OBJECTIVE:Females typically perform slightly better than males on memory tests, but this may be partially explained by gender-related biases in remembering the test content. Sex/gender-related differences are underexplored on tests designed to detect subtle Alzheimer's disease-related memory impairment. We studied sex differences on memory tests among older adults, particularly focusing on the Face-Name test (FNAME-12). Specifically, we investigated whether participants were biased toward remembering stimuli that matched their own sex. METHOD:Cognitively normal participants (n = 452) completed cognitive tests including FNAME-12 at baseline (aged ∼70 years) and follow-up (aged ∼73). FNAME-12 stimuli comprise male and female faces, with names and occupations. Recall and recognition were tested with delays of up to 7 days. We investigated how FNAME-12 outcomes were affected by stimulus gender and participant sex. We examined correlations between "gender bias scores" at baseline and follow-up. RESULTS:Women outperformed men on memory tests including FNAME-12. Men and women recalled more male than female stimuli, with this discrepancy being two to three times greater among men (baseline: men d = 0.52, women d = 0.15; follow-up: men d = 0.58, women d = 0.25). Seven-day retention rates for male stimuli were higher (recall d = 0.32; recognition d = 0.41). Baseline and follow-up "gender bias scores" were weakly to moderately correlated. CONCLUSIONS:We observed a gender bias on FNAME-12-particularly among male participants-where male stimuli were better remembered than female stimuli. This bias showed some consistency over ∼2.5 years. Sex differences on memory tests require careful interpretation, as they may be partially explained by gender-related bias in the learning and recall of test content. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Background. Quality of social support is linked to mental health, but less is known about its long-term effects. We aimed to investigate the effects of the quality of social support on affective symptoms from midlife through later life. Methods. Data were used from the MRC National Survey of Health and Development (NSHD), a prospective birth cohort originally consisting of 5,362 people born in 1946. Affective symptoms were measured at ages 53, 60-64, and 69 years using the General Health Questionnaire (GHQ-28), and longitudinal affective symptom trajectories were derived using growth mixture modeling. Quality of social support (positive and negative) was assessed at age 53 years with an adapted version of the Close Persons Questionnaire. Associations of positive and negative social support with affective symptoms at each age and with the longitudinal trajectories were tested using structural equation modeling and the R3 Step approach. Results. Four distinct affective symptom trajectories were identified: no/low symptoms (83%), low and increasing symptoms (8%), consistently moderate/high symptoms (5%), and moderate/high and decreasing symptoms (4%). In fully adjusted models, negative social support was associated with affective symptoms at all three ages ( beta : 0.09-0.16, all p-values < .001) and with the 'consistently moderate/high symptoms' trajectory (OR = 1.65, 95% CI: 1.36, 2.01, p < .001); no association was found for positive social support. Conclusions. Results highlight the importance of negative social support as a potential modifiable factor in prevention and intervention initiatives for affective symptoms among adults from midlife to later life.

Abstract Background Early-life origins of late-life health are unclear. It is uncertain when in life risk-factors for dementia begin to exert effects. We examined childhood predictors of dementia and mortality in the world’s longest continuously-running birth cohort. Methods Prospective cohort study, 78-year follow-up. Exposures assessed from birth-age 16. Dementia/death identified from national registries. Cox regression identified childhood predictors. Findings Of 5,046 participants, 121 (2·4%) were diagnosed with dementia and 1,243 (24·6%) died by age 78. Independent childhood predictors of dementia were low cognition (HR 2·06, 95% CI 1·31-3·24, P =0·002), pollution exposure (HR 2·05, 1·15-3·65, P =0·02), left-handedness/ambidexterity (HR 1·93, 1·15-3·23, P =0·01), sleep disturbance (HR 1·78, 1·00-3·17, P =0·049), nocturnal enuresis (HR 1·52, 1·06-2·17, P =0·02), and emotional problems (HR 1·38, 1·12-1·69, P =0·003). APOE L4 (HR 3·38, 1·67-6·85, P =0·001), and BMI (HR 1·47, 1·17-1·84, P <0·001) associated with dementia only in females. Independent childhood predictors of mortality were BMI (HR 1·07, 1·01-1·14, P =0·02), lower socioeconomic position (HR 1·25, 1·09-1·42, P =0·001), sleep disturbance (HR 1·27, 1·05-1·53, P =0·02), nocturnal enuresis (HR 1·32, 1·04-1·68, P =0·02) emotional problems (HR males:1·09, 1·00-1·18, P =0·046, females:1·25, 1·14-1·36, P <0·0001), and conduct problems (HR 1·13, 1·06-1·20, P =0·0002). Female sex (HR 0·67, 0·59-0·75, P <0·001), education (HR 0·76, 0·67 to 0·87, P <0·001), and breastfeeding (HR 0·93/3-months, 0·89-0·98, P =0·002) associated with lower mortality. Interpretation Childhood factors predict a significant proportion of dementia and early mortality risk. While some associations are genetically determined or may relate to early brain development, the majority are potentially modifiable. Funding Medical Research Council, Alzheimer’s Research UK, Alzheimer’s Association, NIHR, UK Dementia Research Institute.

INTRODUCTION:Psychological distress has been linked with cognitive impairment. However, whether the relationship is causal, reflects preclinical dementia neuropathology, or confounding by common causes remains unclear. METHODS:In five UK longitudinal studies, we examined associations of psychological distress with subsequent cognition using linear and mixed effects models, and dementia using logistic regression. We examined variation by age-at-assessment, severity, and distress persistence, combining study-specific estimates using two-stage individual participant data meta-analysis. RESULTS:Pooling across studies (N = 24,564), greater baseline psychological distress was associated with lower subsequent cognitive level (β = -0.03 [95% confidence interval [CI]: -0.06; -0.01]; I2 = 70%), and dementia (odd ratio [OR] = 1.1 [1.0; 1.2]; I2 = 0%), but not cognitive change. Associations were found for clinically significant, persistent and intermittent distress. Dementia was associated with distress assessed at ages 65-75, and 55-64, but not 45-54 years. DISCUSSION:Findings highlight the relevance of psychological distress in later cognitive outcomes, with potential future implications for dementia prevention and identifying high-risk groups.

Socioeconomic inequalities may act on affective and cognitive health from early life through later life. This study tested to what extent the association of childhood socioeconomic position (SEP) with later-life cognitive ageing is explained by life course accumulative affective problems. We used data from the MRC National Survey of Health and Development (n = 1,593; 52.6

Sleep and circadian disturbances are associated with increased dementia risk. The mechanism remains poorly understood. We aimed to examine the relationship between night/shift working at age 31 and biomarkers of late-life brain health and to estimate the extent to which these relationships are mediated by unhealthy lifestyle behaviours. A prospective longitudinal cohort study, Insight 46, recruited participants from the Medical Research Council National Survey of Health and Development (NSHD) 1946 British Birth cohort. All born in the same week in 1946, participants were assessed at age 70 with multi-modal structural and molecular brain imaging and fluid biomarkers, from which whole-brain and hippocampal volumes, white matter hyper-intensity volume (WMHV), 18F-florbetapir amyloid-β PET Centiloids and plasma phosphorylated tau (p-tau)217 were derived. Prospective data collection included night/shift working at age 31, alongside smoking, alcohol intake, body mass index, exercise, blood pressure, Framingham risk score (FRS) at multiple timepoints from age 20 to 70 and dementia diagnosis or death by age 78. Analyses were adjusted for sex, age, education, socioeconomic position and, where appropriate, total intracranial volume or apolipoprotein E (APOE) genotype. Night/shift working data were available for 431 Insight 46 participants {50% female, mean age 70.7 years [standard deviation (SD) 0.6]}. Night/shift workers had lower whole-brain volume [-19.9 mL, 95% confidence interval (CI) -31.9, -7.9, P = 0.001], lower amyloid PET Centiloids (-9.45, 95% CI -14.7, -4.1, P = 0.0008) and lower plasma p-tau217 concentration (-0.05 pg/mL, 95% CI -0.10, -0.001, P = 0.04), without significant difference in hippocampal volume or WMHV. p-tau217 concentrations were also lower in night/shift workers from a wider sample from the NSHD cohort [n = 1067, mean age 69.9 (SD 0.7), -0.05 pg/mL, 95% CI -0.08, -0.02, P = 0.004]. By age 78, night/shift workers in the NSHD cohort (n = 3040) had lower rates of all-cause (excluding vascular) dementia (hazard ratio 0.33, 95% CI 0.12, 0.92, P = 0.03). Night/shift workers had 0.6% higher FRS (P = 0.01) at age 36, smoked 5.9 more pack-years by age 53 (P = 0.005), consumed 10.7 g/day more alcohol by age 63 (P = 0.006) and had higher rates of APOE ɛ4 allele carriage. Lifestyle behaviours mediated 28% of the lower brain volume in night/shift workers. Despite less healthy lifestyles, higher rates of APOE ɛ4 allele carriage and smaller brains, night/shift workers had lower levels of Alzheimer's disease pathology as measured by amyloid PET and plasma p-tau217 and approximately one-third of the risk of dementia by age 78 compared with non-night/shift workers. Lower brain volume in night/shift workers was partially mediated by unhealthy behaviours. Reduced dementia risk in night/shift workers is unexpected and will require further study.

Ageing is the strongest risk factor for Alzheimer's disease (AD), but the molecular mechanisms underpinning this link are not established. In an identically aged birth cohort, we: 1) tracked proteomic brain ageing trajectories across the seventh decade; 2) tested associations between ageing trajectories and AD pathology; 3) identified which individual proteins influenced associations. n  = 414 from the 1946 British Birth Cohort had plasma assayed with SomaScan 11k v5 at baseline (age=63.4±1.1yr) and follow-up (70.6±0.7yr). Brain age was estimated from a proteomic clock using 202 brain-enriched proteins. ‘Brain age gap’ (BAG) quantified whether a participant's brain age estimate was older (positive) or younger (negative) than their chronological age. ‘BAG change score’ [ (BAG at follow-up) – (BAG at baseline) ], reflected accelerating (positive) or decelerating (negative) trajectory. Primary outcomes were amyloid-PET positivity (CL cut-point=11.9) and log-transformed plasma p -tau217 (ALZpath SIMOA). Secondary outcomes in a subset ( n  = 114, 72.9±0.59yr) were log-transformed CSF p -tau217 and Aβ42/40 ratio. We used linear/logistic regression for continuous/binary outcomes, adjusted for sex. Individual protein analysis used Feature Importance for Biological Ageing (FIBA). BAG at baseline ranged from -9.1 to +17.6yrs. Even greater divergence was seen at follow-up (range: -16.93, 19.16 years). Whilst measurements were correlated (r=0.59), we observed heterogenous brain ageing trajectories across the seventh decade (BAG change score range: -21.3 to 17.3 years, Figure 1). Baseline BAG did not predict biomarker outcomes some ∼10yr later. BAG at follow-up associated with higher plasma p -tau217 (b=0.18, p  = 1.4x10 -4 ) but not amyloid-PET status. Higher BAG change score (i.e., accelerating brain ageing) was associated with amyloid-PET positivity (OR 1.89, p  = 6.4x10 -3 , Figure 2), higher plasma p -tau217 (b=0.26, p  = 6.2x10 -4 ), higher CSF p -tau217 (b=0.30, p  = 9.5x10 -3 ) and lower CSF Aβ 42/40 ratio (b=-0.35, p  = 2.2 x10 -3 ). Associations remained significant adjusting for APOE 4 status, plasma neurofilament light and GFAP. Influential proteins in associations included Aldolase C, NPTXR and LRRTM2 (Figure 3). An identically-aged population experienced heterogenous trajectories of proteomic brain ageing across their seventh decade. Accelerating brain ageing was predictive of AD biomarker positivity, independent of non-specific measures of neurodegeneration and genetic risk. Future research will explore how implicated proteins may couple brain ageing to AD pathology.

Prior research has highlighted that people living with dementia experiencing depression or anxiety can benefit from psychological therapies delivered in primary care. Yet, studies have mainly focused on common dementia types, leaving a gap in evidence for more atypical dementias, and especially those that are not memory-led. This evaluation is crucial, given the unique challenges posed by these subtypes, such as syndrome-specific symptoms of changes in personality or visual processing. This study assesses the effectiveness of psychological therapies provided in primary care settings for individuals with atypical dementia subtypes. Linked national data from over 2 million individuals in the UK who received a course of therapy in NHS Talking Therapies for Anxiety and Depression services were used to identify 523 individuals with atypical dementias who attended therapy between 2012 and 2019. We compared their depression and anxiety outcomes to a cohort of individuals with no diagnosis of dementia. People with atypical dementia had similar outcomes compared to people with typical dementia [Reliable improvement from depression and anxiety symptoms: AdjOR 1.08 (0.86; 1.36) p = 0.4850], but their therapy outcomes were poorer when compared to the matched cohort without dementia [Reliable improvement: AdjOR 0.70 (0.53; 0.91) p = 0.0150]. People with atypical dementia who experience depression or anxiety may benefit from psychological therapies provided in primary care. Their outcomes are poorer than those of people who do not have dementia. These results suggest a need to increase access to psychological therapies for people with atypical dementia and offer interventions that are better tailored to their specific experiences.

At least one-third of stroke survivors are affected by depression or anxiety, but no large-scale studies of real-world clinical practice have assessed whether psychological therapies are beneficial for these patients. Here we show that psychological treatment is effective for stroke survivors on average, using national healthcare records from National Health Service Talking Therapies services in England, including 7,597 patients with a hospital diagnosis of stroke before attendance. Following psychological treatment, stroke survivors experienced moderate reductions in depression and large reductions in anxiety symptoms. Patients who started attending the services a year or more after a stroke were less likely to reliably recover from symptoms of depression or anxiety than those seen within six months of a stroke, irrespective of differences in baseline characteristics including age, gender, local area deprivation and symptom severity. Compared with a matched sample of patients without a stroke, stroke survivors were less likely to reliably recover and more likely to reliably deteriorate after psychological treatment, although adjusting for level of physical comorbidity attenuated these relationships. It is crucial that clinicians working with stroke survivors screen for symptoms of depression and anxiety and consider referring patients to primary care psychological therapies as early as possible.

Evidence indicates an association between wellbeing (e.g., purpose in life) and cognition over time. However, wellbeing is a multifaceted construct, and most research has focused on purpose in life and positive affect, with less research on other aspects of wellbeing. The aim of this study was to test associations between life satisfaction (LS) and hope with cognitive function and decline. Data were used from Whitehall II, a longitudinal cohort study of people employed by the British Civil Service. Measures of LS and hope were available at Wave 7, and cognitive function (phonemic/semantic verbal fluency, memory and inductive reasoning) at Waves 7, 9, 11, and 12. Linear mixed models were fitted to test associations between LS and hope with cognitive function and decline over 13 years. LS was positively associated with baseline cognitive function (overall cognition, verbal fluency, memory, and inductive reasoning) cross-sectionally but not with decline over time. Hope was positively associated with baseline overall cognition, phonemic fluency and inductive reasoning (but not semantic fluency or memory). Hope was associated with slower decline in inductive reasoning over 13 years. Findings contribute to better understanding of the temporal relationship between wellbeing and cognitive function from middle to older age. People with higher hope show lower baseline cognition and slower decline in inductive reasoning. People with lower LS show lower initial cognitive function and this difference is maintained over time. Although decline is not steeper for those with lower LS, they may reach the threshold for dementia earlier than those with higher LS.

AIMS:In England, psychological therapies provided in primary care are recommended as first-line treatment for people living with mild-to-moderate dementia experiencing depression or anxiety. It is known that people living with dementia experience more barriers to accessing therapy than people without dementia, but such inequalities in terms of rates of access to primary care services are yet to be characterised. METHODS:In this retrospective, observational study of linked electronic healthcare records, the national database of the National Health Service (NHS) Talking Therapies for anxiety and depression programme was used to compare pathways to accessing therapy between 6623 people living with dementia and 4 825 489 without dementia between 2012 and 2019. Outcomes included access to an assessment, to therapy and reasons for discharge. Primary analyses used a propensity-score matched cohort to compare outcomes. Exact matching was used for the NHS service entity. RESULTS:The prevalence of dementia in the study cohort was lower than the prevalence of dementia in a representative population, based on an estimation of prevalence in people with mild-to-moderate age over 35 (0.23% in our study vs 3.82% in previous research). Compared to people without dementia, people living with dementia were less likely to access an assessment (odds ratio [OR] = 0.60; 95% confidence interval [CI]: 0.55-0.65), to subsequently receive therapy (OR = 0.67; 95% CI: 0.61-0.73) and more likely to be discharged because services were deemed not suitable before having an assessment (relative rate ratio [RRR] = 4.90; 95% CI: 4.20-5.72) and starting therapy (RRR = 2.74; 95% CI: 2.24-3.35). Female gender, social deprivation, Asian ethnicity and less common dementia subtypes (such as frontotemporal dementia) were also associated with poorer access rates and a higher likelihood of services being deemed not suitable. Involvement of care partners in the referral process was associated with better access rates. CONCLUSIONS:Pathways to accessing primary care psychological therapy services must be made more accessible for people living with dementia. Better access could be achieved by increasing referrer awareness and training for staff within services to promote access for people living with dementia (especially for groups under-represented in services), better understanding how to involve care partners in the process, as well as when specialist support might be more suited in secondary care. More granularity in the medical coding of rarer dementia diagnoses in electronic health records would also allow for better statistically powered research for these groups.

BACKGROUND:Existing evidence on associations between exposure to air pollution and psychological distress from middle to older age is limited by consideration of short exposure periods, poor historical covariates, exposures and outcomes, and cross-sectional study designs. We aimed to examine this association over a 26-year period between ages 43 and 69. METHODS:We utilised data from the Medical Research Council National Survey of Health and Development Study (the 1946 British birth cohort). Land-use regression models estimated exposure to specific air pollutants using household addresses for 1991 (NO2), 2001 (PM10, NO2), and 2010 (NO2, NOx, PM10, PM2.5, PMcoarse, PM2.5abs). These were linked to the closest data collection wave at ages 43, 53 and 60-64, respectively. Psychological distress was assessed through the 28-item version of the General Health Questionnaire (GHQ-28), at ages 53, 60-64 and 69. Associations between each of the pollutants with psychological distress were analysed using generalised linear mixed models, adjusted for pollution exposure before age 43, assigned sex, social class, smoking status, neighbourhood deprivation, and previous mental health problems. We also examined effect modification by social class. RESULTS:At age 69, 2125 participants completed the GHQ-28. In fully adjusted models, higher NO2 exposure was associated with higher GHQ-28 scores across a 26-year period (β=0.023, 95%CI:0.005, 0.040 per interquartile range increase in exposure), whereas higher exposure to PM10 was associated with lower GHQ-28 scores across a 16-year period (β=-0.021, 95%CI:-0.037, -0.006). There was no evidence of associations between exposure to other pollutants at age 60-64 and GHQ-28 at age 69. We found no effect modification by social class. CONCLUSIONS:In this cohort there was some evidence of an association between higher cumulative exposure to NO2 and higher psychological distress, but mixed associations with other exposures. Policies to reduce pollutant exposure may help improve psychological symptoms in middle to late adulthood.

Understanding when Aβ positive cognitively normal individuals develop tau pathology has important implications for treatment with anti-Aβ therapies. We employed a changepoint regression approach to estimate time from Aβ-PET positivity to regionally elevated tau-PET in a population-based cohort of primarily cognitively unimpaired individuals. Participants from Insight 46 (1946 British birth cohort) underwent two [ 18 F]florbetapir Aβ-PET scans and a sub-sample enriched for Aβ were also scanned with [ 18 F]MK-6240 tau-PET, characteristics are presented in Table 1. Age at Aβ-PET positivity, defined through Gaussian mixture modelling (GMM) as >12 Centiloids, was estimated using the SILA algorithm (Betthauser et al. 2022). Tau-PET SUVRs from a temporal-meta, Braak I-VI and 34 bilateral FreeSurfer7 regions were calculated 90-110 mins post-injection using an inferior cerebellar grey matter reference region. Tau-PET positivity cutpoints for each region were defined using the 99 th percentile of the lower distribution from GMM. For each region, we tested changepoints in the slope of the linear regression between tau-PET SUVR and time from estimated Aβ positivity with Bonferroni correction (5% significance, p<.001). At tau-PET scan, 90 individuals (60%) were >0 years from estimated Aβ positivity. There was a statistically significant difference in slopes before and after the changepoint for all composite regions excluding Braak VI (Figure 1). Changepoint estimates show that tau accumulation started ∼2.5yrs after estimated Aβ positivity in Braak stages I-III; and ∼10-12.5yrs for Braak stages IV-V, and the temporal-meta region (Figure 2A). Regional estimates broadly followed Braak stages for 16/36 regions showing significant evidence of change in slopes (Figure 2B). Tau positivity rates before changepoints did not exceed 5%, whereas post-changepoint tau positivity rates were between ∼10% and ∼50%. Regions with later changepoints tended to exhibit higher post-changepoint slopes with greater uncertainty. Elevated tau-PET signal occurs ∼2.5 years after estimated age of Aβ onset in Braak stages I-III and ∼10-12.5 years in temporal-meta and Braak stages IV-V, with uncertainty within these groupings. These estimates for later Braak stages are consistent with results from previous work on the timing of positive tau PET visual reads. These findings may have implications for determining the optimal time to administer Aβ immunotherapies in asymptomatic individuals.

Cognitive assessments are essential for detecting and monitoring cognitive changes in neurological populations. Compared to standard pen-and-paper tests, online cognitive tasks offer a more accessible, scalable, repeatable and cost-effective approach to assessment. Cognitron is an online cognitive assessment platform with previously demonstrated validity and reliability (1). This study aims to derive meaningful insights into the application of online and computerized assessments in older age cohorts by examine the usability of Cognitron tasks with the MRC National Survey of Health and Development (NSHD; the 1946 British birth cohort). 1753 members of the NSHD cohort (all aged 77) were invited to complete a battery comprising 13 Cognitron tasks, spanning multiple cognitive domains, on their home devices. Each task generated measures of accuracy and reaction time. We examined data quality, completion rates, and levels of engagement and compliance. Qualitative data from email (N = 200) and telephone (N = 78) queries were analysed to determine insights into participant experiences. 990 members (56.47%) consented to participate in the study, of whom 813 attempted the battery (46.34%). 739/813 (90.89%) completed all cognitive tests (average completion time = 40 minutes). 8 tasks (61.53%) were completed by all participants. 4 tasks had <2% of participants incompletely engaging. One task (Choice Reaction Time) had 9% of data with signs of non-compliance and was dropped from further analysis (Figure 1). The most common signs of non-compliance were repetitive clicking in the same screen location, switching of browser page, accuracy scores below minimum expected (e.g. failing the simplest trials) and non-engagement with >90% of trials (Table 1). The qualitative analysis of the reasons participants contacted the study by email or telephone identified five key themes: (1) technical issues (N = 137), (2) general queries (N = 88), (3) reasons for withdrawing (N = 72), (4) providing feedback (N = 43) and (5) subjective reports (N = 28) (Figure 2). Cognitron assessment was characterised by high completion, engagement and compliance rates in the NSHD cohort, suggesting that online cognitive assessments have potential to monitor cognitive changes in older age cohorts, including those at risk of developing dementia. Reference (1) Del Giovane, Martina, et al. (2023) EClinicalMedicine 59 https://doi.org/10.1016/j.eclinm.2023.101980

Psychological therapies are recommended for people living with dementia who experience depression or anxiety. However, people living with dementia often experience specific barriers to accessing services providing such interventions, notably due to the stigma associated with dementia. This study sought to understand pathways to entering and receiving treatment after referral to primary care psychological therapy services for people living with, versus without dementia. Linked national data from England from over 4 million individuals referred to NHS Talking Therapies for anxiety and depression (NHS TTad) services were used to identify 6623 people living with dementia referred to these services between 2012 19. We compared rates of access and entry into treatment between people living with dementia and a propensity score matched cohort of people without a diagnosis of dementia, adjusting for a range of socio-demographic (age, gender, ethnicity) and therapy factors (e.g waiting times). We found that once people living with dementia were referred to NHS TTad, they were less likely to access services (ie actually receive an assessment) [AdjOR = 0.61 (0.56; 0.67) p<.0001]. Once assessed, they were also less likely to receive treatment [AdjOR = 0.68 (0.62;0.75, p<.0001] than people with no diagnosis of dementia. Services were twice as likely to be deemed “not suitable” (based on discharge codes recorded by clinicians) for people living with dementia [AdjRRR = 1.97 (1.68; 2.30) p<.0001]. were similar between typical (e.g., memory-led Alzheimer’s disease) dementias, and atypical dementias (e.g. frontotemporal dementia). This study highlights inequalities in access to psychological therapies for people living with dementia. There is a need to make services more accessible to improve the rate of treatment initiation for people living with dementia that are referred and assessed for psychological therapies.

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. 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 (99 th 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. 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. 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.

Dementia-related biomarkers can detect pathology years before clinical diagnostic criteria are met. Understanding the relationship between biomarkers and early cognitive changes is crucial as disease-modifying therapies may have maximum benefits when delivered early. We aimed to demonstrate the utility of remote computerised cognitive tests in a large cohort of cognitively normal older individuals, comparing these to standard in-person assessments and investigating their associations with biomarkers. Using the Cognitron platform, we remotely deployed 11 computerised tests (Figure 1) in 255 members of the Insight46 study. Participants had previously completed biomarker and in-person standard cognitive assessments at age 71-73 (1). We generated brain, hippocampal, and white matter hyperintensity volumes, rates of brain and hippocampal volume change between age 71-73, amyloid load (SUVR) and positivity as previously described (1). General linear models (GLMs) assessed the relationship between the Cognitron tests and biomarkers. Principal component analysis was used for dimensionality reduction, and bivariate correlations compared the standard tests total composite score with the Cognitron accuracy and response time (RT) composite scores. Canonical Correlation Analysis (CCA) further quantified these associations. Of 255 participants (132 males, 234 right-handed, age at assessment 77), 66 were amyloid positive. Amyloid positivity was significantly predicted by RT for the Objects memory test (delayed recognition) (OR = 1.58 (95% CI 0.09,0.85)). We found an association between the Cognitron Objects memory tests and biomarkers (Table 1). Immediate recognition was significantly associated with hippocampal volume change (F (2,204 ) = 4.34; CI: -7.78, -7.74), while the amount of amyloid positivity was significantly predicted by delayed recognition (F (2,225) = 4.48; CI: -0.06, -0.04) and retention (F (2,204) = 3.47; CI: 0.01, 0.1). Both Cognitron accuracy and RT composites significantly correlated with the standard composite (r = 0.56, p<0.001; r = -0.32, p<0.001) (Figure 2). CCA indicated shared variance with significant canonical variables between the standard tests and the Cognitron accuracy (M1:r = 0.73, p<0.001; M2:r = 0.54, p<0.001; M3:r = 0.49, p = 0.01) and RT (M1:r = 0.54, p<0.001) scores. Remote computerised cognitive testing correlates with standard supervised assessments and holds potential for studying early cognitive changes associated with neurodegenerative biomarkers at scale and longitudinally. Reference 1. Lane et al. (2017) - BMC Neurol , 17(75). https://doi.org/10.1186/s12883-017-0846-x

With an aging population, it is essential to identify subtle features of brain pathology – both neurodegenerative and vascular – at an early stage, which may predict risk of future decline. We used diffusion MRI (dMRI) to assess grey matter cortical microstructure and investigate associations with 1) Alzheimer’s disease (AD) pathology and 2) mid/late-life vascular risk (as measured by blood pressure (BP)). 151 asymptomatic individuals from the British 1946 birth cohort underwent combined PET/MR with [18F]florbetapir Aβ-PET at ∼73yrs, and [18F]MK-6240 tau-PET at ∼76yrs. Multi-shell diffusion MRI was acquired; neurite orientation dispersion and density imaging (NODDI) quantified orientation dispersion index (ODI), a proxy measure of dendritic morphology/complexity, with DTI measuring mean diffusivity (MD), a less specific measure of degenerative change. Cortical volume was estimated using GIF. PET SUVRs were calculated. Amyloid load was assessed in a cortical composite region, with tau PET and MRI measures assessed in 1) a temporal meta-ROI (analogous to early Braak stages), and 2) a larger neocortical meta-ROI, analogous to later Braak stages. BP measurements were taken throughout mid and late life, at ages 43, 53, 63, and 73. Seventy participants were amyloid positive (A+), of whom 27 were tau positive (T+). Global cortical ODI was significantly lower in A+/T+ than A+T- (p=0.005) and in A+/T+ than A-/T- (p=0.001), but with no significant difference between A+/T- and A-/T-. The same pattern was found for ODI in the temporal ROI. No consistent differences were found across A/T groupings for MD or volume. MD (both global and temporal) at aged 76 showed significant associations (p<0.05) with BP at ages 43, 53 and 63, but not at 73. These association remained after adjusting for A/T pathology and cortical volume. For ODI, associations with mid-life BP were less consistent. Mid-life BP is associated with late life cortical microstructural breakdown, as measured by MD, in the absence of detectable volume changes and independent of Alzheimer’s disease (AD) pathology. ODI appears to be more sensitive and specific to dendritic tau-related changes. Cortical dMRI offers promise in the presymptomatic identification, staging and risk stratification of both AD and vascular dementia.

Amyloid lowering therapies for Alzheimer’s disease are most effective in those without significant neocortical tau spread. Currently, the only method for anatomically staging tau is through PET scanning, which is largely unavailable in clinical settings. We assessed whether advanced MRI biomarkers of cortical microstructure may provide a more accessible option for assessing early neocortical tau accumulation. 217 asymptomatic individuals underwent amyloid-β PET, tau PET and multi-shell diffusion 3T MRI. Neurite orientation dispersion and density imaging (NODDI) metrics including orientation dispersion index (ODI; a proxy measure of dendritic complexity), and free water fraction (FWF) were calculated. Analysis focused on a meta-temporal cortical composite region, the first site of neocortical tau beyond the medial temporal lobe (MTL). Meta-temporal tau burden was associated with meta-temporal ODI (Pearson’s r=-0.24, p=0.001), with a weaker association also seen with meta-temporal FWF (r=-0.14, p=0.07). Within the amyloid-β positive group, ODI discriminated between those with and without meta-temporal tau positivity (area under the curve=0.86). NODDI-derived ODI is associated with tau PET signal, even in preclinical disease and may discriminate individuals with-and without tau beyond the MTL. NODDI represents a potential alternative imaging tool for staging tau spread, aiding future treatment stratification and delivery.