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Abstract INTRODUCTION Associations of arterial stiffness, measured through pulse wave velocity (PWV), with incident dementia may be driven by age‐related structural changes to the arterial wall or by elevated blood pressure. METHODS Dementia‐free White or Black participants in the community‐based Atherosclerosis Risk in Communities (ARIC) cohort study with measures of PWV were examined. The associations of carotid‐femoral PWV (cfPWV) and total, structural, and load‐dependent PWV with dementia were estimated using Poisson regression models and Cox proportional hazards models. Dementia cases were defined by physician‐adjudicated review, telephone interviews, hospitalization records, and death certificates. RESULTS Of 4818 participants included in the study population (mean age: 75 years; 41% male, 21% Black), 1067 (22%) developed dementia over a median follow‐up of 9.0 years. Higher cfPWV, total PWV, structural PWV, and load‐dependent PWV were associated with greater dementia risk. DISCUSSION Both structural and pressure‐related arterial stiffness mechanisms may underlie the link between PWV and dementia.

Abstract INTRODUCTION Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.

Abstract Background and aims Dementia represents a growing global health burden, with vascular dementia and Alzheimer's disease accounting for most cases through cumulative cerebrovascular damage. While periodontal disease (PD) is associated with cognitive decline, dental caries represents a distinct oral infection pathway characterized by bacterial invasion and infection, potentially contributing to vascular brain injury through microbial translocation, endothelial dysfunction, systemic inflammation, and cerebral microvascular damage. The relationship between dental caries and incident dementia within a vascular framework remains understudied. Methods We analyzed 6,542 participants from the Atherosclerosis Risk in Communities (ARIC) Study who received dental examinations at Visit 4 (1996–1998) and followed for incident dementia through 2023 using standardized surveillance (Figure-1). Cox proportional hazards models with competing risk accounted for death. Multivariable models adjusted for demographic factors, cardiovascular risk factors, BMI, physical activity, education, income, insurance status, APOE4 genotype, PD, and regular dental care. Results Mean age was 62.4 years; 54% female, 82% White, and 18% Black. Dental caries was present in 20%. Over median 25-year follow-up, individuals with dental caries demonstrated significantly higher cumulative dementia incidence (Gray’s test p<0.0001). After full adjustment, dental caries remained independently associated with increased dementia risk (adjusted HR 1.20, 95% CI 1.02–1.42), independent of PD and APOE4 status (Figure-2). Conclusions Dental caries was independently associated with increased incident dementia risk. These findings support a potential role for caries-related oral infection in vascular brain injury pathways relevant to vascular dementia and stroke-related cognitive impairment. Oral infection prevention may represent a modifiable target within cerebrovascular disease prevention strategies. Conflict of interest Alana E. Barton, Souvik Sen, Kevin Moss, James Selph, Ryan Demmer, Pamela L. Lutsey, Priya Palta, Kamakshi Lakshminarayan, Karly Pikel, Wayne Rosamond: nothing to disclose Figure 1 - belongs to Conclusions Figure 2 - belongs to Conclusions

Introduction: Diabetes, a modifiable risk factor for dementia, is thought to impart increased risk of dementia through cerebral small vessel disease. While the importance of diabetes in midlife is well-documented, the influence of different glycemic levels, duration of diabetes, and Alzheimer’s disease genetic risk (apolipoprotein [ APOE ] ε4 genotype) in late-life on dementia risk remains uncertain. This could have implications for individualized prevention strategies. In this study, we investigated whether a higher glycemic level and longer duration of diabetes in late-life is associated with a higher risk of dementia, and whether associations vary by APOE ε4 genotype. Methods: We performed a prospective cohort analysis with the Atherosclerosis Risk in Communities Study using up to 11 years of follow-up (baseline, 2011-2013). We defined diabetes as glycated hemoglobin A1c (HbA 1c ) ≥6.5%, self-reported physician diagnosis, or use of any diabetes medication. Among those with diabetes, we categorized participants as having a lower glycemic level (HbA 1c <7%) or higher level (HbA 1c ≥7%), and duration as short (<5 years) or long (≥5 years). We estimated hazard ratios (HR) for incident dementia by HbA 1c levels and by diabetes duration in separate multivariable-adjusted Cox regression models. We tested for statistical multiplicative interaction on the relative risk of dementia by fitting interaction terms between diabetes measures and APOE ε4 genotype in separate regression models. Results: In 5030 participants without dementia (mean age, 75.4 years; 58.6% female; 21% Black; 28% with diabetes), there were 1167 (23.2%) incident dementia cases over a median follow-up of 9.0 years. Compared to no diabetes, a lower glycemic level and higher level were both associated with elevated dementia risk ( P -trend <.0001; Table). A higher glycemic level was associated with an elevated risk of dementia relative to a lower level (HR=1.47 [95% CI: 1.22-1.77]; Table). Compared to no diabetes, both shorter duration and longer duration were associated with an increase in dementia risk ( P -trend <.0001; Table). Longer duration was associated with an increased risk of dementia relative to shorter duration (HR=1.57 [95% CI: 1.24-1.98]; Table). Associations for glycemic level and diabetes duration did not significantly differ by APOE ε4 genotype (all P >.05). Conclusions: Diabetes management in older adults that includes lower glycemic goals may help reduce dementia risk.

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) is now the predominant HF subtype, largely driven by the syndemic of physical inactivity and overweight/obesity in an aging population. Deranged skeletal muscle energetics and regional ectopic adipose depots are key cardiometabolic pathways in the pathogenesis of HFpEF, both of which may be favorably modified by 1-2 hours/week of resistance exercise (RE). However, its association with HFpEF risk has not been thoroughly examined. We investigated the association between midlife RE behaviors and incident HFpEF in the Atherosclerosis Risk in Communities (ARIC) study. Hypothesis: Participation in RE at midlife is inversely associated with the risk of incident HFpEF. Methods: Our exposure (RE)—including weightlifting and bodyweight resistance exercises—was assessed using the validated Baecke questionnaire and reported weekly RE duration was averaged across Visits 1 and 3 (1987-1995). We dichotomized averaged RE as 0 hr/wk (‘No RE’, reference) and >0 hr/wk (‘Any RE’). Our outcome (incident HFpEF) was identified through committee-adjudicated HF hospitalizations (January 1, 2005 to December 31, 2023) using medical chart abstraction. Participants with prevalent HF, death, or loss to follow-up before January 1, 2005 were excluded. We constructed Cox regression models to evaluate the association between midlife RE and incident HFpEF. Model 1 adjusted for age, sex, race, field center, education, smoking status, alcohol consumption, and non-RE physical activity. Given that adiposity may lie on the causal pathway, waist-height ratio (WHtR; both measured in cm) was added in Model 2. Results: 10,751 Black and White participants (803 incident HFpEF cases) were analyzed over a median follow-up time of 14.4 years (mean±SD Visit 1 age, 53.3±5.6 years; average Visit 1 and 3 WHtR, 0.58±0.08; 24.7% Black; 57.4% female). 1,217 participants (11.3%) reported engaging in RE at Visits 1 and/or 3, with a median duration of 0.84 hr/wk (IQR, 0.50-1.61). Compared to No RE, the fully adjusted hazard ratio (HR) for Model 1 for Any RE was: 0.78 (95% CI, 0.61-1.00, P = 0.05). The association was attenuated after adjustment for WHtR: HR = 0.84 (0.65-1.07, P = 0.16). Conclusion: Participation in RE at midlife is associated with a 22% lower risk of incident HFpEF. To inform public health and clinical guidelines, further studies are needed to clarify the role of RE in HFpEF prevention.

Introduction: Abnormal sleep has been linked to increased dementia risk, but the pathophysiological processes driving this connection are unclear. To provide insight into the biological pathways underlying the relationship between sleep and brain health, we tested the hypothesis that increased obstructive sleep apnea (OSA) severity and shorter habitual sleep duration are associated with a higher burden of Alzheimer’s disease (AD) pathology, neurodegeneration, and neuroinflammation measured through plasma biomarkers. Methods: ARIC participants who took part in the Sleep Heart Health Study at Visit 4 (1996-98) with stored plasma samples at Visit 3 (1993-95) and Visit 5 (2011-13) were examined (n=261; mean age 61.3 years; 43.3% male). OSA severity, categorized based on the number of apneas and hypopneas per hour of sleep (<5 events/hour [Normal], 5 to <15 events/hour [Mild OSA], or ≥15 events/hour [Moderate/Severe OSA]) was assessed via in-home polysomnography, and average habitual sleep duration (<7 hours, 7 to <8 hours, or ≥8 hours) was self-reported. Plasma biomarkers of amyloid beta (Aβ) 42 and 40, phosphorylated Tau 181 (p-Tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using Quanterix Simoa immunoassays. Covariate-adjusted linear regression models estimated associations of sleep indices in 1996-98 with standardized plasma biomarker measurements in 1993-95 (3 years earlier) and in 2011-13 (15 years later). Covariate-adjusted linear mixed effects models quantified associations of sleep measures with the 5-year rates of change in standardized biomarker levels (1993-2013). Results: Compared to a habitual sleep duration of 8 hours or more, sleeping less than 7 hours per night was associated with higher NfL, a biomarker of neurodegeneration, 15 years later (β = 0.252; 95% confidence interval [CI]: 0.003, 0.501). Sleep indices were not associated with biomarker levels 3 years earlier. Counter to our hypothesis, Moderate/Severe OSA was associated with slower increases in p-Tau181 (β = -0.102; 95% CI: -0.198, -0.006), a biomarker of AD pathology, over a median of 17.9 years. Conclusions: Short habitual sleep duration may impact dementia outcomes through neurodegenerative and other processes rather than through pathways specific to AD pathology or neuroinflammation. Longitudinal studies with sleep measurements in larger, more diverse samples are needed to further distinguish the pathways linking sleep to dementia.

Introduction: Plasma biomarkers of Alzheimer’s disease (AD), including amyloid-β (Aβ42/Aβ40), phosphorylated tau (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) have shown strong reliability in predicting dementia risk. White matter hyperintensities (WMH) represent a major vascular contributor to dementia. We investigated how plasma biomarkers of AD interact with WMH on MRI to influence incident dementia risk. Methods: We included dementia-free participants from the Atherosclerosis Risk in Communities (ARIC) Study who underwent MRI and plasma biomarker assessment at Visit 5 (2011–2013). WMH was quantified and considered continuously (log-transformed and standardized), and in tertiles. Plasma biomarkers were log-base-2-transformed. Cox proportional hazards models were used to estimate dementia risk over 10 years associated with plasma biomarkers and WMH, independently and multiplicatively. Models were adjusted for demographic variables (age, sex, race, and education), vascular risk factors (hypertension, diabetes, smoking status, body mass index, and estimated glomerular filtration rate), and APOE ε4 status. Results: Among 1,538 participants (aged 67- 90 years, 29% Black), 30% ( N = 462) developed dementia over the 10-year follow-up period. For every doubling of plasma Aβ42/Aβ40 , indicating lower amyloid burden, dementia risk decreased, while doubling of p-tau 181 , NfL, and GFAP were each associated with increased dementia risk, in separate models; each of these associations was independent of WMH (Table 1). Additionally, dementia risk increased per SD increase in WMH, independent of each plasma biomarker. Although no multiplicative interaction terms reached statistical significance (p<0.05), there was suggestive evidence that Aβ42/Aβ40 and GFAP have smaller effect sizes on dementia risk in subgroups at the highest WMH tertile (p-interactions<0.10; see Table 2). Discussion: Plasma biomarkers and WMH independently predict dementia risk over 10 years, though there remained limited evidence of multiplicative effects. Plasma biomarkers may be less important for dementia risk in individuals who also have extensive WMH. These findings emphasize the importance of incorporating both AD-specific plasma markers as well as indicators of cerebral small vessel disease, such as WMH, into dementia risk profiling.

Background: Periodontitis is a potential modifiable factor influencing dementia risk. We examined whether improving periodontal health via regular flossing is associated with lower dementia risk. Methods: A total of 9,766 Atherosclerosis Risk in Communities (ARIC) study participants with teeth were followed from visit 4 (1996-1998) through 2021. Cox proportional hazards regression was used to estimate associations between regular dental flossing (≥1/week) and incident dementia. Covariates included age, race, gender, hypertension, diabetes, alcohol use, smoking status, obesity, physical activity, education level, income, insurance status, brushing frequency, regular dental care use and apolipoprotein E4 (APOE4) allele status . Cumulative incidence functions were estimated using death as a competing event. Results: Participants had mean age 62.6 years (SD = 5.6), 56% female, 79% white, 21% black, 63% reported regular flossing and 29.2% participants carry at least one APOE4 allele. The cumulative incidence of dementia was 52.6 % overall over 25 years. Regular flossing was independently and significantly associated with a lower hazard of developing dementia (HR = 0.90, 95% CI: 0.82–0.98, p = 0.02) after adjustment for all the covariates. In contrast, tooth brushing frequency (p=0.55) and regular dental care visit (p=0.22) were not significantly associated with dementia risk. By 25 years of follow-up, the cumulative incidence of dementia was 50% among flossers compared with 57% among non-flossers (Gray’s test p<0.0001, Figure). This translated to an Absolute Risk Reduction of 7%, Relative Risk Reduction of 12%, Number Needed to Floss 14. Conclusion: Flossing, but not tooth brushing or regular dental care, is independently associated with a reduced hazard of incident dementia. Dental flossing may be an additional strategy to reduce dementia risk. For every 14 individuals who floss ≥1/week, one fewer person will develop dementia.