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INTRODUCTION: Plasma biomarkers of Alzheimer's disease and related dementias predict global cognitive performance and decline over time; it remains unclear how they associate with changes in different dementia syndromes affecting distinct cognitive domains. METHODS: In a prospective study with repeated assessments of a randomly selected population‐based cohort (n = 787, median age 73), we evaluated performance and decline in different cognitive domains over up to 8 years in relation to plasma concentrations of amyloid beta 42/40 (Aβ42/40) ratio, phosphorylated tau181 (p‐tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). RESULTS: Cross‐sectionally, memory showed the strongest associations with p‐tau181, and attention, executive, and visuospatial functions with NfL. Longitudinally, memory decline was distinguishable with all biomarker profiles dichotomized according to data‐driven cutoffs, most efficiently with Aβ42/40. GFAP and Aβ42/40 were the best discriminators of decline patterns in language and visuospatial functions, respectively. DISCUSSION: These relatively non‐invasive tests may be beneficial for clinical screening after replication in other populations and validation through neuroimaging or cerebrospinal fluid analysis. Highlights: We performed a prospective study with up to 8 years of repeated domain‐specific cognitive assessments and baseline plasma Alzheimer's disease and related dementias biomarker measurements in a randomly selected population‐based cohort.We considered distinct growth curves of trajectories of different cognitive domains and survival bias induced by missing data by adding quadratic time and applying joint modeling technique.Cross‐sectionally, memory showed the strongest associations with plasma phosphorylated tau181, while attention, executive, and visuospatial functions were most strongly associated with neurofilament light chain.Longitudinally, memory and visuospatial declines were most efficiently distinguished by dichotomized amyloid beta 42/40 profile among all plasma biomarkers, while language was by dichotomized glial fibrillary acidic protein.These relatively non‐invasive tests may be beneficial for clinical screening; however, they will need replication in other populations and validation through neuroimaging and/or cerebrospinal fluid assessments. [ABSTRACT FROM AUTHOR]

INTRODUCTION: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non‐Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology‐affected regions and cognition. METHODS: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions. Individual regression models tested associations of UWMC in beta‐amyloid (Aβ) or tau pathology‐affected regions with cognition overall, stratified by racialized group, and with a racialized group interaction. RESULTS: In 201 older adults ranging from cognitively unimpaired to AD, BA participants exhibited greater UWMC and worse cognition than nHW participants. UWMC was negatively associated with cognition in 17 and 5 Aβ‐ and tau‐affected regions, respectively. Racialization did not modify these relationships. DISCUSSION: Differential UWMC burden, not differential UWMC‐and‐cognition associations, may drive clinical AD disparities between racialized groups. Highlights: Unhealthy white matter connectivity (UWMC) in Alzheimer's disease (AD) pathology–affected brain regions is associated with cognition.Relationships between UWMC and cognition are similar between Black American (BA) and non‐Hispanic White (nHW) individuals.More UWMC may partially drive higher clinical AD burden in BA versus nHW populations.UWMC risk factors, particularly social and environmental, should be identified. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex‐dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging. METHODS: Thirty‐three females and 21 males 65 to 93 years of age with no cognitive impairment performed a face‐name associative memory functional magnetic resonance imaging (fMRI) task with a 2‐year follow‐up. We acquired baseline carbon 11‐labeled Pittsburgh compound B ([11C]PiB) positron emission tomography (PET) and T2‐weighted fluid‐attenuated inversion recovery (T2‐FLAIR) MRI to quantify amyloid β (Aβ) burden and white matter hyperintensity (WMH) volume, respectively. RESULTS: Males had increased hippocampal‐prefrontal connectivity over 2 years, associated with greater Aβ burden. Females had increased bilateral hippocampal functional connectivity, associated with greater WMH volume. DISCUSSION: These findings suggest sex‐dependent compensatory mechanisms in the memory network in the presence of cerebrovascular and AD pathologies and may explain the accelerated trajectory of cognitive decline in females. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Cognitive abilities have substantial heritability throughout life, as shown by twin‐ and population‐based studies. However, there is limited understanding of the genetic factors related to cognitive decline in aging across neurocognitive domains. METHODS: We conducted a meta‐analysis on 3045 individuals aged ≥65, derived from three population‐based cohorts, to identify genetic variants associated with the decline of five neurocognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive decline. We also conducted gene‐based and functional bioinformatics analyses. RESULTS: Apolipoprotein E (APOE)4 was significantly associated with decline of memory (p = 5.58E‐09) and global cognitive function (p = 1.84E‐08). We identified a novel association with attention decline on chromosome 9, rs6559700 (p = 2.69E‐08), near RASEF. Gene‐based analysis also identified a novel gene, TMPRSS11D, involved in the activation of SARS‐CoV‐2, to be associated with the decline in global cognitive function (p = 4.28E‐07). DISCUSSION: Domain‐specific genetic studies can aid in the identification of novel genes and pathways associated with decline across neurocognitive domains. Highlights: rs6559700 was associated with decline of attention.APOE4 was associated with decline of memory and global cognitive decline.TMPRSS11D, a gene involved in the activation of SARS‐CoV‐2, was implicated in global cognitive decline.Cognitive domain abilities had both unique and shared molecular pathways across the domains. [ABSTRACT FROM AUTHOR]

Introduction: Plasma biomarkers—cost effective, non‐invasive indicators of Alzheimer's disease (AD) and related disorders (ADRD)—have largely been studied in clinical research settings. Here, we examined plasma biomarker profiles and their associated factors in a population‐based cohort to determine whether they could identify an at‐risk group, independently of brain and cerebrospinal fluid biomarkers. Methods: We measured plasma phosphorylated tau181 (p‐tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta (Aβ)42/40 ratio in 847 participants from a population‐based cohort in southwestern Pennsylvania. Results: K‐medoids clustering identified two distinct plasma Aβ42/40 modes, further categorizable into three biomarker profile groups: normal, uncertain, and abnormal. In different groups, plasma p‐tau181, NfL, and GFAP were inversely correlated with Aβ42/40, Clinical Dementia Rating, and memory composite score, with the strongest associations in the abnormal group. Discussion: Abnormal plasma Aβ42/40 ratio identified older adult groups with lower memory scores, higher dementia risks, and higher ADRD biomarker levels, with potential implications for population screening. Highlights: Population‐based plasma biomarker studies are lacking, particularly in cohorts without cerebrospinal fluid or neuroimaging data.In the Monongahela‐Youghiogheny Healthy Aging Team study (n = 847), plasma biomarkers associated with worse memory and Clinical Dementia Rating (CDR), apolipoprotein E ε4, and greater age.Plasma amyloid beta (Aβ)42/40 ratio levels allowed clustering participants into abnormal, uncertain, and normal groups.Plasma Aβ42/40 correlated differently with neurofilament light chain, glial fibrillary acidic protein, phosphorylated tau181, memory composite, and CDR in each group.Plasma biomarkers can enable relatively affordable and non‐invasive community screening for evidence of Alzheimer's disease and related disorders pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence indicates that COVID‐19 can negatively impact patient's brain health (Douaud et al., 2022) (Cecchetti et al., 2022). Common clinical symptoms include brain fog, headaches, difficulty concentrating, and loss of sense of smell or taste. Some studies suggest that SARS‐CoV‐2 infection can damage the blood brain barrier either directly or through immune‐inflammatory mechanisms (Zhang, et al. 2021). White matter hyperintensities (WMH) are imaging biomarkers of brain vascular or inflammatory injury. We investigated the association between severity of COVID‐19 infection and burden of white matter hyperintensity volumes within a diverse multi‐nation, multi‐racial cohort using 7 Tesla (7T) MRI that can detect more subtle injury than conventional 1.5 or 3T MRI. Method: Participants were recruited at 4 sites: Pittsburgh, San Antonio and Houston, USA, and Nottingham, UK. To date, we have scanned and included the following participants in our analysis (Table 1). Detailed cognitive, neurological, mood and functional assessments and high‐resolution MRI scans were collected. Subsequent WMH segmentation was performed using our in‐house built deep learning based model (Figure 1). All segmentations were visually inspected and manually corrected before statistical analysis. Normalized WMH is calculated as a ratio of the WMH volume and the intracranial volume (WMH/ICV). Imaging data for an additional 36 age‐matched controls were retrieved from the 7 Tesla Bioengineering Research Program (7TBRP) imaging bank at Pittsburgh. Result: Figure 1 shows the WMH segmentation outputs from our deep learning based model on images acquired at the 3 sites. Our Linear regression models along with our non‐parametric Kruskal‐Wallis test result suggests that compared to mild COVID cases and healthy control, COVID infected individuals that were ICU admitted show elevated WMH burden (Figure 2). Conclusion: Our results demonstrate that white matter hyperintensity volumes were higher among patients who had severe acute COVID infection that required ICU admission, compared to healthy age‐matched controls. In contrast, no difference in white matter burden was observed in patients with mild COVID infection compared to healthy controls. Additional data (both cross‐sectional and longitudinal), including more sensitive MRI measures is being collected to define the full spectrum of brain injury associated with sequelae of COVID infection. [ABSTRACT FROM AUTHOR]

Background: Hippocampal formation atrophy is a well‐established imaging biomarker of several neurological diseases, including Alzheimer's disease, temporal lobe epilepsy, and schizophrenia. The hippocampus is divided into subfields that have different functions and vary in sensitivity to different diseases. This study investigates the potential interaction between COVID‐19 and the various hippocampus subfields, which may shed light on the long‐term neurological consequences of the virus. Method: We obtained high‐resolution T1‐weighted (T1w) and T2‐weighted (T2w) MRI images using 7T scanners located at three sites in two countries: Pittsburgh (n = 14) and Texas (San Antonio and Houston) (n = 40) in the USA, and Nottingham, UK (n = 33). We evaluated the hippocampus subfields using the ASHS package [1‐3]. Imaging sets of 51 subjects with minimal or no manual segmentation corrections (Figures 1 and 2) were included in the analysis. We conducted T‐tests with Bonferroni correction, adjusting for age and intracranial volume to identify the differences in hippocampus subfield volumes across groups. Result: Participants who needed admission into the ICU due to Covid‐19 showed a significantly lower (p‐value = 0.0034) left CA1 volume compared to participants who did not require ICU (Figure 3). In addition, several other non‐significant trends were observed. Conclusion: Our preliminary findings suggest that Covid‐19 may impact the hippocampus, particularly in patients who required intensive care. However, the study ‐ as of to date ‐ has a small sample size and lacks a comparison group with patients who were admitted into ICU for acute illnesses other than Covid‐19. Additionally, longitudinal data is needed to track the long‐term effects of the disease on the hippocampal subfields. Funding: NIH R56AG074467, R01MH111265 and R01AG063525 References: 1. Berron et al. Neuroimage 2017 2. Yushkevich et al. Human Brain Mapping 2015 3. Santini et al. Neuroimage: clinical 2021 [ABSTRACT FROM AUTHOR]

Background: Cardiovascular (CV) disease is associated with dementia and Alzheimer's disease (AD), but its relationship with AD pathology remains elusive. We examined whether mid‐life arterial stiffness, endothelial function, and blood pressure are associated with late‐life beta‐amyloid (Aß) and tau burden. Method: Participants in the Heart Strategies Concentrating on Risk (SCORE) study completed cardiovascular phenotyping between 2003‐2005 (midlife; 45‐59 years) and up to three brain PET sessions between 2018‐2022 (late‐life; >65 years). Mid‐life assessments included augmentation index (AI75; N = 134) as a measure of arterial stiffness, Framingham reactive hyperemia index (fRHI; N = 130) as a measure of endothelial function, and systolic‐blood pressure (SBP; N = 141); late‐life measures were global [11C]Pittsburgh Compound‐B (PiB) standardized uptake value ratio (SUVR) and regional (medial temporal, entorhinal, inferior temporal, amygdala) [18F]flortaucipir (FTP) SUVR as indices of Aß and tau deposition, respectively. In individual linear regression models, we tested associations of mid‐life AI75, RHI, and SBP with late‐life PiB and FTP SUVRs. We used mixed effects models to examine these relationships longitudinally. All models were adjusted for time between CV and PET measurements, baseline age, sex, racialization, apolipoprotein‐E4, BMI, and history of hypertension, high cholesterol, smoking, and diabetes. Result: In multivariable models, higher mid‐life SBP was associated with lower late‐life FTP SUVR in the medial temporal lobe (β = ‐0.20, p = 0.04) and inferior temporal gyrus (β = ‐0.23, p = 0.01; Table 1); higher mid‐life SBP was also negatively associated with FTP SUVR trajectories in these regions (medial temporal lobe: β = ‐0.0004, p = 0.02; inferior temporal gyrus: β = ‐0.001, p = 0.01; Table 2). We did not detect significant relationships of mid‐life AI75 or RHI with late‐life FTP SUVRs (p≥0.05) or between any mid‐life cardiovascular measures and late‐life PiB SUVR (p≥0.08). Conclusion: In this dementia‐free, community‐based cohort, higher mid‐life SBP was associated with lower late‐life regional tau deposition and accumulation. Though counterintuitive, our findings are consistent with results of cross‐sectional studies, which suggest that CV risk factors may be followed by an initial brain arteriole response that is protective against tau accumulation through early years of late‐adulthood1,2. Future studies should interrogate the potential mechanisms and age‐modifying effects that may underlie the relationship between mid‐life CV risk factors and late‐life tau deposition. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has disproportionately affected ethno‐racial minority populations and people with greater social deprivation. It is unknown whether such disparities influence research participation for investigations of long‐term neuro‐cognitive effects of SARS‐CoV‐2 infection. Method: Across 3 US and 1 UK sites, we are enrolling a multi‐racial cohort of SARS‐CoV‐2 infected individuals and age, sex, race‐matched non‐infected controls. Utilizing harmonized protocols for cognitive assessments and 7‐Tesla MRI, we aim to provide ultra‐high‐field data on natural history of COVID‐19 driven microstructural and microvascular cerebral changes and associated cognitive trajectories. We will also compare the imaging markers to those observed in an existing cohort of early onset Alzheimer's Disease and Related Dementias (ADRD). We analyzed screening and enrollment data to determine potential age, sex, race, ethnicity, and social deprivation disparities in research participation. We derived address‐based Area Deprivation Index (ADI) (scale 1 ‐10), with higher ADI indicating greater deprivation. Logistic regression models were fit to evaluate associates of non‐response and refusal. Odds Ratios (OR) and 95% confidence intervals (CI) are reported. Result: Over a 11‐month period, at a single US site, a total of 1,046 SARS‐CoV‐2 infected people and their controls were contacted, and 379 (36.2%) responded. In univariable analyses, non‐response was associated with younger age, male sex, non‐White race, and higher ADI (Table 1). In the fully adjusted model, non‐White race was independently associated with higher likelihood of non‐response [OR (CI) for Black vs. White: 1.49 (1.04, 2.12) and for Asian vs. White: 1.88 (1.28, 2.76)]., Independent of race, higher ADI was also associated with likelihood of non‐response (Table 2 and Figure 1). Among the responders, 228 (60.2%) refused. Although, no socio‐demographic factors were significantly associated with likelihood of refusal, the point estimates in the fully adjusted model suggest potential racial disparities in providing consent (Tables 1 and 2). Aggregated data from all sites will be presented. Conclusion: It is imperative to recognize and mitigate persistent disparities in the COVID‐19 pandemic, particularly pertaining to participation in long‐COVID research. Mechanisms of such persistent disparities need to be studied in context of cultures, beliefs, access, and clinical factors. [ABSTRACT FROM AUTHOR]

Background: Functional MRI (fMRI) studies have associated impaired memory networks with increase in AD pathology. Recently, cross‐sectional analyses found b‐amyloid (Aβ) deposition associated with different patterns of hippocampal connectivity in a memory task based on sex and white matter hyperintensity volume (WMHV). However, cross‐sectional studies don't provide insight into the driving mechanisms of network change. In this longitudinal study, we identify risk factors based on sex that are associated with memory network connectivity changes. Method: Our study included 54 cognitively normal older adults (N = 34 female, mean age 74.6 years) with MRI scans on average 2.43 (SD 0.82) years apart. T1w, T2‐FLAIR MRI, and PiB PET were collected to quantify cortical volume, WMHV and Aβ deposition, respectively. Task fMRI was collected while participants performed face‐name associative memory tasks. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and voxels in the brain. Second‐level analyses were performed to determine regions of interest (ROI) with significant differences in sex by time interaction (p<0.001). The mean beta values were extracted from the significant ROIs for post‐hoc analysis where we performed multivariate linear regression analyses to find correlations with connectivity change (follow‐up minus baseline). Result: Three ROIs presented significant sex by time interactions: left‐right hippocampus, hippocampus‐anterior cingulate cortex (ACC), and hippocampus‐medial frontal gyrus. The change in left‐right hippocampus connectivity increased for women and decreased for men (Fig.1). For the other ROIs, connectivity increased for men and decreased for women (Fig.2). Left‐right hippocampal connectivity change had a significant sex‐WMHV interaction effect (p<0.01), where only women had a positive association between connectivity change and baseline WMHV. Hippocampus‐ACC connectivity change had a significant sex‐Aβ interaction (p<0.01), with greater baseline Aβ associated with increased connectivity change for men and decreased for women. Conclusion: We observed sex‐differences in risk architecture for altered hippocampal connectivity. In the presence of vascular pathology and Aβ, women appear to experience local hippocampal connectivity and decrease hippocampal‐frontal connectivity. Meanwhile, men experienced hippocampal‐frontal connectivity with increased Aβ burden. Characterizing these sex differences in memory network alterations can help guide the development of sex‐specific prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between anxiety and mild cognitive impairment (MCI), and whether it is mediated by perceived stress, at the population level. Method and design: In a longitudinal study of 368 adults aged 65+ from a population‐based cohort, we annually assessed anxiety symptoms (GAD‐7), perceived stress (PSS‐4), and ratings on the Clinical Dementia Rating (CDR®), where CDR = 0.5 was operationalized as MCI. Examining data from three consecutive assessment waves, we first determined the associations between anxiety at the first wave with MCI at the third wave, and vice versa. We then used mediation analyses to determine whether the pathways in both directions were mediated by perceived stress at the second wave, adjusting for demographics and other relevant covariates. Results: We confirmed significant bidirectional longitudinal associations between anxiety and MCI. Perceived stress was detected as a significant mediator for both pathways between anxiety and MCI, explaining 37.1% of the total effect (TE) of anxiety on incident MCI while conversely explaining 27.1% of the TE of MCI on anxiety. Conclusions: A bidirectional relationship with a 2‐year lag between anxiety and MCI was mediated through perceived stress. Clinicians should be sensitive both to potential consequent anxiety when patients present with cognitive impairment, and to potential incipient MCI when the presenting complaint is anxiety. Managing stress may help mitigate adverse outcomes. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease Research Centers (ADRCs) administer prescribed cognitive batteries – the Uniform Data Set (UDS) – and report UDS data to the National Alzheimer's Coordinating Center (NACC). ADRCs may administer other items beyond the UDS. We used data from the University of Pittsburgh ADRC (Pitt) to determine psychometric implications of UDS items alone versus UDS items plus additional Pitt‐specific items. Method: We used confirmatory factor analyses to co‐calibrate Uniform Data Set 1 and 2 (UDS1/2, broadly overlapping, 2005–2015) and UDS3 (2015‐2020) data for memory, executive functioning, and language. We added Pitt‐specific items for each domain. We compared measurement properties of UDS scores vs. UDS plus Pitt scores, including measurement precision and projected sample sizes needed to show a 25% reduction in rate of decline over 12 months for people with Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD). Result: There were 2,726 participants with 8,602 visits across UDS1, 2, and 3 (Table 1). Figure 1 summarizes findings for memory. Figure 1a shows boxplots for memory scores for normal cognition (NC), MCI, and AD for UDS1/2 (green) and UDS3 (purple). Figure 1b shows corresponding boxplots and standard error of measurement (SEM) curves for UDS1/2 (left) and UDS3 (right). Incremental improvements in measurement precision can be seen with the lower SEM curve for the UDS plus Pitt curves. Figures 2 and 3 summarize similar findings for executive functioning and for language. In each case UDS Plus Pitt has less measurement error than UDS alone. Proportions of scores with standard errors >0.30 (a commonly used threshold for individual decision‐making) during UDS1/2 and UDS3 are in Table 2. Pitt‐specific items reduced the proportion with imprecise scores for every comparison with the exception of executive functioning in UDS1/2. Sample sizes needed to show a 25% reduction in the rate of decline are shown in Table 3. Improved precision from additional items was associated with greater power to show change over time. Conclusion: Integrating additional data beyond UDS1/2 and UDS3 results in better measurement precision and increased statistical power. [ABSTRACT FROM AUTHOR]

Background: Cancer-related cognitive impairment (CRCI) has long-term effects on survivor quality of life, but CRCI research on patients with gastrointestinal stromal tumor (GIST) is lacking. The aims of this study were to investigate CRCI and concomitant quality of life among patients with GIST.Methods: An online survey was used to assess CRCI in adult patients with GIST using the validated Functional Assessment of Cancer Therapy-Cognitive-v.3. Age, education, demographically indexed IQ, general health, and quality of life factors (e.g., fatigue, emotional distress) were also assessed. The online survey was administered through five international GIST and sarcoma support organizations.Results: Over the 3-month recruitment period, the survey was completed by 485 participants: mean age, 57.80 (SD, 11.51), median 5 years after diagnosis. A majority (63.91%) reported experiencing cognitive symptoms with a significant negative quality of life impact. Controlling for age, patients with GIST ≥5 years after diagnosis reported worse cognitive function than those <5 years after diagnosis (p < .05) but did not differ in educational level or IQ. Whereas longer term survivors were more likely to have been treated with tyrosine kinase inhibitor (TKI) therapies, there was no observed association of TKI therapy with self-reported cognitive impairments.Conclusions: A majority of GIST patients report cognitive symptoms that have a negative impact on quality of life, with longer term survivors (≥5 years) tending to report more cognitive impairments. Given the success of TKI therapy to substantially increase overall survival of patients with GIST, addressing CRCI in clinical practice may improve long-term GIST survivor function and quality of life. [ABSTRACT FROM AUTHOR]

Introduction: We hypothesized that lower untreated systolic blood pressure (SBP) would be associated with a lower risk of dementia and death up to age 95. Methods: SBP measured between 2000 and 2006 was evaluated in relationship to dementia risk and brain biomarkers from 2009‐2020 (n = 177) in the Gingko Evaluation of Memory Study (GEMS), mean age 95 in 2020. Participants had measurements of brain amyloid beta (Aβ) and repeat clinical‐cognitive evaluations every 6 months. Results: By 2020, only 9 of 177 patients (5%) were alive and cognitively unimpaired (CU). Mean SBP from 2000 to 2006 was 120 mm Hg for nine alive/CU, 125 mm Hg for alive/mild cognitive impairment (MCI), and 130 mm Hg for alive/dementia (P =.03). The amount of Aβ was directly related to SBP levels. In multivariate analysis, Aβ+ in 2009 and thinner cortex were significant predictors of dementia. Excluding Aβ, SBP became a significant predictor of dementia. Discussion: Low SBP untreated by antihypertensive medications was associated with significant decreased risk of dementia and less Aβ. [ABSTRACT FROM AUTHOR]

Introduction: Early detection of cognitive decline in older adults is a public health priority. Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA), a multisite study, is validating cognition, emotion, motor, and sensory modules of the National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in the aging spectrum from cognitively normal to dementia of the Alzheimer's type (DAT). Methods: Participants 65 to 85 years old, in demographic groups racially proportional to the general US population, are recruited in one of three groups to validate the NIHTB: cognitively normal, amnestic mild cognitive impairment (aMCI), or mild DAT. Additional special emphasis cohorts include (1) Blacks in the three clinical groups; (2) Spanish‐speakers in the three clinical groups; (3) cognitively normal, population‐proportional, over age 85. Discussion: Longitudinal study will determine whether NIHTB can predict cognitive decline and is associated with Alzheimer's disease biomarkers. Here, we detail the methods for the ARMADA study. [ABSTRACT FROM AUTHOR]

Background/Objective: Poor air quality is implicated as a risk factor for cognitive impairment and dementia. Few studies have examined these associations longitudinally in well‐characterized population‐based cohorts with standardized annual assessment of both mild cognitive impairment (MCI) and dementia. We investigated the association between estimated ambient fine particulate matter (PM2.5) and risk of incident MCI and dementia in a post‐industrial region known for historically poor air quality. Setting/Participants: Adults aged 65+ years in a population‐based cohort (n = 1572). Measurements: Census tract level PM2.5 from Environmental Protection Agency (EPA) air quality monitors; Clinical Dementia Rating (CDR)®. Design: We estimated ambient PM2.5 exposure (μg/m3, single‐year and 5‐year averages) by geocoding participants' residential addresses to census tracts with daily EPA PM2.5 measurements from 2002 to 2014. Using Bayesian spatial regression modeling adjusted for age, sex, education, smoking history, and household income, we examined the association between estimated PM2.5 exposure and risk of incident MCI (CDR = 0.5) and incident dementia (CDR ≥ 1.0). Results: Modeling estimated single‐year exposure, each 1 μg/m3 higher ambient PM2.5 was associated with 67% higher adjusted risk of incident dementia (hazard ratio [HR] = 1.669, 95% credible interval [CI]: 1.298, 2.136) and 75% higher adjusted risk of incident MCI (HR = 1.746, 95% CI: 1.518, 2.032). Estimates were higher when modeling 5‐year ambient PM2.5 exposure for incident dementia (HR = 2.082, 95% CI: 1.528, 3.015) and incident MCI (HR = 3.419, 95% CI: 2.806, 4.164). Conclusions: Higher estimated ambient PM2.5 was associated with higher risk of incident MCI and dementia, particularly when considering longer‐term exposure, and independent of demographic characteristics and smoking history. Targeting poor air quality may be a reasonable population‐wide intervention to reduce the risk of cognitive impairment in older adults, particularly in regions exceeding current recommendations for safe exposure to PM2.5. [ABSTRACT FROM AUTHOR]

Background: The long‐term impact of COVID‐19 on global health is still unknown. Sensorimotor biomarkers may be promising indicators of lasting effects of COVID‐19. Although normal aging may cause changes in sensorimotor function, more severe changes may indicate the subsequent impacts of COVID‐19 on brain health. The objective of this study was to investigate the association between COVID‐19 and sensorimotor markers (grip strength, gait, and smell) in the 7T neuroCOVID consortium, which is comprised of 5 sites: The University of Texas Health Science Center at San Antonio, Houston Methodist Research Institute, The University of Pittsburgh, Massachusetts General Hospital, and Nottingham University (UK). Methods: We studied 101 adult participants (mean age 60.9 ± 8.5 years, range 45‐80 years, 51% women) without prior cognitive impairment or cerebrovascular disease from the 7T consortium across 3 US and 1 UK sites. The sample included 77 COVID‐19 survivors and 24 healthy controls. Sensorimotor markers were measured for olfaction (n = 59; 12‐item Brief Smell Identification Test (B‐SIT)), grip strength (n = 97; measured using a hand dynamometer), and Gait (n = 101; 4‐meter normal walk time and n = 99; 4‐meter fast‐paced walk time). To assess the association between COVID‐19 and sensorimotor outcomes, we performed a series of linear regression models adjusting for age, sex, site, and handedness (grip strength only). Statistical significance was set at a 5% level. Results: As compared to healthy controls, COVID‐19 survivors, on average had a significantly reduced hand grip in the right hand (β ± standard error: ‐0.18 ± 0.07, p = 0.006). We also observed associations with reduced gait speed. COVID‐19 survivors, on average, had a slower walk time in both normal (0.17 ± 0.06, p = 0.004) and fast‐paced (0.04 ± 0.02, p = 0.022) as compared to healthy controls. We did not observe any statistical associations between COVID‐19 survivors and left‐hand grip strength or B‐SIT. Conclusions: These results highlight that Covid‐19 infection may have a detrimental impact on sensorimotor function. Additional analysis with a larger sample size are ongoing, which will allow us to further assess the effect of infection severity. Future studies will look to evaluate the association between sensorimotor markers, cognition, and ultra‐high field 7T MRI‐based imaging markers. Funding: R56AG074467 P30AG066546 [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by amyloid beta plaques and tau‐containing neurofibrillary tangles with disrupted (high and low) resting state hippocampal connectivity. One potential factor that may underlie these differences is that early stages of disease may contribute to greater connectivity and later stages may contribute to lower connectivity (i.e., quadratic associations between amyloid/tau and connectivity). Early stages may be associated with greater recruitment of intranetwork connectivity to compensate, which fails at later stages. Late stages may be associated with greater recruitment of internetwork connectivity, that fails in advanced cognitive impairment. Understanding these dynamics may help us understand resilience to amyloid and tau in cognitively unimpaired individuals. Method: We recruited 115 adults >65 years old (67‐96, mean 76years) from a population‐based study into a neuroimaging sub‐study. The study area is a formerly heavy manufacturing industrial small‐town area. Participants (106 (92%) CU with CDR = 0) underwent PET imaging for amyloid (PiB) and tau (AV‐1451) and global SUVR measures were computed after appropriate preprocessing. Participants underwent resting state fMRI and hippocampal connectivity was computed for the left/right and anterior/posterior hippocampus. Regression analyses between connectivity and both linear and quadratic terms for amyloid and tau were adjusted for age, sex, race, and education. We adjusted for multiple comparisons using SnPM with FWE correction with α = 0.05 (p‐value threshold of 0.001). Result: We found a negative quadratic association between left anterior hippocampus with default mode network (DMN) including the posterior cingulate and supramarginal gyrus, where greater amyloid and lower amyloid was associated with low connectivity. Similar effects were found for the right anterior hippocampus. Right anterior hippocampus to cuneus connectivity shows positive U‐shape with amyloid but negative linear relationship with tau. Greater right anterior hippocampus‐inferior parietal and right posterior hippocampus‐inferior temporal connectivity was associated with greater tau. Left posterior hippocampus to left middle temporal showed negative U‐shape with tau. Conclusion: Amyloid and tau showed complex inverse U‐shaped associations between heightened intranetwork connectivity and moderate amyloid/tau, but low connectivity with higher severity. Internetwork connectivity was heightened with greater tau. These may reflect altered connectivity due to changes in amyloid and tau in older adults without dementia. [ABSTRACT FROM AUTHOR]

Background: Meaning and purpose in life (M&P) represents goal direction and meaning for an individual. Literature has shown associations between higher M&P and better global cognition. However, papers included either predominantly White or Black samples. We aim to replicate these results in a sample with roughly equal Black and White participants and assess racial differences in the association between M&P and markers of brain health (global cognition and amyloid). We hypothesize that higher M&P scores will be associated with better markers of brain health and that the association will be stronger among Black compared to White individuals. Methods: 263 adults aged 50‐89 years (Table 1) from the Pittsburgh Human Connectome Project were included. M&P was measured by the NIH Toolbox questionnaire. Brain health was characterized as general cognitive function by the Montreal Cognitive Assessment (MoCA) and amyloid burden from positron emission tomography with Pittsburgh compound B (PiB) using a global region of interest. Race was self‐reported as either White or Black/African American; individuals of other races (n = 6) were not included in these analyses. The association of M&P with brain outcomes was assessed by linear regression adjusted for years of education, sex, and age. Effect modification by race was assessed with inclusion of an interaction term in the models. Analyses were conducted in the whole sample and then again, in only those considered cognitively normal. Results: There was no association between M&P and either marker of brain health (global amyloid: β = 0.0008, p = 0.52; cognition: β = 0.019, p = 0.28). There was no statistically significant effect modification by race for either outcome (all p for interaction>0.1). When restricting to those considered cognitively normal, results remained the same. Conclusion: In contrast to prior findings, we found no association between M&P and markers of brain health in contrast to other studies. This difference is not likely due to racial composition as we found no differences by race but may be due to differences in measurements used. Further research should explore potential differences in associations based on cognitive domain. [ABSTRACT FROM AUTHOR]

Background: Black/African American (AA) older adults are twice as likely as Non‐Hispanic White (NHW) older adults to be diagnosed with Alzheimer's Disease (AD) and related dementias. Inflammation and brain beta‐amyloid (Ab) may play a differential role in AD pathophysiology in AA and NHW older adults. We hypothesized that there would be racialized group differences in inflammation, amyloid deposition, and everyday discrimination. Method: One hundred and ninety‐eight participants (Table 1) were recruited in Pittsburgh, PA and the surrounding areas as a part of the Human Connectome Project. Blood‐based biomarkers of inflammatory markers interleukin 6 (IL6) and tumor necrosis factor alpha (TNFa) were examined. Brain Ab was quantified using Pittsburgh Compound‐B (PiB) Positron Emission Tomography (PET) imaging standardized uptake value ratio (SUVr). Experiences of discrimination were measured on a subset of 66 participants (mean age = 62.62±9.37 years, 46.97% AA) using the Everyday Discrimination Scale (EDS). Analysis of covariance, controlling for age, were conducted to examine the racialized group differences for TNFa, IL6, Ab SUVr. Independent samples t‐tests were conducted to compare EDS by racialized group. Result: Participants. AA participants were on average 6.58 years younger than NHW participants and more likely to have a clinical diagnosis of impaired without complaints, mild cognitive impairment (MCI), or AD (all p's<.05) (Table 1). Additionally, in the subset of participants with EDS data, AA participants experienced higher total discrimination than NHW participants (p<.05). Inflammation. NHW participants had higher TNFa inflammation levels than AA participants (p =.029). No differences by racialized group were observed for IL6. PiB‐PET. The frequency of amyloid positivity was higher in NHW than AA participants (p = <.001). Global Ab SUVr was higher in NHW than AA participants (p<.05). Conclusion: The results from this study provide evidence of higher peripheral blood inflammation and PiB PET binding in NHW than AA participants, but higher likelihood of clinical diagnoses and more experiences of discrimination in the AA than in NHW participants. Future investigation of these racialized differences as they relate to age and other determinants of health are needed. [ABSTRACT FROM AUTHOR]

Objectives: To examine the relationship between duration of the cognitive symptoms, from the earliest reported symptom to death, and hippocampal sclerosis (HS) and TAR‐DNA binding protein of 43kDA (TDP‐43) in Alzheimer's disease (AD) patients. Methods: The study was conducted in 359 cognitively impaired patients who met the pathological criteria for AD (NIA‐Reagan intermediate or high). The mean age at onset was 69.5 ± 8.8 years (range 37‐95) and the mean duration of the symptoms was 10.5 ± 4.2 years. The association between symptoms duration and HS and TDP‐43 was examined with logistic regression analyses controlling for age at death, atherosclerosis in the Circle of Willis (CW), cerebral infarcts, gender, baseline Mini Mental State Examination scores, APOE‐4 allele, and presence of Lewy bodies (LB). Results: HS was present in 18% (n = 64) and TDP‐43 in 51.5% (n = 185) of the patients. HS and TDP‐43 were more frequent in patients whose symptoms lasted more than 10 years. LBs were present in 72% of the patients with HS and in 64% of the patients with TDP‐43. Age at onset was not associated with TDP‐43 or HS. HS was associated with duration of symptoms and LB, TDP‐43, and atherosclerosis in the CW. TDP‐43 was associated with duration of symptoms, LB, and HS. Interpretation: HS and TDP‐43 are present in early and late onset AD. However, their presence is mainly driven by the duration of symptoms and the presence of LB. This suggests that HS and TDP‐43 are part of the later neuropathological changes in AD. [ABSTRACT FROM AUTHOR]

Background: Engagement in lifestyle activities may be neuroprotective, but longitudinal data is needed to best inform health interventions. Characterizing the prospective impact of shared lifestyle activities among older adults may both identify subgroups who could benefit most from intervention and reveal contextual/motivational differences in lifestyle that are relevant to group‐level intervention design. We used latent class analysis to characterize qualitatively distinct lifestyle engagement groups and examined whether they had differential declines in global and domain‐specific cognition. Method: Participants were 3068 individuals from the Ginkgo Evaluation of Memory (GEM) Study who completed neuropsychological testing up to 8 years (M=5.0, SD=2.4). We assessed 18 physical, intellectual, and social activities using the Lifestyle Activity Questionnaire. Linear mixed effects models adjusted for demographic and health covariates were used to examine lifestyle engagement group differences in cognitive level and changes over time. Result: The four‐class model fit best (Figure 1). The Variety lifestyle group (22%) had high engagement in both intellectual (e.g., taking classes) and social activities (e.g., concerts, church, social clubs). The Intellectual (18%) group had high engagement in intellectual and some social leisure activities (e.g., concerts). The Social (32%) group had high engagement in social institutional activities (e.g., church). Compared to the Least Active (28%) group, the Variety (B's=.14‐.25, p's<.05) and Intellectual (B's=.10‐.29, p's<.05) groups had greater levels of cognitive performance across all domains, whereas the Social group was only higher in memory (B=.11, SE=.04, p=.013; Table 1). The Variety group also had attenuated declines in memory (B=.02, SE=.01, p=.035) and attention (B=.02, SE=.01, p=.023) over time. Conclusion: Higher lifestyle engagement, especially in intellectual activities, was associated with higher levels of cognition later in life. Yet, only those with the greatest diversity of activities (Variety group) were protected against subsequent declines in memory and attention. These results extend prior findings that these lifestyle groups differ in risk of incident dementia, by suggesting that memory and attention (vs. visuospatial construction) drive this protective relationship. Our findings also highlight subgroup differences in activity types (e.g., primarily social vs. intellectual) that may lead to more targeted interventions to reduce cognitive declines with age. [ABSTRACT FROM AUTHOR]

Background: Most previous studies of amyloid[A], tau[T], and/or neurodegeneration[(N)] prevalence have been completed in highly selected samples, leaving low SES older adults from medically underserved areas underrepresented in research. Furthermore, women consistently have greater T and sometimes greater A accumulation than men, but clear characterizations of AT(N) biomarker positivity overall and by sex in different populations are lacking. Methods: Neuroimaging (NI) sub‐study participants in a population‐representative study of older adults from a low SES, medically underserved US Rust Belt area underwent PET and MRI. We calculated overall and sex‐specific AT(N) biomarker positivity within the NI sub‐study (Table 2) and population‐representative prevalence (Table 3) with inverse probability of selection weighting (IPSW). We calculated age and education adjusted odds ratios (ORs) for women vs men. Results: The overall sample (N = 1226) was 61% female, 94% white, and 98% dementia‐free. NI study participants (N = 115) were older, likelier to be from the parent study's original (vs. replenishment) cohort, and less likely to report diabetes than non‐NI participants (N = 1111; Table 1). IPSW based on variables associated with AT(N) biomarkers (age, cohort, sex, race, education, hypertension, diabetes, and number of medications) successfully balanced these characteristics across NI and non‐NI samples. Population‐weighted prevalence of the A‐T‐(N)‐ profile was 18.8%. Based on 2018 NIA‐AA Research Framework terminology, prevalence of AD continuum biomarkers (any A+) was 24.4%; about 2/3 of these cases were specifically due to AD (A+T+ biomarkers). Prevalence of any T+ was 34.7%, and any (N)+ was the most common at 63.0%. Prevalence of A‐ with T+ and/or (N)+ was 56.8%. Any T+ and AD continuum/AD+ biomarkers were non‐significantly more common in women than men (weighted ORs ranging from 1.20 to 1.69, Table 3). Conclusions: Completely normal AD biomarkers (A‐T‐(N)‐) were comparatively rare in older participants in this community, while any N+ and A‐ with T+ and/or (N)+ were quite common. Women trended toward a greater prevalence of AD+ biomarkers than men. These results are more applicable to other primarily white, low SES, and medically underserved populations than results from highly selected samples. Characterizing brain health across varying cohorts is essential to advance precision medicine and population health. [ABSTRACT FROM AUTHOR]

Introduction: Both high or low plasma amyloid levels have been associated with risk of dementia in nondemented subjects. Methods: We examined baseline plasma β‐amyloid (Aβ) levels in relationship to incident dementia during a period of 8.5 years in 2840 subjects age >75 years; 2381 were cognitively normal (CN) and 450 mild cognitive impairment. Results: Increased plasma Aβ1‐40 and Aβ1‐42 levels were associated with gender (women), age, low education, creatinine levels, history of stroke, and hypertension. CN participants who developed dementia had lower levels of Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio compared with those who did not. Aβ levels did not predict dementia in mild cognitive impairment participants. Discussion: There was an inverse association between Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio to risk of dementia in CN participants. Cerebral and cardiovascular disease and renal function are important determinants of increased Aβ levels and must be considered in evaluations of relationship of plasma Aβ and subsequent risk of dementia. [ABSTRACT FROM AUTHOR]

Background/Objective: In population studies, most individuals with mild cognitive impairment (MCI) do not progress to dementia in the near term, but rather remain stable MCI or revert to normal cognition. Here, we characterized MCI subgroups with different outcomes over 5 years. Setting/Participants: A population‐based cohort (N=1603). Measurements: Clinical Dementia Rating (CDR); self‐reported medical conditions, subjective cognitive concerns, self‐rated health, depressive symptoms, blood pressure, medications, blood pressure, APOE genotype, cognitive domain composite scores. Design: We compared 3 MCI subgroups who progressed to dementia (n=86), stabilized at MCI (n=384), or reverted to normal (n=252), to those who remained consistently normal (n=881), defining MCI as CDR = 0.5 and dementia as CDR≥1. Using multinomial logistic regression models adjusted for demographics, we examined the associations of each group with selected baseline characteristics. Results: With the normal group for reference, worse subjective cognitive concerns, functional impairments, self‐rated health, and depressive symptoms were associated with being in any MCI group. Taking more prescription medications was associated with being in the stable MCI and reverter groups; diabetes and low diastolic blood pressure were associated with stable MCI. The APOE4 genotype was associated with stable and progressive MCI; stroke was associated with progressive MCI. All MCI subgroups were likely to have lower mean composite scores in all cognitive domains and more operationally defined impairments in attention, language, and executive function; reverters were more likely to lack memory and visuospatial impairments. Conclusions: MCI subgroups with different 5‐year outcomes had some distinct characteristics suggesting different underlying causes. The progressors, unlike the reverters, had a profile broadly typical of Alzheimer's disease; the stable MCIs had other, including vascular, morbidity. These data shed light on the heterogeneity of MCI in the population. J Am Geriatr Soc 67:232–238, 2019. [ABSTRACT FROM AUTHOR]

Introduction: We compared risk of progression from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) in an academic memory clinic versus a population‐based study. Methods: Older adults presenting at a memory clinic were classified as SCD (n = 113) or as noncomplainers (n = 82). Participants from a population study were classified as SCD (n = 592) and noncomplainers (n = 589) based on a memory complaint score. Annual follow‐up performed for a mean of 3 years. Results: The adjusted hazard ratio for SCD was 15.97 (95% confidence interval: 6.08–42.02, P <.001) in the memory clinic versus 1.18 (95% confidence interval: 1.00–1.40, P =.047) in the population study, where reported "worry" about memory further increased SCD‐associated risk for MCI. Discussion: SCD is more likely to progress to MCI in a memory clinic than the general population; participants' characteristics vary across settings. Study setting should be considered when evaluating SCD as a risk state for MCI and dementia. [ABSTRACT FROM AUTHOR]

Background: Cognition is a highly complex polygenic trait. A limited number of studies have explored the genetic basis of cognitive decline in aging populations using cognitive domain specific measures. Method: To identify genetic markers for cognitive decline, we conducted a genome‐wide association meta‐analysis and gene‐based tests on five different cognitive domains (attention, language, executive function, visuospatial abilities, memory) and global cognition on 3,068 older individuals (≥65 years) of European ancestry derived from three prospective cohorts: Gingko Evaluation Memory Study (GEMS), Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). All subjects completed a comprehensive neuropsychological battery of tests covering the examined domains. A linear mixed effects model was used to estimate the longitudinal decline in cognitive scores after adjusting for sex, baseline age and education. Global cognitive decline was defined as a decline in average performance in neuropsychological tests across the five domains. Result: Genome‐wide significant association of APOE*4 was observed with decline in the memory domain (p= 8.93E‐09) and global cognitive function (p= 2.69E‐08).We identified a novel locus for decline in the attention domain on chromosome 9 in an intergenic region between RASEF/FRMD3 (p = 3.17E‐08). Gene‐based analysis identified TMPRSS11D as the top gene for decline in global cognition (Bonferroni corrected p= 2.48E‐06). TMPRSS11D plays a role in host‐defense system and recent studies have shown that it activates spike protein of SARS‐CoV‐2 and facilitates viral entry to cell (Viruses 2021;13:384; J Biol Chem 2021; 296:100135). Conclusion: We have identified a novel locus for longitudinal decline in the attention domain, replicated the association of APOE*4 with the global and memory domains, and potentially implicated the role of TMPRS11D in cognitive decline through gene‐based analysis. The association of TMPRSS11D with cognitive decline might help to explain cognitive impairment observed in some patients after COVID‐19 infection (Br J Anaesth 2021; 25:e54; JAMA Netw Open 2021; 4(10):e2130645). While functional studies might help to understand the underlying molecular mechanism of the associated loci, cognitive decline studies with larger samples are essential to establish these findings. [ABSTRACT FROM AUTHOR]

Purpose Mild cognitive impairment (MCI) is a well-recognized risk state for Alzheimer's disease and other dementias. MCI is rapidly increasing among older adults in general and has not yet been examined in older adults within the Appalachian region. Our objective was to compare MCI symptom severity among older rural and urban Appalachian adults with MCI at an initial neuropsychological testing visit. Methods A cross-sectional, descriptive study of older Appalachian adults with MCI was conducted using data from the National Alzheimer's Coordinating Center Uniform Data Set. Symptom severity was conceptualized as neuropsychological composite scores across 4 cognitive domains and Clinical Dementia Rating-Sum of Boxes (CDR-SOB) score. For group comparisons, MANCOVA was used for cognitive domains and ANCOVA for CDR-SOB. Results The sample (N = 289) was about half male (54.3%), predominantly white (91.7%), and living with others (83.5%), with a mean (±SD) 74.6 ± 6.2 years of age and 15.4 ± 3.0 years of education. Rural and urban groups differed significantly in years since onset of cognitive symptoms (2.98 ± 1.91 in rural and 3.89 ± 2.70 in urban adults, t[260] = -2.23, P = .03), but they did not differ across sociodemographic features or comorbid conditions. Rural and urban participants were similar across the 4 cognitive domains and CDR-SOB ( P ≥ .05). Discussion No differences were found between rural and urban Appalachian residents on MCI symptom severity. However, urban residents reported a longer time lapse from symptom identification to diagnosis than their rural counterparts. Future studies using more representative population samples of Appalachian and non-Appalachian adults will provide an important next step to identifying disparate cognitive health outcomes in this traditionally underserved region. [ABSTRACT FROM AUTHOR]

Introduction Subjective cognitive decline (SCD) manifesting before clinical impairment could serve as a target population for early intervention trials in Alzheimer's disease (AD). A working group, the Subjective Cognitive Decline Initiative (SCD-I), published SCD research criteria in the context of preclinical AD. To successfully apply them, a number of issues regarding assessment and implementation of SCD needed to be addressed. Methods Members of the SCD-I met to identify and agree on topics relevant to SCD criteria operationalization in research settings. Initial ideas and recommendations were discussed with other SCD-I working group members and modified accordingly. Results Topics included SCD inclusion and exclusion criteria, together with the informant's role in defining SCD presence and the impact of demographic factors. Discussion Recommendations for the operationalization of SCD in differing research settings, with the aim of harmonization of SCD measurement across studies are proposed, to enhance comparability and generalizability across studies. [ABSTRACT FROM AUTHOR]

Background: Dementia broadly describes conditions that affect a person's memory, cognition, and behavior with Alzheimer's disease (AD) being the most common cause. AD affects millions of people in the U.S. and around the world causing a significant financial burden and placing significant stress on caretakers. AD is a complex disease influenced by both the environment and genetics, however, much of the genetic component remains unaccounted for. The purpose of this work was to use genome‐wide association analyses to detect genetic associations with incident AD in a sample of older adults age 75 and above. Method: We performed a genome‐wide association study (GWAS) on the genome‐wide genotyped and imputed data (14,113,004 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia cases (mean age ± sd = 84.64±3.95) and 2,206 non‐demented subjects (mean age ± sd = 84.55±3.23). Result: The established association of APOE*4 with AD was confirmed in this community‐based sample of older subjects (OR = 2.22; P = 9.36E‐14). In addition, a genome‐wide significant novel locus on chromosome 12 was observed near FAR2 and CCDC91 genes (OR = 3.31; P = 1.66E‐08). Sex‐stratified analyses showed a stronger association of APOE*4 with AD in females (P = 1.74E‐10) than in males (P = 2.43E‐05). In males, a novel SNP on chromosome 1 near LOC729987 and SNX7 genes reached genome‐wide significance (OR = 4.51; P = 3.72E‐08). Of the known AD genes, SNPs near or at TREM2, NME8/EPDR1, MS4A6A/MS4A4E, PICALM, APH1B, and PLCG2 showed nominal significance. Conclusion: The use of community‐based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case‐control studies. Replication of these signals and further study of these regions and genes will help to provide a clearer picture for their role in AD. [ABSTRACT FROM AUTHOR]

Background: A rare missense APOE variant (L28P; APOE*4Pittsburgh) has been reported to be a risk factor for Alzheimer's disease (AD). However, sinceL28P has been observed only among APOE*4 carriers, its independent genetic association is uncertain. In this study, we re‐evaluated this association in a large case‐control sample of 15,762 U.S. Whites aged ≥60 years and investigated its independent effect. Method: Samples were derived from three sources: University of Pittsburgh, Alzheimer's Disease Sequencing Project and the Gingko Evaluation Memory Study. Due to variation in the age distribution between cases and controls in the three studies, each study sample was analyzed separately, and the results then combined by meta‐analysis. To distinguish the independent effect of L28P from APOE*4, we restricted the analysis to subjects with the APOE 3/4 genotype, as L28P has been observed only in the heterozygous state in the APOE*4‐background and 3/4 is the most common genotype containing the APOE*4 allele. Result: A total of 80 L28P heterozygotes were observed in the combined case‐control sample, all in those containing only the APOE*4 allele, confirming the complete linkage disequilibrium between the two sites. The age‐ and sex‐adjusted meta‐analysis odds ratio (OR) was 2.87 (95% CI: 1.34 – 6.13; p = 0.0066). There were a total of 4,138 cases and controls with the 3/4 genotype. The age‐ and sex‐adjusted meta‐analysis OR was 1.53 (95% CI: 0.70 – 3.36; p = 0.28). The lack of significance is mainly due to the low power with the ∼4,100 sample size (12% power at α = 0.80), as compared to the required sample size of ∼151,000 to detect an OR of 1.5 at α = 0.80. Conclusion: Even with non‐significant p‐value, the OR of 1.53 among 3/4 subjects suggests that the effect of L28P on AD risk is independent of APOE*4. Our genetic finding is reinforced by an earlier experimental finding showing that this mutation leads to significant structural and conformational alterations in ApoE and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress (J Biol Chem 2014; 289:12931). Additional studies in cell‐based systems and animal models will help to delineate its functional significance in the AD etiology. [ABSTRACT FROM AUTHOR]

Objective: To examine the impact of subjective depressive symptoms on objective performance on tests of several cognitive domains, in a community-based sample of older adults.Methods: An age-stratified sample of 2036 individuals aged 65+ years was drawn from the electoral rolls of a U.S. community, excluding individuals with moderate to severe cognitive impairment. A cognitive test battery and a modified Center for Epidemiologic Studies-Depression scale (mCES-D) were completed by 1982 participants. Cognitive test scores were compared across levels of depressive symptoms, and composite scores created to represent cognitive domains of attention, language, memory, visuospatial, and executive function. Multivariable regression models tested the association of depressive symptoms with cognitive domain composite scores, adjusting for age, sex, race, and education.Results: Most participants reported no depressive symptoms. Small differences in cognitive scores were observed on all tests among those with 0, 1-2, and > or = 3 symptoms. Adjusting for demographic variables, depressive symptoms remained associated with lower performance on all cognitive composites except attention, most strongly with executive function. Depressive symptoms explained <2% of the variance in test scores, less than that explained by age or education.Conclusion: In this population-based sample of older adults, restricted to those with normal or only mildly impaired cognition, a relatively small proportion reported any depressive symptoms. The number of depressive symptoms had strong statistically significant associations with performance in most cognitive domains. However, depressive symptoms explained little of the variance in cognitive performance, with relatively small differences in scores among those with and without symptoms. [ABSTRACT FROM AUTHOR]

Background: Incident dementia increases with age and is associated with amyloid deposition. There is little knowledge about the progression of amyloid deposition in non‐demented individuals age 80+. The purpose of this study was to determine the relationship between changes in amyloid deposition over time and incident dementia in non‐demented individuals followed for a period of 11 years. Methods: We examined a group of elderly participants (baseline age: 85.86 + 2.84) who had clinical evaluations from 2009 to 2020 and up to 5 measurements of Pittsburgh compound‐B (PiB)‐PET. 94 participants had two PiB‐PET scans, 76 three, 18 four, and 10 five. Mean age was 95 at 2020, at which time 49% of the participants with two or more scans developed dementia and 61% were deceased. Results: There was a gradual increase in amyloid deposition in all participants whether they were considered amyloid positive or negative at baseline. Time to dementia in baseline amyloid negative participants was 7.09 + 2.90 years (range 2.92 – 11.22), and in amyloid positive participants 5.6 + 2.10 (range 2.27 – 9.67). Baseline amyloid deposition was a significant predictor of increase deposition over time. In a Cox model controlled for age, sex, education level, APOE‐4 allele, mortality, and baseline MMSE, change in amyloid deposition from 2009 to 2010‐11 was not significantly associated with incident dementia (HR 2.19 (0.41‐11.73). Baseline continuous measures of amyloid deposition, cortical thickness and white matter lesions (WMLs) were strong predictors of dementia. Approximately 70% of the participants who converted to dementia had either significant amyloid deposition (SUVR ≥1.67), cortical thickness, or WMLs positivity at baseline. Conclusions: There was a substantial and steady amyloid deposition in this age group. There were very few (10%) participants who developed dementia without being amyloid positive. Individuals classified as amyloid negative at baseline became incident amyloid positive (SUVR > 1.67) prior to the dementia diagnosis, and most individuals who were amyloid positive at baseline developed dementia, especially when neurodegeneration was present. [ABSTRACT FROM AUTHOR]

Background: The APOE 2/3/4 polymorphism is the greatest risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE levels and explains about 20‐25% of its genetic variance; while APOE*4 lowers, APOE*2 increases ApoE levels. Lower plasma ApoE levels have also been reported to be a risk factor of future AD and all dementia, independent of the APOE 2/3/4 polymorphism (Ann Neurol 2015;77:301). To our knowledge, no genome‐wide association study (GWAS) has been reported on plasma ApoE levels. This study was aimed to identify novel genetic factors affecting plasma ApoE levels as well as to confirm if baseline plasma ApoE levels predict future AD dementia in an older and longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Method: Baseline plasma ApoE levels were measured using an immunoturbidimetric assay in 3,031 older subjects (aged 72 to 96 years; 94.1% White). Genome‐wide genotype was performed on the available 2,737 DNA samples (96% White). Due to the small number in other ethnicities, we only included the 2,852 White subjects (2,412 cognitively normal, 440 with incident AD dementia) for plasma ApoE analysis. GWAS analysis on plasma ApoE levels was performed on 2,580 White subjects where both genotype and ApoE level data were available. Result: As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (p for trend =1.7E‐10). There was no significant difference in plasma ApoE levels between cognitively normal and AD dementia subjects (p=0.55). GWAS analysis revealed the expected associations of APOE*2 (β= 1.12; p= 3.57E‐79) and APOE*4 (β= ‐0.35; p= 2.21E‐11) with plasma ApoE levels. In addition, we observed 5 novel genome‐wide significant associations on chromosomes 1 (β= 0.921; p= 5.36E‐10), 4 (β= 0.796; p= 4.31E‐08;), 7 (β= 0.722; p= 9.64E‐09), 11 (β= 0.268; p= 2.58E‐08), and 20 (β= 1.379; p=8.25E‐09). Conclusion: We have identified multiple novel associations affecting plasma ApoE levels in addition to the established APOE association. However, we could not replicate the reported association of plasma ApoE levels with future AD, probably because of the older nature of our cohort. [ABSTRACT FROM AUTHOR]

Objectives To determine whether older adults with mild cognitive impairment ( MCI), a condition not previously explored as a risk factor, have more hospitalizations and 30-day readmissions than those with normal cognition. Design Post hoc analysis of prospectively gathered data on incident hospitalization and readmission from the Ginkgo Evaluation of Memory Study ( GEMS), a randomized, double-blind, placebo-controlled trial designed to assess the effect of Ginkgo biloba on incidence of dementia. Setting GEMS was conducted in five academic medical centers in the United States. Participants Community-dwelling adults aged 75 and older with normal cognition (n = 2,314) or MCI (n = 428) at baseline cognitive testing (N = 2,742). Measurements Index hospitalization and 30-day hospital readmission, adjusted for age, sex, race, education, clinic site, trial assignment status, comorbidities, number of prescription medications, and living with an identified proxy. Results MCI was associated with a 17% greater risk of index hospitalization than normal cognition (adjusted hazard ratio ( aHR) = 1.17, 95% confidence interval ( CI) = 1.02-1.34)). In participants who lived with a proxy, MCI was associated with a 39% greater risk of index hospitalization ( aHR = 1.39, 95% CI = 1.17-1.66). Baseline MCI was not associated with greater odds of 30-day hospital readmission (adjusted odds ratio = 0.90, 95% CI = 0.60-1.36). Conclusion MCI may represent a target condition for healthcare providers to coordinate support services in an effort to reduce hospitalization and subsequent disability. [ABSTRACT FROM AUTHOR]

Introduction. A family history of Alzheimer’s disease is a significant risk factor for its onset, but the genetic risk associated with possessing multiple risk alleles is still poorly understood. Methods. In a sample of 95 older adults (Mean age = 75.1, 64.2% female), we constructed a genetic risk score based on the accumulation of risk alleles in BDNF, COMT, and APOE. A neuropsychological evaluation and consensus determined cognitive status (44 nonimpaired, 51 impaired). Logistic regression was performed to determine whether the genetic risk score predicted cognitive impairment above and beyond that associated with each gene. Results. An increased genetic risk score was associated with a nearly 4-fold increased risk of cognitive impairment (OR = 3.824, P = .013) when including the individual gene polymorphisms as covariates in the model. Discussion. A risk score combining multiple genetic influences may be more useful in predicting late-life cognitive impairment than individual polymorphisms. [ABSTRACT FROM AUTHOR]

Objective: This study examined amyloid-β (Aβ) deposition in 190 nondemented subjects aged ≥82 years to determine the proportion of Aβ-positive scans and associations with cognition, apolipoprotein E (APOE) status, brain volume, and Ginkgo biloba (Gb) treatment.Methods: Subjects who agreed to participate had a brain magnetic resonance imaging and positron emission tomography scan with (11) C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82 years, and the mean age of the subjects was 85.5 years at the time of the scans; 152 (80%) were cognitively normal, and 38 (20%) were diagnosed with mild cognitive impairment (MCI) at the time of the PiB study.Results: A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language, and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however, no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aβ deposition as determined by PiB.Interpretation: The data revealed a 55% prevalence of PiB positivity in nondemented subjects age >80 years and 85% PiB positivity in the APOE*4 nondemented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aβ deposition. [ABSTRACT FROM AUTHOR]

Abstract: Background: With the potential emergence of disease specific therapies, an accurate biomarker of Alzheimer’s Disease pathology is needed in cases in which the underlying etiology is uncertain. We explored the potential value of amyloid imaging in patients with atypical presentations of dementia. Methods: Twenty-eight patients with atypical dementia underwent positron emission tomography imaging with the amyloid imaging tracer Pittsburgh compound B (PiB). Twenty-six had [18F]fluoro-2-deoxy-D-glucose positron emission tomography scans. After extensive clinical evaluation, this group of patients generated considerable diagnostic uncertainty and received working diagnoses that included possible Alzheimer’s disease (AD), focal dementias (e.g., posterior cortical atrophy [PCA]), or cases in which no clear diagnostic category could be determined (dementia of uncertain etiology). Patients were classified as PiB-positive, PiB-negative, or PiB-intermediate, based on objective criteria. Anterior–posterior and left–right indices of PiB and [18F]fluoro-2-deoxy-D-glucose uptake were calculated to examine differences in distribution of amyloid pathology and metabolic changes associated with clinical phenotype. Results: Eleven patients (39%) were PiB positive, 16 were PiB negative (57%), and one (4%) was PiB intermediate. By diagnostic category, three of 10 patients (30%) with dementia of uncertain etiology, one of five (20%) with primary progressive aphasia, three of five (60%) with PCA, and four of seven (57%) with possible AD were PiB positive. Brain metabolism of both PiB-positive and PiB-negative patients was generally similar by phenotype, but appeared to differ from typical AD. PCA patients also appeared to differ in their relative distribution of PiB compared with typical AD, consistent with their atypical phenotype. Conclusions: AD pathology is frequently present in atypical presentations of dementia and can be identified by amyloid imaging. Clinical phenotype is more related to the pattern of cerebral hypometabolism than the presence/absence of amyloid pathology. These findings have diagnostic, prognostic, and therapeutic implications. [Copyright &y& Elsevier]

Objective We utilized the amyloid imaging ligand Pittsburgh Compound B (PiB) to determine the presence of Alzheimer's disease (AD) pathology in different mild cognitive impairment (MCI) subtypes and to relate increased PiB binding to other markers of early AD and longitudinal outcome. Methods Twenty-six patients with MCI (13 single-domain amnestic-MCI [a-MCI], 6 multidomain a-MCI, and 7 nonamnestic MCI) underwent PiB imaging. Twenty-three had clinical follow-up (21.2 ± 16.0 [standard deviation] months) subsequent to their PiB scan. Results Using cutoffs established from a control cohort, we found that 14 (54%) patients had increased levels of PiB retention and were considered 'amyloid-positive.' All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 single-domain a-MCI, 5/6 multidomain a-MCI, 3/7 nonamnestic MCI). There were no obvious differences in the distribution of PiB retention in the nonamnestic MCI group. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up demonstrated 5 of 13 amyloid-positive patients, but 0 of 10 amyloid-negative patients, converted to clinical AD. Further, 3 of 10 amyloid-negative patients 'reverted to normal.' Interpretation These data support the notion that amyloid-positive patients are likely to have early AD, and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data are consistent with longitudinal studies that suggest a significant percentage of all MCI subtypes will develop AD. Ann Neurol 2009;65:557-568 [ABSTRACT FROM AUTHOR]

OBJECTIVES: To compare, in a longitudinal cohort study, declines in specific cognitive domains on their ability to predict time to death, in the presence and absence of dementia, and to explore an explanatory role for vascular disease. DESIGN: Prospective population-based epidemiological study. SETTING: The mid-Monongahela valley of southwestern Pennsylvania from 1987 to 2002. PARTICIPANTS: Nine hundred eighty-nine community-dwelling adults aged 65 and older enrolled in the Monongahela Valley Independent Elders Survey. MEASUREMENTS: Biennial assessments of a range of cognitive domains for up to 12 years. Mortality was modeled as a function of decline in each domain, adjusting for vascular diseases and stratified according to age (≤75 (younger-old) and >75 (older-old)) using Cox proportional hazards modeling. RESULTS: Average annual declines in almost all cognitive domains were significant predictors of mortality in the cohort as a whole. However, after adjustment for dementia, only general cognition, processing speed, the language composite, and the executive function composite remained significant. Adjustment for vascular diseases did not alter the results. In the younger-old group, decline in memory (hazard ratio (HR)=21.4) and executive function (HR=25.5) remained strong predictors after adjustment for dementia and vascular disease. In the older-old group, decline in processing speed was a strong predictor of mortality before (HR=7.4) and after (HR=5.3) controlling for dementia and vascular diseases. CONCLUSION: Decline in most cognitive domains predicted mortality across the cohort, but declines in memory and learning were not independent of dementia. Different domains predicted mortality in the younger and older subgroups. [ABSTRACT FROM AUTHOR]

Background: Social isolation and loneliness have detrimental effects on the health of older adults. Being socially isolated and lonely are likely both predictors and consequences of cognitive impairment with aging. However, isolation and loneliness may be differentially associated with cognitive impairment and may operate through both shared and unique pathways. The present study aimed to examine the association of social isolation and loneliness with concurrent cognitive impairment, and to explore potential mechanisms of the association. Methods: Participants (n =1,982; Mage = 77.65 years, 1,210 (61.1%) female, 1,877 (94.7%) white, 815 (41.12% > high school education) were from a population‐based study of mild cognitive impairment and dementia. Three composite measures derived from factor analysis, representing social network structure, social connectedness, and loneliness were examined in relation to clinical dementia rating (CDR normal = 0 vs. CDR impaired >= 0.5) at baseline, adjusted for demographic characteristics. The indirect effects of the composite measures were also estimated conditioned on general health and function, lifestyle factors, vascular health, depressive symptoms, and sleep. Results: Of the participants, 569 (28.71%) were cognitively impaired at baseline. Social connectedness (OR 1.48, 95% CI=1.33‐1.64) and loneliness (OR 1.38, 95% CI=1.24‐1.54), but not social network structure, were significantly associated with greater likelihood of being cognitively impaired after adjustment for demographics. These effects remained significant after separate adjustments for general health and function, lifestyle factors, vascular health, depressive symptoms, sleep, and other composites. The effect of social connectedness was appreciably attenuated by general health status and function (OR 1.37, 95% CI=1.22‐1.54), while loneliness was appreciably attenuated by depressive symptoms (OR 1.26, 95% CI=1.12‐1.42). Conclusions: Older adults with lower levels of social connectedness and higher perception of loneliness are more likely to be cognitively impaired, which were partially explained by health and function and depressive symptoms, respectively. Addressing these factors may reduce risk for cognitive impairment, or conversely, reduce risk for disconnectedness and loneliness among those with cognitive impairment. These results have implications for the impact that limited social contact and feelings of loneliness during the COVID‐19 pandemic may have on older adults with or at risk for cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Recently developed immuno‐precipitation mass spectrometry (IP‐MS) assays to measure blood‐based amyloid‐β with high accuracy holds exciting potential. Adoption of amyloid‐β measurement will be especially valuable in large population studies where not previously feasible. We evaluated the correspondence between a new IP‐MS assay developed on a commercially available platform with brain amyloid PET imaging as the gold standard. Method: N=99 older participants without dementia, active in the population‐based Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) study, underwent blood draws at the time of brain amyloid imaging with PiB‐PET (50‐70 minutes post‐injection, SUVR with cerebellar reference). Adapting methods of Nakamura et al. (2018), immunoprecipitation from plasma was followed by time‐of‐flight MS, using a benchtop mass spectrometer, to measure relative amounts of endogenous peptides Aβ1‐40, Aβ1‐42, APP669‐711, and a stable‐isotope‐labeled internal standard. A composite plasma biomarker was calculated as the mean of the normalized ratios APP669711/Aβ142 and Aβ140/Aβ142. Result: n= 24 (24%) of participants were PiB‐positive by a global cutoff, 7 (7%) were CDR 0.5, and 13 (13%) were APOE*4 carriers. Higher global PiB SUVR was associated with older age, higher CDR (0.5 vs. 0) and APOE*4 genotype (p's <.05), while higher plasma composite biomarker was similarly associated with CDR and APOE*4 but not age. ROC analysis yielded an AUC of 0.78 (SE 0.05) for the composite plasma biomarker predicting PiB‐PET status, with an optimized cut‐point corresponding to sensitivity of 0.75 and specificity of 0.69. Including age and APOE*4 into the model yielded an overall AUC of 0.89, and plasma biomarker sensitivity of 0.91 and specificity of 0.77. Conclusion: This IP‐MS assay was successfully implemented using a commercially‐available, benchtop MALDI‐TOF instrument that is easy to operate and already used in clinic settings. Concurrent prediction of amyloid status from plasma amyloid alone was significant, with moderately high accuracy. Combining plasma amyloid with age and APOE genotype improved prediction to high accuracy. Planned follow‐up of the sample with repeat PiB scans will yield yet further information about prospective prediction of brain amyloid status. This non‐invasive approach using a peripheral biomarker could be highly useful and feasible to apply in large population studies of AD risk. [ABSTRACT FROM AUTHOR]

Background: Cognitive decline is a major characteristic of aging and neurogenerative diseases such as Alzheimer's disease (AD), Parkinson's disease and other dementias. With worldwide increases in life‐expectancy and elderly population, cognitive decline is a major public health concern. Understanding genetic contributors to age‐related decline in cognition may facilitate identification of the molecular mechanisms of cognitive decline. Method: To discover genetic influences on cognitive decline, we conducted genome‐wide meta‐analyses on longitudinal performance of five cognitive domains (attention, language, executive function, visuospatial, memory) and the global domain, constructed from five domains, using 3068 individuals aged 65 and above across three longitudinal cohorts: the Gingko biloba Memory Evaluation Study (GEMS), Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). A linear mixed effect model was used to find individual specific slopes by adjusting for baseline age, years of education and sex. Results: APOE*4 (rs429358), a well‐known risk factor for AD, demonstrated a genome‐wide significant association with the memory (P= 1.37E‐09) and global (P= 9.26E‐10) domains. Previous studies have also reported APOE*4 's association with memory decline. In addition to APOE*4, multiple suggestive associations of gene loci with cognition were also observed for each domain as follows: attention on chromosome 9 near RASEF/FRMD3 (P = 8.29E‐08), memory on chromosome 6 near ID4/MBOAT1(P = 1.27E‐07), visuospatial function on chromosome 11 near PAMR (P = 2.74E‐07), language on chromosome 9 near PSAT1 (P = 4.08E‐07), executive function on chromosome 4 near SNHG27 (P = 6.49E‐07), and global function on chromosome 4 near LINC00290 (P=8.80E‐07). Conclusion: Our result suggests that in addition to APOE, multiple genetic loci affect cognitive decline in older individuals. These findings may offer new insights into understanding the genetic architecture of cognitive decline. [ABSTRACT FROM AUTHOR]

Background: The AT(N) model of Alzheimer's disease (AD) posits a temporal evolution of β‐amyloid (Aβ) accumulation followed by tau then neurodegeneration. We investigated whether longitudinal relationships of these pathologies varied by sex and cerebral small vessel disease burden (cSVD), hypothesizing stronger associations in women and those with high baseline cSVD. Method: Participants included 37 non‐demented older adults (mean 74 y/o at inclusion; 59% female; 89% white; 29% APOE4+). Tau was measured once at time 0 using 18F‐AV‐1451 in an AD composite region of interest. Global amyloid and cerebral metabolism in lateral temporal lobe (neurodegeneration) were measured at repeated annual visits (8 years before tau‐PET to 2 years after), using 11C‐PiB and 18F‐fluorodeoxyglucose (FDG)‐PET. cSVD at study inclusion was characterized by high or low white matter hyperintensity (WMH) volume on MRI. We calculated individual slopes of Aβ and cerebral metabolism up to the tau‐PET visit (time ‐8 to 0) using linear mixed effects models. Using age‐adjusted linear regression models, we examined associations of Aβ slope, tau, and cerebral metabolism slope or metabolism at the final visit (time≥0). We tested effect modification by sex and WMH using interaction terms and stratified analyses when interaction p<0.10. Result: Associations of Aβ slope with tau varied by sex (p‐interaction=0.007) but not WMH. Greater increase in Aβ slope was associated with greater tau in women (β=3.5, p=0.004), but not men (β= ‐1.2, p=0.34). Tau did not predict cerebral metabolism at the final FDG visit (β=0.10, p=0.67), but increasing Aβ slope predicted hypometabolism at the final FDG visit (β= ‐2.1, p=0.01). Neither of these relationships varied by sex or WMH. Associations of cerebral metabolism slope with tau varied by sex (p‐interaction=0.08), but not WMH. Decreasing cerebral metabolism slope was associated with greater tau in women (β= ‐16.3, p=0.05), but not men (β=4.7, p=0.59). Further adjustment for APOE4 (N=31) did not appreciably alter results. Conclusion: In non‐demented older adults, we found that associations of Aβ and cerebral hypometabolism with later increased tau were stronger in women than men; cSVD did not modify these associations. Tau did not predict later cerebral metabolism, while Aβ did. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions The associations between community‐wide social determinants of health and mild cognitive impairment (MCI) among individuals warrant investigation.Among 2830 dementia‐free individuals aged 65+ years in a community‐based US study, we examined cross‐sectional associations of MCI (Clinical Dementia Rating = 0.5) with the following potential social determinants of health: at the census tract or block group level obtained from public sources: neighborhood disadvantage (Area Deprivation Index, ADI), air pollution with fine particulate matter (PM2.5), greenspace, Walkability Index, ambulatory healthcare availability per square mile, homicide rate; and at the individual participant level, birth/schooling in a southern US state.Unadjusted logistic regression models found higher odds ratios (OR, 95% CI) for MCI with higher ADI (1.01, 1.003–1.02), higher PM2.5 (1.16, 1.07–1.26), higher homicide rate (1.007, 1.001–1.012), lesser greenspace (0.99, 0.90–0.99), and southern schooling (2.06, 1.6–3.54). Adjusting for age, race, sex, and educational level, ADI remained statistically significant (1.04, 1.01–1.06), while PM2.5 and Southern state schooling interacted significantly with race and were more strongly affected in Black participants than in White participants.In this cohort, several community‐wide social/environmental factors were associated with MCI. While clinicians should continue to encourage older adults to modify their individual risk factors, policy changes are needed to mitigate social determinants of health in the community. [ABSTRACT FROM AUTHOR]

Background: Engagement in lifestyle activities may be neuroprotective, but it remains unclear what aspects of engagement are most beneficial. For self‐reported activity inventories, examining response patterns may better characterize both quantitative (e.g., number) and qualitative (e.g., characteristic/motivational) differences in engagement. Method: Participants were 3069 individuals from the Gingko Evaluation of Memory (GEM) Study who were evaluated for dementia and completed neuropsychiatric testing over 8 years. We used a subset of 18 physical, intellectual, or social activities from the Lifestyle Activity Questionnaire. We performed latent class analysis to characterize subgroups with distinct activity response patterns and examined whether they have differential risk of incident dementia and domain‐specific cognitive impairments over time. Cox proportional hazards models were used to examine subgroup differences in risk of cognitive impairments. Result: A three‐class model was chosen based on fit statistics and interpretability. Class 1 (Highly intellectually/socially active) participated in more social leisure activities (e.g., movies) than Classes 2 (Socially/less intellectually active) and 3 (Less intellectually/socially active). Class 2 participated in more institutional social activities (e.g., church) than Class 3. In an unadjusted Cox proportional hazard model, Class 1 had a reduced risk of dementia compared to Classes 2 (HR=1.32, 95% CI: [1.1,1.6], p=.013) and 3 (HR=1.53, 95% CI: [1.2,1.9], p<.001). After adjusting for potential demographic and health confounders, Class 1 had a statistically significant reduced risk of dementia compared to Class 3 (HR=1.40, 95% CI: [1.1,1.8], p=.003), but the reduction in risk compared to Class 2 was only trending (HR=1.26,95% CI: [1.0,1.6], p=.051). Conclusion: These results suggest that subgroups characterized by less engagement in leisure social and intellectual activities have increased risk for dementia. Our findings also highlight subgroup differences in activity types (e.g., participation in social institutions in Class 2) that may be leveraged by further behavioral interventions to reduce risk of dementia with age. [ABSTRACT FROM AUTHOR]

In this article, the author explores whether or not dementia can be predicted from a decline in gait speed. Topics discussed include include the risk of cognitive decline and dementia among adults aged 50 and older, a conference from the National Institute on Aging that explored the topic and how lifestyle modification including diet and exercise can reduce dementia risk.