caregiver distress may inform diagnosis, guide management, and improve outcomes. This study examines the prevalence and correlates of NPS and caregiver distress in a real-world memory clinic cohort at the time of diagnostic assessment. Methods Patients aged ≥ 65 who underwent initial assessment at the Oxford Brain Health Clinic, subsequently attended the memory clinic for diagnosis, and completed the Neuropsychiatric Inventory Questionnaire (NPI-Q) were included. NPS prevalence, co-occurrence, and caregiver distress were described descriptively. Associated factors were analysed using Spearman’s correlations and multivariable linear regression. Results A total of 242 met the inclusion criteria, with a mean age of 77.5 ± 6.3. Of them, 129 received a subsequent diagnosis of dementia, 59 were considered to have mild cognitive impairment (MCI), and 54 had no memory disorder diagnosis. NPS were prevalent (83.5%) in the cohort, generally of mild to moderate severity, with individuals exhibiting a mean of 2.8 symptoms. The no memory disorder and dementia groups showed higher NPS counts than the MCI group (means of 3.1 and 2.9 vs. 2.1). Co-occurrence patterns were complex and depression-centered in the no memory disorder group, limited in MCI, and apathy-centered in dementia. Caregiver distress was also higher in the dementia (mean 15.0) and no memory disorder groups (mean 13.3) than in MCI (mean 10.1). In multivariable analyses, cognitive decline (β = 1.23, p < 0.001) and caregiver distress (β = 0.09, p < 0.001) were independently associated with higher total NPS scores. Diagnostic group also remained significant, with the no memory disorder group exhibiting higher scores than the MCI group (β = − 0.98, p = 0.013). Conclusions NPS and caregiver distress were already common when patients sought diagnostic assessments for memory concerns. Notably, individuals without memory disorders showed preserved cognition but more frequent and complex NPS. These findings highlight the importance of timely recognition of NPS and early caregiver support in diagnostic practice.

Cerebrovascular reactivity (CVR) is implicated in the progression of dementia, though the underlying mechanisms is not understood. This study examines the relationships between CVR and brain structure and cognitive decline, moderated by mid-life dementia risk. 163 participants from the Whitehall-II cohort underwent neuropsychological testing and MRI, including T1-weighted, FLAIR, and DTI sequences, at two phases (Phase-I: mean age=68.2±4.4; Phase-II: mean age=76.9±4.5). CVR was quantified via BOLD response to 5% CO 2 only at Phase-II. Linear regression tested the Phase-II and Phase-I to Phase-II associations between CVR and brain and cognitive outcomes (Table 1), alongside its interaction with dementia risks. Post-hoc analysis clarified the extent of these associations among different risk groups. Tables 2 and 3 list significant cross-sectional and longitudinal results, respectively. At Phase-II, global CVR was positively associated with volume of left nucleus accumbens, and temporoparietal junction (p<0.03). Parietal CVR was positively associated with left hippocampus volume (p=0.03). These associations were more pronounced in the low-risk group. Temporal CVR was related to thalamus volume (p<0.05) across all participants, with associations of the right thalamus exclusive to the high-risk group (p=0.03). Longitudinally, lower global and regional CVR at Phase-II was linked to greater reduction in temporoparietal junction volume (p<0.04). In high-risk individuals, lower frontal, parietal, or global CVR was linked to larger volume declines in total grey matter or right thalamus respectively (p<0.05). Across all participants, lower parietal CVR at follow-up was linked to greater FA reductions and RD increases between examinations in the corpus callosum (p=0.02) and to greater declines in FA and increases in MD, RD, and L1 in the cingulum bundle (p<0.04), with these effects being more pronounced in the low-risk group. At Phase-II, lower parietal and temporal CVR was associated with worse fluency and intelligence, respectively, in high-risk individuals (p<0.05). Lower frontal CVR was linked to more executive function decline in the low-risk group over-time (p=0.03). This study highlights the differential impacts of global and regional CVR on brain structure and cognitive changes dependent on mid-life dementia risks, which provides evidence for CVR as a potential biomarker for dementia and age-related cognitive change.

T1-weighted (T1w) MRI is widely used in clinical neuroimaging for studying brain structure and its changes, including those related to neurodegenerative diseases, and as anatomical reference for analysing other modalities. Ensuring high-quality T1w scans is vital as image quality affects reliability of outcome measures. However, visual inspection can be subjective and time consuming, especially with large datasets. The effectiveness of automated quality control (QC) tools for clinical cohorts remains uncertain. In this study, we used T1w scans from elderly participants within ageing and clinical populations to test the accuracy of existing QC tools with respect to visual QC and to establish a new quality prediction framework for clinical research use. Four datasets acquired from multiple scanners and sites were used (N = 2438, 11 sites, 39 scanner manufacturer models, 3 field strengths—1.5T, 3T, 2.9T, patients and controls, average age 71 ± 8 years). All structural T1w scans were processed with two standard automated QC pipelines (MRIQC and CAT12). The agreement of the accept–reject ratings was compared between the automated pipelines and with visual QC. We then designed a quality prediction framework that combines the QC measures from the existing automated tools and is trained on clinical research datasets. We tested the classifier performance using cross-validation on data from all sites together, also examining the performance across diagnostic groups. We then tested the generalisability of our approach when leaving one site out and explored how well our approach generalises to data from a different scanner manufacturer and/or field strength from those used for training, as well as on an unseen new dataset of healthy young participants with movement-related artefacts. Our results show significant agreement between automated QC tools and visual QC (Kappa = 0.30 with MRIQC predictions; Kappa = 0.28 with CAT12’s rating) when considering the entire dataset, but the agreement was highly variable across datasets. Our proposed robust undersampling boost (RUS) classifier achieved 87.7% balanced accuracy on the test data combined from different sites (with 86.6% and 88.3% balanced accuracy on scans from patients and controls, respectively). This classifier was also found to be generalisable on different combinations of training and test datasets (average balanced accuracy of leave-one-site-out = 78.2%; exploratory models on field strengths and manufacturers = 77.7%; movement-related artefact dataset when including 1% scans in the training = 88.5%). While existing QC tools may not be robustly applicable to datasets comprising older adults, they produce quality metrics that can be leveraged to train more robust quality control classifiers for ageing and clinical cohorts.

We conducted PET imaging with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits. LRRK2 mutant rats displayed no deficit in [18F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype. These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.

Cardiovascular disease has been associated with an increased dementia risk, but the underlying mechanisms for this heart-brain link are unclear. This study sought to examine associations between aortic and carotid artery structure with cerebrovascular reactivity (CVR), white matter hyperintensities (WMHs), and cognition in later-life. One hundred sixty three participants (25.8

With promising disease-modifying therapies (DMTs) emerging and good evidence to support risk reduction in the delay of dementia onset and progression, it is important to understand the profile of patients attending memory assessment services to estimate what proportion of patients might benefit from different types of interventions. The Oxford Brain Health Clinic (OBHC) is a psychiatry-led, clinical-research service that offers memory clinic patients detailed clinical assessments and equal access to research opportunities as part of their secondary care pathway. In this work, we describe the characteristics of OBHC patients in terms of demographics, diagnoses and prevalence of potentially modifiable risk factors compared with a cohort of healthy volunteers and the average memory clinic population. Our results suggest that high research consent rates (91.5%) in the OBHC resulted in a highly representative cohort of the clinical population. Based on Lecanemab trial inclusion criteria, 24.6% of the OBHC population may be suitable for further investigation into DMTs. Furthermore, 67.4% of OBHC patients have at least one potentially modifiable risk factor that may benefit from lifestyle interventions, particularly those focused on depression, sleep and physical activity.

Background:Hairpulling (HP) is a body-focused repetitive behaviour that typically begins in early adolescence. However, most research on HP has focused on adults, with large gaps in our understanding of the phenomenology and mechanisms involved in HP in adolescence. A key empirically unexplained phenomenon in pediatric HP is the common co-occurrence of depression, and anxiety symptoms. Shame is a prevalent self-critical emotion in adults with BFRBs and a significant predictor of depression and anxiety in adolescence, and therefore may partially explain relationships between adolescent HP and depressive and anxiety symptoms. Methods:This cross-sectional, survey-based study examined HP phenomenology and the mediating role of shame in relationships between HP severity and symptoms of depression and anxiety in a community-based sample of adolescents who hair-pull. One hundred twenty-eight adolescents aged 13-18 completed measures of HP phenomenology, HP severity, shame, depression symptoms, and anxiety symptoms. Results:Phenomenological findings demonstrated a relatively high prevalence of trance HP (61.8% usually/always), trichophagia (26.6% at least sometimes), and pulling from multiple sites (80.5%). Mediational analyses revealed HP severity was significantly associated with both depression (β = 0.355, p < 0.001) and anxiety symptoms (β = 0.266, p = 0.003). Shame was a significant partial mediator in the depression relationship (indirect effect = 0.192, 95% CI [0.078, 0.308]) and full mediator in the anxiety relationship (indirect effect = 0.146, 95% CI [0.053, 0.257]). Conclusions:Our phenomenological findings highlight the need for further examination of trance HP and other HP features in youth. Our mediational results suggest that shame may play a crucial role in relationships between HP and co-occurring depression and anxiety symptomology in adolescence, underscoring the potential importance of targeting shame in improved HP interventions.

The number of people living with dementia worldwide is projected to reach 150 million by 2050, making prevention a crucial priority for health services. The co-occurrence of two or more chronic health conditions, termed multimorbidity, occurs in up to 80% of dementia patients, making multimorbidity an important risk factor for dementia. However, we lack an understanding of the specific health conditions, and their age of onset, that drive the link between multimorbidity and dementia. Using data from 282 712 participants of the UK Biobank, we defined the sequential patterns of accumulation of 46 chronic conditions over the life course. By grouping individuals based on their life history of chronic illness, we show here that the risk of incident dementia can be stratified by both the type and timing of their accumulated chronic conditions. We identified several distinct clusters of multimorbidity throughout the lifespan (cardiometabolic, mental health, neurovascular, peripheral vascular, eye diseases and low/no multimorbidity). We observed that the odds of developing dementia varied based on when these comorbidities were diagnosed. Until midlife (age 55), the accumulation of cardiometabolic conditions, such as coronary heart disease, atrial fibrillation, and diabetes, was most strongly associated with dementia risk. However, from 55 to 70 years, the accumulation of mental health conditions, such as anxiety and depression, as well as neurovascular conditions, such as stroke and transient ischaemic attack, was associated with an over 2-fold increase in dementia risk compared with low multimorbidity. Importantly, individuals who continuously and sequentially accumulate cardiometabolic, mental health, and neurovascular conditions were at greatest risk. The age-dependent role of multimorbidity in predicting dementia risk could be used for early stratification of individuals into high- and low-risk groups and could inform targeted prevention strategies based on a person’s prior history of chronic disease.

Given the relationship between hippocampal atrophy and cognitive impairment in various pathological conditions, hippocampus segmentation from MRI is an important task in neuroimaging. Manual segmentation, though considered the gold standard, is time-consuming and error-prone, leading to the development of numerous automatic segmentation methods. However, no study has yet independently compared the performance of traditional, deep learning-based and hippocampal subfield segmentation methods within a single investigation. We evaluated 10 automatic hippocampal segmentation methods (FreeSurfer, SynthSeg, FastSurfer, FIRST, e2dhipseg, Hippmapper, Hippodeep, FreeSurfer-Subfields, HippUnfold and HSF) across 3 datasets with manually segmented hippocampus labels. Performance metrics included overlap with manual labels, correlations between manual and automatic volumes, volume similarity, diagnostic group differentiation and systematically located false positives and negatives. Most methods, especially deep learning-based ones that were trained on manual labels, performed well on public datasets but showed more error and variability on clinical data. Many methods tended to over-segment, particularly at the anterior hippocampus border, but were able to distinguish between healthy controls, MCI, and dementia patients based on hippocampal volume. Our findings highlight the challenges in hippocampal segmentation from MRI and the need for more publicly accessible datasets with manual labels across diverse ages and pathological conditions.

ABSTRACT The analysis tools and statistical methods used in large neuroimaging research studies differ from those applied in clinical contexts, making it unclear whether these techniques can be translated to a memory clinic setting. The Oxford Brain Health Clinic (OBHC) was established in 2020 to bridge this gap between research studies and memory clinics. We optimised the UK Biobank imaging framework for the memory clinic setting by integrating enhanced quality control (QC) processes (MRIQC, QUAD, and DSE decomposition) and supplementary dementia‐informed analyses (lobar volumes, NBM volumes, WMH classification, PSMD, cortical diffusion MRI metrics, and tract volumes) into the analysis pipeline. We explored associations between resultant imaging‐derived phenotypes (IDPs) and clinical phenotypes in the OBHC patient population ( N = 213), applying hierarchical FDR correction to account for multiple testing. 14%–24% of scans were flagged by automated QC tools, but upon visual inspection, only 0%–2.4% of outputs were excluded. The pipeline successfully generated 5683 IDPs aligned with UK Biobank and 110 IDPs targeted towards dementia‐related changes. We replicated established associations and found novel associations between brain metrics and age, cognition, and dementia‐related diagnoses. The imaging protocol is feasible, acceptable, and yields high‐quality data that is usable for both clinical and research purposes. We validated the use of this methodology in a real‐world memory clinic population, which demonstrates the potential of this enhanced pipeline to bridge the gap between big data studies and clinical settings.

Introduction The mechanistic associations between small vessel disease (SVD) and dementia are still poorly understood. The APOE ε4 allele, recognised as the strongest genetic risk factor for Alzheimer's disease, has been previously implicated in SVD, although it remains unclear whether this association is gene-dose dependent. An emerging neuroimaging biomarker of SVD is Peak Width of Skeletonised Mean Diffusivity (PSMD), obtained from histogram analyses of diffusion weighted imaging (DWI) datasets. Here, we investigated the relationship between APOE ε4 gene dose and PSMD, as a surrogate marker of SVD, in a group of cognitively normal middle-aged adults. Methods The study included data from 1954 asymptomatic middle-aged adults from the ALFA (ALzheimer and FAmilies) and PREVENT-Dementia cohorts (See Table 1 for sample characteristics). PSMD was calculated from the DWI datasets using a publicly available script, and harmonised using COMBAT to account for site-related differences. Using non-parametric permutation models, our primary analyses focused on the (a) comparison of group differences (APOE ε4 heterozygotes vs homozygotes vs non-carriers) in PSMD, adjusting for age, sex, years of formal education, and sites; and (b) potential interactions between APOE ε4 gene dose and age on PSMD values. Marginal predictions were used to estimate the earliest age at which differences might emerge between the APOE ε4 groups and non-carriers. Results There were no significant differences in PSMD values across the non-carriers (n=1,197), heterozygous carriers (n=659), and homozygous APOE ε4 carriers (n=98) (p = 0.6; Figure 1). However, there was a statistically significant interaction between APOE ε4 gene dose and age on PSMD. Specifically, homozygous APOE ε4 carriers exhibited a steeper increase in PSMD with age compared to non-carriers and heterozygous carriers (T = 4.7, p<0.01; Figure 2). Marginal effect analyses revealed higher PSMD values in homozygous APOE ε4 carriers at the estimated age of 57 relative to non-carriers and heterozygous carriers. Discussion Homozygosity for APOE ε4 could hasten dementia onset by accelerating age-dependent increases in PSMD. Future studies with a longitudinal design are warranted to clarify the molecular mechanisms through which the APOE ε4 allele influences PSMD and if this contributes to the contributes to the development of dementia.

BackgroundRecent evidence suggests that anosognosia or unawareness of cognitive impairment in Alzheimer’s Disease (AD) may be explained by a disconnection between brain regions involved in accessing and monitoring information regarding self and others. It has been demonstrated that AD patients with anosognosia have reduced connectivity within the default mode network (DMN) and that anosognosia in people with prodromal AD is positively associated with bilateral anterior cingulate cortex (ACC), suggesting a possible role of this region in mechanisms of awareness in the early phase of disease. We hypothesized that anosognosia in AD is associated with an imbalance between the activity of large-scale resting-state functional magnetic resonance imaging (fMRI) networks, in particular the DMN, the salience network (SN), and the frontoparietal network (FPN).MethodsSixty patients with MCI and AD dementia underwent fMRI and neuropsychological assessment including the Anosognosia Questionnaire Dementia (AQ-D), a measure of anosognosia based on a discrepancy score between patient’s and carer’s judgments. After having applied Independent Component Analysis (ICA) to resting fMRI data we performed: (i) correlations between the AQ-D score and functional connectivity in the DMN, SN, and FPN, and (ii) comparisons between aware and unaware patients of the DMN, SN, and FPN functional connectivity.ResultsWe found that anosognosia was associated with (i) weak functional connectivity within the DMN, in posterior and middle cingulate cortex particularly, (ii) strong functional connectivity within the SN in ACC, and between the SN and basal ganglia, and (iii) a heterogenous effect concerning the functional connectivity of the FPN, with a weak connectivity between the FPN and PCC, and a strong connectivity between the FPN and ACC. The observed effects were controlled for differences in severity of cognitive impairment and age.ConclusionAnosognosia in the AD continuum is associated with a dysregulation of the functional connectivity of three large-scale networks, namely the DMN, SN, and FPN.

The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein epsilon 4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein epsilon 4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia. Dounavi and McKiernan et al. used Magnetic Resonance Spectroscopy in a large mid-life cohort with varying future dementia risk. Lower N-acetylaspartate associated with parental dementia; lifestyle risk correlated with higher myo-inositol, choline, creatine and glutamate+glutamine. Neurochemical changes were found at mid-life in relation to inherited and potentially modifiable dementia risk. Graphical abstract

Brain atrophy assessment in MRI, particularly of the hippocampus, is commonly used to support diagnosis and monitoring of dementia. Consequently, there is a demand for accurate automated hippocampus quantification. Most existing segmentation methods have been developed and validated on research datasets and, therefore, may not be appropriate for clinical MR images and populations, leading to potential gaps between dementia research and clinical practice. In this study, we investigated the performance of segmentation models trained on research data that were style-transferred to resemble clinical scans. Our results highlighted the importance of intensity normalisation methods in MRI segmentation, and their relation to domain shift and style-transfer. We found that whilst normalising intensity based on min and max values, commonly used in generative MR harmonisation methods, may create a need for style transfer, Z-score normalisation effectively maintains style consistency, and optimises performance. Moreover, we show for our datasets spatial augmentations are more beneficial than style harmonisation. Thus, emphasising robust normalisation techniques and spatial augmentation significantly improves MRI hippocampus segmentation.

The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer’s disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E ɛ4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E ɛ4, and (ii) the interactions of apolipoprotein E ɛ4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E ɛ4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E ɛ4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E ɛ4 carriers with lower years of education. We demonstrated that apolipoprotein E ɛ4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer’s disease. This finding also suggests that apolipoprotein E ɛ4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index.

AbstractWith promising disease-modifying therapies (DMTs) emerging and good evidence to support risk reduction in the delay of dementia onset and progression, it is important to understand the profile of patients attending memory assessment services to estimate what proportion of patients might benefit from different types of interventions. The Oxford Brain Health Clinic (OBHC) is a psychiatry-led, clinical-research service that offers memory clinic patients detailed clinical assessments and equal access to research opportunities as part of their secondary care pathway. In this work, we describe the characteristics of OBHC patients in terms of demographics, diagnoses and prevalence of potentially modifiable risk factors compared with a cohort of healthy volunteers and the average memory clinic population. Our results suggest that high research consent rates (91.5%) in the OBHC resulted in a highly representative cohort of the clinical population. Based on Lecanemab trial inclusion criteria, 24.6% of the OBHC population may be suitable for further investigation into DMTs. Furthermore, 67.4% of OBHC patients have at least one potentially modifiable risk factor that may benefit from lifestyle interventions, particularly those focused on depression, sleep and physical activity.

Alzheimer’s disease (AD) risk is increased in carriers of the apolipoprotein E ( APOE ) ε4 allele and decreased in ε2 allele carriers compared with the ε3ε3 genotype. The aim of this study was to determine whether: the APOE genotype affects brain grey (GM) or white matter (WM) structure; and if differences exist, the age when they become apparent and whether there are differential effects by sex. We used cross-sectional magnetic resonance imaging data from ~43,000 (28,494 after pre-processing) white British cognitively healthy participants (7,446 APOE ε4 carriers) aged 45–80 years from the UK Biobank cohort and investigated image-derived phenotypes (IDPs). We observed no statistically significant effects of APOE genotype on GM structure volumes or median T2* in subcortical structures, a measure related to iron content. The volume of white matter hyperintensities differed significantly between APOE genotype groups with higher volumes in APOE ε4ε4 (effect size 0.14 standard deviations [SD]) and ε3ε4 carriers (effect size 0.04 SD) but no differences in ε2 carriers compared with ε3ε3 carriers. WM integrity measures in the dorsal (mean diffusivity [MD]) and ventral cingulum (MD and intracellular volume fraction), posterior thalamic radiation (MD and isotropic volume fraction) and sagittal stratum (MD) indicated lower integrity in APOE ε4ε4 carriers (effect sizes around 0.2–0.3 SD) and ε3ε4 (effect sizes around 0.05 SD) carriers but no differences in ε2 carriers compared with the APOE ε3ε3 genotype. Effects did not differ between men and women. APOE ε4 homozygotes had lower WM integrity specifically at older ages with a steeper decline of WM integrity from the age of 60 that corresponds to around 5 years greater “brain age”. APOE genotype affects various white matters measures, which might be indicative of preclinical AD processes. This hypothesis can be assessed in future when clinical outcomes become available.