👤 Samantha L Gardener

Chemokines C-X-C Motif Chemokine Ligand 9 (CXCL9) and C-C Motif Chemokine Ligand 2 (CCL2) were previously linked to incident cognitive impairment and dementia in the Northern Manhattan Study (NOMAS). We investigated whether circulating CXCL9 and CCL2 are independently associated with the cerebral white matter disease (WMD) burden and whether WMD mediates their association with prospective cognitive outcomes. In the stroke-free, prospective, community-dwelling NOMAS cohort (age≥50) we examined white matter hyperintensity volume (WMHV) on brain MRI and serum chemokine levels. WMHV was normalized, log-transformed, and standardized. Cognitive status was assessed at MRI and again 12.2±1.3 years later to adjudicate incident cognitive decline and dementia. Multivariable linear regression models with either CXCL9 or CCL2 (in quartiles) as exposures and WMHV as the outcome were adjusted for socio-demographics and key contributors to WMD, including vascular risk factors (Model 1), kidney function (2), and APOE ε4 status (3). Mediation of the CXCL9-cognitive outcome association by WMHV was tested using Monte Carlo integration. Among 1,179 participants (mean age 70±9 years; 60% female), elevated CXCL9 (Q4 vs. Q1) was associated with greater WMHV (Model 1: β=0.20, 95%CI 0.06-0.34). This association persisted even after adjusting for kidney function (Model 2: β=0.17, 95%CI 0.03-0.34) and APOE ε4 status (Model 3: β=0.19, 95%CI 0.04-0.33). CXCL9 (Q4 vs. Q1) effect magnitude in Model 3 approximated ~4 years of aging (β=0.05/year, 95%CI 0.04-0.06), exceeding that of hypertension (β=0.16, 95%CI 0.05-0.27), with a stepwise trend present across quartiles (β/quartile increase=0.07, 95%CI 0.02-0.12, p=0.003). Among 1,166 participants (dementia-free at MRI), the indirect, WMHV-mediated pathway was statistically significant for the association of CXCL9 with incident cognitive decline (ACME 0.009, 95%CI 0.002-0.018, p=0.016) and with dementia (ACME 0.008, 95%CI 0.003-0.016, p=0.004). CCL2 showed no association with WMHV. Greater CXCL9 levels were associated with greater white matter lesion load, independent of vascular, renal, and genetic factors, suggesting a role in WMD pathogenesis. WMHV mediated CXCL9's association with cognitive decline and dementia risk. This IFN-γ-induced monokine (MIG) warrants further evaluation as a biomarker of white matter and cognitive health as well as a potentially modifiable therapeutic target. Show less

Apolipoprotein E (APOE) genotype influences the presence, course and severity of sporadic cerebral amyloid angiopathy (sCAA). We investigated the effect of the APOE ε4-allele on clinical and neuroradiological outcomes in mutation-carriers with Dutch-type hereditary (D-)CAA. Participants with D-CAA from a prospective cohort study, with data collected on history of symptomatic intracerebral hemorrhages (sICH) and vascular risk factors, underwent 3 Tesla magnetic resonance imaging (MRI) scans to assess macrobleeds, cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), enlarged perivascular spaces (EPVS), white matter hyperintensity (WMH) volume and WMH multispot lesions. Global cognition was measured using Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) scores. Associations between ≥1 APOE ε4-allele and age of first sICH, time to recurrence, cognition and radiological data were analyzed with adjustments for confounders. Eighty-one participants (mean age 47 years, 54% women, 38% with sICH history) were included. The APOE ε4-allele was not associated with earlier sICH onset (median age 56 versus 57 years; p = 0.6) or time to recurrence (5.0 versus 3.9 years; p = 0.4), nor was it associated with macrobleeds (β 2.0; 95%CI 2.4- -2.7; p = 0.4), CMBs (β 2.9; 95%CI 1.0-8.9; p = 0.06), cSS (aOR 0.5; 95%CI 0.1-2.0; p = 0.3), EPVS (aOR 0.4; 95%CI 0.1-1.5; p = 0.6), WMH volume (β 6.8; 95%CI -1.9-15.4; p = ), a multispot pattern (OR 0.7; 95%CI 0.2-2.7, p = 0.6), or cognition (β -0.3; 95%CI -0.4- -0.5; p = 0.5). APOE ε4 does not affect key clinical parameters or D-CAA neuroradiological markers and therefore does not explain the large variation in disease course in D-CAA. Show less

A substantial proportion of dementia risk may be attributable to modifiable factors, yet these are often examined in isolation despite their interrelated nature and tendency to co-occur. It remains unclear whether the relationship between modifiable factors and dementia risk is influenced by individual characteristics such as sex and genetic susceptibility. We investigated longitudinal associations between the Lifestyle for Brain health (LIBRA) score and risk of dementia, cognitive performance, and brain structure, and whether relationships differed by sex and APOE ɛ4 carrier status.Participants were aged > 50 years, dementia-free at baseline, 50% female and predominantly (97%) white/Caucasian. The LIBRA score included 11 modifiable factors (e.g., hypertension, obesity, physical inactivity). Magnetic resonance imaging estimated brain volume, domain-specific cognitive composite scores were calculated, and dementia diagnoses were determined based on self-reported and linked healthcare data.Across a mean follow-up of 10.2 years, a higher LIBRA score was associated with greater odds of developing dementia (OR = 1.20, 95% CI 1.18-1.22). This association was stronger in APOE ɛ4 non-carriers compared to ɛ4 carriers. Cross-sectionally, higher LIBRA scores related to poorer cognition, smaller whole-brain gray and white matter volumes, and increased ventricular cerebrospinal fluid (CSF), however, only the association with increased ventricular CSF persisted longitudinally (mean follow-up 3.4 years).Each one-point increase on the LIBRA score was associated with 20% increased odds of developing dementia. These results reinforce the need to target modifiable dementia risk factors and to tailor dementia prevention strategies to individual risk profiles to maximize the impact on brain health. Show less

As dementia cases continue to rise, effective prevention strategies are urgently needed. However, objective biomarkers that directly reflect lifestyle factors remain limited. Life's Essential 8 (LE8) is a composite of modifiable cardiovascular health metrics, and lower LE8 has been consistently associated with increased risk of dementia. In this study, we aimed to identify DNA methylation biomarkers associated with LE8 scores and investigate their relevance for dementia risk. We performed an epigenome-wide association study of 273 stroke-free, self-identified Hispanic adults aged 40 and older from the Northern Manhattan Study (NOMAS), a community-based urban cohort study. DNA methylation (DNAm) was assessed using Illumina MethylationEPIC arrays. Robust linear models identified CpGs associated with LE8 score, a composite score on eight health metrics including diet quality, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. Differentially methylated regions were identified by combining P-values in sliding windows while accounting for spatial correlations across the genome. We also performed functional annotation, pathway analyses, and integrative analyses with gene expression, genetic variants, brain-blood correlations, and comparisons with previous dementia studies to identify the most biologically meaningful DNAm sites. After adjusting for age, sex, APOE ε4, immune cell composition, and ancestry, we found 11 CpGs with suggestive evidence of association with LE8 (P-value < 1 × 10 Our comparison with published results showed that a number of LE8-associated DNA methylation sites are associated with dementia, highlighting the possible connection between cardiovascular health and dementia risk and pointing to potential actionable targets for dementia prevention. Moreover, DNAm biomarkers have clinical potential as objective measures to identify individuals at elevated risk, stratify participants based on biologically informed risk profiles, and monitor epigenetic responses to lifestyle interventions in dementia prevention trials. Future studies in larger and more diverse cohorts are needed to validate and refine these methylation biomarkers for clinical applications. Show less