Considerations for Use of Blood-Based Biomarkers in Epidemiologic Dementia Research.

Dementia represents a growing public health burden with large social, racial, and ethnic disparities. The etiology of dementia is poorly understood, and the lack of robust biomarkers in diverse, population-representative samples is a barrier to moving dementia research forward. Existing biomarkers and other measures of pathology-derived from neuropathology, neuroimaging, and cerebrospinal fluid samples-are commonly collected from predominantly White and highly educated samples drawn from academic medical centers in urban settings. Blood-based biomarkers are noninvasive and less expensive, offering promise to expand our understanding of the pathophysiology of dementia, including in participants from historically excluded groups. Although largely not yet approved by the Food and Drug Administration or used in clinical settings, blood-based biomarkers are increasingly included in epidemiologic studies on dementia. Blood-based biomarkers in epidemiologic research may allow the field to more accurately understand the multifactorial etiology and sequence of events that characterize dementia-related pathophysiological changes. As blood-based dementia biomarkers continue to be developed and incorporated into research and practice, we outline considerations for using them in dementia epidemiology, and illustrate key concepts with Alzheimer's Disease Neuroimaging Initiative (2003-present) data. We focus on measurement, including both validity and reliability, and on the use of dementia blood-based biomarkers to promote equity in dementia research and cognitive aging. This article is part of a Special Collection on Mental Health.

Interactions among neighborhood conditions, sleep quality, and episodic memory across the adult lifespan.

OBJECTIVES: On average, adults racialized as non-Hispanic Black and Hispanic sleep more poorly than adults racialized as non-Hispanic White (hereafter, Black, Hispanic, White), but associations between factors that may moderate sleep-memory associations in these groups, such as neighborhood conditions, are unclear. Poorer neighborhood conditions (e.g. lower neighborhood cohesion) may be negatively associated with sleep quality and multiplicatively influence sleep-memory associations. We hypothesized lower ratings of neighborhood conditions would be associated with poorer sleep quality and moderate the association between sleep quality and episodic memory, especially in Black and Hispanic adults, who are disproportionately situated in poor neighborhood conditions. DESIGN: Seven-hundred-thirty-six adults across the adult lifespan (27-89 years) were recruited from the northern Manhattan community as a part of the Offspring Study of Racial and Ethnic Disparities in Alzheimer's disease. Sleep quality was assessed using a modified version of the Pittsburgh Sleep Quality Index, and episodic memory was evaluated with the Buschke Selective Reminding Test. With multiple regression models, we measured associations between perceived neighborhood conditions and sleep quality and the interaction between sleep quality and neighborhood conditions on episodic memory stratified by racial/ethnic and gender identity groups. RESULTS: Overall, poorer neighborhood conditions were associated with poorer sleep quality. In Black and Hispanic women, the sleep-memory association was moderated by neighborhood conditions. With more favorable neighborhood conditions, Black women showed an association between higher sleep quality and higher memory performance, and Hispanic women showed a protective effect of neighborhood (higher memory even when sleep quality was poor). CONCLUSION: Poorer neighborhood experiences may contribute to poorer sleep quality across groups. In Black and Hispanic women, the association between sleep quality and episodic memory performance was dependent upon neighborhood conditions. These findings may inform tailored, structural level sleep interventions, aimed to improve neighborhood experiences and thereby sleep quality and episodic memory.

Testing Black-White Disparities in Biological Aging Among Older Adults in the United States: Analysis of DNA-Methylation and Blood-Chemistry Methods.

Biological aging is a proposed mechanism through which social determinants drive health disparities. We conducted proof-of-concept testing of 8 DNA-methylation (DNAm) and blood-chemistry quantifications of biological aging as mediators of disparities in healthspan between Black and White participants in the 2016 wave of the Health and Retirement Study (n = 9,005). We quantified biological aging from 4 DNAm "clocks" (Horvath, Hannum, PhenoAge, and GrimAge clock), a DNAm pace-of-aging measure (DunedinPoAm), and 3 blood-chemistry measures (PhenoAge, Klemera-Doubal method biological age, and homeostatic dysregulation). We quantified Black-White disparities in healthspan from cross-sectional and longitudinal data on physical performance tests, self-reported limitations in activities of daily living, and physician-diagnosed chronic diseases, self-rated health, and survival. DNAm and blood-chemistry quantifications of biological aging were moderately correlated (Pearson's r = 0.1-0.4). The GrimAge clock, DunedinPoAm, and all 3 blood-chemistry measures were associated with healthspan characteristics (e.g., mortality effect-size hazard ratios were 1.71-2.32 per standard deviation of biological aging) and showed evidence of more advanced/faster biological aging in Black participants than in White participants (Cohen's d = 0.4-0.5). These measures accounted for 13%-95% of Black-White differences in healthspan-related characteristics. Findings suggest that reducing disparities in biological aging can contribute to building health equity.

Elucidating the neural correlates of related false memories using a systematic measure of perceptual relatedness.

Previous memory research has exploited the perceptual similarities between lures and targets in order to evoke false memories. Nevertheless, while some studies have attempted to use lures that are objectively more similar than others, no study has systematically controlled for perceptual overlap between target and lure items and its role in accounting for false alarm rates or the neural processes underlying such perceptual false memories. The current study looked to fill this gap in the literature by using a face-morphing program to systematically control for the amount of perceptual overlap between lures and targets. Our results converge with previous studies in finding a pattern of differences between true and false memories. Most importantly, expanding upon this work, parametric analyses showed false memory activity increases with respect to the similarity between lures and targets within bilateral middle temporal gyri and right medial prefrontal cortex (mPFC). Moreover, this pattern of activation was unique to false memories and could not be accounted for by relatedness alone. Connectivity analyses further find that activity in the mPFC and left middle temporal gyrus co-vary, suggestive of gist-based monitoring within the context of false memories. Interestingly, neither the MTL nor the fusiform face area exhibited modulation as a function of target-lure relatedness. Overall, these results provide insight into the processes underlying false memories and further enhance our understanding of the role perceptual similarity plays in supporting false memories.

Exploring the influence of encoding format on subsequent memory.

Distinctive encoding is greatly influenced by gist-based processes and has been shown to suffer when highly similar items are presented in close succession. Thus, elucidating the mechanisms underlying how presentation format affects gist processing is essential in determining the factors that influence these encoding processes. The current study utilised multivariate partial least squares (PLS) analysis to identify encoding networks directly associated with retrieval performance in a blocked and intermixed presentation condition. Subsequent memory analysis for successfully encoded items indicated no significant differences between reaction time and retrieval performance and presentation format. Despite no significant behavioural differences, behaviour PLS revealed differences in brain-behaviour correlations and mean condition activity in brain regions associated with gist-based vs. distinctive encoding. Specifically, the intermixed format encouraged more distinctive encoding, showing increased activation of regions associated with strategy use and visual processing (e.g., frontal and visual cortices, respectively). Alternatively, the blocked format exhibited increased gist-based processes, accompanied by increased activity in the right inferior frontal gyrus. Together, results suggest that the sequence that information is presented during encoding affects the degree to which distinctive encoding is engaged. These findings extend our understanding of the Fuzzy Trace Theory and the role of presentation format on encoding processes.

The effects of item familiarity on the neural correlates of successful associative memory encoding.

Associative memory is considered to be resource-demanding, requiring individuals to learn individual items and the specific relationships between those items. Previous research has shown that prior studying of items aids in associative memory for pairs composed of those same items, as compared to pairs of items that have not been prelearned (e.g., Kilb & Naveh-Benjamin, 2011). In the present study, we sought to elucidate the neural correlates mediating this memory facilitation. After being trained on individual items, participants were scanned while encoding item pairs composed of items from the pretrained phase (familiarized-item pairs) and pairs whose items had not been previously learned (unfamiliarized-item pairs). Consistent with previous findings, the overall subsequent recollection showed the engagement of bilateral parahippocampal gyrus (PHG) and hippocampus, when compared to subsequent forgetting. However, a direct comparison between familiarized- and unfamiliarized-item pairs showed that subsequently recollected familiarized-item pairs were associated with decreased activity across much of the encoding network, including bilateral PHG, hippocampus, prefrontal cortex, and regions associated with item-specific processing within occipital cortex. Increased activity for familiarized-item pairs was found in a more limited set of regions, including bilateral parietal cortex, which has been associated with the formation of novel associations. Additionally, activity in the right parietal cortex correlated with associative memory success in the familiarized condition. Taken together, these results suggest that prior exposure to items can reduce the demands incurred on neural processing throughout the associative encoding network and can enhance associative memory performance by focusing resources within regions supporting the formation of associative links.

"Hang Ups, Let Downs, Bad Breaks, Setbacks": Impact of Structural Socioeconomic Racism and Resilience on Cognitive Change Over Time for Persons Racialized as Black.

Introduction: Older adults racialized as Black experience higher rates of dementia than those racialized as White. Structural racism produces socioeconomic challenges, described by artist Marvin Gaye as "hang ups, let downs, bad breaks, setbacks" that likely contribute to dementia disparities. Robust dementia literature suggests socioeconomic factors may also be key resiliencies. Methods: We linked state-level data reflecting the racialized landscape of economic opportunity across the 20th Century from the U.S. Census (1930-2010) with individual-level data on cognitive outcomes from the U.S. Health and Retirement Study participants racialized as Black. A purposive sample of participants born after the Brown v. Board ruling (born 1954-59) were selected who completed the modified Telephone Interview for Cognitive Status between 2010 and 2020 (N=1381). We tested associations of exposure to structural racism and resilience before birth, and during childhood, young-adulthood, and midlife with cognitive trajectories in mid-late life using mixed-effects regression models. Results: Older adults born in places with higher state-level structural socioeconomic racism experienced a more rapid cognitive decline in later life compared to those with lower levels of exposure. In addition, participants born in places with higher levels of state-level structural socioeconomic resilience experienced slower cognitive change over time than their counterparts. Discussion: These findings reveal the impact of racist U.S. policies enacted in the past that influence cognitive health over time and dementia risk later in life.

Racial and ethnic differences in the relationship between financial worry and white matter hyperintensities in Latinx, non-Latinx Black, and non-Latinx White older adults.

Socioeconomic status (SES) is associated with white matter hyperintensities (WMHs) and contributes to racial and ethnic health disparities. However, traditional measures of SES may not accurately represent individual financial circumstances among non-Latinx Black and Latinx older adults due to longstanding structural inequities. This study examined associations between multiple SES indicators (education, income, subjective financial worry) and WMHs across non-Latinx Black, Latinx, and non-Latinx White older adults in the Washington Heights-Inwood Columbia Aging Project (N = 662). Latinx participants reported the lowest SES and greatest financial worry, while Black participants evidenced the most WMHs. Greater financial worry was associated with higher WMHs volume above and beyond education and income, which were not associated with WMHs. However, this association was only evident among Latinx older adults. These results provide evidence for the minority poverty hypothesis and highlight the need for systemic socioeconomic interventions to alleviate brain health disparities in older adulthood.

Brain Aging Among Racially and Ethnically Diverse Middle-Aged and Older Adults.

Importance: Neuroimaging studies have documented racial and ethnic disparities in brain health in old age. It remains unclear whether these disparities are apparent in midlife. Objective: To assess racial and ethnic disparities in magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration in midlife and late life. Design, Setting, and Participants: Data from 2 community-based cohort studies, Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Offspring Study of Racial and Ethnic Disparities in Alzheimer Disease (Offspring), were used. Enrollment took place from March 2011 and June 2017, in WHICAP and Offspring, respectively, to January 2021. Of the 822 Offspring and 1254 WHICAP participants approached for MRI scanning, 285 and 176 refused participation in MRI scanning, 36 and 76 were excluded for contraindications/ineligibility, and 4 and 32 were excluded for missing key variables, respectively. Main Outcomes and Measures: Cortical thickness in Alzheimer disease-related regions, white matter hyperintensity (WMH) volume. Results: The final sample included 1467 participants. Offspring participants (497 [33.9%]) had a mean (SD) age of 55 (10.7) years, had a mean (SD) of 13 (3.5) years of education, and included 117 Black individuals (23.5%), 348 Latinx individuals (70%), 32 White individuals (6.4%), and 324 women (65.2%). WHICAP participants (970 [66.1%]) had a mean (SD) age of 75 (6.5) years, had a mean (SD) of 12 (4.7) years of education, and included 338 Black individuals (34.8%), 389 Latinx individuals (40.1%), 243 White individuals (25.1%), and 589 women (65.2%). Racial and ethnic disparities in cerebrovascular disease were observed in both midlife (Black-White: B = 0.357; 95% CI, 0.708-0.007; P = .046) and late life (Black-Latinx: B = 0.149, 95% CI, 0.068-0.231; P < .001; Black-White: B = 0.166; 95% CI, 0.254-0.077; P < .001), while disparities in cortical thickness were evident in late life only (Black-Latinx: B = -0.037; 95% CI, -0.055 to -0.019; P < .001; Black-White: B = -0.064; 95% CI -0.044 to -0.084; P < .001). Overall, Black-White disparities were larger than Latinx-White disparities for cortical thickness and WMH volume. Brain aging, or the association of age with MRI measures, was greater in late life compared with midlife for Latinx (cortical thickness: B = 0.006; 95% CI, 0.004-0.008; P < .001; WMH volume: B = -0.010; 95% CI, -0.018 to -0.001; P = .03) and White (cortical thickness: B = 0.005; 95% CI, 0.002-0.008; P = .001; WMH volume: B = -0.021; 95% CI -0.043 to 0.002; P = .07) participants but not Black participants (cortical thickness: B = 0.001; 95% CI, -0.002 to 0.004; P =.64; WMH volume: B = 0.003; 95% CI, -0.010 to 0.017; P = .61), who evidenced a similarly strong association between age and MRI measures in midlife and late life. Conclusions and Relevance: In this study, racial and ethnic disparities in small vessel cerebrovascular disease were apparent in midlife. In Latinx and White adults, brain aging was more pronounced in late life than midlife, whereas Black adults showed accelerated pattern of brain aging beginning in midlife.

Socioeconomic Status, Biological Aging, and Memory in a Diverse National Sample of Older US Men and Women.

BACKGROUND AND OBJECTIVES: Exposure to socioeconomic disadvantage is associated with early-onset cognitive aging. Biological aging, the progressive loss of system integrity that occurs as we age, is proposed as a modifiable process mediating this health inequality. We examined whether socioeconomic disparities in cognitive aging in mid-to late-life adults is explained by accelerated biological aging similarly across race, ethnicity, and sex/gender. METHODS: Data were from a prospective cohort study of the US Health and Retirement Study DNA methylation substudy. Socioeconomic status (SES) was measured from years of education and household wealth at baseline. The extent and pace of biological aging were quantified using 3 DNA methylation measures: PhenoAge, GrimAge, and DunedinPoAm. Cognitive aging was measured from repeated longitudinal assessments of immediate and delayed word recall. Latent growth curve modeling estimated participants' level of memory performance and rate of decline over 2-11 follow-up assessments spanning 2-20 years. Multiple-group models were estimated to assess whether the relationship between SES and memory trajectories was mediated by biological aging across racial-ethnic by sex/gender subgroups. RESULTS: Data from a total of 3,997 adults aged 50-100 years were analyzed. Participants with lower SES had a lower memory performance, had a faster decline, and exhibited accelerated biological aging (SES effect size associations [ß] ranged from 0.08 to 0.41). Accelerated biological aging was associated with decreased memory performance and faster memory decline (effect size range 0.03-0.23). SES-biological aging associations were the strongest for White men and women and weakest for Latinx women. The relationship between biological aging measures and memory was weaker for Black participants compared with that for White and Latinx people. In mediation analysis, biological aging accounted for 4%-27% of the SES-memory gradient in White participants. There was little evidence of mediation in Black or Latinx participants. DISCUSSION: Among a national sample of mid-to late-life adults, DNA methylation measures of biological aging were variably associated with memory trajectories and SES across White, Black, and Latinx mid-to late-life adults. These results challenge the assumption that DNA methylation biomarkers of aging that were developed in primarily White people can equivalently quantify aging processes affecting cognition in Black and Latinx mid-to late-life adults.

Research priorities for measuring biologic age: summary and future directions from the Research Centers Collaborative Network Workshop.

Biologic aging reflects the genetic, molecular, and cellular changes underlying the development of morbidity and mortality with advancing chronological age. As several potential mechanisms have been identified, there is a growing interest in developing robust measures of biologic age that can better reflect the underlying biology of aging and predict age-related outcomes. To support this endeavor, the Research Centers Collaborative Network (RCCN) conducted a workshop in January 2022 to discuss emerging concepts in the field and identify opportunities to move the science forward. This paper presents workshop proceedings and summarizes the identified research needs, priorities, and recommendations for measuring biologic age. The highest priorities identified were the need for more robust measures, longitudinal studies, multidisciplinary collaborations, and translational approaches.

Cross-national harmonization of cognitive measures across HRS HCAP (USA) and LASI-DAD (India).

BACKGROUND: As global populations age, cross-national comparisons of cognitive health and dementia risk are increasingly valuable. It remains unclear, however, whether country-level differences in cognitive function are attributable to population differences or bias due to incommensurate measurement. To demonstrate an effective method for cross-national comparison studies, we aimed to statistically harmonize measures of episodic memory and language function across two population-based cohorts of older adults in the United States (HRS HCAP) and India (LASI-DAD). METHODS: Data for 3,496 HRS HCAP (≥65 years) and 3,152 LASI-DAD (≥60 years) participants were statistically harmonized for episodic memory and language performance using confirmatory factor analysis (CFA) methods. Episodic memory and language factor variables were investigated for differential item functioning (DIF) and precision. RESULTS: CFA models estimating episodic memory and language domains based on a priori adjudication of comparable items fit the data well. DIF analyses revealed that four out of ten episodic memory items and five out of twelve language items measured the underlying construct comparably across samples. DIF-modified episodic memory and language factor scores showed comparable patterns of precision across the range of the latent trait for each sample. CONCLUSIONS: Harmonization of cognitive measures will facilitate future investigation of cross-national differences in cognitive performance and differential effects of risk factors, policies, and treatments, reducing study-level measurement and administrative influences. As international aging studies become more widely available, advanced statistical methods such as those described in this study will become increasingly central to making universal generalizations and drawing valid conclusions about cognitive aging of the global population.

Fornix white matter microstructure differentially predicts false recollection rates in older and younger adults.

Healthy aging is accompanied by increased false remembering in addition to reduced successful remembering in older adults. Neuroimaging studies implicate age-related differences in the involvement of medial temporal lobe and fronto-parietal regions in mediating highly confident false recollection. However, no studies have directly examined the relationship between white matter microstructure and false recollection in younger and older adults. Using diffusion-weighted imaging and probabilistic tractography, we examined how white matter microstructure within tracts connecting the hippocampus and the fronto-parietal retrieval network contribute to false recollection rates in healthy younger and older adults. We found only white matter microstructure within the fornix contributed to false recollection rates, and this relationship was specific to older adults. Fornix white matter microstructure did not contribute to true recollection rate, nor did common white matter contribute to false recollection, suggesting fornix microstructure is explicitly associated with highly confident false memories in our sample of older adults. These findings underlie the importance of examining microstructural correlates associated with false recollection in younger and older adults.

APOE ε4 and resting-state functional connectivity in racially/ethnically diverse older adults.

INTRODUCTION: Numerous neuroimaging studies demonstrated an association between the apolipoprotein E (APOE) ε4 allele and resting-state functional connectivity (rsFC) of regions within the default mode network (DMN), both in healthy populations and patients with AD. It remains unclear whether the APOE ε4 allele differentially affects the brain's functional network architecture across race/ethnicity. METHODS: We investigated rsFC within DMN subsystems in 170 APOE ε4 carriers compared to 387 APOE ε4 non-carriers across three major racial/ethnic groups, including non-Hispanic Whites (n = 166), non-Hispanic Blacks (n = 185), and Hispanics (n = 206) from the Washington Heights-Inwood Columbia Aging Project. RESULTS: Compared to APOE ε4 non-carriers, APOE ε4 carriers had lower rsFC in temporal DMN, but only in non-Hispanic Whites. Non-Hispanic Black and Hispanic APOE ε4 carriers had slightly higher or similar rsFC compared with non-Hispanic White APOE ε4 non-carriers. DISCUSSION: These findings suggest that APOE ε4 modulates DMN rsFC differently in non-Hispanic Whites compared with non-Hispanic Blacks and Hispanics.

The influence of perceptual similarity and individual differences on false memories in aging.

Previous false memory research has suggested that older adults' false memories are based on an overreliance on gist processing in the absence of item-specific details. Yet, false memory studies have rarely taken into consideration the precise role of item-item similarity on the cognitive and neural mechanisms underlying perceptual false memories in older adults. In addition, work in our laboratory has suggested that when investigating the neural basis of false memories in older adults, it is equally as critical to take into account interindividual variability in behavior. With both factors in mind, the present study was the first to examine how both controlled, systematic differences in perceptual relatedness between targets and lures and individual differences in true and false recognition contribute to the neural basis of both true and false memories in older adults. Results suggest that between-subject variability in memory performance modulates neural activity in key regions associated with false memories in aging, whereas systematic differences in perceptual similarity did not modulate neural activity associated with false memories.

What's the gist? The influence of schemas on the neural correlates underlying true and false memories.

The current study used a novel scene paradigm to investigate the role of encoding schemas on memory. Specifically, the study examined the influence of a strong encoding schema on retrieval of both schematic and non-schematic information, as well as false memories for information associated with the schema. Additionally, the separate roles of recollection and familiarity in both veridical and false memory retrieval were examined. The study identified several novel results. First, while many common neural regions mediated both schematic and non-schematic retrieval success, schematic recollection exhibited greater activation in visual cortex and hippocampus, regions commonly shown to mediate detailed retrieval. More effortful cognitive control regions in the prefrontal and parietal cortices, on the other hand, supported non-schematic recollection, while lateral temporal cortices supported familiarity-based retrieval of non-schematic items. Second, both true and false recollection, as well as familiarity, were mediated by activity in left middle temporal gyrus, a region associated with semantic processing and retrieval of schematic gist. Moreover, activity in this region was greater for both false recollection and false familiarity, suggesting a greater reliance on lateral temporal cortices for retrieval of illusory memories, irrespective of memory strength. Consistent with previous false memory studies, visual cortex showed increased activity for true compared to false recollection, suggesting that visual cortices are critical for distinguishing between previously viewed targets and related lures at retrieval. Additionally, the absence of common visual activity between true and false retrieval suggests that, unlike previous studies utilizing visual stimuli, when false memories are predicated on schematic gist and not perceptual overlap, there is little reliance on visual processes during false memory retrieval. Finally, the medial temporal lobe exhibited an interesting dissociation, showing greater activity for true compared to false recollection, as well as for false compared to true familiarity. These results provided an indication as to how different types of items are retrieved when studied within a highly schematic context. Results both replicate and extend previous true and false memory findings, supporting the Fuzzy Trace Theory.