Examining risk factors collectively provides a clearer understanding of brain health vulnerability and supports multidomain prevention strategies that target clustered modifiable risks.
Abstract
Dementia reflects vascular and neurodegenerative processes in late life, yet studies often examine risks and outcomes individually. This study tested whether the cumulative burden of risks relate to vascular brain injury and cognitive performance and whether brain markers are associated with part of these associations through cross-sectional indirect pathways. Cross-sectional data were drawn from 38,414 older adults in the National Alzheimer's Coordinating Center database. A composite index summed ten binary risk factors: hypertension, diabetes, hypercholesterolemia, alcohol misuse, smoking, depression, obesity, hearing loss, vision loss, and low education. Outcomes included white matter hyperintensities (WMHs), infarcts, hippocampal atrophy, global cognition, cognitive status, delayed recall, and semantic fluency. Higher cumulative risk burden was associated with poorer cognitive outcomes and greater structural brain injury. Each additional risk factor was linked to worse global cognitive status, greater clinical severity, lower delayed recall, lower semantic fluency, and higher odds of WMHs, cerebral infarcts, and hippocampal atrophy. Hippocampal atrophy demonstrated the largest indirect pathway among the evaluated MRI markers, whereas WMHs and infarcts showed smaller indirect pathways. The findings suggest that cumulative modifiable risk burden is associated with poorer brain health and cognitive functioning in later life. Examining risk factors collectively provides a clearer understanding of brain health vulnerability and supports multidomain prevention strategies that target clustered modifiable risks.
Background Hearing impairment (HI) has been identified as a potentially modifiable risk factor for dementia, yet its relationship with Alzheimer's disease (AD) neuropathology and the temporal directionality remain unclear, particularly in late life. Objective To examine cross-sectional and longitudinal associations between HI, clinical cognitive status, and AD biomarkers in community-dwelling older adults. Methods We included 474 DRIVES Project participants (mean age 73.5 ± 5.2 years). Hearing was assessed using the NIH Toolbox Words-in-Noise (WIN) test. Clinical cognitive status was assessed using Clinical Dementia Rating (CDR). AD biomarkers included cerebrospinal fluid (CSF) Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42 ratios and amyloid PET imaging. Multivariable linear, logistic, Cox proportional hazards, and Fine–Gray competing-risk models were used. Results HI was more prevalent among participants with mild cognitive impairment (MCI; defined as CDR = 0.5) than cognitively normal individuals (50% versus 24%, p < 0.001), and MCI status was independently associated with worse baseline WIN thresholds (β = 1.55 dB SNR; 95% CI 0.72–2.37). HI was not cross-sectionally associated with CSF amyloid or tau ratios or amyloid PET positivity. Longitudinally, baseline MCI was associated with a higher risk of incident HI (Cox HR = 2.63, 95% CI 1.48–4.67; Fine–Gray sHR = 2.79, 95% CI 1.06–7.40), whereas baseline HI was not associated with subsequent CDR progression. Conclusions In older adults, HI was associated with MCI but not core AD biomarkers or future CDR progression, suggesting that late-life HI may reflect cognitive vulnerability or broader brain aging rather than independently driving AD pathology.
Semere Bekena, R. Singh, Subrata Pal et al.· Journal of Alzheimer's Disea...· 0 citations
BackgroundWhite matter hyperintensity (WMH) is linked to mild cognitive impairment (MCI) and vascular dementia, but its longitudinal change as an independent risk factor remains unclear.ObjectiveThis study aims to compare baseline WMH across diagnostic outcomes, and evaluate how WMH trajectory relates to outcomes, cognition, and amyloid-β (Aβ) deposition.MethodsData from the Alzheimer's Disease Neuroimaging Initiative (ADNI) included demographics, medical history, WMH, diagnosis, cognition, and amyloid-PET. A total of 857 participants (372 cognitively normal [CN], 485 MCI) were categorized by diagnostic outcome. Baseline WMH differences were analyzed. WMH trajectories (higher/lower) were used in logistic models to predict outcomes, and in linear models to assess cognitive and Aβ changes, adjusting for age, sex, hypertension, BMI, education level, total brain volume and APOE ε4.ResultsBaseline WMH was significantly higher in the CN-MCI group compared to the CN-CN group and lower in the MCI-CN group than in the MCI-MCI and MCI-AD dementia groups (p < 0.05). Controlling for covariates, regression models found that CN participants with higher WMH trajectories had higher odds of MCI (OR = 3.710, 95%CI [1.836,7.499], p < 0.001), and that participants with higher WMH trajectories had greater impairments in domains of memory (β=-0.331, 95%CI[-0.454,-0.208], p < 0.001), executive function (β=-0.275, 95%CI[-0.370,-0.179], p < 0.001), and language (β=-0.248, 95%CI[-0.344,-0.152], p < 0.001). In [18F] florbetapir (FBP) tracers, increased Aβ deposition was also observed in higher WMH groups (β = 0.056, 95% CI[0.018,0.095], p = 0.004).ConclusionsWMH baseline and trajectory changes are key risk factors for CN cognitive decline. WMH trajectory changes are linked to cognitive function and brain Aβ deposition.
W. Ba, Cui-Ping Bao, Ying-Xun Gong et al.· Journal of Alzheimer's Disea...· 0 citations
BAG is a reliable non-invasive marker of structural brain health sensitive to AD pathology and to modifiable AD risk and supports its relevance for early risk stratification and prevention-oriented research.
E. Kuhn, G. Antopoulos, L. Kleineidam et al.· medRxiv· 0 citations
Elevated circulating MMP-7 at 12 months was associated with cognitive decline suggesting a potential role for BBB remodeling in vascular contributions to cognitive impairment, and should be considered exploratory and require validation in larger studies.
I. López-Dequidt, Y. Leira, S. Cinza-Sanjurjo et al.· Journal of Alzheimer's Disea...· 0 citations
Dementia affects over 55 million individuals worldwide, and its prevalence is projected to triple by 2050. Vascular dementia (VaD) is the second most common cause of cognitive impairment after Alzheimer’s disease (AD), accounting for roughly 20% of all cases. VaD represents a heterogeneous yet mechanistically convergent group of disorders in which vascular injury, blood–brain barrier (BBB) disruption, and neuroinflammation synergistically drive progressive cognitive decline. It arises from diverse etiologies including small-vessel and large-artery disease, chronic cerebral hypoperfusion, and hereditary arteriopathies such as CADASIL, but converges on shared downstream pathways that impair cerebral perfusion, white-matter integrity, and neuronal connectivity. As the global burden of cardiovascular disease rises, vascular contributions to dementia are expected to increase disproportionately, particularly in aging populations. Importantly, epidemiologic evidence consistently links VaD risk to modifiable cardiovascular and metabolic disorders, most notably hypertension, diabetes, and obesity, underscoring its largely preventable nature. Advances in single-cell and spatial transcriptomics, vascularized human brain organoids, and experimental models have revealed how endothelial senescence, oxidative stress, impaired glymphatic clearance, and immune dysregulation disrupt the neurovascular unit. Furthermore, mounting evidence supports bidirectional interactions between vascular injury and amyloid-β and tau pathology, suggesting shared mechanisms between VaD and AD. This Review synthesizes current mechanistic, epidemiologic, and translational insights into vascular contributions to cognitive decline. By emphasizing the interplay between systemic vascular health and brain resilience, we highlight opportunities to target endothelial dysfunction, neuroinflammation, and metabolic stress as promising strategies for prevention and therapy of vascular dementia.
Shivi Garg, L. McCullough· npj Dementia· 0 citations
Type 2 diabetes mellitus is associated with cognitive impairment and greater Alzheimer's disease risk, with cross-sectional studies suggesting that this is driven by neurodegeneration and vascular changes. Longitudinal studies, however, report similar rates of total brain atrophy over time in diabetic and non-diabetic adults. We recently showed that diabetes-related neurodegeneration in cognitively unimpaired adults is regional and may not be evident in longitudinal studies of global brain atrophy. The mechanisms driving diabetes-related neurodegeneration are unknown; glycemic control may play an important role but the relative influence of Alzheimer's and cerebrovascular pathology is unclear. Here, we longitudinally examined regional patterns of cortical thinning associated with diabetes and glycemic control over nearly 3 years. We controlled for Alzheimer's disease neuropathology and white matter hyperintensity burden. We also examined whether subsequent changes in hemoglobin A1c (HbA1c) levels correlated with rates of cortical thinning in diabetes-associated regions and tested whether faster cortical thinning in diabetes-relevant regions mediated a relationship between diabetes and decline in cognitive performance. Among 1,298 cognitively unimpaired participants (mean age=65.0 years, 305 diabetic, 869 female) from the Health and Aging Brain Study-Health Disparities cohort who completed baseline and follow-up MRI scans, we used linear mixed-effects models to examine the relationship between diabetes and cortical thickness changes across 34 brain regions, controlling for socioeconomic factors and comorbidities. We further adjusted for amyloid-PET, tau-PET, white matter hyperintensities, and APOE ε4 carrier status. We also examined associations between baseline and longitudinal HbA1c levels and cortical thinning rates in diabetes-related regions in the whole sample and separately in diabetic and non-diabetic participants. P-values were corrected using the false discovery rate method. Path analysis tested whether diabetes-related cortical thinning mediated the relationship between diabetes and decline in cognitive performance. Diabetic participants exhibited faster cortical thinning in seven frontal, parietal, and occipital regions (-0.060≤βs≤-0.046, corrected Ps<0.017). Associations remained unchanged after accounting for socioeconomic factors, comorbidities, amyloid, tau, white matter hyperintensities, and APOE ε4. Higher baseline HbA1c predicted faster thinning in diabetes-vulnerable regions (corrected Ps<0.032), independent of subsequent HbA1c changes. Diabetes was associated with faster decline in processing speed (β=-0.022, P=0.033), with cortical thinning in diabetes-related regions mediating approximately 13% of this effect (indirect effect β=-0.034, P=0.019). Diabetes-related cortical thinning in cognitively unimpaired older adults follows a regional pattern independent of Alzheimer's and cerebrovascular pathology and partially mediates accelerated decline in processing speed. Chronic hyperglycemia may contribute to diabetes-related neurodegeneration, regardless of subsequent short-term changes in glycemic control.
A. Tsiknia, Victoria R. Tennant, Marylan Davison et al.· Brain : a journal of neurolo...· 1 citation
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