Abstract Objectives To investigate the association between pulse pressure and dementia incidence, independent of other blood pressure measurements and established risk factors, and to assess whether this association differs across dementia subtypes. Design Prospective population-based study. Setting UK Biobank. Participants Of the 502,211 participants in the UK Biobank, 470,986 completed at least one blood pressure measurement and were included in the analysis. These participants were recruited between March 2006 and July 2010 and were followed for up to four assessments through to February 2024. Main outcome measures Incidence of dementia, identified through linked health records using ICD-9 and ICD-10 diagnosis codes, self-reported diagnoses or records of dementia-specific medication use. The association between pulse pressure and risk of dementia was investigated using Cox proportional hazard models. Models were adjusted for age, sex, education, hearing problems, lipid levels, depression, traumatic brain injury, physical activity, diabetes, smoking, hypertension, body mass index, alcohol consumption and mean arterial pressure. Dementia subtype-specific associations were examined using competing risk models, with cause-specific Cox analyses included as supplementary sensitivity analyses. Results During a median follow-up of 13 years, 9,028 persons developed dementia (Alzheimer’s disease: 3,011; Vascular dementia: 1,270; Dementia with Lewy bodies: 234; Frontotemporal dementia: 191; Other/Mixed dementia: 4,322). Each 10mm Hg increase in pulse pressure was associated with a 5.4% higher risk of dementia (95% confidence interval on hazard ratio: 1.036 to 1.071), even after adjustment for age, mean arterial pressure and other established dementia risk factors. The effects were disproportionately stronger for Alzheimer’s disease and vascular dementia, with no clear evidence for increased risk for dementia with Lewy bodies or frontotemporal dementia. Results were robust across sensitivity analyses including alternative blood pressure metrics, complete-case models, and alternative dementia classifications. Conclusions Pulse pressure is independently associated with incidence of dementia beyond conventional blood pressure measures.

BACKGROUND:Individuals living in socioeconomically disadvantaged areas are disproportionately affected by dementia. However, the pathway leading from neighbourhood deprivation to cognitive symptoms is not well understood. To test our hypothesis that this relationship is associated with cerebral small vessel disease (SVD), we examined (1) whether neighbourhood deprivation related to midlife SVD burden and cognition, and (2) whether these links can be explained by modifiable lifestyle risk factors. METHOD:In this multi-centre cross-sectional study, 514 cognitively healthy midlife participants aged 40-59 years (median 52 years, 64.6% female) underwent clinical assessment and 3T MRI. Postcode data were used to obtain national indices of neighbourhood deprivation. To quantify SVD, we assessed white matter hyperintensities (WMH), perivascular spaces, cerebral microbleeds, and lacunes. Cognition was assessed using the Computerized Assessment of Information Processing (COGNITO) battery. Lifestyle risk factors were evaluated based on clinical data. Using multivariate statistics like structural equation modelling (SEM) and canonical correlation analysis (CCA), we examined associations between these constructs both globally and at the item-level (i.e., distinction between domains of cognition/deprivation), to shed light on specific domains that could inform targeted prevention strategies. RESULT:Neighbourhood deprivation related to greater prevalence of lifestyle risk factors (r = 0.36, p < .001), greater SVD burden (b=0.18, p = .01; Figure 1), and greater cognitive impairment (r = 0.36, p < .001), independent of educational attainment, sex, and age. These links with neighbourhood deprivation were largely driven by lifestyle factors relating to vascular health (sleep, physical activity, obesity, hypertension) (Figure 2), and cognitive deficits consistent with SVD (processing speed, visuospatial) (Figure 3). Residents of deprived neighbourhoods displayed greater prevalence of lifestyle risk factors, except alcohol consumption. Lower cognitive scores were most closely associated with deprivation domains of Crime and Living Environment (Figure 3). The DEPRIVATION→SVD path was mediated by lifestyle risk factors (z=2.57, p = .010), and the DEPRIVATION→COGNITION path was mediated by SVD (z=-2.14, p = .032) (global SVD & hypertensive subtype, but not CAA-SVD). CONCLUSION:The pathway linking neighbourhood disadvantage to cognitive impairment at midlife is influenced by vascular risk factors and cerebrovascular burden. Tailored strategies could promote resilience against dementia by promoting health behaviours aligned with the community's unique needs.

Functional brain changes such as altered cerebral blood flow occur long before the onset of clinical symptoms in Alzheimer’s disease (AD) and other neurodegenerative disorders. While cerebral hypoperfusion occurs in established AD, middle-aged carriers of genetic risk factors for AD, including APOE ε4, display regional hyperperfusion due to hypothesised pleiotropic or compensatory effects, representing a possible early biomarker of AD and facilitating earlier AD diagnosis. However, it is not clear whether hyperperfusion already exists even earlier in life. Here, 160 young and cognitively healthy participants from the Chinese PREVENT cohort underwent 3 T arterial spin labelling and T1 MRI and genetic testing for APOE and MAPT rs242557 status. Using FSL, we performed a whole brain voxel-wise analysis and a global mean grey matter analysis comparing for the effects of both risk genes on cerebral perfusion. No significant alterations were seen for APOE genotype, but in MAPT rs242557 A carriers, we observed a significantly hyperperfusion in the left anterior cingulate cortex and left insular cortex. There were no effects of APOE or MAPT status on the global perfusion. These results are novel and may suggest that MAPT genotypes demonstrated a distinct hemodynamic profile in a very young age.

Dementia, particularly Alzheimer's disease (AD), is a significant public health concern, with midlife emerging as a critical period for preventive intervention (Livingston, 2017). Dementia's heterogeneity renders single risk factor insufficient for accurate identification of individuals at risk (Stephen, 2021). Multifactorial risk scores, such as the cardiovascular risk factors, aging, and dementia (CAIDE) score (Kivipelto, 2006), which include both cardiovascular (blood pressure, cholesterol, BMI, physical inactivity) and non-modifiable factors (age, sex, APOE ε4 genotype), are vital in assessing dementia risk. This study, using the network-based statistic (NBS)-Predict model (Serin, 2021), aimed to explore the functional brain architecture associated with these risk factors, aiding in personalized prevention and intervention strategies for dementia. Resting-state fMRI data, CAIDE, cardiovascular and non-modifiable risk scores, and lifetime of experiences questionnaire (LEQ) data were analyzed from 585 healthy participants (females/males=207/378, mean age=50.9) in the PREVENT-Dementia study (Ritchie, 2023). Using the Dosenbach atlas, functional connectivity (FC) matrices were constructed post-data preprocessing. The NBS-Predict model, employing a linear support vector machine with 10-fold cross-validation, feature selection at p<0.05, and 1000 permutations, predicted CAIDE, cardiovascular, and non-modifiable risk scores (Figure 1). A hierarchical regression model assessed the impact of midlife LEQ score on FC linked to cardiovascular risk factors, with LEQ scores, age, sex, education years, and mean framewise displacement as independent variables. NBS-Predict models significantly predicted the CAIDE (r=0.214, p<0.001), cardiovascular (r=0.201, p<0.001), and non-modifiable (r=0.237, p<0.001) risk factors scores. Similar FC patterns were observed between the CAIDE and cardiovascular risk scores, particularly involving the somatomotor and cingulo-opercular networks (Figure 2a), contrasting with distinct patterns for non-modifiable risk factors. The non-specific LEQ score positively correlated with FC in regions affected by cardiovascular risk factors (β=0.001, p=0.017). The study demonstrated a significant overlap in FC patterns between CAIDE and cardiovascular risk factors in midlife, distinct from patterns associated with non-modifiable risk. This suggested different neurobiological pathways influencing dementia risk in midlife, emphasizing the importance of personalized dementia prevention strategies. The findings highlighted the positive impact of an active and engaged lifestyle on brain health, reinforcing the need for early intervention targeting cardiovascular health for dementia risk reduction.

Aims: Sleep dysfunction is common in the prodromal stages of Alzheimer’s disease. Several thalamic nuclei are implicated in promoting and maintaining sleep. We investigated the relationship between thalamic nuclei volumes and sleep in people without dementia with respect to dementia family history (FHD) and apolipoprotein e4 allele (APOE4) carriership. Methods: 700 participants aged 40–59 years were recruited into the PREVENT Dementia study. 645 participants underwent T1-weighted 3T MRI scans. The thalamus was segmented into six regions; 1) anterior, 2) lateral, 3) ventral, 4)intralaminar, 5) medial and 6) posterior using Freesurfer 7.1.0 and underwent ComBAT harmonisation. Subjective sleep data was assessed using the Pittsburgh sleep quality index, which quantifies sleep using seven components and a total score. 586 participants were included for analysis with respect to FHD and 590 for APOE4 carriership. Logistic regression or robust linear regression with age, sex, total intracranial volume and depression as covariates and false discovery rate correction (FDR) for multiple comparisons was used. Results: Smaller volumes of the whole thalamus (p=0.0391), posterior region (pFDR=0.042), and within the posterior region the lateral geniculate (pFDR=0.019), and pulvinar anterior (pFDR=0.019) and medial nuclei (pFDR=0.019), were associated with worse perceived quality of sleep in the FHD positive group. Smaller volumes of the thalamus (p=0.041) in the FHD positive group were associated with greater sleep disturbances. We did not find any relationship between thalamic volumes and FHD in predicting total scores, sleep duration, latency, efficiency, use of medications to aid sleep or daytime dysfunction. However, larger thalamic volumes were associated with a significantly lower total Pittsburgh score, indicating less overall sleep dysfunction (p=0.014) in non-carriers. A similar trend was seen with the lateral, ventral and intralaminar subregions, but they did not survive correction for multiple comparisons. We did not find any association between thalamic volumes and APOE4 carriership in predicting sleep quality, duration, latency, efficiency, sleep disturbances, use of sleep medications or daytime dysfunction. Conclusion: Our results suggest some early sleep changes related to thalamic volume, particularly in individuals with dementia family history. It is possible the thalamus and nuclei within the posterior thalamus may exert beneficial effects in preserving the quality of sleep in this group.

INTRODUCTION:Neighborhood deprivation increases dementia risk, although mechanisms remain unclear. We tested a framework in which modifiable risk factors and cerebral small vessel disease (SVD) mediate the link between neighborhood deprivation and cognition. METHODS:In 585 cognitively healthy midlife adults (ages 40-59), neighborhood deprivation was derived from postcodes, cognition was assessed using the COGNITO, lifestyle risk factors were measured using clinical assessments, and SVD (white matter hyperintensities, lacunes, microbleeds, perivascular spaces) was assessed on 3T magnetic resonance imaging. Multivariate analyses examined association pathways among these variables. RESULTS:Neighborhood deprivation was associated with poorer cognition (r = 0.36, p < 0.001), greater prevalence of modifiable risk factors (r = 0.36, p < 0.001), and greater SVD burden (β = 0.18, p = 0.008). Serial mediation showed that the effects of deprivation on cognition were indirect, possibly operating via lifestyle risk and SVD, explaining 20% of the total effect, whereas SVD alone explained 28%. DISCUSSION:Neighborhood disadvantage relates to poorer cognition, possibly mediated through vascular risk factors and cerebrovascular disease. HIGHLIGHTS:Neighborhood deprivation linked to poorer cognition in healthy midlife adults Deprivation linked to small vessel disease (SVD) and modifiable risk factors (chiefly cardiovascular risk) Association between deprivation and cognition mediated by modifiable risk and SVD Mediation was exclusive to hypertensive SVD, but not cerebral amyloid angiopathy (CAA)-related SVD.

Two-thirds of Alzheimer’s Disease (AD) cases occur in women. Compared to men, women exhibit more rapid cognitive decline and brain atrophy in the presence of AD-related neuropathology (Gamache et al., 2020). It is now acknowledged that AD processes are present decades before the onset of clinical symptoms (Jack et al., 2013). However, whether there are sex differences in cognition-brain structure coupling and how AD risk affects their relationships in midlife remain unclear. In this study, we investigated associations between sex, AD risk, brain structure and cognition. Structural Magnetic Resonance Imaging and detailed neuropsychological assessments were obtained for 614 cognitively healthy individuals (40-59 years, 233 M/ 381 F) from the PREVENT-Dementia study. Dementia risk factors were assessed by Apolipoprotein E [APOE] ε4 allele status, and the Cardiovascular Risk Factors Aging and Dementia (CAIDE) score. Multiple linear regression model was used to investigate the associations between sex, AD risk, brain structure and cognition. CAIDE was negatively associated with global cortical thickness, and negatively associated with episodic and relational memory (Figure 1). We didn’t find a significant association between global cortical thickness and cognition (Figure 2a) but found a sex-specific coupling of global cortical thickness and episodic and relational memory (Figure 2b). Such sex-specific coupling between global cortical thickness and cognition was absent in APOE ε4 carriers, and only shown in APOE ε4 non-carriers (Figure 2c, 2d). Furthermore, among the selected AD signature regions, cognition was decoupled from the precuneus cortical thickness in APOE ε4 carriers, and only coupled with cortical thickness of precuneus in APOE ε4 non-carriers (Figure 2e, 2f). We found inherent sex-specific differences in the coupling between brain structure and cognition. Our results suggest that these sex-specific differences are being eroded by APOE ε4 carriership in mid-life. Longitudinal follow-up in this cohort will shed light on the long-term sex-specific impact of APOE genotype on brain structure and cognition in preclinical populations with risk for AD.

INTRODUCTION:Sleep dysfunction in those at higher risk of dementia may be associated with early structural changes to the hypothalamus. METHODS:We used multivariate regression to analyze self-reported sleep (Pittsburgh Sleep Quality Index [PSQI]) from cognitively healthy participants in the PREVENT Dementia and Alzheimer's and Families (ALFA) studies (n = 1939), stratified by apolipoprotein E (APOE) genotype as homozygotes, heterozygotes, and non-carriers. FreeSurfer was used to extract hypothalamic subunit volumes from T1-weighted magnetic resonance images. RESULTS:APOE ε4 homozygotes had a larger anterior-superior hypothalamus compared to heterozygotes and non-carriers, an effect which was driven by younger people in the cohort. APOE ε4 carriers had a higher PSQI global score after age 55, and smaller anterior-superior and tubular-superior subunits were associated with more sleep disturbances. Sleep duration and efficiency worsened with age, but only in participants with a small anterior-inferior hypothalamus. DISCUSSION:This suggests that aging and APOE ε4 are associated with hypothalamic changes, highlighting mechanisms linking sleep dysfunction to dementia. HIGHLIGHTS:Apolipoprotein E (APOE) ε4 homozygotes ha a larger anterior-superior hypothalamus. APOE ε4 carriers have worse sleep, but only after age 55. Worse sleep in APOE ε4 carriers was associated with smaller hypothalamic subunits. Higher age was associated with worse sleep in people with a small hypothalamus.

Individuals living in socioeconomically disadvantaged areas are disproportionately affected by dementia. However, the pathway leading from neighbourhood deprivation to cognitive symptoms is not well understood. To test our hypothesis that this relationship is associated with cerebral small vessel disease (SVD), we examined (1) whether neighbourhood deprivation related to midlife SVD burden and cognition, and (2) whether these links can be explained by modifiable lifestyle risk factors. In this multi-centre cross-sectional study, 514 cognitively healthy midlife participants aged 40-59 years (median 52 years, 64.6% female) underwent clinical assessment and 3T MRI. Postcode data were used to obtain national indices of neighbourhood deprivation. To quantify SVD, we assessed white matter hyperintensities (WMH), perivascular spaces, cerebral microbleeds, and lacunes. Cognition was assessed using the Computerized Assessment of Information Processing (COGNITO) battery. Lifestyle risk factors were evaluated based on clinical data. Using multivariate statistics like structural equation modelling (SEM) and canonical correlation analysis (CCA), we examined associations between these constructs both globally and at the item-level (i.e., distinction between domains of cognition/deprivation), to shed light on specific domains that could inform targeted prevention strategies. Neighbourhood deprivation related to greater prevalence of lifestyle risk factors ( r  = 0.36, p  < .001), greater SVD burden (b=0.18, p  = .01; Figure 1), and greater cognitive impairment ( r  = 0.36, p  < .001), independent of educational attainment, sex, and age. These links with neighbourhood deprivation were largely driven by lifestyle factors relating to vascular health (sleep, physical activity, obesity, hypertension) (Figure 2), and cognitive deficits consistent with SVD (processing speed, visuospatial) (Figure 3). Residents of deprived neighbourhoods displayed greater prevalence of lifestyle risk factors, except alcohol consumption. Lower cognitive scores were most closely associated with deprivation domains of Crime and Living Environment (Figure 3). The DEPRIVATION→SVD path was mediated by lifestyle risk factors (z=2.57, p  = .010), and the DEPRIVATION→COGNITION path was mediated by SVD (z=-2.14, p  = .032) (global SVD & hypertensive subtype, but not CAA-SVD). The pathway linking neighbourhood disadvantage to cognitive impairment at midlife is influenced by vascular risk factors and cerebrovascular burden. Tailored strategies could promote resilience against dementia by promoting health behaviours aligned with the community's unique needs.

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.

ObjectivesWe assessed the modulation of allostatic load (AL) by engagement in healthy habits and life stressors, mediated through resilience and the perceived influence of the stressors. Sleep was included as third mediator given extensive evidence associating to all the analysed factors.MethodsStructural equation models to assess the modulation of AL by either traumatic or psychosocial stressors and healthy habits were generated with data from 620 mid-life adults (age 51.3 ± 5.48 years). Model 1 included self-reported life stressors, engagement in cognitive and physical activities, resilience and a pyramid score for diet. In Model 2, self-reported sleep quality was included in the mediation analysis between resilience and perceived stress on AL.ResultsDirect effects of sports and diet on AL, and on resilience by sports were found in all the evaluated models. The modulation of AL by both types of stressors was only revealed in model 2, through indirect effects of perceived influence via sleep quality. An effect of sport habits on AL via resilience was found to be mediated by sleep, and equivalent but opposed effects of perceived influence of stressors and resilience on sleep quality emerged as critical factor for AL modulation.ConclusionOur results suggest that sleep plays a pivotal role in the modulation of AL by both life stressors and sport habits, balancing the harmful and protective effects of perceived stress and resilience. The relative weight of one over the other to worsen or improve sleep quality will determine the resulting level of AL.

Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)–based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

Alzheimer's Disease (AD) neuropathology start decades before clinical manifestations, but whether risk factors are associated with early cognitive and brain changes in midlife remains poorly understood. We examined whether AD risk factors were associated with cognition and functional connectivity (FC) between the Locus Coeruleus (LC) and hippocampus - two key brain structures in AD neuropathology - cross-sectionally and longitudinally in cognitively healthy midlife individuals. Neuropsychological assessments and functional Magnetic Resonance Imaging were obtained at baseline (N=210), and two-years follow-up (N=188). Associations of cognition and FC with apolipoprotein ε4 (APOE ε4) genotype, family history of dementia, and the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score were investigated. Cross-sectionally, higher CAIDE scores were associated with worse cognition. Menopausal status interacted with the CAIDE risk on cognition. Furthermore, the CAIDE score significantly moderated the relationship between cognition and LC-Hippocampus FC. Longitudinally, the LC-Hippocampus FC decreased significantly over 2 years. These results suggest that cardiovascular risk of dementia is associated with brain-behaviour changes in cognitively healthy, middle-aged individuals.

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

In the last decade, extensive research has emerged into understanding the impact of risk factors for Alzheimer’s Disease (AD) on brain in pre-symptomatic stages. We investigated the neuroimaging correlates of the APOEe4 genetic risk factor for (AD) in young adulthood, its relationship with cognition, and potential effects of other variables on the findings. While conventional volumetric analyses revealed no consistent differences, more sophisticated analyses identified subtle structural differences between APOEe4-carriers and non-carriers. Findings from diffusion studies were limited, but functional studies demonstrated consistent alterations in connectivity and activity. The complex relationship between APOE genotype, neuroimaging variables, and cognition revealed no consensus on the directionality of findings. Methodological choices, including analytical approaches, sample size, and the influence of other genes, gender, and ethnicity, varied across studies, impacting comparability and generalizability. Recommendations for future research include multimodal and longitudinal imaging, standardisation of pipelines, advanced analytical techniques, and collaborative data pooling.

Brain Age Gap has been associated with dementia in old age. Less is known relating brain age gap to dementia risk-factors or cognitive performance in middle-age. Cognitively healthy, middle-aged subjects from PREVENT-Dementia had comprehensive neuropsychological, neuroimaging and genetic assessments. Brain Ages were predicted from T1-weighted 3T MRI scans. Cognition was assessed using the COGNITO computerized test battery. 552 middle-aged participants (median [interquartile range] age 52.8 [8.7] years, 60.0% female) had baseline data, of whom 95 had amyloid PET data. Brain age gap in middle-age was associated with hypertension (P = 0.007) and alcohol intake (P = 0.008) but not apolipoprotein E epsilon 4 allele (P = 0.14), amyloid centiloids (P = 0.39) or cognitive performance (P = 0.74). Brain age gap in middle-age is associated with modifiable dementia risk-factors, but not with genetic risk for Alzheimer's disease, amyloid deposition or cognitive performance. These results are important for understanding brain-age in middle-aged populations, which might be optimally targeted by future dementia-preventing therapies.

Background and purpose: The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. Methods: This study used data from the PREVENT dementia programme. Three MedDiet scores were created (the Pyramid, Mediterranean Diet Adherence Screener [MEDAS] and MEDAS continuous) from a self-reported food frequency questionnaire. Primary outcomes were hippocampal volume and cube-transformed white matter hyperintensity volume. Secondary outcomes included cornu ammonis 1 and subiculum hippocampal subfield volumes, cortical thickness and measures of cognition. Sex-stratified analyses were run to explore differential associations between diet and brain health by sex. An exploratory path analysis was conducted to study if any associations between diet and brain health were mediated by cardiovascular risk factors for dementia. Results: In all, 504 participants were included in this analysis, with a mean Pyramid score of 8.10 (SD 1.56). There were no significant associations between any MedDiet scoring method and any of the primary or secondary outcomes. There were no differences by sex in any analyses and no significant mediation between the Pyramid score and global cognition by cardiovascular risk factors. Conclusions: Overall, this study did not find evidence for an association between the MedDiet and either neuroimaging or cognition in a midlife population study. Future work should investigate associations between the MedDiet and Alzheimer's disease and related dementias biomarkers as well as functional neuroimaging in a midlife population.

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.

Efforts to prevent dementia can benefit from precision interventions delivered to the right population at the right time; that is, when the potential to reduce risk is the highest. Young adults (aged 18-39 years) are a neglected population in dementia research and policy making despite being highly exposed to several known modifiable risk factors. The risk and protective factors that have the biggest effect on dementia outcomes in young adulthood, and how these associations differ across regions and groups, still remain unclear. To address these uncertainties, the Next Generation Brain Health team convened a multidisciplinary expert group representing 15 nations across six continents. We identified several high-priority modifiable factors in young adulthood and devised five key recommendations for promoting brain health, ranging from individual to policy levels. Increasing research and policy focus on brain health across the life course, inclusive of younger populations, is the next crucial step in the efforts to prevent dementia at the global level.

PURPOSE:Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. METHODS:Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. RESULTS:Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12 mL/100 g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59 mL/100 g/min) compared to submitted results. CONCLUSIONS:Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization.