A Critique and Examination of the Polysocial Risk Score Approach: Predicting Cognition in the Health and Retirement Study.

Polysocial risk scores were recently proposed as a strategy to improve clinical relevance of knowledge about social determinants of health. The objective of this paper was to assess if the polysocial risk score model improves prediction of cognition and all-cause mortality in middle-aged and older adults beyond simpler models including a smaller set of key social determinants of health. We used a sample of 13,773 individuals aged 50+ at baseline from the 2006 to 2018 waves of the Health and Retirement Study, a US population-based longitudinal cohort. Four linear mixed models were compared: two simple models including a priori selected covariates and two polysocial risk score models which used LASSO regularization to select covariates among 9 or 21 candidate social predictors. All models included age. Predictive accuracy was assessed via R-squared and root mean-squared prediction error (RMSPE) using training/test split and cross-validation. For predicting cognition, the simple model including age, race, gender, and education had an R-squared of 0.31 and an RMSPE of 0.880. Compared with this, the most complex polysocial risk score selected 12 predictors (R-squared=0.35 and RMSPE=0.858; 2.2% improvement). For all-cause mortality, the simple model including age, race, gender, and education had an AUROC of 0.747, while the most complex polysocial risk score did not demonstrate improved performance (AUROC = 0.745). Models built on a smaller set of key social determinants performed comparably to models built on a more complex set of social "risk factors".

Representativeness of Participants in the ACCORD Trial Compared to Middle-aged and Older Adults Living with Diabetes in the United States.

BACKGROUND: We evaluated whether participants in the landmark Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial represent U.S. adults aged ≥40 with diabetes. METHODS: Using the nationally representative 2017-2020 pre-pandemic National Health and Nutrition Examination Survey (NHANES) data, we made operational definitions of ACCORD eligibility criteria. We calculated the percentage of individuals aged ≥40 with diabetes and HbA1c ≥6.0% or ≥7.5% who met operational ACCORD eligibility criteria. RESULTS: Applying survey sampling weights to 715 NHANES participants aged ≥40 with diabetes and HbA1c ≥6.0% (representing 29,717,406 individuals), 12% (95% confidence interval [CI]: 8-18%) met the operational ACCORD eligibility criteria. Restricting to HbA1c ≥7.5%, 39% (95% CI: 28-51%) of respondents met the ACCORD criteria. CONCLUSIONS: ACCORD represented a minority of U.S. middle-aged and older adults with diabetes. Given the differential risk profile between ACCORD participants and the general population with diabetes, extrapolating the trial findings may not be appropriate.

School racial composition, effect modification by caring teacher/staff presence, and mid/late-life depressive symptoms: findings from the Study of Healthy Aging among African Americans.

For Black students in the United States, attending schools with a higher proportion of White students is associated with worse mental and physical health outcomes in adolescence/early adulthood. No prior studies evaluate K-12 school racial composition and later-life mental health. In a cohort of Black adults ages 50+ in Northern California who retrospectively self-reported school racial composition for grades 1, 6, 9, and 12, we assessed the association between attending a school with mostly Black students vs. not and mid/late-life depressive symptoms (8-item PROMIS depression score, standardized to US adult population) using age-, sex/gender-, southern US birth-, and parental education-adjusted generalized estimating equations, and assessed effect modification by caring teacher/staff presence. Later-life depressive symptoms were lower among those who attended schools with mostly Black students in grades 1 and 6 (b=-0.12, 95% CI: -0.23, 0.00 and b=-0.11, 95% CI: -0.22, 0.00, respectively). In grade 6, this difference was larger for students without an adult at school who cared about them (b=-0.29, 95% CI: -0.51, -0.07 vs. b=-0.04, 95% CI: -0.17, 0.09). Among Black Americans, attending early school with mostly Black students may have later life mental health benefits; this protective association appears more important for students without caring teachers/staff.

The Association Between Physical Activity and Cognition in a Racially/Ethnically Diverse Cohort of Older Adults: Results From the Kaiser Healthy Aging and Diverse Life Experiences Study.

OBJECTIVE: Most prior research on physical activity (PA) and cognition is based on predominantly white cohorts and focused on associations of PA with mean (average) cognition versus the distribution of cognition. Quantile regression offers a novel way to quantify how PA affects cognition across the entire distribution. METHODS: The Kaiser Healthy Aging and Diverse Life Experiences study includes 30% white, 19% black, 25% Asian, and 26% Latinx adults age 65+ living in Northern California (n = 1600). The frequency of light or heavy PA was summarized as 2 continuous variables. Outcomes were z-scored executive function, semantic memory, and verbal episodic memory. We tested associations of PA with mean cognition using linear regression and used quantile regression to estimate the association of PA with the 10th-90th percentiles of cognitive scores. RESULTS: Higher levels of PA were associated with higher mean semantic memory (b = 0.10; 95% CI: 0.06, 0.14) and executive function (b = 0.05; 95% CI: 0.01, 0.09). Associations of PA across all 3 cognitive domains were stronger at low quantiles of cognition. CONCLUSION: PA is associated with cognition in this racially/ethnically diverse sample and may have larger benefits for individuals with low cognitive scores, who are most vulnerable to dementia.

First-generation college graduates have similar depressive symptoms in midlife as multi-generational college graduates.

Purpose: Higher education may protect an individual against depressive symptoms, yet, disadvantaged socioeconomic status (SES) during childhood, often measured by lower parental education, may put them at higher risk for depressive symptoms later in life. This study evaluates if midlife depression is similar for first-generation and multi-generation college graduates. Methods: For US Health and Retirement Study (HRS) participants ages 55-63 (N = 16,752), we defined a 4-category exposure from parents' (highest of mother or father's) and participant's own years of education, with 16 years indicating college completion: multi-gen (both ≥ 16 years: reference); first-gen (parents <16; own ≥ 16); only parent(s) (parents ≥ 16; own <16); and neither (both <16) college graduates across three birth cohorts. We used linear regressions to evaluate relationships between college completion and depressive symptoms measured by an 8-item Center for Epidemiologic Studies - Depression (CES-D) scale. Models pooled over time evaluated differences by sex, race/ethnicity, and birthplace. Results: First-gen and multi-gen college graduates averaged similar depressive symptoms in midlife (ß: 0.01; 95% CI: 0.15, 0.13). Results were similar by sex and race/ethnicity. Conclusion: Consistent with resource substitution theory, college completion may offset the deleterious effects of lower parental education on midlife depressive symptoms for first-generation graduates.

Does schooling attained by adult children affect parents' psychosocial well-being in later life? Using Mexico's 1993 compulsory schooling law as a quasi-experiment.

Higher adult child educational attainment may benefit older parents' psychosocial well-being in later life. This may be particularly important in low- and middle-income countries, where recent generations have experienced comparatively large increases in educational attainment. We used data from the 2012 Mexican Health and Aging Study, a nationally representative study of adults aged ≥50 years and leveraged the exogenous variation in adult child education induced by Mexico's compulsory schooling law passed in 1993. We employed two-stage least squares (2SLS) regression to estimate the effects of increased schooling among adult children on parents' (respondents') depressive symptoms and life satisfaction scores, controlling for demographic and socioeconomic characteristics. We considered heterogeneity by parent and child gender and other sociodemographic characteristics. Our study included 7186 participants with an average age of 60.1 years; 54.9% were female. In the 2SLS analyses, increased schooling among oldest adult children was associated with fewer depressive symptoms (ß = -0.25; 95% CI: -0.51, 0.00) but no difference in life satisfaction (ß = 0.01; 95% CI: -0.22, 0.25). Stratified models indicated differences in the magnitude of association with depressive symptoms for mothers (ß = -0.27, 95% CI: -0.56, 0.01) and fathers (ß = -0.18, 95% CI: -0.63, 0.26) and when considering increased schooling of oldest sons (ß = -0.37; 95% CI: -0.73, -0.02) and daughters (ß = -0.05, 95% CI: -0.23, 0.13). No parent and child gender differences were found for life satisfaction. Power was limited to detect heterogeneity across other sociodemographic characteristics in the second stage although first-stage estimates were larger for urban (vs. rural) dwelling and more (vs. less) highly educated respondents. Results were similar when considering the highest educated child as well as increased schooling across all children. Our findings suggest that longer schooling among current generations of adult children, particularly sons, may benefit their older parents' psychosocial well-being.

Comparison of approaches to control for intracranial volume in research on the association of brain volumes with cognitive outcomes.

Most neuroimaging studies linking regional brain volumes with cognition correct for total intracranial volume (ICV), but methods used for this correction differ across studies. It is unknown whether different ICV correction methods yield consistent results. Using a brain-wide association approach in the MRI substudy of UK Biobank (N = 41,964; mean age = 64.5 years), we used regression models to estimate the associations of 58 regional brain volumetric measures with eight cognitive outcomes, comparing no correction and four ICV correction approaches. Approaches evaluated included: no correction; dividing regional volumes by ICV (proportional approach); including ICV as a covariate in the regression (adjustment approach); and regressing the regional volumes against ICV in different normative samples and using calculated residuals to determine associations (residual approach). We used Spearman-rank correlations and two consistency measures to quantify the extent to which associations were inconsistent across ICV correction approaches for each possible brain region and cognitive outcome pair across 2320 regression models. When the association between brain volume and cognitive performance was close to null, all approaches produced similar estimates close to the null. When associations between a regional volume and cognitive test were not null, the adjustment and residual approaches typically produced similar estimates, but these estimates were inconsistent with results from the crude and proportional approaches. For example, when using the crude approach, an increase of 0.114 (95% confidence interval [CI]: 0.103-0.125) in fluid intelligence was associated with each unit increase in hippocampal volume. However, when using the adjustment approach, the increase was 0.055 (95% CI: 0.043-0.068), while the proportional approach showed a decrease of -0.025 (95% CI: -0.035 to -0.014). Different commonly used methods to correct for ICV yielded inconsistent results. The proportional method diverges notably from other methods and results were sometimes biologically implausible. A simple regression adjustment for ICV produced biologically plausible associations.

Evaluation of racial and ethnic heterogeneity in the associations of sleep quality and sleep apnea risk with cognitive function and cognitive decline.

INTRODUCTION: The prevalence of poor sleep quality and sleep apnea differs by race and ethnicity and may contribute to racial disparities in cognitive aging. We investigated whether sleep quality and sleep apnea risk were associated with cognitive function and decline and whether the associations differed by race/ethnicity. METHODS: Participants from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE; N = 1690; mean age: 75.7 years) study, a cohort of Asian, Black, Latino, and White participants, completed a modified Pittsburgh Sleep Quality Index assessing subjective sleep quality, latency, duration, disturbances, sleep medication use, and daytime dysfunction. Sleep apnea risk was measured by questions about snoring, tiredness, and whether apnea was observed. Executive function and verbal episodic memory were assessed at three time points over an average of 2.7 years with the Spanish and English Neuropsychological Assessment Scale. We fit linear mixed-effect models and stratified analyses by race/ethnicity. RESULTS: Higher sleep apnea risk was associated with faster declines in verbal episodic memory (ß^ sleep apnea = -0.02, 95% confidence interval [CI], -0.04, -0.001) but not in executive function. Poorer sleep quality was associated with lower levels of and faster decline in executive function but not in verbal episodic memory. Race/ethnicity modified these associations: compared to estimated effects among White participants, poorer global sleep quality (ß^ sleep*time = -0.02, 95% CI, -0.02, -0.01) was associated with larger effects on decline in executive function among Black participants. Estimated effects of some individual sleep quality components were also modified by race/ethnicity; for example, sleep medication use was associated with faster declines in executive function (ß^ sleep*time = -0.05, 95% CI, -0.07, -0.03) and verbal episodic memory ß^ sleep*time = -0.04, 95% CI, -0.07, -0.02) among Black participants compared to White participants. DISCUSSION: Observational evidence indicates sleep quality is a promising target for addressing racial/ethnic disparities in cognitive aging, especially among Black older adults. Highlights: Sleep apnea risk was associated with faster declines in verbal episodic memory but not executive function among all participants.Global sleep quality was associated with lower levels of and faster decline in executive function but not verbal episodic memory among all participants.Black older adults were particularly susceptible to the estimated adverse cognitive impacts of global sleep quality, particularly the use of sleep medication.

Excess natural-cause mortality in US counties and its association with reported COVID-19 deaths.

In the United States, estimates of excess deaths attributable to the COVID-19 pandemic have consistently surpassed reported COVID-19 death counts. Excess deaths reported to non-COVID-19 natural causes may represent unrecognized COVID-19 deaths, deaths caused by pandemic health care interruptions, and/or deaths from the pandemic's socioeconomic impacts. The geographic and temporal distribution of these deaths may help to evaluate which explanation is most plausible. We developed a Bayesian hierarchical model to produce monthly estimates of excess natural-cause mortality for US counties over the first 30 mo of the pandemic. From March 2020 through August 2022, 1,194,610 excess natural-cause deaths occurred nationally [90% PI (Posterior Interval): 1,046,000 to 1,340,204]. A total of 162,886 of these excess natural-cause deaths (90% PI: 14,276 to 308,480) were not reported to COVID-19. Overall, 15.8 excess deaths were reported to non-COVID-19 natural causes for every 100 reported COVID-19 deaths. This number was greater in nonmetropolitan counties (36.0 deaths), the West (Rocky Mountain states: 31.6 deaths; Pacific states: 25.5 deaths), and the South (East South Central states: 26.0 deaths; South Atlantic states: 25.0 deaths; West South Central states: 24.2 deaths). In contrast, reported COVID-19 death counts surpassed estimates of excess natural-cause deaths in metropolitan counties in the New England and Middle Atlantic states. Increases in reported COVID-19 deaths correlated temporally with increases in excess deaths reported to non-COVID-19 natural causes in the same and/or prior month. This suggests that many excess deaths reported to non-COVID-19 natural causes during the first 30 mo of the pandemic in the United States were unrecognized COVID-19 deaths.

Long-term cognitive outcome after elective hip or knee total joint arthroplasty: A population-based observational study.

BACKGROUND: One year after elective hip or knee total joint arthroplasty (TJA), >30% of older adults meet criteria for postoperative neurocognitive disorder. However, this is not contextualized with long-term cognitive outcomes in comparable surgical and nonsurgical controls. We analyzed population-based data to compare long-term cognitive outcomes in older adults after TJA, other surgeries, and with and without arthritis pain. METHODS: This was a retrospective observational analysis of United States older adults in the Health and Retirement Study (HRS) who underwent elective TJA, or elective surgery without expected functional benefits (e.g., cholecystectomy; inguinal herniorrhaphy), between 1998 and 2018 at aged 65 or older. TJA recipients were also age- and sex-matched to nonsurgical controls who reported moderate-severe arthritic pain or denied pain, so that comparison groups included surgical and nonsurgical (pain-suffering and pain-free) controls. We modeled biennially-assessed memory performance, a measure of direct and proxy cognitive assessments, before and after surgery, normalized to the rate of memory decline ("cognitive aging") in controls to express effect size estimates as excess, or fewer, months of memory decline. We used linear mixed effects models adjusted for preoperative health and demographic factors, including frailty, flexibly capturing time before/after surgery (knots at -4, 0, 8 years; discontinuity at surgery). RESULTS: There were 1947 TJA recipients (average age 74; 63% women; 1358 knee, 589 hip) and 1631 surgical controls (average age 76; 38% women). Memory decline 3 years after TJA was similar to surgical controls (5.2 [95% confidence interval, CI -1.2 to 11.5] months less memory decline in the TJA group, p = 0.11) and nonsurgical controls. At 5 years, TJA recipients experienced 5.0 [95% CI -0.9 to 10.9] months less memory decline than arthritic pain nonsurgical controls. CONCLUSION: There is no systematic accelerated memory decline at 3 years after TJA compared with surgical or nonsurgical controls.

Genetic risk score for Alzheimer's disease predicts brain volume differences in mid and late life in UK biobank participants.

INTRODUCTION: We estimated the ages when associations between Alzheimer's disease (AD) genes and brain volumes begin among middle-aged and older adults. METHODS: Among 45,616 dementia-free participants aged 45-80, linear regressions tested whether genetic risk score for AD (AD-GRS) had age-dependent associations with 38 regional brain magnetic resonance imaging volumes. Models were adjusted for sex, assessment center, genetic ancestry, and intracranial volume. RESULTS: AD-GRS modified the estimated effect of age (per decade) on the amygdala (-0.41 mm3 [-0.42, -0.40]); hippocampus (-0.45 mm3 [-0.45, -0.44]), nucleus accumbens (-0.55 mm3 [-0.56, -0.54]), thalamus (-0.38 mm3 [-0.39, -0.37]), and medial orbitofrontal cortex (-0.23 mm3 [-0.24, -0.22]). Trends began by age 45 for the nucleus accumbens and thalamus, 48 for the hippocampus, 51 for the amygdala, and 53 for the medial orbitofrontal cortex. An AD-GRS excluding apolipoprotein E (APOE) was additionally associated with entorhinal and middle temporal cortices. DISCUSSION: APOE and other genes that increase AD risk predict lower hippocampal and other brain volumes by middle age.

Report on the Joint Workshop on the Relations between Health Inequalities, Ageing and Multimorbidity, Iceland, May 3-4, 2023.

This paper is a summary of key presentations from a workshop in Iceland on May 3-4, 2023 arranged by Aarhus University and with participation of the below-mentioned scientists. Below you will find the key messages from the presentations made by: Professor Jan Vandenbroucke, Department of Clinical Epidemiology, Aarhus University, Emeritus Professor, Leiden University; Honorary Professor, London School of Hygiene & Tropical Medicine, UKProfessor, Chair Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, DenmarkProfessor David H. Rehkopf, Director, the Stanford Center for Population Health Sciences, Stanford University, CA., USProfessor Jaimie Gradus, Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USProfessor Johan Mackenbach, Emeritus Professor, Department of Public Health, Erasmus University Rotterdam, HollandProfessor, Chair M Maria Glymour, Department of Epidemiology, Boston University School of Public Health, Boston University, Boston, Massachusetts, USProfessor, Dean Sandro Galea, School of Public Health, Boston University, Boston, Massachusetts, USProfessor Victor W. Henderson, Departments of Epidemiology & Population Health and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, US; Department of Clinical Epidemiology, Aarhus University, Aarhus, DK.

Associations of Everyday and Lifetime Experiences of Discrimination With Willingness to Undergo Alzheimer Disease Predictive Testing.

BACKGROUND AND OBJECTIVES: Rapid developments in Alzheimer disease (AD) biomarker research suggest that predictive testing may become widely available. To ensure equal access to AD predictive testing, it is important to understand factors that affect testing interest. Discrimination may influence attitudes toward AD testing, particularly among racially and ethnically minoritized populations, because of structural racism in health care systems. This study examined whether everyday or lifetime discrimination experiences shape interest in AD predictive testing. METHODS: In the 2010 and 2012 biennial Health and Retirement Study waves, respondents were randomly selected to complete questions on interest in receiving free testing that could determine whether they would develop AD in the future. The exposures were everyday discrimination (6 items) and lifetime discrimination (7 items); both were transformed into a binary variable. Logistic regression models predicting interest in AD testing were controlled for deciles of propensity scores for each discrimination measure. Odds ratios were re-expressed as risk differences (RDs). RESULTS: Our analytic sample included 1,499 respondents. The mean age was 67 (SD = 10.2) years, 57.4% were women, 65.7% were White, and 80% endorsed interest in AD predictive testing. Most of the participants (54.7%) experienced everyday discrimination in at least one domain; 24.1% experienced major lifetime discrimination in at least one domain. Those interested in predictive testing were younger (66 vs 70 years) and more likely to be Black (20% vs 15%) or Latinx (14% vs 8%) than participants uninterested in testing. The probability of wanting an AD test was not associated with discrimination for Black (RD everyday discrimination = -0.026; 95% CI [-0.081 to 0.029]; RD lifetime discrimination = -0.012; 95% CI [-0.085 to 0.063]) or Latinx (RD everyday discrimination = -0.023, 95% CI [-0.082 to 0.039]; RD lifetime discrimination = -0.011; 95% CI [-0.087 to 0.064]) participants. DISCUSSION: Despite historical and contemporary experiences of discrimination, Black and Latinx individuals express interest in AD testing. However, Black and Latinx individuals remain underrepresented in AD research, including research on AD testing. Interest in personalized information about dementia risk may be a pathway to enhance their inclusion in research and clinical trials.

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.

Timing and level of educational attainment and late-life cognition in the KHANDLE study.

INTRODUCTION: The timing of educational attainment may modify its effects on late-life cognition, yet most studies evaluate education only at a single time point. METHODS: Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study cohort participants (N = 554) reported educational attainment (dichotomized at any college education) at two time points, and we classified them as having low, high, or later-life high educational attainment. Linear mixed-effects models estimated associations between educational attainment change groups and domain-specific cognitive outcomes (z-standardized). RESULTS: Compared to low educational attainment, high (ß= 0.59 SD units; 95% confidence interval [CI]: 0.39, 0.79) and later-life high educational attainment (ß = 0.22; 95% CI: 0.00, 0.44) were associated with higher executive function. Only high educational attainment was associated with higher verbal episodic memory (ß = 0.27; 95% CI: 0.06, 0.48). DISCUSSION: Level and timing of educational attainment are both associated with domain-specific cognition. A single assessment for educational attainment may inadequately characterize protective associations with late-life cognition. HIGHLIGHTS: Few studies have examined both level and timing of educational attainment on cognition. Marginalized populations are more likely to attain higher education in adulthood. Higher educational attainment in late life is also associated with higher cognition.

Association of cancer history with structural brain aging markers of Alzheimer's disease and related dementias risk.

INTRODUCTION: Cancer survivors are less likely than comparably aged individuals without a cancer history to develop Alzheimer's disease and related dementias (ADRD). METHODS: In the UK Biobank, we investigated associations between cancer history and five structural magnetic resonance imaging (MRI) markers for ADRD risk, using linear mixed-effects models to assess differences in mean values and quantile regression to examine whether associations varied across the distribution of MRI markers. RESULTS: Cancer history was associated with smaller mean hippocampal volume (b = -19 mm3 , 95% CI = -36, -1) and lower mean cortical thickness in the Alzheimer's disease signature region (b = -0.004 mm, 95% CI = -0.007, -0.000). Quantile regressions indicated individuals most vulnerable to ADRD were more affected by cancer history. DISCUSSION: Some brain MRI markers associated with ADRD risk were elevated in adults with a history of cancer. The magnitude of the adverse associations varied across quantiles of neuroimaging markers, and the pattern suggests possible harmful associations for individuals already at high ADRD risk. HIGHLIGHTS: We found no evidence of an inverse association between cancer history and ADRD-related neurodegeneration. Cancer history was associated with smaller mean hippocampal volume and lower mean cortical thickness in the Alzheimer's disease signature region. Quantile regressions indicated individuals most vulnerable to ADRD were more affected by cancer history.

Estimated effects of amyloid reduction on cognitive change: A Bayesian update across a range of priors.

INTRODUCTION: The results of the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials have rekindled discussion on the impact of amyloid-targeting drugs. We use a Bayesian approach to quantify how rational observers would have updated their prior beliefs based on new trial results. METHODS: We used publicly available data from the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials to estimate the effect of reducing amyloid on the clinical dementia rating scale, sum of boxes (CDR-SB) score. A range of prior positions were then updated according to Bayes' theorem using these estimates. RESULTS: After updating with new trial data, a wide range of starting positions resulted in credible intervals that did not include no effect of amyloid reduction on CDR-SB score. DISCUSSION: For a range of starting beliefs and assuming the veracity of the underlying data, rational observers would conclude there is a small benefit of amyloid reductions on cognition. This benefit must be weighed against opportunity cost and side-effect risk. HIGHLIGHTS: The results of recent trials of amyloid-targeting drugs have rekindled discussion on the impact of amyloid reductions achieved with amyloid-targeting drugs on cognition. Prior to the announcement of trial results, beliefs about the effects of altering amyloid levels varied. For a range of starting beliefs, one would conclude there is a small benefit of amyloid reductions due to amyloid-targeting drugs on cognition. The perceived value of individual drugs must balance the magnitude of this benefit against opportunity cost and risk of side effects.

State home and community-based services expenditures and unmet care needs in the United States: Has everyone benefitted equally?

OBJECTIVE: To test whether the impacts of Medicaid's Home and Community-Based Services (HCBS) expenditures have been equitable. DATA SOURCES AND STUDY SETTING: This is a secondary data analysis. We linked annual data on state-level Medicaid HCBS expenditures with individual data from U.S. Health and Retirement Study (HRS; 2006-2016). STUDY DESIGN: We evaluated the association between state-level HCBS expenditure quartiles and the risk of experiencing challenges in basic or instrumental activities of daily living (I/ADLs) without assistance (unmet needs for care). We fitted generalized estimating equations (GEE) with a Poisson distribution, log link function, and an unstructured covariance matrix. We controlled demographics, time, and place-based fixed effects and estimated models stratified by race and ethnicity, gender, and urbanicity. We tested the robustness of results with negative controls. DATA COLLECTION/EXTRACTION METHODS: Our analytic sample included HRS Medicaid beneficiaries, aged 55+, who had difficulty with ≥1 I/ADL (n = 2607 unique respondents contributing 4719 person-wave observations). PRINCIPAL FINDINGS: Among adults with IADL difficulty, higher quartiles of HCBS expenditure (vs. the lowest quartile) were associated with a lower overall prevalence of unmet needs for care (e.g., Prevalence Ratio [PR], Q4 vs. Q1: 0.91, 95% CI: 0.84-0.98). This protective association was concentrated among non-Hispanic white respondents (Q4 vs. Q1: 0.82, 95% CI: 0.73-0.93); estimates were imprecise for Hispanic individuals and largely null for non-Hispanic Black participants. We found no evidence of heterogeneity by gender or urbanicity. Negative control robustness checks indicated that higher quartiles of HCBS expenditure were not associated with (1) the risk of reporting I/ADL difficulty among 55+ Medicaid beneficiaries, and (2) the risk of unmet care needs among non-Medicaid beneficiaries. CONCLUSION: The returns to higher state-level HCBS expenditures under Medicaid for older adults with I/ADL disability do not appear to have been equitable by race and ethnicity.

Food Insecurity, Memory, and Dementia Among US Adults Aged 50 Years and Older.

Importance: Despite existing federal programs to increase access to food, food insecurity is common among US older adults. Food insecurity may affect Alzheimer disease and Alzheimer disease-related dementias via multiple mechanisms, yet there is almost no quantitative research evaluating this association. Objective: To examine whether food insecurity in older adults is associated with later-life cognitive outcomes. Design, Setting, and Participants: This cohort study of US residents aged 50 years and older from the US Health and Retirement Study was restricted to respondents with food insecurity data in 2013 and cognitive outcome data between calendar years 2014 and 2018. Analyses were conducted from June 1 to September 22, 2023. Exposure: Food insecurity status in 2013 was assessed using the validated US Department of Agriculture 6-item Household Food Security Module. Respondents were classified as being food secure, low food secure, and very low food secure. Main Outcomes and Measures: Outcomes were dementia probability and memory score (standardized to 1998 units), estimated biennially between 2014 and 2018 using a previously validated algorithm. Generalized estimation equations were fit for dementia risk and linear mixed-effects models for memory score, taking selective attrition into account through inverse probability of censoring weights. Results: The sample consisted of 7012 participants (18 356 person-waves); mean (SD) age was 67.7 (10.0) years, 4131 (58.9%) were women, 1136 (16.2%) were non-Hispanic Black, 4849 (69.2%) were non-Hispanic White, and mean (SD) duration of schooling was 13.0 (3.0) years. Compared with food-secure older adults, experiencing low food security was associated with higher odds of dementia (odds ratio, 1.38; 95% CI, 1.15-1.67) as was experiencing very low food security (odds ratio, 1.37; 95% CI, 1.11-1.59). Low and very low food security was also associated with lower memory levels and faster age-related memory decline. Conclusions and Relevance: In this cohort study of older US residents, food insecurity was associated with increased dementia risk, poorer memory function, and faster memory decline. Future studies are needed to examine whether addressing food insecurity may benefit brain health.

Metformin Cessation and Dementia Incidence.

Importance: Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends. Cessation of metformin therapy in people with diabetes typically occurs due to signs of kidney dysfunction but sometimes is due to less serious adverse effects associated with metformin. Objective: To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence. Design, Setting, and Participants: This cohort study was conducted at Kaiser Permanente Northern California, a large integrated health care delivery system, among a cohort of metformin users born prior to 1955 without history of diagnosed kidney disease at metformin initiation. Dementia follow-up began with the implementation of electronic health records in 1996 and continued to 2020. Data were analyzed from November 2021 through September 2023. Exposures: A total of 12 220 early terminators, individuals who stopped metformin with normal estimated glomerular filtration rate (eGFR), were compared with routine metformin users, who had not yet terminated metformin treatment or had terminated (with or without restarting) after their first abnormal eGFR measurement. Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration. Main outcomes and measures: The outcome of interest was all-cause incident dementia. Follow-up for early terminators and their matched routine users was started at age of termination for the early terminator. Survival models adjusted for sociodemographic characteristics and comorbidities at the time of metformin termination (or matched age). Mediation models with HbA1c level and insulin usage 1 and 5 years after termination tested whether changes in blood glucose or insulin usage explained associations between early termination of metformin and dementia incidence. Results: The final analytic sample consisted of 12 220 early terminators (5640 women [46.2%]; mean [SD] age at start of first metformin prescription, 59.4 [9.0] years) and 29 126 routine users (13 582 women [46.6%]; mean [SD] age at start of first metformin prescription, 61.1 [8.9] years). Early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users (hazard ratio, 1.21; 95% CI, 1.12 to 1.30). In mediation analysis, contributions to this association by changes in HbA1c level or insulin use ranged from no contribution (0.00 years; 95% CI, -0.02 to 0.02 years) for insulin use at 5 years after termination to 0.07 years (95% CI, 0.02 to 0.13 years) for HbA1c level at 1 year after termination, suggesting that the association was largely independent of changes in HbA1c level and insulin usage. Conclusions and Relevance: In this study, terminating metformin treatment was associated with increased dementia incidence. This finding may have important implications for clinical treatment of adults with diabetes and provides additional evidence that metformin is associated with reduced dementia risk.