Trajectories in depressive symptoms and midlife brain health.

Depressive symptoms may either be a risk factor or prodromal to dementia. Investigating this association in midlife may help clarify the role of depression in cognitive aging. We aimed to identify trajectories in depressive symptoms in early to mid-life and related cognitive and brain outcomes in midlife. This study includes 3944 Black and White participants (ages 26-45 years at baseline) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with 20 years of follow-up. Depressive symptoms were assessed using the Center for Epidemiological Studies Depression scale at five time points over 20 years. Growth mixture modeling (GMM) was used to identify depressive symptom trajectories. Participants completed a neuropsychological battery 20 years after baseline, including the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment (MoCA), and category and letter fluency tests. A sub-sample of participants (n = 662) underwent brain magnetic resonance imaging (MRI) to characterize gray matter volumes and white matter hyperintensities (WMHs). We identified four classes of depressive symptom trajectories: a "declining" class (n = 286, 7.3%) with initially high symptoms and subsequent decline, a class with consistently high symptoms ("steady high"; n = 264, 6.7%), a class with late increases in symptoms ("increasing"; n = 277, 7%), and a class with consistently low symptoms ("steady low"; n = 3117, 79.0%). The steady high and the increasing classes had poorer performance on all cognitive tests, while the declining class had poorer performance on the DSST, verbal fluency, and MoCA. Compared to the steady low symptom class, the steady high class had lower volumes in the entorhinal cortex (ß: -180.80, 95% CI: -336.69 to -24.91) and the amygdala (ß: -40.97, 95% CI: -74.09 to -7.85), the increasing class had more WMHs (ß: 0.55, 95% CI: 0.22 to 0.89), and the declining class was not significantly different in any brain measures. Trajectories in depressive symptoms in young to mid-adulthood show distinct cognitive and brain phenotypes in midlife. Steady high depressive symptoms may represent a group that is at risk for dementia, whereas increasing symptoms in midlife may be associated with white matter damage.

Dementia Risk and Disadvantaged Neighborhoods.

Importance: Residence in a disadvantaged neighborhood may be associated with an increased risk for cognitive impairment and dementia but is understudied in nationally representative populations. Objective: To investigate the association between the Area Deprivation Index (ADI) and dementia. Design, Setting, and Participants: Retrospective cohort study within the US Veterans Health Administration from October 1, 1999, to September 30, 2021, with a national cohort of older veterans receiving care in the largest integrated health care system in the United States. For each fiscal year, a 5% random sample was selected from all patients (n = 2 398 659). Patients with missing ADI information (n = 492 721) or missing sex information (n = 6) and prevalent dementia cases (n = 25 379) were excluded. Participants had to have at least 1 follow-up visit (n = 1 662 863). The final analytic sample was 1 637 484. Exposure: Neighborhoods were characterized with the ADI, which combines several sociodemographic indicators (eg, income, education, employment, and housing) into a census block group-level index of disadvantage. Participants were categorized into ADI rank quintiles by their census block group of residence (higher ADI rank quintile corresponds with more deprivation). Main Outcome and Measures: Time to dementia diagnosis (using International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes) was estimated with Cox proportional hazards models with age as the time scale, and the sensitivity of the findings was evaluated with Fine-Gray proportional hazards models, accounting for competing risk of death. Results: Among the 1 637 484 Veterans Health Administration patients, the mean (SD) age was 68.6 (7.7) years, and 1 604 677 (98.0%) were men. A total of 7318 patients were Asian (0.4%), 151 818 (9.3%) were Black, 10 591 were Hispanic (0.6%), 1 422 713 (86.9%) were White, and 45 044 (2.8%) were of other or unknown race and ethnicity. During a mean (SD) follow-up of 11.0 (4.8) years, 12.8% of veterans developed dementia. Compared with veterans in the least disadvantaged neighborhood quintile, those in greater disadvantage groups had an increased risk of dementia in models adjusted for sex, race and ethnicity, and psychiatric and medical comorbid conditions (first quintile = reference; second quintile adjusted hazard ratio [HR], 1.09 [95% CI, 1.07-1.10]; third quintile adjusted HR, 1.14 [95% CI, 1.12-1.15]; fourth quintile adjusted HR, 1.16 [95% CI, 1.14-1.18]; and fifth quintile adjusted HR, 1.22 [95% CI, 1.21-1.24]). Repeating the main analysis using competing risk for mortality led to similar results. Conclusions and Relevance: Results of this study suggest that residence within more disadvantaged neighborhoods was associated with higher risk of dementia among older veterans integrated in a national health care system.

Association Between Sensory Impairment and Dementia: The Roles of Social Network and Leisure Activity.

BACKGROUND: Evidence suggests that sensory impairment is linked to dementia; however, the role of social network and leisure activity in this relationship is unclear. OBJECTIVE: Examine the association of hearing and visual impairment with dementia, and whether a rich social network and leisure activity moderates this association. METHODS: Dementia-free older adults from the Swedish National Study on Aging and Care in Kungsholmen (n = 2,579) were followed up for up for a median of 10 years (interquartile range = 6). Visual impairment was assessed with a reading acuity test, and hearing impairment was ascertained via self-report and medical records. Dementia was diagnosed following international criteria. Data on social network and leisure activity was collected via self-report. Hazard ratios (HRs) of dementia risk were derived from Cox regression models. RESULTS: Dual impairment, but not single impairment in hearing and vision was associated with a higher risk of dementia (HR: 1.62, 95% CI: 1.16 to 2.27). Compared to participants with no sensory impairment and a moderate-to-rich social network, those with dual impairment and low social network or leisure activity had higher dementia risk (HR: 2.08, 95% CI: 1.43 to 3.22; HR: 2.08, 95% CI: 1.43 to 3.22, respectively), whereas participants with dual impairment with a moderate-to-rich social network or leisure activity did not have significantly higher dementia risk (HR; 1.42, 95% CI: 0.87 to 2.33; HR; 1.42, 95% CI: 0.87 to 2.33, respectively). CONCLUSION: A richer social network and participation in stimulating activities may mitigate the higher dementia risk in older adults with dual impairment in vision and hearing.

Long-term depressive symptoms and midlife brain age.

BACKGROUND: Evidence suggests that depression may be a risk factor for dementia in older adults, but the link between depressive symptoms and brain health earlier in life is less understood. Our aim was to investigate the association between long-term depressive symptoms in young to mid-adulthood and a measure of brain age derived from structural MRI. METHODS: From the Coronary Artery Risk Development in Young Adults study, we identified 649 participants (age 23-36 at baseline) with brain MRI and cognitive testing. Long-term depressive symptoms were measured with the Center for Epidemiological Studies Depression scale (CESD) six times across 25 years and analyzed as time-weighted averages (TWA). Brain age was derived using previously validated high dimensional neuroimaging pattern analysis, quantifying individual differences in age-related atrophy. Elevated depressive symptoms were defined as CES-D ≥16. Linear regression was used to test the association between TWA depressive symptoms, brain aging, and cognition. RESULTS: Each standard deviation (5-points) increment in TWA depression symptoms over 25 years was associated with one-year greater brain age (ß: 1.14, 95 % confidence interval [CI]: 0.57 to 1.71). Participants with elevated TWA depressive symptoms had on average a 3-year greater brain age (ß: 2.75, 95 % CI: 0.43 to 5.08). Moreover, elevated depressive symptoms were associated with higher odds of poor cognitive function in midlife (OR: 3.30, 95 % CI: 1.37 to 7.97). LIMITATIONS: Brain age was assessed at one time, limiting our ability to evaluate the temporality of depressive symptoms and brain aging. CONCLUSIONS: Elevated depressive symptoms in early adulthood may have implications for brain health as early as in midlife.

Epidemiology and Risk Factors for Dementia.

In this article, the authors discuss primarily what is known about the epidemiology of all-cause dementia. Dementia is caused by a complex interplay of genetics, comorbidities, and lifestyle factors, and drug development has been challenging. However, evidence from large, prospective, observational studies has identified a variety of factors that may prevent or delay the onset of dementia. Several of these factors are modifiable and lend themselves to well to treatments currently available. The authors discuss the state of current evidence on dementia risk factors, the most promising avenues, and future directions for dementia prevention and management.

The Metabolic Syndrome Is Associated With Lower Cognitive Performance and Reduced White Matter Integrity in Midlife: The CARDIA Study.

Background: Cardiovascular disease risk factors play a critical role in brain aging. The metabolic syndrome (MetS), a constellation of cardiovascular risk factors, has been associated with poorer cognition in old age; however, it is unclear if it is connected to brain health earlier in life. Methods: We investigated the association of MetS (n = 534, 18.5%) vs. no MetS (n = 2,346, 81.5%) with cognition in midlife within the prospective study, Coronary Artery Risk Development in Young Adults (CARDIA). At midlife (mean age 50), MetS was defined using National Cholesterol Education Program guidelines. At the 5-year follow-up, a cognitive battery was administered including tests of processing speed (Digit Symbol Substitution Test, DSST), executive function (the Stroop Test), verbal memory (Rey Auditory Verbal Learning Test, RAVLT), verbal fluency (category and letter fluency), and global cognitive function (Montreal Cognitive Assessment, MoCA). A sub-sample (n = 453) underwent brain MRI. Results: Participants with MetS had worse performance on tests of verbal fluency, processing speed, executive function, and verbal memory (p < 0.05), but not on global cognition. MetS was also associated with lower frontal, parietal, temporal, and total white matter integrity (p < 0.05), as assessed with fractional anisotropy. Conclusions: MetS is associated with lower cognition and microstructural brain alterations already at midlife, suggesting that MetS should be targeted earlier in life in order to prevent adverse brain and cognitive outcomes.

Elevated blood pressure is associated with advanced brain aging in mid-life: A 30-year follow-up of The CARDIA Study.

BACKGROUND: High blood pressure (BP) is a risk factor for late-life brain health; however, the association of elevated BP with brain health in mid-life is unclear. METHODS: We identified 661 participants from the Coronary Artery Risk Development in Young Adults Study (age 18-30 at baseline) with 30 years of follow-up and brain magnetic resonance imaging at year 30. Cumulative exposure of BP was estimated by time-weighted averages (TWA). Ideal cardiovascular health was defined as systolic BP < 120 mm Hg, diastolic BP < 80 mm Hg. Brain age was calculated using previously validated high dimensional machine learning pattern analyses. RESULTS: Every 5 mmHg increment in TWA systolic BP was associated with approximately 1-year greater brain age (95% confidence interval [CI]: 0.50-1.36) Participants with TWA systolic or diastolic BP over the recommended guidelines for ideal cardiovascular health, had on average 3-year greater brain age (95% CI: 1.00-4.67; 95% CI: 1.45-5.13, respectively). CONCLUSION: Elevated BP from early to mid adulthood, even below clinical cut-offs, is associated with advanced brain aging in mid-life.

Loneliness, Not Social Support, Is Associated with Cognitive Decline and Dementia Across Two Longitudinal Population-Based Cohorts.

BACKGROUND: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health. OBJECTIVE: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association. METHODS: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71±7SD years) followed up to 14 years (median 10.8, interquartile range 7.4-11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72±10SD years) followed up to 10 years (mean 5.9±1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) ≥26 for RS and ≥25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor). RESULTS: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95%CI 1.08-1.67; SNAC-K: HR 2.16, 95%CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk. CONCLUSION: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms.

Joint trajectories of episodic memory and odor identification in older adults: patterns and predictors.

Emerging evidence suggests that olfactory function is closely linked to memory function. The aims of this study were to assess whether olfactory and episodic memory functions follow similar age-related decline trajectories, to identify different patterns of decline, as well as predictors of the patterns. 1023 participants from the Memory and Aging Project were followed for up to 8 years with annual episodic memory and odor identification assessments. Trajectories were modelled using growth mixture models. Multivariate logistic regression was used to identify pattern predictors. Three patterns of joint trajectories were identified; Class 1- stable average performance in both functions (n=690, 67.4%); Class 2- stable average episodic memory and declining odor identification (n=231, 22.6%); and Class 3- decline in both functions (n= 102, 10.0%). Class predictors included age, sex, APOE ε4 status, cognitive activity level and BMI. Participants in Class 3 were most likely to develop dementia. Episodic memory and olfactory function show similar trajectories in aging. Such classification can contribute to a better understanding of the factors related to cognitive decline and dementia.

Shared risk and protective factors between Alzheimer's disease and ischemic stroke: A population-based longitudinal study.

INTRODUCTION: Stroke, especially ischemic stroke's (IS) link with Alzheimer's disease (AD) remains unclear. METHODS: This prospective cohort study included 2459 AD- and cerebrovascular disease-free older adults at baseline (mean age 71.9 ± 10.3 years, Stockholm, Sweden). Using Cox regressions, shared risk factors (SRFs) and shared protective factors (SPFs) between AD and IS were recognized when their hazard ratios in both AD and IS models were significant and in the same direction. RESULTS: During the follow-up period of up to 15 years, 132 AD and 260 IS mutually exclusive cases were identified. SRFs were low education, sedentary lifestyle, and heart diseases. High levels of psychological well-being, actively engaging in leisure activities, and a rich social network were SPFs. Having ≥1 SPF reduced 47% of AD and 28% of IS risk among people with a low risk profile (<2 SRFs), and 38% of AD and 31% of IS risk with a high risk profile (≥2 SRFs). In total, 57.8% of AD/IS cases could be prevented if individuals have ≥1 SPF and no SRF. DISCUSSION: AD and IS share risk/protective profiles, and SPFs seem to counteract the adverse effects of SRFs on both AD and IS.

The relation of poor mastication with cognition and dementia risk: a population-based longitudinal study.

We investigated the effect of poor masticatory ability on cognitive trajectories and dementia risk in older adults. 544 cognitively intact adults aged ≥50 were followed for up to 22 years. Cognitive domains (verbal, spatial/fluid, memory, and perceptual speed) were assessed at baseline and follow-ups. Dementia was ascertained according to standard criteria. Masticatory ability was assessed using the Eichner Index and categorized according to the number of posterior occlusal zones: A (all four), B (3-1), and C (none).At baseline, 147 (27.0%) participants were in Eichner category A, 169 (31.1%) in B and 228 (41.9%) in C. After the age of 65, participants in Eichner category B and C showed an accelerated decline in spatial/fluid abilities (ß: -0.16, 95% CI: -0.30 to -0.03) and (ß: -0.15, 95% CI: -0.28 to -0.02), respectively. Over the follow-up, 52 incident dementia cases were identified. Eichner categories B or C were not associated with an increased risk of dementia, compared to category A (Hazard Ratio [HR]: 0.83, 95% CI: 0.39 to 1.76 and HR: 0.63, 95% CI: 0.30 to 1.29, respectively).Poor masticatory ability is associated with an accelerated cognitive decline in fluid/spatial abilities, however it was not related to a higher risk of dementia.

Associations Between Cardiovascular Risk, Structural Brain Changes, and Cognitive Decline.

BACKGROUND: The impact of cardiovascular risk burden on cognitive trajectories and brain structure changes remains unclear. OBJECTIVES: This study aimed to examine whether cardiovascular risk burden assessed by the Framingham General Cardiovascular Risk Score (FGCRS) is associated with cognitive decline and structural brain differences. METHODS: Within the Rush Memory and Aging Project, 1,588 dementia-free participants (mean age: 79.5 years) were followed for up to 21 years. FGCRS was assessed at baseline and categorized into tertiles (lowest, middle, and highest). Episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with a battery of 19 tests, from which composite scores were derived. A subsample (n = 378) of participants underwent magnetic resonance imaging. Structural total and regional brain volumes were estimated. Data were analyzed using linear mixed-effects models and linear regression models. RESULTS: In all participants, FGCRS ranged from 4 to 28 (mean score: 15.6 ± 3.7). Compared with the lowest tertile of FGCRS, the highest tertile was associated with faster decline in global cognition (ß = -0.019; 95% confidence interval [CI]: -0.035 to -0.003), episodic memory (ß = -0.023; 95% CI: -0.041 to -0.004), working memory (ß = -0.021; 95% CI: -0.035 to -0.007), and perceptual speed (ß = -0.027; 95% CI: -0.042 to -0.011) over the follow-up. In magnetic resonance imaging data analyses, higher FGCRS was related to smaller volumes of the hippocampus (ß = -0.021; 95% CI: -0.042 to -0.000), gray matter (ß = -1.569; 95% CI: -2.757 to -0.382), and total brain (ß = -1.588; 95% CI: -2.832 to -0.344), and greater volume of white matter hyperintensities (ß = 0.035; 95% CI: 0.001 to 0.069). CONCLUSIONS: Higher cardiovascular risk burden may predict decline in episodic memory, working memory, and perceptual speed and is associated with neurodegeneration and vascular lesions in the brain.

Impaired olfaction is associated with cognitive decline and neurodegeneration in the brain.

OBJECTIVE: We aimed to examine whether impaired olfaction is associated with cognitive decline and indicators of neurodegeneration in the brain of dementia-free older adults. METHODS: Within the Rush Memory and Aging Project, 380 dementia-free participants (mean age = 78 years) were followed for up to 15 years, and underwent MRI scans. Olfactory function was assessed using the Brief Smell Identification Test (B-SIT) at baseline, and categorized as anosmia (B-SIT <6), hyposmia (B-SIT 6-10 in men and 6-10.25 in women), and normal (B-SIT 10.25-12 in men and 10.5-12 in women). Cognitive function was annually assessed with a battery of 21 tests, from which composite scores were derived. Structural total and regional brain volumes were estimated. Data were analyzed using linear regression and mixed-effects models. RESULTS: At study entry, 138 (36.3%) had normal olfactory function, 213 (56.1%) had hyposmia, and 29 (7.6%) had anosmia. In multiadjusted mixed-effects models, hyposmia (ß = -0.03, 95% confidence interval [CI] -0.05 to -0.02) and anosmia (ß = -0.13, 95% CI -0.16 to -0.09) were associated with faster rate of cognitive decline compared to normal olfaction. On MRI, impaired olfaction (hyposmia or anosmia) was related to smaller volumes of the hippocampus (ß = -0.19, 95% CI -0.33 to -0.05), and in the entorhinal (ß = -0.16, 95% CI -0.24 to -0.08), fusiform (ß = -0.45, 95% CI -0.78 to -0.14), and middle temporal (ß = -0.38, 95% CI -0.72 to -0.01) cortices. CONCLUSION: Impaired olfaction predicts faster cognitive decline and might indicate neurodegeneration in the brain among dementia-free older adults.

Tooth loss is associated with accelerated cognitive decline and volumetric brain differences: a population-based study.

Tooth loss has been related to cognitive impairment; however, its relation to structural brain differences in humans is unknown. Dementia-free participants (n = 2715) of age ≥60 years were followed up for up to 9 years. A subsample (n = 394) underwent magnetic resonance imaging at baseline. Information on tooth loss was collected at baseline, and cognitive function was assessed using the Mini-Mental State Examination at baseline and at follow-ups. Data were analyzed using linear mixed effects models and linear regression models. At baseline, 404 (14.9%) participants had partial tooth loss, and 206 (7.6%) had complete tooth loss. Tooth loss was significantly associated with a steeper cognitive decline (ß: -0.18, 95% confidence interval [CI]: -0.24 to -0.11) and remained significant after adjusting for or stratifying by potential confounders. In cross-sectional analyses, persons with complete or partial tooth loss had significantly lower total brain volume (ß: -28.89, 95% CI: -49.33 to -8.45) and gray matter volume (ß: -22.60, 95% CI: -38.26 to -6.94). Thus, tooth loss may be a risk factor for accelerated cognitive aging.