Incident Dementia Cases Research Articles

Longitudinal Changes in Peak Expiratory Flow Predict Risk for Incident Dementia.

Impaired respiratory function, measured via peak expiratory flow (PEF), has been associated with increased dementia risk. However, much of the current literature uses cross-sectional measures of PEF, whereas longitudinal relationships between changes in respiratory function and dementia risk are underexplored. Using 10 years of data (2011-2021) from 2,439 adults ages 65 and older in the National Health and Aging Trends Study (NHATS), we examined whether 5-year changes in PEF (2011-2016) were associated with risk for incident dementia over the subsequent 5-year period (2017-2021). PEF slopes for each participant were estimated using linear mixed-effects models and then grouped into quartiles: rapid, moderate, mild, and no declines. Discrete-time Cox proportional hazards models were used to estimate the risk for incident dementia by PEF slope category, while controlling for several health and sociodemographic characteristics. After excluding dementia cases during the exposure window (2011-2016), we identified 338 cases of incident dementia (13.9%) between 2017-2021. Rapid PEF declines between 2011-2016 were associated with 85% higher risk for incident dementia between 2017-2021 compared to those with no declines in PEF (HR=1.85; 95% CI [1.24, 2.76]). Results were robust to several sensitivity analyses. These findings demonstrate that declines in PEF may precede declines in cognition, suggesting that respiratory function may be an important dementia risk factor in older adults. Additionally, these findings highlight the utility of measuring PEF via a peak flow meter, which is a simple and inexpensive measure of respiratory function.

Sex-specific dementia risk in known or suspected obstructive sleep apnea: A 10-year longitudinal population-based study

Abstract Study Objective To evaluate sex-specific associations between known or suspected OSA and dementia risk over 10-years among older women and men. Methods This study included 18,815 women and men age 50+ years (dementia-free at baseline) who participated in the Health and Retirement Study (HRS), a nationally representative cohort of US adults. Presence of OSA was defined by self-reported diagnosis or key HRS items that correspond to elements of a validated OSA screening tool (STOP-Bang). Incident dementia cases were identified using a validated, HRS-based algorithm derived from objective cognitive assessments. Survey-weighted regression models based on pseudo-values were utilized to estimate sex- and age-specific differences in cumulative incidence of dementia by OSA status. Results Data from 18,815 adults were analyzed, of which 9% of women and 8% of men (weighted proportions) met criteria for incident dementia. Known/suspected OSA was more prevalent in men than in women (weighted proportions 68% vs. 31%). Unadjusted sex-stratified analyses showed that known/suspected OSA was associated with higher cumulative incidence of dementia across ages 60–84 years for women and men. By age 80, relative to adults without known/suspected OSA, the cumulative incidence of dementia was 4.7% higher (CI 2.8%,6.7%) for women with known/suspected OSA, and 2.5% (CI 0.5%,4.5%) for men with known/suspected OSA, respectively. Adjusted associations between age-specific OSA and cumulative incidence of dementia attenuated for both women and men but remained statistically significant. Discussion OSA contributes to dementia risk in older adults, particularly women. This study illuminates the impact of a potentially modifiable yet frequently overlooked risk factor for dementia onset.

Psychosocial Health and the Association Between Cerebral Small Vessel Disease Markers With Dementia: The ARIC Study.

Associations between magnetic resonance imaging markers of cerebral small vessel disease (CSVD) and dementia risk in older adults have been established, but it remains unclear how lifestyle factors, including psychosocial health, may modify this association. Social support and social isolation were assessed among participants of the community-based ARIC (Atherosclerosis Risk in Communities) Study, via self-reported questionnaires (1990-1992). Following categorization of both factors, participants were classified as having strong or poor mid-life social relationships. At visit 5 (2011-2013), participants underwent 3T brain magnetic resonance imaging quantifying CSVD measures: white matter hyperintensity volume, microbleeds (subcortical), infarcts (lacunar), and white matter integrity (diffusion tensor imaging). Incident dementia cases were identified from the time of imaging through December 31, 2020 with ongoing surveillance. Associations between CSVD magnetic resonance imaging markers and incident dementia were evaluated using Cox proportional-hazard regressions adjusted for demographic and additional risk factors (from visit 2). Effect modification by mid-life social relationships was evaluated. Of the 1977 participants with magnetic resonance imaging, 1617 participants (60.7% women; 26.5% Black participants; mean age at visit 2, 55.4 years) were examined. In this sample, mid-life social relationships significantly modified the association between white matter hyperintensity volume and dementia risk (P interaction=0.001). Greater white matter hyperintensity volume was significantly associated with risk of dementia in all participants, yet, more substantially in those with poor (hazard ratio, 1.84 [95% CI, 1.49-2.27]) versus strong (hazard ratio, 1.26 [95% CI, 1.08-1.47]) mid-life social relationships. Although not statistically significant, subcortical microbleeds in participants with poor mid-life social relationships were associated with a greater risk of dementia, relative to those with strong social relationships, in whom subcortical microbleeds were no longer associated with elevated dementia risk. The elevated risk of dementia associated with CSVD may be reduced in participants with strong mid-life social relationships. Future studies evaluating psychosocial health through the life course and the mechanisms by which they modify the relationship between CSVD and dementia are needed.

Low Intake of Total Antioxidant Nutrients as a Risk Factor for Incident Dementia in Older Adults: The Shanghai Aging Study

Introduction: Previous longitudinal studies reported the impact of antioxidant nutrients (ANs) on cognitive impairment in the older population, but the conclusions were inconsistent. This study aimed to verify the hypothesis that dietary intake of total AN was associated with incident dementia among older individuals. Methods: Community residents without dementia aged ≥60 years were prospectively followed up for an average of 5.2 years in the Shanghai Aging Study. At baseline, daily intakes of total dietary AN (the sum of carotene, vitamin C, vitamin E, lutein, and flavonoids) and energy were calculated based on an interviewer-administered food frequency questionnaire measuring the dietary intake over the past 1 year for each participant. A battery of neuropsychological tests was used to evaluate cognitive function, and a consensus diagnosis of dementia was made according to the DSM-IV criteria at baseline and follow-up. Results: Among 1,550 dementia-free participants, 135 (8.7%) incident dementia cases were identified during the average of 5.2 years of follow-up. Participants with low AN intake (<112 mg/day) had a significantly higher risk of incident dementia than those with high AN intake (≥112 mg/day) (hazard ratio 1.87, 95% confidence interval 1.26–2.77) after adjusting for age, gender, education, obesity, APOE-ε4, hypertension, diabetes, depression, baseline Mini-Mental State Examination score, and total energy intake. The significant association of total AN intake with incident dementia was only found in individuals ≥70 years. Conclusion: Low total AN intake may be a risk factor for incident dementia among older adults. Maintaining sufficient AN intake may be beneficial against age-related cognitive decline.

Association of birthweight and risk of incident dementia: a prospective cohort study.

Given the epidemiological studies investigating the relationship between birthweight and dementia are limited. Our study aimed to explore the association between birthweight and the risk of dementia, cognitive function, and brain structure. We included 275,648 participants from the UK Biobank, categorizing birthweight into quartiles (Q1 ≤ 2.95 kg; Q2 > 2.95 kg, ≤ 3.32 kg; Q3 > 3.32 kg, ≤ 3.66 kg; Q4 > 3.66 kg), with Q3 as the reference. Cox regression models and restricted cubic splines estimated the relationship between birthweight and the risk of all causes of dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VD). Multivariable linear regression models assessed the relationship between birthweight, cognitive function, and MRI biomarkers. Over a median follow-up of 13.0 years, 3103 incident dementia cases were recorded. In the fully adjusted model, compared to Q3 (> 3.32 kg, ≤ 3.66 kg), lower birthweight in Q1 (≤ 2.95 kg) was significantly associated with increased risk of ACD (HR = 1.18, 95%CI 1.06-1.30, P = 0.001) and VD (HR = 1.32, 95%CI 1.07-1.62, P = 0.010), but no significant association with AD was found. Continuous birthweight showed a U-shaped nonlinear association with dementia. Lower birthweight was associated with worse performance in cognitive tasks, including reaction time, fluid intelligence, numeric, and prospective memory. Additionally, certain brain structure indices were identified, including brain atrophy and reductions in area, thickness, and volume of regional subcortical areas. Our study emphasizes the association between lower birthweight and increased dementia risk, correlating cognitive function and MRI biomarkers of brain structure, suggesting that in utero or early-life exposures might impact cognitive health in adulthood.

Exposure to source-specific air pollution in residential areas and its association with dementia incidence: a cohort study in Northern Sweden

The aim of this study was to investigate the relationship between source-specific ambient particulate air pollution concentrations and the incidence of dementia. The study encompassed 70,057 participants from the Västerbotten intervention program cohort in Northern Sweden with a median age of 40 years at baseline. High-resolution dispersion models were employed to estimate source-specific particulate matter (PM) concentrations, such as PM10 and PM2.5 from traffic, exhaust, and biomass (mainly wood) burning, at the residential addresses of each participant. Cox regression models, adjusted for potential confounding factors, were used for the assessment. Over 884,847 person-years of follow-up, 409 incident dementia cases, identified through national registers, were observed. The study population’s average exposure to annual mean total PM10 and PM2.5 lag 1–5 years was 9.50 µg/m3 and 5.61 µg/m3, respectively. Increased risks were identified for PM10-Traffic (35% [95% CI 0–82%]) and PM2.5-Exhaust (33% [95% CI − 2 to 79%]) in the second exposure tertile for lag 1–5 years, although no such risks were observed in the third tertile. Interestingly, a negative association was observed between PM2.5-Wood burning and the risk of dementia. In summary, this register-based study did not conclusively establish a strong association between air pollution exposure and the incidence of dementia. While some evidence indicated elevated risks for PM10-Traffic and PM2.5-Exhaust, and conversely, a negative association for PM2.5-Wood burning, no clear exposure–response relationships were evident.

The role of dementia in the association between APOE4 and all-cause mortality: pooled analyses of two population-based cohort studies

The ε4 allele of the apolipoprotein E gene (APOE4) plays a role in neurodegeneration and in cardiovascular disease, but findings on its association with mortality are inconsistent. We aimed to examine the association between APOE4 and mortality, and the role of dementia in this association. In this pooled analysis, data on White participants aged 45-90 years who underwent APOE genotyping were drawn from two population-based cohorts: the Whitehall II study (UK), which began in 1985 and is ongoing, and the Three-City study (France), initiated in 1999 and ended in 2012. In the Three-City study, vital status was ascertained through linkage to the national registry of death Institut National de la Statistique des Études économiques, and dementia was ascertained via a neuropsychological evaluation and validation of diagnoses by an independent committee of neurologists and geriatricians. In the Whitehall II study, vital status was ascertained through linkage to the UK national mortality register, and dementia cases were ascertained by linkage to three national registers. Participants with prevalent dementia at baseline and participants missing an APOE genotype were excluded from analyses. Cox regression proportional hazard models were used to examine the association of APOE4 with all-cause, cardiovascular, and cancer mortality. The role of dementia in the association between APOE4 status and mortality was examined by excluding participants who developed dementia during follow-up from the analyses. An illness-death model was then used to examine the role of incident dementia in these associations. 14 091 participants (8492 from the Three-City study and 5599 from the Whitehall II study; 6668 [47%] of participants were women and 7423 [53%] were men), with a median follow-up of 15·4 years (IQR 10·6-21·2), were included in the analyses. Of these participants, APOE4 carriers (3264 [23%] of the cohort carried at least one ε4 allele) had a higher risk of all-cause mortality compared with non-carriers, with hazard ratios (HR) of 1·16 (95% CI 1·07-1·26) for heterozygotes and 1·59 (1·24-2·06) for homozygotes. Compared with APOE3 homozygotes, higher cardiovascular mortality was observed in APOE4 carriers, with a HR of 1·23 (1·01-1·50) for heterozygotes, and no association was found between APOE4 and cancer mortality. Excluding cases of incident dementia over the follow-up resulted in attenuated associations with mortality in homozygotes but not in heterozygotes. The illness-death model indicated that the higher mortality risk in APOE4 carriers was not solely attributable to dementia. We found a robust association between APOE4 and all-cause and cardiovascular mortality but not cancer mortality. Dementia explained a significant proportion of the association with all-cause mortality for APOE4 homozygotes, while non-dementia factors, such as cardiovascular disease mortality, are likely to play a role in shaping mortality outcomes in APOE4 heterozygotes. National Institutes of Health. For the French translation of the abstract see Supplementary Materials section.

Systemic inflammation, lifestyle behaviours and dementia: A 10-year follow-up investigation

ObjectivesLifestyle behaviours have been linked to dementia incidence, but their cumulative impact on dementia and the underlying mechanisms remain poorly understood. This study investigated the association of co-occurring lifestyle behaviours with dementia incidence and the mediating role of systemic inflammation in this association. MethodsThe sample comprised 3131 participants (55.2% female) from the English Longitudinal Study of Ageing aged 52–92 years at baseline (2008/09). Self-reported baseline lifestyle behaviours (alcohol intake, fruit and vegetable consumption, smoking, physical activity, sleep duration, social engagement, and cognitive activity) were summed to derive an index of lifestyle behaviours, ranging from 0 to 7, with higher scores denoting a higher number of health-risk behaviours. Incident dementia cases (n = 130, 4.2%) were identified through doctor-diagnosed dementia, informant interviews, and health records between 2014/15 and 2018/19. Systemic inflammation was measured through fasting plasma concentrations of C-reactive protein in 2012/13. ResultsBinary logistic regression models indicated that the odds of subsequent dementia increased by 1.19 for each additional health-risk behaviour (95% confidence intervals: 1.04, 1.37, p = 0.014) after adjusting for age, sex, ethnicity, wealth, education, marital status, body mass index, coronary heart disease, hypertension, stroke, and depression. However, this association was not mediated by C-reactive protein. ConclusionsCo-occurring health-risk behaviours were associated with higher dementia incidence up to 10 years later, underscoring the importance of modifying health-risk behaviours for the prevention of dementia. Systemic inflammation did not explain the association between behaviours and dementia.

Social relationships, amyloid burden, and dementia: The ARIC-PET study.

This study aimed to assess whether social relationships in mid-life reduce the risk of dementia related to amyloid burden. Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990-1992). A composite measure, "social relationships," was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012-2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid-life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models. Among 310 participants without dementia, strong mid-life social relationships were associated independently with lower dementia risk. Elevated late-life brain amyloid was associated with greater dementia risk. Although mid-life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia.

Abstract P329: Lifetime Risk of Dementia: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Prior studies suggest that 15-20% of adults will develop dementia after midlife. However, current lifetime risk estimates are based on limited dementia ascertainment, potentially resulting in underestimation. Methods: We conducted a prospective cohort analysis using data from the Atherosclerosis Risk in Communities Study (ARIC) (baseline 1990-1992). We used non-parametric cumulative incidence function estimation to calculate lifetime risk of dementia while accounting for the competing risk of death, overall and stratified by demographics and APOE ε 4 status. Dementia was ascertained until December 31, 2019 by: (1) cognitive testing at study visits, with diagnoses generated using a standardized computer algorithm and confirmed by a panel of experts; (2) semiannual telephone cognitive testing and Clinical Dementia Rating interviews with informants; and (3) ICD codes from hospital records and death certificates. Results: We included 13,358 participants (mean age: 57 years; 25% of Black race; 55% female sex; 31% carried at least one APOE ε 4 allele). Over a median follow-up of 24 (IQR: 20, 29) years, there were 2,812 incident cases of dementia. At age 55, the lifetime risk of dementia (up to age 95) was 43% (Fig A) . Adults with two copies of the APOE ε 4 allele had substantially higher lifetime risk (61%) of dementia compared to those with one copy (48%) and those none (40%), with differences beginning at age ~70 years (Fig B) . Lifetime risk was higher in women and Black adults (Fig C-D) . Conclusion: More than 4 in 10 adults will develop dementia after midlife. Comprehensive capture of dementia in the ARIC study results in lifetime risk estimate substantially exceeding prior research.

Seasonal Variations in Vitamin D Levels and the Incident Dementia Among Older Adults Aged ≥60 Years in the UK Biobank.

Limited knowledge exists regarding the association between dementia incidence and vitamin D insufficiency/deficiency across seasons. This study aimed to evaluate the impact of seasonal serum vitamin D (25(OH)D) levels on dementia and its subtypes, considering potential modifiers. We analyzed 193,003 individuals aged 60-73 at baseline (2006-2010) from the UK Biobank cohort, with follow-up until 2018. 25(OH)D were measured at baseline, and incident dementia cases were identified through hospital records, death certificates, and self-reports. Out of 1,874 documented all-cause dementia cases, the median follow-up duration was 8.9 years. Linear and nonlinear associations between 25(OH)D and dementia incidence across seasons were observed. In multivariable-adjusted analysis, 25(OH)D deficiency was associated with a 1.5-fold (95% CIs: 1.2-2.0), 2.2-fold (1.5-3.0), 2.0-fold (1.5-2.7), and 1.7-fold (1.3-2.3) increased incidence of all-cause dementia in spring, summer, autumn, and winter, respectively. Adjusting for seasonal variations, 25(OH)D insufficiency and deficiency were associated with a 1.3-fold (1.1-1.4) and 1.8-fold (1.6-2.2) increased dementia incidence, respectively. This association remained significant across subgroups, including baseline age, gender, and education levels. Furthermore, 25(OH)D deficiency was associated with a 1.4-fold (1.1-1.8) and 1.5-fold (1.1-2.0) higher incidence of Alzheimer's disease and vascular dementia, respectively. These associations remained significant across all subgroups. 25(OH)D deficiency is associated with an increased incidence of dementia and its subtypes throughout the year.

Role of cardiovascular health factors in mediating social inequalities in the incidence of dementia in the UK: two prospective, population-based cohort studies

The contribution of modifiable risk factors to social inequalities in dementia, observed in longitudinal studies, remains unclear. We aimed to quantify the role of cardiovascular health factors, assessed using Life's Essential 8 (LE8) score, in mediating social inequalities in incidence of dementia and, for comparison, in incidence of stroke, coronary heart disease, and mortality. In this prospective, population-based cohort study, we collected data from the UK Whitehall II Study and UK Biobank databases. Participants were included if data were available on SEP, outcomes and LE8 (smoking, physical activity, diet, body mass index, blood pressure, fasting blood glucose, lipid levels, sleep duration). The primary outcome was incident dementia and secondary outcomes were stroke, coronary heart disease, and mortality. Outcomes were derived from electronic healthcare records. Socioeconomic position (SEP) was measured by occupation in Whitehall II and education in UK Biobank. Counterfactual mediation analysis was used to quantify the extent to which LE8 score explained the associations of SEP with all outcomes. Analyses involved Cox regression, accelerated failure time models, and linear regression; and were adjusted for age, sex, and ethnicity. Between 10.09.1985 and 29.03.1988, a total of 9688 participants (mean age±SD 44.9±6.0; 67% men) from the Whitehall II study, and between 19.12.2006 and 01.10.2010, 278,215 participants (mean age±SD 56.0±8.1; 47% men) from the UK Biobank were included. There were 606 and 4649 incident dementia cases over a median (interquartile range) follow-up of 31.7 (31.1-32.7) and 13.5 (12.7-14.1) years respectively in Whitehall II and UK Biobank. In Whitehall II, the hazard ratio was 1.85 [95% CI 1.42, 2.32] for the total effect of SEP on dementia and 1.20 [1.12, 1.28] for the indirect effect via the LE8, the proportion mediated being 36%. In UK Biobank, the total effect of SEP on dementia was 1.65 [1.54, 1.78]; the indirect effect was 1.11 [1.09, 1.12], and the proportion mediated was 24%. The proportions mediated for stroke, coronary heart disease, and mortality were higher, ranging between 34% and 63% in Whitehall II and between 36% and 50% in UK Biobank. In two well-characterised cohort studies, up to one third of the social inequalities in incidence of dementia was attributable to cardiovascular health factors. Promotion of cardiovascular health in midlife may contribute to reducing social inequalities in risk of dementia, in addition to cardiovascular diseases and all-cause mortality. This study used adult measures of SEP, further research is warranted using lifecourse measures of SEP. NIH (RF1AG062553).

Microvascular burden and long-term risk of stroke and dementia in type 2 diabetes mellitus

ObjectiveTo examine the associations between microvascular disease (MVD) and risk of stroke, dementia, and their major subtypes among individuals with type 2 diabetes mellitus (T2DM). MethodsWe included 26,173 participants with T2DM from the UK Biobank who had no known stroke or dementia at baseline. MVD burden was reflected by the presence of retinopathy, peripheral neuropathy, and chronic kidney disease. Cox regression models were used to estimate hazard ratios (HRs) and 95 % confidential intervals (CIs) of stroke and dementia associated with overall MVD burden and individual MVD. ResultsDuring a median follow-up of 11.5 years, 1103 incident stroke (964 ischemic and 269 hemorrhagic stroke) and 813 incident dementia (312 Alzheimer's disease and 304 vascular dementia) cases were identified. The risk of stroke, dementia, and their major subtypes all increased with an increasing number of MVD (all P-trend <0.001). The adjusted HRs (95 % CIs) comparing three with no MVD were 5.03 (3.16, 8.02) for all stroke, 4.57 (2.75, 7.59) for ischemic stroke, and 6.60 (2.65, 16.43) for hemorrhagic stroke. The corresponding estimates were 4.28 (2.33, 7.86) for all-cause dementia, 6.96 (3.02, 16.01) for Alzheimer's disease, and 3.81 (1.40, 10.42) for vascular dementia. Among the three MVD, chronic kidney disease showed the strongest associations with both stroke subtypes, while peripheral neuropathy was most strongly associated with both dementia subtypes. ConclusionsRisk of stroke, dementia, and their major subtypes increased with an increasing number of MVD. The associations of individual MVD with stroke and dementia varied substantially by types of MVD.

Prospective cohort study evaluating the association between influenza vaccination and neurodegenerative diseases

The effect of influenza vaccination (FluVac) on the risk of neurodegenerative diseases has not been well evaluated in prospective populations. We aimed to assess the association between FluVac and the risk of dementia and Parkinson’s disease (PD) in people aged 60 years or older through a prospective population-based cohort from the UK Biobank. A time-varying Cox regression model adjusted for baseline and repeatedly measured covariates was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the association between influenza vaccination and risk of dementia/PD. We took into account 70,938 participants in the cohort, including 38,328 participants who got vaccinated. During a median follow-up period of 12.2 years, 2087 incident dementia cases occurred, including 281 cases who received FluVac and 1806 cases who were not vaccinated. In addition, 742 incident PD cases occurred, among whom 131 cases received FluVac and 611 PD cases did not receive FluVac. FluVac was associated with reduced dementia risk with an HR of 0.83 (95% CI, 0.72–0.95) but was not associated with PD incidence (HR = 1.07; 95% CI, 0.87–1.32) after controlling baseline and repeatedly measured covariates. Further, among all dementia cases, there were 733 Alzheimer’s disease (AD) (94 vaccinated cases and 639 non-vaccinated cases), 307 vascular dementia (VD) (34 vaccinated cases and 273 non-vaccinated cases), and 1047 cases with other dementias (OD) (153 vaccinated cases and 894 non-vaccinated cases). The HRs for the associations between FluVac and AD, VD, and OD were 0.79 (95% CI, 0.63–1.00), 0.58 (95% CI, 0.39–0.86), and 0.94 (95% CI, 0.78–1.14) respectively. A dose-response relationship was found in the association between FluVac and dementia but not in the association with PD. A major limitation of the study is the low accuracy in the diagnosis of dementia subtypes, namely AD, VD, and OD. However, Results of sensitivity analyses were consistent with the primary analyses. In conclusion, influenza vaccination is significantly associated with a reduced risk of incident dementia but not PD in community-dwelling adults in the UK Biobank population.

Abstract WMP13: The Modifying Effects of Psychosocial Health on the Association Between Cerebrovascular Health and Dementia Risk: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study

Introduction: Associations between magnetic resonance imaging (MRI) markers of vascular pathology and dementia risk in older adults have been established, but it remains less clear how lifestyle factors may modify this association. We hypothesized that a weaker association between MRI markers of vascular pathology and incident dementia will be present among older adults with strong as compared to poor psychosocial health in mid-life. Methods: Social support and social isolation were assessed among ARIC participants, aged 46 - 68, via self-reported questionnaires (1990 - 1992). Following categorization of both factors, participants were classified as having strong or poor mid-life psychosocial health. From 2011 - 2013, 1977 participants, aged 67 - 90, underwent 3T brain MRI quantifying white matter hyperintensity (WMH) volume, subcortical cerebral microbleeds (sCMB), infarcts, and white matter integrity through diffusion tensor imaging. Incident dementia cases were identified from time of imaging through December 31, 2019 (median follow-up: 6.4 years) with ongoing surveillance. Relative contributions of psychosocial health and MRI markers to incident dementia were evaluated with demographic and vascular risk factor-adjusted Cox-proportional hazard regression models. Results: Among 1612 dementia-free participants with measures of psychosocial health, MRI markers were associated with dementia risk in the hypothesized direction. Mid-life psychosocial health significantly modified the associations between sCMB and WMH, each, with incident dementia risk (Table 1; greater risk of dementia shown in individuals with poor psychosocial health). Conclusions: The elevated risk of dementia associated with sCMB and WMH is reduced in participants with strong psychosocial health in mid-life. Future studies evaluating social factors through the life course and the mechanisms by which they modify the relationship between pathology and dementia are needed.

Association of the Sleep Regularity Index With Incident Dementia and Brain Volume.

Irregular sleep may increase the risk of cardiometabolic conditions, but its association with incident dementia is unclear. The aim of this study was to assess the association between sleep regularity, that is, the day-to-day consistency in sleep-wake patterns and the risk of incident dementia and related brain MRI endophenotypes. We used Cox proportional hazard models to investigate the relationships between sleep regularity and incident dementia in 88,094 UK Biobank participants. The sleep regularity index (SRI) was calculated as the probability of being in the same state (asleep/awake) at any 2 time points 24 hours apart, averaged over 7 days of accelerometry. The mean age of the sample was 62 years (SD = 8), 56% were women, and the median SRI was 60 (SD = 10). There were 480 cases of incident dementia over a median 7.2 years of follow-up. Following adjustments for demographic, clinical, and genetic confounders (APOE ε4), there was a nonlinear association between the SRI and dementia hazard (p [global test of spline term] < 0.001) with hazard ratios (HRs) following a U-shape pattern. HRs, relative to the median SRI, were 1.53 (95% CI 1.24-1.89) for participants with SRI at the 5th percentile (SRI = 41) and 1.16 (95% CI 0.89-1.50) for those with SRI at the 95th percentile (SRI = 71). In a subset with brain MRI (n = 15,263), gray matter and hippocampal volume tended to be lowest at the extremes of the SRI. Sleep regularity displayed a U-shaped association with risk of incident dementia. Irregular sleep may represent a novel dementia risk factor.

Association between Helicobacter pylori infection and incident risk of dementia: The AMI cohort.

Chronic infectious diseases are increasingly being considered as potential contributors to dementia risk. Among those infections, Helicobacter pylori, the main cause of chronic gastritis worldwide, has been suggested. As the prevalence of H. pylori infection has decreased, the main objective of this work was to reconsider the association between H. pylori infection and the risk of incident dementia, including Alzheimer's disease. Prospective cohort of 689 older (≥65 years) agricultural workers from Southwest France. Descriptive and comparative analyses were performed according to H. pylori status determined by serology at baseline. The risk of incident dementia according to H. pylori status over a 7-year follow-up was explored by survival analyses: Kaplan-Meier curve and Cox proportional hazards models. Two-hundred (29.0%) participants were H. pylori-positive at baseline. Compared to H. pylori-negative participants, they showed worse cognitive performances at baseline. Eighty-five incident dementia cases were diagnosed during the follow-up period. After adjustment for age, sex, education, apolipoprotein ε4, and several cardiovascular risk factors, H. pylori remained associated with an increased risk of dementia (HR 1.70, 95% CI, 1.05-2.74). The risk was stronger for Alzheimer's disease (HR 2.85, 95% CI, 1.58-5.12). Despite an observed decrease in H. pylori infection prevalence, this study provides evidence for the association between H. pylori infection and dementia. These results should encourage further research on the mechanisms underlying the contribution of infectious diseases to pathological brain aging, especially the influence of gut inflammation on the brain.

Hearing Loss, Hearing Aid Use, and Risk of Dementia in Older Adults

Hearing loss has been suggested as a risk factor for dementia, but there is still a need for high-quality research to better understand the association between these 2 conditions and the underlying causal mechanisms and treatment benefits using larger cohorts and detailed data. To investigate the association between hearing loss and incident dementia, as well as how hearing aid use contributes to this association. This population-based cohort study was conducted in Southern Denmark between January 2003 and December 2017 and included all residents 50 years and older. We excluded all persons with dementia before baseline as well as those who did not live in the region 5 years before baseline, with incomplete address history, or who had missing covariate information. Individual hearing status based on the Hearing Examinations in Southern Denmark database, which contains data on all pure-tone audiometry examinations performed at public hearing rehabilitation clinics in Southern Denmark. Incident cases of dementia and Alzheimer disease as identified from national registries. The study population comprised 573 088 persons (298 006 women [52%]; mean [SD] age, 60.8 [11.3] years) with 23 023 cases of dementia and mean (SD) follow-up of 8.6 (4.3) years. Having a hearing loss was associated with an increased risk of dementia, with an adjusted hazard ratio (HR) of 1.07 (95% CI, 1.04-1.11) compared with having no hearing loss. Severe hearing loss in the better and worse ear was associated with a higher dementia risk, with an HR of 1.20 (95% CI, 1.09-1.32) and 1.13 (95% CI, 1.06-1.20), respectively, compared with having no hearing loss in the corresponding ear. Compared with people without hearing loss, the risk of dementia was higher among people with hearing loss who were not using hearing aids than those who had hearing loss and were using hearing aids, with HRs of 1.20 (95% CI, 1.13-1.27) and 1.06 (95% CI, 1.01-1.10), respectively. The results of this cohort study suggest that hearing loss was associated with increased dementia risk, especially among people not using hearing aids, suggesting that hearing aids might prevent or delay the onset and progression of dementia. The risk estimates were lower than in previous studies, highlighting the need for more high-quality longitudinal studies.

Identifying individuals at high risk for dementia in primary care: Development and validation of the DemRisk risk prediction model using routinely collected patient data.

Health policy in the UK and globally regarding dementia, emphasises prevention and risk reduction. These goals could be facilitated by automated assessment of dementia risk in primary care using routinely collected patient data. However, existing applicable tools are weak at identifying patients at high risk for dementia. We set out to develop improved risk prediction models deployable in primary care. Electronic health records (EHRs) for patients aged 60-89 from 393 English general practices were extracted from the Clinical Practice Research Datalink (CPRD) GOLD database. 235 and 158 practices respectively were randomly assigned to development and validation cohorts. Separate dementia risk models were developed for patients aged 60-79 (development cohort n = 616,366; validation cohort n = 419,126) and 80-89 (n = 175,131 and n = 118,717). The outcome was incident dementia within 5 years and more than 60 evidence-based risk factors were evaluated. Risk models were developed and validated using multivariable Cox regression. The age 60-79 development cohort included 10,841 incident cases of dementia (6.3 per 1,000 person-years) and the age 80-89 development cohort included 15,994 (40.2 per 1,000 person-years). Discrimination and calibration for the resulting age 60-79 model were good (Harrell's C 0.78 (95% CI: 0.78 to 0.79); Royston's D 1.74 (1.70 to 1.78); calibration slope 0.98 (0.96 to 1.01)), with 37% of patients in the top 1% of risk scores receiving a dementia diagnosis within 5 years. Fit statistics were lower for the age 80-89 model but dementia incidence was higher and 79% of those in the top 1% of risk scores subsequently developed dementia. Our models can identify individuals at higher risk of dementia using routinely collected information from their primary care record, and outperform an existing EHR-based tool. Discriminative ability was greatest for those aged 60-79, but the model for those aged 80-89 may also be clinical useful.

TRAJECTORIES OF DEPRESSIVE SYMPTOMS BEFORE THE ONSET OF DEMENTIA: EXAMINING RACIAL/ETHNIC DISPARITIES

Abstract Biological and cognitive changes can often be detected up to 16 years prior to a formal diagnosis of Alzheimer’s disease (AD). Psychological symptoms of AD (e.g., depression) may also start to develop during this prodromal phase. Depressive symptoms may be an early marker of neurodegeneration and/or a reaction to early cognitive decline. Higher levels of depressive symptoms could create additional burdens for individuals with preclinical AD and their families. Unfortunately, little is known about the trajectory of depression during the preclinical phase of AD. Using the Langa-Weir method for algorithmic classification, a sample of incident dementia cases (n=2168) was identified from longitudinal data from the Health and Retirement Study (2000-2018). Depressive symptoms were measured with eight dichotomous items from the Center for Epidemiologic Studies Depression (CES-D). Latent growth curve models estimated the trajectory of depressive symptoms over up to 10 waves prior to dementia classification, and disparities across racial/ethnic groups were examined. Results show that depressive symptoms increased slightly over time throughout the preclinical phase of AD, following a quadratic trajectory. Older Hispanic adults reported consistently higher levels of depressive symptoms across timepoints, followed by older non-Hispanic Black and older non-Hispanic White adults. These findings highlight the importance of examining the psychological changes occurring during the preclinical phase of dementia for understanding the disease progression of AD and racial/ethnic disparities in psychological burden. The implications of using algorithmic dementia classifications in studying cognitive race/ethnic disparities will also be discussed.