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Background: Sleep and circadian disruption are associated with increased dementia risk, yet the mechanism remains poorly understood. We examined the relationship between night/shift working in the fourth decade and late‐life brain health. We explored whether significant relationships were mediated by life course factors including cardiovascular risk. Methods: Night/shift working (yes/no) was recorded prospectively at age 31. Smoking, alcohol intake, body mass index, exercise, blood pressure, and Framingham risk scores (FRS) were determined at 3‐6 timepoints across the life course (age 20, 36, 43, 53, 60‐64, 68‐70). Whole‐brain and hippocampal volumes, white matter hyperintensity volume (WMHV), and β‐amyloid PET SUVr were derived from T1, fluid‐attenuated inversion recovery, and 18F‐Florbetapir PET, respectively, at age ∼73. Associations between night/shift working, life course cardiovascular risk factors, and imaging metrics were examined with linear regression. Causal mediation analysis (gformula approach in R), examined whether significant relationships between night/shift working and imaging metrics were mediated by life course cardiovascular risk factors. Analyses were adjusted for gender, adult socioeconomic status, educational attainment, age at imaging, and intracranial volume for volumetric measures. Results: 432 participants had available data, of whom 74 (17.1%) were night/shift workers. Night/shift workers had lower whole brain volume (‐26.2 ml, 95% CI ‐39.3, ‐13.0, P < 0.001, Figure 1), without evidence of a significant difference in hippocampal volume, WMHV, or amyloid‐β SUVr. Night/shift workers had 0.6% higher FRS (95% CI; 0.23%, 0.91%; P = 0.001) and higher alcohol consumption age 36 (5.7 g/day, 95% CI, 0.3, 11.2, P = 0.04); higher alcohol consumption age 60‐64 (10.7 g/day, 95% CI, 4.5, 16.9; P < 0.001); and smoked an additional 5.7 pack‐years by age 60‐64 (95% CI 1.9, 9.4; P = 0.003, Figure 2). 35% of the brain volume reduction in shift workers was mediated by cardiovascular risk factors (Figure 3). Conclusion: Shift working in the early 30s is associated with lower brain volume in late‐life independent of amyloidogenic pathways. While partially mediated by increased cardiovascular risk factors in night/shift workers, the majority of the effect is unexplained and may be a direct effect of night/shift working on brain health. [ABSTRACT FROM AUTHOR]

Background: Accelerated long‐term forgetting (ALF) is a form of episodic memory impairment where information is retained normally over 30‐60 minutes but lost at an accelerated rate over subsequent days to weeks, and is a very early – perhaps the earliest – cognitive change in both autosomal dominant and sporadic Alzheimer's disease (AD). However, the neuroanatomical changes underlying ALF in AD have remained elusive. We explored associations between ALF and focal cortical thickness in presymptomatic autosomal dominant AD (ADAD). Method: Eighteen asymptomatic ADAD mutation carriers (mean estimated years to symptom onset = 7.3) (SD = 4.4) and twelve non‐carrier controls underwent ALF testing for three tasks (list, story, figure). After learning, recall was tested at 1) 30 minutes and 2) seven days. ALF score was calculated as 7‐day recall/30‐minute recall. T1‐weighted MRI was acquired at baseline and annually over five years. Cortical thickness was estimated using FreeSurfer. Thirteen regions of interest were selected based on either a known vulnerability to AD‐related neurodegeneration or a known role in memory. Serum NfL– a neurodegeneration marker– was measured on the single molecule array platform. Spearman coefficients explored associations between ALF and 1) focal baseline cortical thickness, 2) future rates of thinning, and 3) serum NFL. Result: Across all three tasks, ALF scores were significantly lower in mutation carriers than non‐carriers, despite no difference at 30‐minutes. In mutation carriers, verbal ALF (list and story) was associated with lower baseline cortical thickness in the prefrontal cortex (PFC) across four contiguous regions bilaterally (p<0.001 for each). This association was not present in non‐carriers. No associations were found between ALF and the thickness/volume of medial temporal lobe (MTL) structures. ALF was predictive of future cortical thinning across AD vulnerable regions. Higher serum NFL was associated with poorer long‐term list recall. Forgetting at 30 minutes was not associated with cortical thickness or NfL, i.e. associations were specific to ALF. Conclusion: ALF is an early presymptomatic marker of AD‐related cognitive decline, underscored by changes in the PFC but not the MTL. These findings advance our understanding of the neuroanatomical substrate of early AD memory decline. ALF could be used as a biologically relevant measure in future presymptomatic trials. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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 [ABSTRACT FROM AUTHOR]

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

Background: Cardiovascular and cerebrovascular pathology may accelerate brain aging and cognitive decline. Structural cerebrovascular imaging biomarkers, such as white matter hyperintensities, reflect mostly irreversible accumulated damage. In contrast, cerebral blood flow (CBF), measured with arterial spin labelling (ASL) perfusion MRI, is a potential early haemodynamic biomarker of cognitive impairment. However, our understanding of physiological CBF variability and its relation with cognition is limited. Method: We included 245 cognitively unimpaired participants from the Insight 46 birth cohort study, who underwent 3D T1‐weighted and pseudo‐continuous ASL‐MRI (labelling duration = 1800ms; post‐labelling delay = 1800ms) on a 3T Siemens Biograph mMR PET‐MRI scanner. Cognitive assessment included tests for logical memory (Wechsler Memory Scale‐Revised), associative memory (Face‐Name Associative Memory Exam), attention and processing speed (Digit‐symbol substitution and response inhibition test), non‐verbal reasoning (Matrix test), executive functioning (Choice Reaction Time), visuomotor integration (circle‐tracing task), and two composite scores (Mini‐Mental State Examination (MMSE) and the Preclinical Alzheimer Cognitive Composite). Result: Sample characteristics are reported in Table 1. Associations were found between GM sCoV and MMSE (Male/Female ß = 0.74/‐0.75, p = 0.028, Figure 1), and GM sCoV and Logical Memory (Male/Female ß = 1.05/‐0.25, p = 0.005, Figure 2), but not between CBF and any cognitive scores (p>0.05). Conclusion: In a cognitively unimpaired population, cognitive performance was associated with GM sCoV but not with other CBF parameters. However, in males, the relationship was opposite to what we expected. Further work should investigate to what extent this indicates macrovascular change occurs before perfusion alterations and could relate to future cognitive decline, and how they differ between sex. [ABSTRACT FROM AUTHOR]

Background: Subjective Cognitive Decline (SCD) may represent the onset of cognitive decline before impairment on standard cognitive tests occurs (Jessen et al., 2014). Previous cross‐sectional studies were shown to have limited ability to capture objective differences in cognitive performance between groups with and without SCD (Cacciamani et al., 2017). Understanding the interplay between changes in subjective memory ratings and objective cognitive function over time may have utility in identifying people at risk of dementia. Method: 370 cognitively normal (CN) individuals with complete cognitive data (Table 1 for characteristics) from Insight 46, a longitudinal neuroscience sub‐study of the MRC National Survey for Health and Development (the British 1946 Birth Cohort), underwent cognitive, clinical, and physical assessments, and neuroimaging (combined MRI/18F‐Florbetapir‐PET). SCD was measured using MyCog (Rami et al., 2014) a validated tool, from the SCD‐Questionnaire, where higher scores indicate greater subjective complaints. Linear regression models were used to test whether longitudinal cognitive change as measured using the Preclinical Alzheimer Cognitive Composite (PACC) and a visual short‐term memory binding task were influenced by baseline MyCog and whether there are parallel associations between rates of change in MyCog and longitudinal cognitive change. Covariates were sex, age at baseline visit, childhood cognitive ability, educational attainment, and adult socioeconomic position. Result: Baseline MyCog scores did not predict rates of change in PACC or visual short‐term memory binding outcome measures (Table 2). Rates of MyCog change alone did not predict rate of change in PACC, localisation error, total correct number of trials or proportion of misbinding errors (Table 3). However, we observed an interaction effect with baseline amyloid‐b status, whereby greater rates of subjective memory concerns predicted faster rates of decline in the proportion of misbinding errors in amyloid‐b positive participants only (Table 3; Figure 1). Conclusion: These findings suggest that higher amyloid‐b burden in CN individuals with subjective memory complaints is associated with faster rates of decline in visual working memory. Corroborating previous reports that feature binding tasks can objectify subtle cognitive deficits found in SCD (Koppara et al., 2015) and serve as a promising tool for identifying people at risk of dementia. [ABSTRACT FROM AUTHOR]

Background: Peripheral hearing impairment has been proposed as a risk factor for dementia. However, the relationship between hearing ability, neurodegeneration and cognitive decline, and the extent to which pathological processes associated with increased risk of specific causes of dementia, such as β‐amyloid and small vessel disease, influence these relationships, is unclear. Method: Data were analysed from 287 cognitively normal adults born in the same week of 1946 who underwent pure tone audiometry testing at baseline (mean age = 70.6 years), with cognitive assessment and brain imaging at baseline and at follow‐up on average 2.4 years later. Peripheral hearing impairment was defined as a pure tone average of greater than 25 decibels in the best hearing ear. Rates of change for whole brain, hippocampal and ventricle volume were estimated from structural MRI using the Boundary Shift Integral. Cognition was assessed using the Pre‐clinical Alzheimer's Cognitive Composite. Regression models were performed to evaluate how baseline hearing impairment associated with subsequent brain atrophy and cognitive decline after adjustment for a range of variables including baseline β‐amyloid deposition (assessed using florbetapir‐PET) and baseline small vessel disease burden (estimated using white matter hyperintensity volume). Results: 111 out of 287 participants were defined as having peripheral hearing impairment. Hearing impaired individuals demonstrated faster rates of whole brain atrophy (p = 0.031 – figure/table 1) compared with those with normal hearing. Peripheral hearing impairment did not predict change in PACC performance, but there was evidence of an interaction between hearing impairment and whole brain atrophy rates in terms of effect on change in PACC performance. Specifically, faster rates of whole brain atrophy predicted greater cognitive decline in participants with hearing impairment (p = 0.004), whilst there was no evidence of an association between cognitive change and atrophy in participants with preserved hearing (figure/table 2). There was no evidence that β‐amyloid deposition or white matter hyperintensity volume modified these relationships. Conclusion: We present evidence of associations between peripheral hearing ability at age 70, brain atrophy and cognitive decline independent of β‐amyloid and small vessel disease, suggesting hearing may associate with brain health via mechanisms distinct from those typically implicated in pre‐clinical Alzheimer's disease and vascular cognitive impairment. [ABSTRACT FROM AUTHOR]

• Older age at menopause is associated with better cognition at around 70 years of age. • Visual processing, associative learning, and memory showed the strongest effects. • Life course covariables explained most, but not all, associations. Associations between age at menopause and cognition post-menopause are examined to determine whether relationships are stronger for certain cognitive domains. Women from the Medical Research Council National Survey of Health and Development and its neuroscience sub-study, Insight 46, were included if they had known age at menopause (self-reported via questionnaire) and complete cognitive outcome data at age 69 (n = 746) or at Insight 46 wave I (n = 197). Multivariable linear regression analyses adjusting for life course confounders were run; interactions with menopause type (natural/surgical) and APOE-ε4 status were examined; and the potential contribution of hormone therapy was assessed. Cognitive measures were standardized Addenbrooke's Cognitive Examination - third edition total and sub-domain scores at age 69 (whole cohort) and Preclinical Alzheimer's Cognitive Composite total and sub-test scores at age ~70 (Insight 46). Older age at menopause was associated with better performance across all outcomes, most strongly for the Addenbrooke's Cognitive Examination memory and visuospatial function sub-domains, and the Preclinical Alzheimer's Cognitive Composite digit-symbol substitution test and face-name associative memory examination sub-tests. Adjusting for early-life factors attenuated all effect estimates, driven by childhood cognition, and accounting for menopause type revealed negative confounding for some outcomes. No significant interactions with menopause type or APOE-ε4 status were detected. Further adjustment for hormone therapy did not meaningfully alter the estimated effects. Older age at menopause is associated with better later-life cognitive performance, particularly for visual processing and associative learning and memory domains. Childhood cognition was an important contributor. [ABSTRACT FROM AUTHOR]

Objective: The BRAIN Study was established to assess the associations between self‐reported concussions and cognitive function among retired rugby players. Methods: Former elite‐level male rugby union players (50+ years) in England were recruited. Exposure to rugby‐related concussion was collected using the BRAIN‐Q tool. The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC). Linear regressions were conducted for the association between concussion and PACC score, adjusting for confounders. Results: A total of 146 participants were recruited. The mean (standard deviation) length of playing career was 15.8 (5.4) years. A total of 79.5% reported rugby‐related concussion(s). No association was found between concussion and PACC (β –0.03 [95% confidence interval (CI): –1.31, 0.26]). However, participants aged 80+ years reporting 3+ concussions had worse cognitive function than those without concussion (β –1.04 [95% CI: –1.62, –0.47]). Conclusions: Overall there was no association between concussion and cognitive function; however, a significant interaction with age revealed an association in older participants. [ABSTRACT FROM AUTHOR]