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Traumatic brain injury (TBI) is an established risk factor for dementia. However, the magnitude of risk is highly variable across studies. Identification of sub-populations at highest risk, with careful consideration of potential sources of bias, is urgently needed to guide public health policy and research into mechanisms and treatments. We conducted a systematic review and meta-analysis of risk of all-cause dementia after all-severity TBI. We assessed for effect of participant age and sex, Veteran status, research methods, and region. The search window covered 1/1990 -1/2019. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. 32 studies met inclusion criteria. Data were pooled using random effects models. Population attributable risk (PAR) of dementia due to TBI in the U.S. was calculated by sex and Veteran status. Pooled risk ratio (RR) for dementia after TBI was 1.66 (95% CI 1.42-1.93). Younger age, male sex, and studies from Asia were associated with significantly higher risk; Veteran status was not. Risk of dementia associated with "head injury/trauma" was not significantly different from that associated with "TBI" diagnosis specifically. PAR of dementia due to TBI among U.S. Veterans was twice that of the general U.S. population, largely due to the high prevalence of TBI exposure in the majority male Veteran population. This meta-analysis found that TBI is associated with nearly 70% increased risk of dementia. Risk may be highest among younger adults, men, and cohorts in Asia. Efforts to prevent TBI and also to prevent post-TBI dementia are of high importance. Additionally, improved methods for diagnosing and tracking TBI on a public health level, such as national registries, may improve the quality and generalizability of future epidemiological studies investigating the association between TBI and dementia.

Much of the heterogeneity in the rate of cognitive decline and the age of dementia onset remains unexplained, and there is compelling data supporting psychosocial stressors as important risk factors. However, the literature has yet to come to a consensus on whether there is a causal relationship and, if there is, its direction and strength. This study estimates the relationship between lifecourse traumatic events and cognitive trajectories and predicted dementia incidence.Using data on 7,785 participants aged ≥65 years from the Health and Retirement Study, this study estimated the association between lifecourse experience of 10 traumatic events (e.g., losing a child) and trajectories of Telephone Interview for Cognitive Status from 2006 to 2016 using linear mixed-effects models and predicted incident dementia from 2006 to 2014 using cumulative incidence functions (data analysis was in 2020-2022). Inverse probability weights accounted for loss to follow-up and confounding by sex, education, race/ethnicity, and age.Experiencing 1 or more traumatic events over the lifecourse was associated with accelerated decline compared with experiencing no events (e.g., β= -0.05 [95% CI= -0.07, -0.02] Health and Retirement Study-Telephone Interview for Cognitive Status units/year; 1 vs 0 events). In contrast, experiencing traumatic events was associated with better cognitive function cross-sectionally. Furthermore, the impact of trauma on cognitive decline was of greater magnitude when it occurred after the age of 64 years. However, the magnitude and direction of association varied by the specific traumatic event. There were no associations with predicted incident dementia.These results suggest that researchers and clinicians should not aggregate traumatic events for understanding the risk of accelerated cognitive decline.

INTRODUCTION The aim of this research was to assess the association between inflammation and oral health and diabetes, as well as the mediating role of oral hygiene practice in this association. METHODS Data were from the 2009-2010 National Health and Nutrition Examination Survey. The analytical sample consisted of 2,191 respondents aged 50 and older. Poor oral health was clinically defined by significant tooth loss (STL) and periodontal disease (PD). Diabetes mellitus (DM) was determined by glycemic levels. The outcome variable was serum C-reactive protein (CRP) level, dichotomised as ≥1 mg/dL (elevated CRP) vs

PURPOSE: To assess baseline differences and longitudinal rate of change in retinal and choroidal imaging parameters between APOE ε4 carriers and non-carriers with normal cognition. DESIGN: Prospective study. SUBJECTS: 413 eyes of 218 individuals with normal cognition aged ≥55 years with known APOE status (98 ε4 carriers, 120 non-carriers). Exclusion criteria included diabetes mellitus, uncontrolled hypertension, glaucoma, and vitreoretinal or neurodegenerative disease. METHODS: Optical coherence tomography (OCT) and OCT angiography (OCTA) was performed at baseline and at 2 years [Zeiss Cirrus HD-OCT 5000 with AngioPlex (Zeiss Meditec, Dublin, CA)]. Groups were compared using sex- and age-adjusted generalized estimating equations. MAIN OUTCOME MEASURES: OCT: retinal nerve fiber layer thickness, macular ganglion cell-inner plexiform layer thickness, central subfield thickness (CST), choroidal vascularity index. OCTA: foveal avascular zone area, perfusion density (PD), vessel density, peripapillary capillary perfusion density and capillary flux index (CFI). Rate of change per year was calculated. RESULTS: At baseline, ε4 carriers had lower CST (p=0.018), PD in the 6mm Early Treatment Diabetic Retinopathy Study (ETDRS) circle (p=0.049), and temporal CFI (p=0.047). Seventy-one ε4 carriers and 78 non-carriers returned at 2 years; at follow-up, the 6mm ETDRS circle (p=0.05) and outer ring (p=0.049) showed lower PD in ε4 carriers, with no differences in rates of change between groups (all p>0.05). CONCLUSIONS: There was exploratory evidence of differences in CST, PD, and peripapillary CFI between APOE ε4 carriers and non-carriers, both with normal cognition. Larger and longer-term studies may further elucidate the potential value of these findings.

This study leveraged the twin study design, which controls for shared genetic and early life exposures, to investigate the association between traumatic brain injury (TBI) and dementia.Members of the National Academy of Sciences-National Research Council's Twins Registry of World War II male veterans were assigned a cognitive outcome based on a multi-step assessment protocol. History of TBI was obtained via interviews.Among 8302 individuals, risk of non-Alzheimer's disease (non-AD) dementia was higher in those with TBI (hazard ratio [HR] = 2.00, 95% confidence interval [CI], 0.97-4.12), than for AD (HR = 1.23, 95% CI, 0.76-2.00). To add more control of genetic and shared environmental factors, we analyzed 100 twin pairs discordant for both TBI and dementia onset, and found TBI-associated risk for non-AD dementia increased further (McNemar odds ratio = 2.70; 95% CI, 1.27-6.25).These findings suggest that non-AD mechanisms may underlie the association between TBI and dementia, potentially providing insight into inconsistent results from prior studies.

Background Dysregulation of some metabolic factors increases the risk of dementia. It remains unclear if overall metabolic dysregulation, or only certain components, contribute to cognitive aging and if these associations are sex specific. Methods Data from the 2006–2016 waves of the Health and Retirement Study (HRS) was used to analyze 7 103 participants aged 65 and older at baseline (58% women). We created a metabolic-dysregulation risk score (MDRS) composed of blood pressure/hypertension status, glycosylated hemoglobin (HbA1c)/diabetes status, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and waist circumference, and assessed cognitive trajectories from repeated measures of the HRS-Telephone Interview for Cognitive Status (HRS-TICS) over 10 years of follow-up. Linear mixed-effects models estimated associations between MDRS or individual metabolic factors (biomarkers) with mean and change in HRS-TICS scores and assessed sex-modification of these associations. Results Participants with higher MDRSs had lower mean HRS-TICS scores, but there were no statistically significant differences in rate of decline. Sex stratification showed this association was present for women only. MDRS biomarkers revealed heterogeneity in the strength and direction of associations with HRS-TICS. Lower HRS-TICS levels were associated with hypertension, higher HbA1c/diabetes, and lower HDL-C and TC, whereas faster rate of cognitive decline was associated with hypertension, higher HbA1c/diabetes, and higher TC. Participants with higher HbA1c/diabetes presented worse cognitive trajectories. Sex differences indicated that women with higher HbA1c/diabetes to have lower HRS-TICS levels, whereas hypertensive males presented better cognitive trajectory. Conclusions Our results demonstrate that metabolic dysregulation is more strongly associated with cognition in women compared with men, though sex differences vary by individual biomarker.

Background: Diagnostic tests, such as amyloid-β positron emission tomography (PET) scans, can increase appropriate therapeutic management for the underlying causes of cognitive decline. To evaluate the full utility of this diagnostic tool, information is needed on whether results from amyloid-β PET scans influence care-partner outcomes. Objective: This study examines the extent to which previous disclosure of elevated amyloid (suggestive of Alzheimer’s disease (AD) etiology) versus not-elevated amyloid (not suggestive of AD etiology) is associated with changes in care-partner wellbeing. Methods: The study used data derived from a national longitudinal survey of Medicare beneficiaries (n = 921) with mild cognitive impairment (MCI) or dementia and their care-partners. Care-partner wellbeing outcomes included depressive symptoms (PHQ-8), subjective burden (4-item Zarit burden score), and a 3-item measure of loneliness. Change was measured between 4 (Time 1) and 18 (Time 2) months after receiving the scan results. Adjusted linear regression models regressed change (Time 2-Time 1) in each outcome on scan result. Results: Care-partners were primarily white, non-Hispanic, college-educated, and married to the care recipient. Elevated amyloid was not associated with statistically significant Time 1 differences in outcomes or with statistically significant changes in depressive symptoms 0.22 (–0.18, 0.61), subjective burden 0.36 (–0.01, 0.73), or loneliness 0.15 (–0.01, 0.32) for care-partners from one time point to another. Conclusion: Given advances in AD biomarker testing, future research in more diverse samples is needed to understand the influence of scan results on care-partner wellbeing across populations.

Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

Contains fulltext : 282473.pdf (Publisher’s version ) (Open Access) Observational studies suggest that nutritional factors have a potential cognitive benefit. However, systematic reviews of randomised trials of dietary and nutritional supplements have reported largely null effects on cognitive outcomes and have highlighted study inconsistencies and other limitations. In this Personal View, the Nutrition for Dementia Prevention Working Group presents what we consider to be limitations in the existing nutrition clinical trials for dementia prevention. On the basis of this evidence, we propose recommendations for incorporating dietary patterns and the use of genetic, and nutrition assessment tools, biomarkers, and novel clinical trial designs to guide future trial developments. Nutrition-based research has unique challenges that could require testing both more personalised interventions in targeted risk subgroups, identified by nutritional and other biomarkers, and large-scale and pragmatic study designs for more generalisable public health interventions across diverse populations.

The primary objective of this paper was to examine perspectives and experiences of individuals with cognitive impairment who received an amyloid PET scan and their care partners, with regard to the process, logistics, and decision-making associated with receiving an amyloid PET scan and its results.Structured telephone interviews were conducted with 200 randomly sampled scan recipient/care partner dyads from the CARE IDEAS study. The audio-recorded, transcribed responses were analyzed using an inductive qualitative content analytic approach.Participating individuals and care partners described their experiences in seeking a diagnosis for memory issues, including decision-making and logistics involved with receiving an amyloid PET scan. Participants discussed the factors contributing to their decision to seek a diagnosis for their memory issues and their hopes and expectations in completing the scan. Participants also described the trajectory of this process, and although some described relatively straightforward trajectories, others described problems associated with identifying appropriate providers and coordinating care across numerous providers to obtain a diagnosis for their memory issues. Participants described an additional challenge of physicians attributing cognitive decline to normal aging, rather than signs of a neurodegenerative disorder.Findings shed light on the barriers and delays that individuals and care partners experience in connecting with physicians and obtaining a comprehensive evaluation for cognitive problems. Results from this study have implications for physicians who provide care to older adults, and specifically highlight the need for greater care coordination and clearer communication with and systems of referral for patients.

BACKGROUND/OBJECTIVES To better understand the role of sensory loss as a potentially modifiable risk factor for cognitive decline, this study examined cognitive decline in relation to single modality hearing or vision loss and dual sensory loss. DESIGN Longitudinal secondary data analysis. SETTING The Health and Retirement Study (HRS) and its supplement: The Aging, Demographics, and Memory Study (ADAMS). PARTICIPANTS Individuals aged 73 and older (N = 295). MEASUREMENTS Hearing loss was defined by an inability to hear sounds of 25 dB at frequencies between 0.5 and 4.0 kHz in either ear. Vision loss was defined as having corrected binocular vision worse than 20/40. Dual sensory loss was defined as having both hearing and vision loss. We used one time point of hearing and vision data objectively measured in ADAMS Wave C (June 2006-May 2008) and five waves of cognitive function data measured by the HRS version of the Telephone Interview for Cognitive Status in HRS (2006-2014). Multilevel mixed models were used. RESULTS Among the participants, 271 completed a hearing assessment and 120 had hearing loss; 292 completed a vision assessment and 115 had vision loss; 52 had dual sensory loss. Older adults with hearing loss had a significantly faster rate of cognitive decline as they aged compared to those with normal hearing (β = -0.16, P

ObjectiveTo investigate whether sex and race differences exist in dementia diagnosis risk associated with traumatic brain injury (TBI) among older veterans.MethodsUsing Fine-Gray regression models, we investigated incident dementia diagnosis risk with TBI exposure by sex and race.ResultsAfter the exclusion of baseline prevalent dementia, the final sample (all veterans ≥55 years of age diagnosed with TBI during the 2001–2015 study period and a random sample of all veterans receiving Veterans Health Administration care) included nearly 1 million veterans (4.3% female; 81.8% White, 11.5% Black, and 1.25% Hispanic), 96,178 with TBI and 903,462 without TBI. Compared to those without TBI, Hispanic veterans with TBI were almost 2 times more likely (17.0% vs 10.3%; hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.51–2.01), Black veterans with TBI were >2 times more likely (11.2% vs 6.4%; HR 2.15, 95% CI 2.02–2.30), and White veterans with TBI were nearly 3 times more likely to receive a dementia diagnosis (12.0% vs 5.9%; HR 2.71, 95% CI 2.64–2.77). A significant interaction between TBI and race for dementia diagnosis was observed (p < 0.001). Both male and female veterans with TBI were more than twice as likely (men 11.8% vs 5.9%, HR 2.60, 95% CI 2.54–2.66; women 6.3% vs 3.1%, HR 2.36, 95% CI 2.08–2.69) to receive a diagnosis of dementia compared to those without. There was a significant interaction effect between sex and TBI (p = 0.02), but the magnitude of differences was small.ConclusionsIn this large, nationwide cohort of older veterans, all race groups with TBI had increased risk of dementia diagnosis, but there was an interaction effect such that White veterans were at greatest risk for dementia after TBI. Further research is needed to understand the mechanisms for this discrepancy. Differences in dementia diagnosis risk for men and women after TBI were significant but small, and male and female veterans had similarly high risks of dementia diagnosis after TBI.

Consideration of place of care is the first step in long-term care (LTC) planning and is critical for patients diagnosed with Alzheimer’s disease; yet, drivers of consideration of place of care are unknown. We apply machine learning algorithms to cross-sectional data from the CARE-IDEAS (Caregivers’ Reactions and Experience: Imaging Dementia—Evidence for Amyloid Scanning) study ( n = 869 dyads) to identify drivers of patient consideration of institutional, in-home paid, and family care. Although decisions about LTC are complex, important drivers included whether patients consulted with a financial planner about LTC, patient demographics, loneliness, and geographical proximity of family members. Findings about consulting with a financial planner match literature showing that perceived financial constraints limit the range of choices in LTC planning. Well-documented drivers of institutionalization, such as care partner burden, were not identified as important variables. By understanding which factors drive patients to consider each type of care, clinicians can guide patients and their families in LTC planning.

Dream-enacting behavior is a characteristic feature of rapid eye movement sleep behavior disorder, the most specific prodromal marker of synucleinopathies. Pesticide exposure may be associated with dream-enacting behaviors, but epidemiological evidence is limited.To examine high pesticide exposure events in relation to dream-enacting behaviors among farmers in the Agricultural Health Study.We conducted multivariable logistic regression analyses to examine high pesticide exposure events reported from 1993 to 1997 in relation to dream-enacting behaviors assessed from 2013 to 2015 among 11,248 farmers (age 47 ± 11 years).A history of dream-enacting behaviors was reported by 939 (8.3%) farmers. Compared with farmers who did not report any high pesticide exposure event, those who reported were more likely to endorse dream-enacting behaviors 2 decades later (odds ratio = 1.75; 95% confidence interval [CI], 1.49-2.05). The association appeared stronger when there was a long delay in washing with soap and water after the event (2.63 [95% CI, 1.62-4.27] for waiting6 hours vs. 1.71 [95% CI, 1.36-2.15] for washing within 30 minutes) and when the exposure involved the respiratory or digestive tract (2.04 [95% CI, 1.62-2.57] vs. 1.58 [95% CI, 1.29-1.93] for dermal contact only). In the analyses of specific pesticides involved, we found positive associations with two organochlorine insecticides (dichlorodiphenyltrichloroethane and lindane), four organophosphate insecticides (phorate, ethoprop, terbufos, and parathion), two herbicides (alachlor and paraquat), and fungicides as a group.This study provides the first epidemiological evidence that high pesticide exposures may be associated with a higher risk of dream-enacting behaviors. © 2022 International Parkinson and Movement Disorder Society.

Background: Older patients (≥65 years) with mild cognitive impairment (MCI) are undertreated for cardiovascular disease (CVD). One reason for this disparity could be that patients with MCI might underestimate the chances of CVD and overestimate dementia. Objective: To compare conceptions of health risk between older patients with MCI and normal cognition (NC) and their care partners. Methods: We conducted a multi-center mixed-methods study of patient-care partner dyads completing written quantitative surveys (73% response rate; 127 dyads: 66 MCI and 61 NC) or semi-structured interviews (20 dyads: 11 MCI, and 9 NC). Surveys assessed two-year patient risks of dementia, heart attack, stroke, and fall. Interviews assessed similar health risks and reasons for risk perceptions. Results: On surveys, a similarly low proportion of MCI and NC patients felt they were at risk of stroke (5% versus 2%; p = 0.62) and heart attack (2% versus 0%; p = 0.99). More MCI than NC patients perceived dementia risk (26% versus 2%; p

To address the rising prevalence of Alzheimer's disease and related dementias, effective interventions that can be widely disseminated are warranted. The Preventing Alzheimer's with Cognitive Training study (PACT) investigates a commercially available computerized cognitive training program targeting improved Useful Field of View Training (UFOVT) performance. The primary goal is to test the effectiveness of UFOVT to reduce incidence of clinically defined mild cognitive impairment (MCI) or dementia with a secondary objective to examine if effects are moderated by plasma β-amyloid level or apolipoprotein E e4 (APOE e4) allele status.This multisite study utilizes a randomized, controlled experimental design with blinded assessors and investigators. Individuals who are 65 years of age and older are recruited from the community. Eligible participants who demonstrate intact cognitive status (Montreal Cognitive Assessment score 25) are randomized and asked to complete 45 sessions of either a commercially available computerized-cognitive training program (UFOVT) or computerized games across 2.5 years. After three years, participants are screened for cognitive decline. For those demonstrating decline or who are part of a random subsample, a comprehensive neuropsychological assessment is completed. Those who perform below a pre-specified level are asked to complete a clinical evaluation, including an MRI, to ascertain clinical diagnosis of normal cognition, MCI, or dementia. Participants are asked to provide blood samples for analyses of Alzheimer's disease related biomarkers.The PACT study addresses the rapidly increasing prevalence of dementia. Computerized cognitive training may provide a non-pharmaceutical option for reducing incidence of MCI or dementia to improve public health.The PACT study is registered at http://Clinicaltrials.govNCT03848312.

Objectives To better understand the temporal dynamics of progression from cognitive decline to onset of dementia in the dementia-free older population in the United States. Methods We used longitudinal data from a diverse national population-based sample of older adults (N = 531) in the Aging, Demographics, and Memory Study from the Health and Retirement Study with repeated measures of cognitive function and dementia diagnosis during 12 years of follow-up from 1996 to 2009. We employed joint latent class mixed models to estimate the association between cognitive change and competing risks of dementia and nondementia death and identify heterogeneity in the age profiles of such association adjusting for baseline characteristics. Results Our analyses found 3 latent classes with distinct age profiles of cognitive decline and associated risk of dementia and mortality: “Rapid Cognitive Decline” (19.6%), “Moderate Progression” (44.6%), and “Optimal Cognitive Aging” (35.8%). When simultaneously accounting for cognitive trajectories and time-to-dementia/death, we also found associations of baseline covariates with slope of cognitive decline (e.g., steeper decline among non-Hispanic Blacks and more educated) and risk of dementia (e.g., greater risk for females and apolipoprotein E-4 carriers, but no difference by education level) that differ substantially from those in separate longitudinal mixed models or survival models. Discussion The differential age patterns of cognitive decline predicting dementia incidences identified in this study suggest variation in the course of cognitive aging in older adults that may inform future etiological and intervention studies.

Objective: Both diabetes mellitus (DM) and poor oral health are common chronic conditions and risk factors of Alzheimer’s disease and related dementia among older adults. This study assessed the effects of DM and complete tooth loss (TL) on cognitive function, accounting for their interactions. Methods: Longitudinal data were obtained from the 2006, 2012, and 2018 waves of the Health and Retirement Study. This cohort study included 7,805 respondents aged 65 years or older with 18,331 person-year observations. DM and complete TL were self-reported. Cognitive function was measured by the Telephone Interview for Cognitive Status. Random-effect regressions were used to test the associations, overall and stratified by sex. Results: Compared with older adults without neither DM nor complete TL, those with both conditions (b = -1.35, 95% confidence interval [CI]: -1.68, -1.02), with complete TL alone (b = -0.67, 95% CI: -0.88, -0.45), or with DM alone (b = -0.40, 95% CI: -0.59, -0.22), had lower cognitive scores. The impact of having both conditions was significantly greater than that of having DM alone (p Conclusion: The co-occurrence of DM and complete TL poses an additive risk for cognition. Healthcare and family-care providers should pay attention to the cognitive health of patients with both DM and complete TL. Continued efforts are needed to improve older adults’ access to dental care, especially for individuals with DM.

Introduction Alzheimer's disease (AD) is a continuum with neuropathologies manifesting years before clinical symptoms; thus, AD research is attempting to identify more disease-modifying approaches to test treatments administered before full disease expression. Designing such trials in cognitively normal elderly individuals poses unique challenges. Methods The TOMMORROW study was a phase 3 double-blind, parallel-group study designed to support qualification of a novel genetic biomarker risk assignment algorithm (BRAA) and to assess efficacy and safety of low-dose pioglitazone to delay onset of mild cognitive impairment due to AD. Eligible participants were stratified based on the BRAA (using TOMM40 rs 10524523 genotype, Apolipoprotein E genotype, and age), with high-risk individuals receiving low-dose pioglitazone or placebo and low-risk individuals receiving placebo. The primary endpoint was time to the event of mild cognitive impairment due to AD. The primary objectives were to compare the primary endpoint between high- and low-risk placebo groups (for BRAA qualification) and between high-risk pioglitazone and high-risk placebo groups (for pioglitazone efficacy). Approximately 300 individuals were also asked to participate in a volumetric magnetic resonance imaging substudy at selected sites. Results The focus of this paper is on the design of the study; study results will be presented in a separate paper. Discussion The design of the TOMMORROW study addressed many key challenges to conducting a dual-objective phase 3 pivotal AD clinical trial in presymptomatic individuals. Experiences from planning and executing the TOMMORROW study may benefit future AD prevention/delay-of-onset trials., Highlights • Applied a genetics-based algorithm to enrich for near-term risk of mild cognitive impairment due to Alzheimer's disease. • Assessed early cognitive decline with a multidomain neuropsychological test battery. • Utilized time to mild cognitive impairment due to Alzheimer's disease as study endpoint. • Simultaneous evaluation of a biomarker and therapeutic.

Objective To evaluate determinants of willingness to accept a treatment to return memory to normal among persons with cognitive impairment who received an amyloid positron emission tomography (PET) scan and their care partner and discordance in risk taking. Methods Using data from CARE-IDEAS (n=1872 dyads), a supplement of the Imaging Dementia-Evidence for Amyloid Scanning study, we predicted scan recipient's willingness to accept a risky treatment, the risk care partners believed their care recipient would accept, and discordance in these perceptions. Results Scan recipients were willing to accept a treatment with a 27.94% (SD=34.36) risk of death. Care partners believed their care recipient would accept a 29.68% (SD=33.74) risk of death; thus, overestimating risk acceptance by 1.74 (SD=41.88) percentage points. A positive amyloid PET scan was associated with willingness to accept greater risk. Poorer functioning of the care recipient was associated with care partners believing their care recipient would accept more risk. The amyloid PET scan result was not significantly associated with discordance, but poorer functioning of the care recipient resulted in care partners overestimating risk. Conclusions Scan recipients were willing to accept a treatment with a high risk of death. Discordance was affected by scan recipient's having poorer functioning.

The National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry is one of the oldest, national population-based twin registries in the USA. It comprises 15,924 White male twin pairs born in the years 1917–1927 (N = 31.848), both of whom served in the armed forces, chiefly during World War II. This article updates activities in this registry since the most recent report in Twin Research and Human Genetics (Page, 2006). Records-based data include information from enlistment charts and Veterans Administration data linkages. There have been three major epidemiologic questionnaires and an education and earnings survey. Separate data collection efforts with the NAS-NRC registry include the National Heart, Lung, and Blood Institute (NHLBI) subsample, the Duke Twins Study of Memory in Aging and a clinically based study of Parkinson’s disease. Progress has been made on consolidating the various data holdings of the NAS-NRC Twin Registry. Data that had been available through the National Academy of Sciences are now freely available through National Archive of Computerized Data on Aging (NACDA).

We pilot tested a carepartner-assisted intervention to improve oral hygiene in persons with cognitive impairment (participants) and help carepartners become leaders who can adapt approaches that foster participants' ability to develop new skills for oral hygiene care. Following the intervention, we conducted interviews with participants and carepartners to understand their challenges in working together to learn new oral hygiene skills. Participants reported challenges such as frustration using the electric toothbrush correctly, lack of desire to change, uncertainty about correctness of technique, and difficulty sustaining two minutes of toothbrushing. Carepartners reported challenges such as learning a new way of toothbrushing, learning new communication techniques, switching from instructing to working together, learning to balance leading with being too bossy, and being mindful of word choices. Findings suggested that despite challenges, participants were able to learn adaptive strategies to support new oral hygiene behaviors with support of the carepartner as the adaptive leader.

Introduction Mitochondrial dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). Accordingly, drugs that positively influence mitochondrial function are being evaluated in delay-of-onset clinical trials with at-risk individuals. Such ongoing clinical research can be advanced by developing a better understanding of how these drugs affect intermediate brain phenotypes associated with both AD risk and pathophysiology. Methods Using a randomized, parallel-group, placebo-controlled design in 55 healthy elderly volunteers, we explored the effects of oral, low-dose pioglitazone, a thiazolidinedione with promitochondrial effects, on hippocampal activity measured with functional magnetic resonance imaging during the encoding of novel face–name pairs. Results Compared with placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg, or 6.0 mg) administered daily for 14 days was associated with significant increases in right hippocampal activation during encoding of novel face–name pairs at day 7 and day 14, relative to baseline. Discussion Our exploratory analyses suggest that low-dose pioglitazone has measurable effects on mnemonic brain function associated with AD risk and pathophysiology., Highlights • Right hippocampal activity increased after 7 and 14 days of 0.6 mg of oral pioglitazone administration. • Pioglitazone-associated hippocampal effects were not manifested at the level of memory performance. • Nonspecific increases in distributed brain activity at higher pioglitazone doses (>0.6 mg).

BACKGROUND: Older patients (65+) with mild cognitive impairment (MCI) receive less guideline-concordant care for cardiovascular disease (CVD) and other conditions than patients with normal cognition (NC). One potential explanation is that patients with MCI want less treatment than patients with NC; however, the treatment preferences of patients with MCI have not been studied. OBJECTIVE: To determine whether patients with MCI have different treatment preferences than patients with NC. DESIGN: Cross-sectional survey conducted at two academic medical centers from February to December 2019 PARTICIPANTS: Dyads of older outpatients with MCI and NC and patient-designated surrogates. MAIN MEASURES: The modified Life-Support Preferences-Predictions Questionnaire score measured patients’ preferences for life-sustaining treatment decisions in six health scenarios including stroke and acute myocardial infarction (range, 0–24 treatments rejected with greater scores indicating lower desire for treatment). KEY RESULTS: The survey response rate was 73.4%. Of 136 recruited dyads, 127 (93.4%) completed the survey (66 MCI and 61 NC). The median number of life-sustaining treatments rejected across health scenarios did not differ significantly between patients with MCI and patients with NC (4.5 vs 6.0; P=0.55). Most patients with MCI (80%) and NC (80%) desired life-sustaining treatments in their current health (P=0.99). After adjusting for patient and surrogate factors, the difference in mean counts of rejected treatments between patients with MCI and patients with NC was not statistically significant (adjusted ratio, 1.08, 95% CI, 0.80–1.44; P=0.63). CONCLUSION: We did not find evidence that patients with MCI want less treatment than patients with NC. These findings suggest that other provider and system factors might contribute to patients with MCI getting less guideline-concordant care. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06839-w.

Objectives To quantify the dose-response associations between tooth loss and risk of cognitive impairment and dementia. Design Longitudinal studies that examined the association between tooth loss and cognitive function were systematically searched on 6 databases through March 1, 2020. The study adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Risk estimates were pooled using random-effects models. The dose-response associations were assessed using generalized least squares spline models. Setting and Participants Adults from community, institution, outpatient or in-hospital were included in the meta-analysis. Measures Cognitive impairment and dementia were defined by neuropsychological tests, diagnostic criteria, or medical records. Tooth loss was self-reported or assessed by clinical examinations. Results Fourteen studies were entered into the meta-analysis, including 34,074 participants and 4689 cases with diminished cognitive function. Participants with more tooth loss had a 1.48 times higher risk of developing cognitive impairment [95% confidence interval (CI) 1.18–1.87] and 1.28 times higher risk of being diagnosed with dementia (95% CI 1.09–1.49); however, the association was nonsignificant for participants using dentures (relative risk = 1.10, 95% CI 0.90–1.11). Eight studies were included in the dose-response analysis, and data supported the use of linear models. Each additional tooth loss was associated with a 0.014 increased relative risk of cognitive impairment and 0.011 elevated relative risks of dementia. Edentulous participants faced a 1.54 times higher risk of cognitive impairment and a 1.40 times higher risk of being diagnosed with dementia. Conclusions and Implications Moderate-quality evidence suggested tooth loss was independently associated with cognitive impairment and dementia; risk of diminished cognitive function increased with incremental numbers of teeth lost. Furthermore, timely prosthodontic treatment with dentures may reduce the progression of cognitive decline related to tooth loss.

Background and objectivesOlder adults with cognitive impairment often experience poor oral health outcomes due to inadequate oral hygiene practices. This pilot study aimed to evaluate the feasibility of a care partner-assisted intervention to improve the oral hygiene of community-dwelling older adults with cognitive impairment.Material and methodsThe 6-month intervention included 25 older adults with mild dementia or mild cognitive impairment, who were randomly assigned to Treatment Group 1 or Treatment Group 2. Treatment Group 1 (n=7) received an educational booklet. Treatment Group 2 (n=18) received a booklet, a tailored care plan for the participants with cognitive impairment and the care partner received four coaching sessions to learn to facilitate good oral hygiene. Both groups received electric toothbrushes. The study consisted of a 3-month active intervention and 3-month maintenance phase. The outcomes of gingival index, plaque index and overall oral health status based on the Oral Health Assessment Tool were measured at baseline, 3months (end of active intervention) and 6months of the study.ResultsThis study had very low dropout rate. Participants' oral hygiene improved in this study. In comparison to Treatment Group 1, participants in Treatment Group 2 had a greater reduction in plaque level and gingival inflammation, and greater improvement in overall oral health status.ConclusionThis study demonstrates the feasibility of this intervention designed to improve the oral health of persons with cognitive impairment and it lays the foundation for using this protocol in a future large randomised clinical trial.

Purpose: This work assesses the intrasession repeatability of capillary perfusion density (CPD) and capillary flux index (CFI) measurements on peripapillary optical coherence tomography angiography (OCTA) in healthy eyes of older adults. Methods: In this cross-sectional study, healthy volunteers aged 50 years or older underwent 4.5 × 4.5 mm OCTA imaging centered on the optic nerve head using Zeiss Cirrus HD-5000 AngioPlex (Carl Zeiss Meditec). Two consecutive images were acquired in the same eye during a single study session. CPD and CFI were assessed using AngioPlex Software (version 11.0.0.29946) for the radial peripapillary capillary plexus (average over whole scan area) and 4 quadrants (superior, inferior, temporal, and nasal). CPD and CFI repeatability was assessed by intraclass correlation (ICC), mean interocular differences using 2-tailed t test, and association with age using generalized estimating equations. Results: A total of 150 images were acquired from 75 eyes of 47 patients. For CPD, ICC results ranged from 0.7160 (nasal CPD) to 0.9218 (average CPD). For CFI, ICC results ranged from 0.6167 (temporal CFI) to 0.8976 (inferior CFI). Temporal CFI was significantly different between right and left eyes of the same patient ( P = .03). CPD and CFI decreased with age in all analyses (average CPD β coefficient –0.00172, P < .001; average CFI β coefficient −0.00278, P < .001). Conclusions: Moderate to good repeatability was observed for most peripapillary OCTA metrics; temporal measurements were least repeatable for CPD and CFI. Peripapillary CPD and CFI decrease with age even beyond the fifth decade in healthy older adults.

Background The CAregiver Perceptions About CommunIcaTion with Clinical Team members (CAPACITY) instrument measures how care partners perceive themselves to be supported by the patient's health care team and their experiences communicating with the team. Objectives The objective of this study was to assess the measurement properties (ie, structural validity of the construct and internal consistency) of the CAPACITY instrument in care partners of patients with cognitive impairment, and to examine whether care partner health literacy and patient cognitive impairment are associated with a higher or lower CAPACITY score. Research design This was a retrospective cohort study. Subjects A total of 1746 dyads of community-dwelling care partners and older adults in the United States with cognitive impairment who obtained an amyloid positron emission tomography scan. Measures The CAPACITY instrument comprises 12 items that can be combined as a total score or examined as subdomain scores about communication with the team and care partner capacity-assessment by the team. The 2 covariates of primary interest in the regression model are health literacy and level of cognitive impairment of the patient (Modified Telephone Interview Cognitive Status). Results Confirmatory factor analysis showed the CAPACITY items fit the expected 2-factor structure (communication and capacity). Higher cognitive functioning of patients and higher health literacy among care partners was associated with lower communication domain scores, lower capacity domain scores, and lower overall CAPACITY scores. Conclusions The strong psychometric validity of the CAPACITY measure indicates it could have utility in other family caregivers or care partner studies assessing the quality of interactions with clinical teams. Knowing that CAPACITY differs by care partner health literacy and patient impairment level may help health care teams employ tailored strategies to achieve high-quality care partner interactions.

Objective This pilot study assessed feasibility of video-enhanced care management for complex older veterans with suspected mild cognitive impairment (CI) and their care partners, compared with telephone delivery. Design Pilot randomized controlled trial. Setting Durham Veterans Affairs Health Care System. Participants Participants were enrolled as dyads, consisting of veterans aged 65 years or older with complex medical conditions (Care Assessment Need score ≥90) and suspected mild CI (education-adjusted Modified Telephone Interview for Cognitive Status score 20-31) and their care partners. Intervention The 12-week care management intervention consisted of monthly calls from a study nurse covering medication management, cardiovascular disease risk reduction, physical activity, and sleep behaviors, delivered via video compared with telephone. Measurements Dyads completed baseline and follow-up assessments to assess feasibility, acceptability, and usability. Results Forty veterans (mean (standard deviation (SD)) age = 72.4 (6.1) years; 100% male; 37.5% Black) and their care partners (mean (SD) age = 64.7 (10.8) years) were enrolled and randomized to telephone or video-enhanced care management. About a third of veteran participants indicated familiarity with relevant technology (regular tablet use and/or experience with videoconferencing); 53.6% of internet users were comfortable or very comfortable using the internet. Overall, 43 (71.7%) care management calls were completed in the video arm and 52 (86.7%) were completed in the telephone arm. Usability of the video telehealth platform was rated higher for participants already familiar with technology used to deliver the intervention (mean (SD) System Usability Scale scores: 65.0 (17.0) vs 55.6 (19.6)). Veterans, care partners, and study nurses reported greater engagement, communication, and interaction in the video arm. Conclusion Video-delivered care management calls were feasible and preferred over telephone for some complex older adults with mild CI and their care partners. Future research should focus on understanding how to assess and incorporate patient and family preferences related to uptake and maintenance of video telehealth interventions.

Background Amyloid-β PET scans will likely become an integral part of the diagnostic evaluation for Alzheimer's disease if Medicare approves reimbursement for the scans. However, little is known about patients' and their care partners' interpretation of scan results. Objective This study seeks to understand how accurately patients with mild cognitive impairment (MCI) or dementia and their care partners report results of amyloid-β PET scans and factors related to correct reporting. Methods A mixed-methods approach was used to analyze survey data from 1,845 patient-care partner dyads and responses to open-ended questions about interpretation of scan results from a sub-sample of 200 dyads. Results Eighty-three percent of patients and 85% of care partners correctly reported amyloid-β PET scan results. Patients' higher cognitive function was associated with a small but significant decrease in the predicted probability of not only patients accurately reporting scan results (ME: -0.004, 95% CI: -0.007, -0.000), but also care partners accurately reporting scan results (ME: -0.006, 95% CI: -0.007, -0.001), as well as decreased concordance between patient and care partner reports (ME: -0.004, 95% CI: -0.007, -0.001). Content analysis of open-ended responses found that participants who reported the scan results incorrectly exhibited more confusion about diagnostic terminology than those who correctly reported the scan results. Conclusion Overall, patients with MCI or dementia showed high rates of accurate reporting of amyloid-β PET scan results. However, responses to questions about the meaning of the scan results highlight the need for improved provider communication, including providing written explanations and better prognostic information.

Introduction Assessment of preclinical Alzheimer's disease (AD) requires reliable and validated methods to detect subtle cognitive changes. The battery of standardized cognitive assessments that is used for diagnostic criteria for mild cognitive impairment due to AD in the TOMMORROW study have only been fully validated in English-speaking countries. We conducted a validation and normative study of the German language version of the TOMMORROW neuropsychological test battery, which tests episodic memory, language, visuospatial ability, executive function, and attention. Methods German-speaking cognitively healthy controls (NCs) and subjects with AD were recruited from a memory clinic at a Swiss medical center. Construct validity, test–retest, and alternate form reliability were assessed in NCs. Criterion and discriminant validities of the cognitive measures were tested using logistic regression and discriminant analysis. Cross-cultural equivalency of performance of the German language tests was compared with English language tests. Results A total of 198 NCs and 25 subjects with AD (aged 65–88 years) were analyzed. All German language tests discriminated NCs from persons with AD. Episodic memory tests had the highest potential to discriminate with almost twice the predictive power of any other domain. Test-retest reliability of the test battery was adequate, and alternate form reliability for episodic memory tests was supported. For most tests, age was a significant predictor of group effect sizes; therefore, normative data were stratified by age. Validity and reliability results were similar to those in the published US cognitive testing literature. Discussion This study establishes the reliability and validity of the German language TOMMORROW test battery, which performed similarly to the English language tests. Some variations in test performance underscore the importance of regional normative values. The German language battery and normative data will improve the precision of measuring cognition and diagnosing incident mild cognitive impairment due to AD in clinical settings in German-speaking countries.

Introduction We evaluated the association between neighborhood socioeconomic status (NSES) and sleep quality on cognitive decline in the Health and Retirement Study. Methods Health and Retirement Study participants (n = 8090), aged 65+ with DNA and multiple biennial cognitive observations (abbreviated Telephone Interview for Cognitive Status), were included. Participants were grouped into quartiles of NSES and sleep quality scores. We adjusted for apolipoprotein E e4, demographic, and cardiovascular risk factors. Random effects modeling evaluated cognitive change over time. Results NSES and sleep were significantly associated with cognitive decline, and there was a significant interaction between them ( P = .02). Significant differences between high/low NSES and high/low sleep quality ( P Discussion Sleep and NSES were associated with cognitive decline; the association between sleep and cognition appeared stronger among those with low NSES. The association between low NSES, poor sleep quality, and cognitive decline was roughly equivalent to the association between apolipoprotein E e4 and cognitive decline.

Background The etiology of dementias and cognitive decline remain largely unknown. It is widely accepted that inflammation in the central nervous system plays a critical role in the pathogenesis of dementia. However, less is known about the role of the peripheral immune system and interactions with cortisol, though evidence suggests that these, too, may play a role. Methods Using data from 1337 participants aged 60+ years from the Sacramento Area Latino Study of Aging (observational cohort) we investigated variation in trajectories of cognitive decline by pathogen IgG and cytokine levels. Linear mixed effects models were used to examine the association between baseline Interleukin (IL)−6, C-reactive protein, tumor necrosis factor (TNF)- α , and five persistent pathogens’ IgG response and trajectories of cognition over 10 years, and to examine interactions between immune biomarkers and cortisol. Stratified cumulative incidence functions were used to assess the relation between biomarkers and incident dementia. Inverse probability weights accounted for loss-to-follow-up and confounding. Results IL-6, TNF- α , and CMV IgG were statistically significantly associated with a higher log of Modified Mini-Mental State Examination errors (IL-6, β = 0.0935 (95%CI: 0.055, 0.13), TNF-alpha β = 0.0944 (95%CI: 0.032, 0.157), and CMV, β = 0.0409 (95%CI: 0.013, 0.069)). Furthermore, cortisol interacted with HSV-1 and IL-6, and CRP for both cross-sectional cognitive function and rate of decline. No statistically significant relationship was detected between biomarkers and incidence of dementia. Conclusions These findings support the theory that the peripheral immune system may play a role in cognitive decline but not incident dementia. Furthermore, they identify specific markers amenable for intervention for slowing decline.