APOE Effects on Late Life Cognitive Trajectories in Diverse Racial/Ethnic Groups.

OBJECTIVE: This study evaluated: (1) apolipoprotein E (APOE) ϵ4 prevalence among Black, Latino, and White older adults, (2) associations of APOE ϵ4 status with baseline level and change over time of cognitive outcomes across groups, and (3) combined impact of APOE ϵ4 prevalence and magnitude of effect on cognitive decline within each racial/ethnic group. METHOD: Participants included 297 White, 138 Latino, and 149 Black individuals from the longitudinal UC Davis Diversity Cohort who had APOE genotyping and ≥2 cognitive assessments. Magnitude of associations of ϵ4 with cognitive baseline and change across racial/ethnic groups was tested with multilevel parallel process longitudinal analyses and multiple group models. RESULTS: ϵ4 prevalence in Black (46%) and White participants (46%) was almost double that of Latino participants (24%). ϵ4 was associated with poorer baseline episodic memory only in White participants (p = .001), but had a moderately strong association with episodic memory change across all racial/ethnic groups (Blacks= -.061 SD/year, Latinos = -.055,Whites= -.055). ϵ4 association with semantic memory change was strongest in White participants (-.071), intermediate in Latino participants (-.041), and weakest in Black participants (-.022). CONCLUSION: Calculated cognitive trajectories across racial/ethnic groups were influenced in an additive manner by ϵ4 prevalence and strength of association with cognitive decline within the group. Group differences in ϵ4 prevalences and associations of ϵ4 with cognition may suggest different pathways from APOE to cognitive decline, and, AD possibly having less salient impact on cognitive decline in non-White participants. Differential effects of APOE on episodic memory and non-memory cognition have important implications for understanding how APOE influences late life cognitive decline.

Effects of early-life environment and adulthood SES on cognitive change in a multiethnic cohort.

OBJECTIVES: Early-life socioeconomic status (SES) and adversity are associated with late-life cognition and risk of dementia. We examined the association between early-life SES and adversity and late-life cross-sectional cognitive outcomes as well as global cognitive decline, hypothesizing that adulthood SES would mediate these associations. METHODS: Our sample (N = 837) was a racially and ethnically diverse cohort of non-Hispanic/Latino White (48%), Black (27%), and Hispanic/Latino (19%) participants from Northern California. Participant addresses were geocoded to the level of the census tract, and US Census Tract 2010 variables (e.g., percent with high school diploma) were extracted and combined to create a neighborhood SES composite. We used multilevel latent variable models to estimate early-life (e.g., parental education, whether participant ever went hungry) and adult (participant's education, main occupation) SES factors and their associations with cross-sectional and longitudinal cognitive outcomes of episodic memory, semantic memory, executive function, and spatial ability. RESULTS: Child and adult factors were strongly related to domain-specific cognitive intercepts (0.20-0.48 SD per SD of SES factor); in contrast, SES factors were not related to global cognitive change (0.001-0.01 SD per year per SD of SES factor). Adulthood SES mediated a large percentage (68-75%) of the total early-life effect on cognition. CONCLUSIONS: Early-life sociocontextual factors are more strongly associated with cross-sectional late-life cognitive performance compared to cognitive change; this effect is largely mediated through associations with adulthood SES.

The Measurement of Everyday Cognition (ECog): Revisions and Updates.

INTRODUCTION: The Everyday Cognition scale (ECog), a measure of everyday functioning developed in 2008, is sensitive to early detection and progression of neurodegenerative disease. The goal was to update ECog item content to ensure relevancy to contemporary older adults from diverse backgrounds. METHODS: Participants included 44 culturally diverse older adults (18 with normal cognition, 11 with mild cognitive impairment) and their study partners. Item understandability and relevance was evaluated using iterative interviewing methods that were analyzed using standard qualitative methods. On the basis of this information, items were modified, deleted, or developed as needed. RESULTS: Of the 39 original items, 19 were revised, 3 new items were added (primarily to cover contemporary activities such as the use of technology), and 1 was deleted. The revised version (ECog-II) includes 41 items. DISCUSSION: To ensure strong psychometric properties, and to facilitate harmonization of previously collected data, we preserved well over half of the items. Future work will validate the revised ECog by measuring associations with neuropsychological performance, external measures of disease, and other functional measures. Overall, the revised ECog will continue to be a useful tool for measuring cognitively relevant everyday abilities in clinical settings and intervention clinical trials.

Stressors in Midlife and Risk of Dementia: The Role of Race and Education.

BACKGROUND: Posttraumatic stress disorder is associated with increased dementia risk but less is known about stress because of everyday problems in diverse populations. METHODS: A total of 9605 health care plan members who provided information regarding midlife stressors in 1972 to 1973 (ages, 40 to 55 y) were followed for dementia diagnosis between 1996 and 2017. Cox proportional hazard models evaluated associations between midlife stressors and dementia adjusting for demographics and lifecourse health indicators. RESULTS: Reporting at least 1 midlife stressor was associated with 17% greater dementia risk [hazard ratio (HR), 1.17; 95% confidence interval (CI),1.07-1.27] versus 0 midlife stressors and 26% increased risk among those with less than equal to high school education (HR, 1.26; 95% CI,1.09-1.44) adjusting for demographics. Compared with whites without stressors, whites with ≥1 stressor had 13% greater dementia risk (HR, 1.13; 95% CI, 1.02-1.24), blacks without stressors 19% greater risk (HR, 1.19; 95% CI,1.08-1.32), and blacks with ≥1 stressors 47% greater risk (HR, 1.47; 95% CI,1.27-1.69) in fully adjusted models. Resource problems were associated with 20% greater risk (HR, 1.20; 95% CI, 1.01-1.42) than interpersonal problems. CONCLUSION: Reporting ≥1 serious midlife stressor was associated with elevated dementia risk, especially stressors related to resources problems and for those with less than equal to high school education. Everyday stressors can impact brain health over the long term and may contribute to racial inequities in dementia rates, though education can be a mitigating factor.

Deficits in Everyday Function Differ in AD and FTD.

Alzheimer disease (AD) and frontotemporal dementia (FTD) are 2 neurodegenerative diseases with differing cognitive and neuropathologic profiles. Although both diseases ultimately result in functional disability, differences in the profiles of everyday functioning between the 2 groups have not been well characterized. The present study examines potential differences in the types of everyday functional limitations present in these 2 dementias. The present study compared individuals with AD (N=240) or FTD (N=13). The Everyday Cognition (ECog) scale was used to measure distinct domains of everyday cognition: everyday memory, everyday language, everyday visuospatial ability, and a variety of everyday executive abilities. A total ECog score was used to represent global disability level. The groups showed equivalent levels of global disability. However, AD group exhibited worse Everyday Memory and Everyday Visuospatial abilities than the FTD group. Contrary to expectation, FTD was not more impaired in everyday executive abilities. Results remained similar when accounting for severity of cognitive impairment or disease duration. Findings suggest that a somewhat different pattern of everyday functional difficulties can be seen across dementia types.

Perceptions of greenspace and social determinants of health across the life course: The Life Course Sociodemographics and Neighborhood Questionnaire (LSNEQ).

We developed the Life Course Sociodemographics and Neighborhood Questionnaire (LSNEQ) to query older adults about perceived neighborhood greenspaces across the life course (i.e., distance to park, number of neighborhood parks/playgrounds, and neighborhood greenness) and about characteristics hypothesized to confound or moderate/mediate greenspace-health associations. Six perceived life course indices are derived from the LSNEQ: neighborhood socioeconomic status, neighborhood walking/biking, urbanicity, neighborhood amenities, neighborhood park access, and neighborhood greenness. Older adults from St. Louis, Missouri, and Sacramento, California, completed the LSNEQ in 2020-2021. The indices demonstrated borderline acceptable to good internal consistency (alpha = 0.60-0.79) and good to excellent test-retest reliability (ICC = 0.71-0.96) and detected different patterns of park access and neighborhood greenness by racialized group and location. Individuals with index scores indicating more neighborhood walking/biking and greater presence of neighborhood amenities over their life course were more likely to report neighborhood-based walking in older age. Overall, the LSNEQ is a reliable instrument to assess perceptions of life course social determinants of health including neighborhood greenspaces.

High-Density Lipoprotein Changes in Alzheimer's Disease Are APOE Genotype-Specific.

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer's disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer's disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer's disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer's disease and an association between HDL function, size, and cognitive function.

Assessment of cognition in early dementia.

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

Depression in epilepsy is associated with lack of seizure control.

Depression is common in patients with epilepsy and the strongest predictor of poor quality of life. Few studies have assessed the association of uncontrolled seizures with depression. We used the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), a validated six-item self-report questionnaire, to assess the relationship between depression, seizure control, and antiepileptic drug (AED) and antidepressant drug usage. Two hundred ninety-eight patients were studied. Twenty percent of patients with any epileptic seizures over a 6-month period had NDDI-E scores >15, consistent with major depression. Higher NDDI-E scores were associated with higher seizure frequency (P<0.0002). The prevalence ratio of NDDI-E scores >15 in patients with no seizures versus any seizure in the past 6 months was 0.48 (95% CI = 0.26-0.88). Higher NDDI-E scores were associated with the number of AEDs taken (P = 0.0023). Major depression is associated with uncontrolled seizures, with a prevalence double that of patients whose seizures are controlled.

Association of vascular brain injury, neurodegeneration, amyloid, and cognitive trajectory.

OBJECTIVE: To determine whether vascular and neurodegenerative factors influence cognition before clinically relevant Alzheimer disease pathology, we analyzed MRI measures and amyloid imaging in an ethnoracially diverse cohort of cognitively normal individuals older than 60 years. METHODS: Participants (n = 154; mean age 74.15 ± 6.94; 50% female; 54% Caucasian, 22.1% Hispanic, 14.9% African American) were recruited from the University of California, Davis Alzheimer's Disease Research Center, who were cognitively normal at baseline, time of PET, and MRI, and received yearly cognitive assessment for 6.23 ± 4.16 years. Mixed model regression with random slope and intercept was calculated for episodic memory and executive function, adjusting for age, sex, education, and ethnicity. RESULTS: Vascular burden score was associated with total white matter hyperintensity (WMH) volume (ß, 0.171; 95% confidence interval [CI], 0.024-0.318). WMH volume was associated with low baseline executive function (-0.115; -0.226 to -0.003) and rate of change in memory (-0.029; -0.045 to -0.012). Hippocampal volume was associated with the rate of change in memory (0.040; 0.021-0.059) and executive function (0.024; 0.008-0.039). Continuous measures of amyloid status influenced change in memory (-0.026; -0.044 to -0.008) and executive function (-0.033; -0.046 to -0.021) independently of MRI measures. CONCLUSION: Vascular brain injury and neurodegeneration are associated with baseline cognitive performance and the rate of longitudinal change independent of amyloid status among community-dwelling, ethnicity diverse cognitively normal individuals, supporting the role of vascular diseases as risk factors for later-life dementia.

Cerebral white matter free water: A sensitive biomarker of cognition and function.

OBJECTIVE: To determine whether free water (FW) content, initially developed to correct metrics derived from diffusion tensor imaging and recently found to be strongly associated with vascular risk factors, may constitute a sensitive biomarker of white matter (WM) microstructural differences associated with cognitive performance but remains unknown. METHODS: Five hundred thirty-six cognitively diverse individuals, aged 77 ± 8 years, received yearly comprehensive clinical evaluations and a baseline MRI examination of whom 224 underwent follow-up MRI. WM microstructural measures, including FW, fractional anisotropy, and mean diffusivity corrected for FW and WM hyperintensity burden were computed within WM voxels of each individual. Baseline and change in MRI metrics were then used as independent variables to explain baseline and change in episodic memory (EM), executive function (EF), and Clinical Dementia Rating (CDR) scores using linear, logistic, and Cox proportional-hazards regressions. RESULTS: Higher baseline FW and WM hyperintensity were associated with lower baseline EM and EF, higher baseline CDR, accelerated EF and EM decline, and higher probability to transition to a more severe CDR stage (p values <0.01). Annual change in FW was also found to be associated with concomitant change in cognitive and functional performance (p values <0.01). CONCLUSIONS: This study finds cross-sectional and longitudinal associations between FW content and trajectory of cognitive and functional performance in a large sample of cognitively diverse individuals. It supports the need to investigate the pathophysiologic process that manifests increased FW, potentially leading to more severe WM territory injury and promoting cognitive and functional decline.

Neuropathological Diagnoses of Demented Hispanic, Black, and Non-Hispanic White Decedents Seen at an Alzheimer's Disease Center.

Our nation is becoming increasingly diverse; however, few autopsy studies examine multiple ethnoracial groups, especially Hispanics. We examined differences in neuropathological diagnoses of 423 deceased participants with dementia from three ethnoracial groups (35 Black, 28 Hispanic, and 360 non-Hispanic White) evaluated at the University of California Davis Alzheimer's Disease Center. We used novel applications of bootstrap resampling and logistic regression standardization to project neuropathological diagnostic rates for non-Hispanic Whites to minority sample characteristics to improve inference of findings. Alzheimer's disease (AD) without significant cerebrovascular disease (CVD) or other dementia-related pathologies (AD (non-mixed)) was present in 15 Black (43%), 4 Hispanic (14%), and 156 (43%) non-Hispanic Whites. CVD sufficient to contribute to dementia was confirmed in 14 Black (40%), 15 Hispanic (54%), and 101 (28%) non-Hispanic White decedents. The observed CVD prevalence of 40% in Blacks exceeded the predicted 29% [95% CI: 22%-36%]. Despite being outside the 95% confidence interval, the difference between observed and predicted was not statistically significant after bootstrap testing. Conversely, for Hispanics, the observed proportion at 54% exceeded significantly the predicted prevalence of 24% from non-Hispanic Whites [95% CI: 16%-34%], avg. p = 0.008). An identical analysis using AD (non-mixed) as the outcome predicted AD (non-mixed) in Blacks averaging 41% [95% CI: 34%-48%], nearly equal to observed prevalence. For Hispanics, however, the observed proportion at 14%, was well below predictions (mean = 42%, 95% CI: 32%-53%], avg. p = 0.008). We conclude mixed diagnoses and CVD are more common in Hispanic and Black decedents than Non-Hispanic Whites with dementia in our cohort. The increased prevalence of vascular co-morbidity may be a potential opportunity to intervene more effectively in dementia treatment of those individuals.

The Brain Health Assessment for Detecting and Diagnosing Neurocognitive Disorders.

BACKGROUND/OBJECTIVES: Brief cognitive screens lack the sensitivity to detect mild cognitive impairment (MCI) or support differential diagnoses. The objective of this study was to validate the 10-minute, tablet-based University of California, San Francisco (UCSF) Brain Health Assessment (BHA) to overcome these limitations. DESIGN: Cross-sectional. SETTING: UCSF Memory and Aging Center. PARTICIPANTS: Older adults (N = 347) (neurologically healthy controls (n = 185), and individuals diagnosed with MCI (n = 99), dementia (n = 42), and as normal with concerns (n = 21)). MEASUREMENTS: The BHA includes subtests of memory, executive function and speed, visuospatial skills, and language and an optional informant survey. Participants completed the Montreal Cognitive Assessment (MoCA) and criterion-standard neuropsychological tests. Standardized structural 3T brain magnetic resonance imaging was performed in 145 participants. RESULTS: At a fixed 85% specificity rate, the BHA had 100% sensitivity to dementia and 84% to MCI; the MoCA had 75% sensitivity to dementia and 25% to MCI. The BHA had 83% sensitivity to MCI likely due to AD and 88% to MCI unlikely due to AD, and the MoCA had 58% sensitivity to MCI likely AD and 24% to MCI unlikely AD. The BHA subtests demonstrated moderate to high correlations with the criterion-standard tests from their respective cognitive domains. Memory test performance correlated with medial temporal lobe volumes; executive and speed with frontal, parietal, and basal ganglia volumes; and visuospatial with right parietal volumes. CONCLUSION: The BHA had excellent combined sensitivity and specificity to detect dementia and MCI, including MCI due to diverse etiologies. The subtests provide efficient, valid measures of neurocognition that are critical in making a differential diagnosis.

Early life development in a multiethnic sample and the relation to late life cognition.

OBJECTIVES: Poor quality of early life conditions has been associated with poorer late life cognition and increased risk of dementia. Early life physical development can be captured using adult measures of height and head circumference. Availability of resources may be reflected by socioeconomic indicators, such as parental education and family size. We sought to determine the association between early life development and experience and late life semantic memory, episodic memory, and executive functioning abilities, as well as rate of cognitive decline. METHOD: This study was conducted using the UC Davis Aging Diversity cohort, an ethnically diverse sample of Caucasian, African American, and Hispanic individuals from northern California. We used latent variable modeling to measure growth and childhood socioeconomic environment (SES) and examine their associations with longitudinal cognitive outcomes using mixed effects modeling. RESULTS: Growth was positively related to higher childhood SES. Higher childhood SES was associated with better semantic memory. Both low growth and low SES were associated with increased rate of cognitive decline. DISCUSSION: These findings demonstrate that early life experiences influence the trajectory of cognitive aging. Early life development and experience appears to provide a distal basis upon which additional risk and protective factors interact in the development of dementia.

AD pathology and cerebral infarctions are associated with memory and executive functioning one and five years before death.

We provide rigorous psychometric evidence for distinct patterns of cognitive impairment for Alzheimer's disease (AD) and cerebral infarctions using 440 participants from the Religious Order Study. Latent variable models were used to decompose the effects of AD pathology and cerebral infarctions assessed at autopsy on overall cognition and specific neuropsychological tests at one and five years prior to death. Results support clinical and univariate psychometric analyses that memory impairment is more pronounced in AD, and executive impairment is more pronounced in the presence of cerebral infarctions. These specific effects are subtle relative to the stronger associations of both AD neuropathology and cerebral infarctions with overall levels of cognitive impairment.

MCI is associated with deficits in everyday functioning.

The purpose of the present study was to examine the types of impairments in everyday function that accompany mild cognitive impairment (MCI). Data for this study was collected from 434 individuals consecutively evaluated at a university-based Alzheimer's Center. A total of 96 participants were diagnosed with MCI, 105 were cognitively normal, and 233 had dementia. Informant ratings of participants' abilities were obtained across different functional domains reflecting everyday abilities related to memory, language, visual spatial abilities, planning, organization, and divided attention. As expected, the demented group was significantly more impaired than the healthy control and MCI groups across all of the functional domains. The MCI group also showed significantly more functional impairment relative to healthy controls in all of the functional domains. Examination of the effect sizes as a measure of the magnitude of functional impairment in the MCI groups relative to controls showed that the greatest degree of impairment occurred within the Everyday Memory domain. The current findings suggest that individuals with MCI demonstrate deficits in a wide range of everyday functions but that the magnitude of these changes is greatest for those functional abilities that rely heavily on memory.

Psychogenic nonepileptic seizures are associated with an increased risk of obesity.

Psychogenic nonepileptic seizures (NES) are somatic manifestations of psychological distress. There is some evidence that weight problems are more common in patients with psychiatric illness. We have observed that patients admitted for video-EEG monitoring who we diagnosed with NES commonly have a larger body habitus than patients with epilepsy. The goal of this study was to test our hypothesis that there was a significant difference in body mass index (BMI) in patients with nonepileptic seizures compared with their epileptic counterparts. We compared the BMIs of 46 NES patients and 46 age- and gender-matched epileptic controls and found that the NES patients had significantly higher BMIs (30.5 vs 26.1, P=0.006) than controls. This remained true after controlling for weight-gain properties of antiepileptic drugs. These results are compared with the prevalence of overweight and obesity in the general population. Possible explanations of the findings and limitations of the study are discussed.