Ritchie, Karen

Abstract 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.

ABSTRACT 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

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.