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We recently nominated cytokine signaling through the Janus-kinase–signal transducer and activator of transcription (JAK/STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from routine clinical care, HCQ initiation was associated with a lower risk of incident AD compared to methotrexate initiation across 4 alternative analyses schemes addressing specific types of biases including informative censoring, reverse causality, and outcome misclassification (hazard ratio [95% confidence interval] of 0.92 [0.83–1.00], 0.87 [0.81–0.93], 0.84 [0.76–0.93], and 0.87 [0.75–1.01]). We additionally show that HCQ exerts dose-dependent effects on late long-term potentiation (LTP) and rescues impaired hippocampal synaptic plasticity prior to significant accumulation of amyloid plaques and neurodegeneration in APP/PS1 mice. Additionally, HCQ treatment enhances microglial clearance of Aβ1-42, lowers neuroinflammation, and reduces tau phosphorylation in cell culture-based phenotypic assays. Finally, we show that HCQ inactivates STAT3 in microglia, neurons, and astrocytes suggesting a plausible mechanism associated with its observed effects on AD pathogenesis. HCQ, a relatively safe and inexpensive drug in current use may be a promising disease-modifying AD treatment. This hypothesis merits testing through adequately powered clinical trials in at-risk individuals during preclinical stages of disease progression.

Cellular senescence is linked to chronic age-related diseases including atherosclerosis, diabetes, and neurodegeneration. Compared to proliferating cells, senescent cells express distinct subsets of proteins. In this study, we used cultured human diploid fibroblasts rendered senescent through replicative exhaustion or ionizing radiation to identify proteins differentially expressed during senescence. We identified acid ceramidase (ASAH1), a lysosomal enzyme that cleaves ceramide into sphingosine and fatty acid, as being highly elevated in senescent cells. This increase in ASAH1 levels in senescent cells was associated with a rise in the levels of ASAH1 mRNA and a robust increase in ASAH1 protein stability. Furthermore, silencing ASAH1 in pre-senescent fibroblasts decreased the levels of senescence proteins p16, p21, and p53, and reduced the activity of the senescence-associated β-galactosidase. Interestingly, depletion of ASAH1 in pre-senescent cells sensitized these cells to the senolytics Dasatinib and Quercetin (D+Q). Together, our study indicates that ASAH1 promotes senescence, protects senescent cells, and confers resistance against senolytic drugs. Given that inhibiting ASAH1 sensitizes cells towards senolysis, this enzyme represents an attractive therapeutic target in interventions aimed at eliminating senescent cells.

The role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

BACKGROUND: There is emerging evidence about possible involvement of the renin-angiotensin system (RAS) in the pathogenesis of Alzheimer’s disease (AD) and decline of cognitive function. However, little is known about associations with brain biomarkers. OBJECTIVE: Our study aimed to examine associations between blood ACE-1 and ANG II levels and brain MRI based volumes in non-demented participants, and whether these associations were mediated by blood pressure. METHODS: This cross-sectional study was conducted in 34 older participants from the Baltimore Experience Corps Trial (BECT) Brain Health Sub-study (BHS). Blood ANGII and ACE-1 levels were measured by ELISA and brain MRI volumes were generated using FreeSurfer 6.0. Multiple linear regression analysis, adjusting for intracranial volume and confounders, was used to determine associations between log transformed ANGII and ACE-1 levels and MRI volumes (mm(3)). RESULTS: Participants were predominantly female (76%), African-American (94%), with mean age of 66.9 and education of 14.4 years. In the fully adjusted model we observed significant inverse associations between log ANGII levels and total grey matter (β=Angiotensin II associated with smaller hippocampus 14,935.50, ±7,444.83, p = 0.05), total hippocampus (β=−129.97, ±105.27, p = 0.03), rostral middle frontal (β = −1580.40, ±584.74, p = 0.02), and supramarginal parietal (β = −978.90, ±365.54, p = 0.02) volumes. There were no associations between ANGII levels and total white matter or entorhinal cortex volumes, or ACE-1 levels and any brain volumes. CONCLUSION: We observed that increased blood ANGII levels were associated with lower total grey matter, hippocampal, rostral middle frontal, and supramarginal parietal volumes, which are associated with cognitive domains that decline in preclinical AD.

We evaluated the hypothesis that phosphodiesterase-5 inhibitors, including sildenafil and tadalafil, may be associated with reduced incidence of Alzheimer’s disease and related dementia using a patient-level cohort study of Medicare claims and cell culture-based phenotypic assays. We compared incidence of Alzheimer’s disease and related dementia after phosphodiesterase-5 inhibitor initiation versus endothelin receptor antagonist initiation among patients with pulmonary hypertension after controlling for 76 confounding variables through propensity score matching. Across four separate analytic approaches designed to address specific types of biases including informative censoring, reverse causality, and outcome misclassification, we observed no evidence for a reduced risk of Alzheimer’s disease and related dementia with phosphodiesterase-5 inhibitors;hazard ratio (95% confidence interval): 0.99 (0.69–1.43), 1.00 (0.71–1.42), 0.67 (0.43–1.06), and 1.15 (0.57–2.34). We also did not observe evidence that sildenafil ameliorated molecular abnormalities relevant to Alzheimer’s disease in most cell culture-based phenotypic assays. These results do not provide support to the hypothesis that phosphodiesterase-5 inhibitors are promising repurposing candidates for Alzheimer’s disease and related dementia.

Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer’s disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 ± 9 years...

Description, Brain proteins altered in young APOE ε4 carriers are found decades later in Alzheimer’s disease and present novel drug targets., Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer’s disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 ± 9 years). A subset of these proteins was also differentially abundant in the brains of young APOE ε4 carriers relative to noncarriers (mean age, 39 ± 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture–based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD.

OBJECTIVES: Cognitive frailty is a state at the lower end of the continuum of cognitive resilience in which one is at elevated risk for cognitive impairment and dementia. Metrics of a newly developed Cognitive Frailty Index (CFI) were examined for their association with objective functional limitations. METHODS: We used baseline data from 607 participants from the Baltimore Experience Corps Trial with measures on the CFI, a computerized Stroop test, and Short Physical Performance Battery (SPPB) score≤9. Multivariable log-binomial regression models were used to evaluate the associations of CFI metrics (mean reaction time (RT) for total, first-half and second-half trials per condition) with the SPPB. Latent growth models were used to create additional CFI metrics of initial level (intercept) and change (slope) in RT across accurate trials by easy (Color-X) and difficult (Color-Word) conditions. Models were adjusted for race, sex, age, income, major morbidities, depressive symptoms, self-reported health, and Stroop interference (for Color-Word condition only). RESULTS: All CFI RT metrics were associated with SPPB

Background While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis. Methods and findings We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = 4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72–1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose–response relationship between BAS use and risk of VaD (p-trend = 0.045) in males. Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings. Conclusions We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia., Vijay Varma and co-workers study cholesterol and bile acid metabolism in dementia., Author summary Why was this study done? Hypercholesterolemia is associated with increased risk of Alzheimer disease (AD) and vascular dementia (VaD). However, cholesterol is impermeable to the blood–brain barrier (BBB), and it is unclear how peripheral cholesterol mediates risk of dementia. While prior research has examined the relationship between de novo cholesterol biosynthesis and dementia, few studies have assessed the role of cholesterol catabolism and its principal breakdown products, oxysterols, and primary bile acids (BAs) in dementia. What did the researchers do and find? We examined the role of cholesterol catabolism in dementia pathogenesis by first testing the association between serum oxysterols and BAs and neuroimaging markers of dementia. We also tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia in a large, real-world clinical dataset. Finally, we tested plausible mechanisms underlying these associations by examining whether primary BAs and mRNA of their receptors were altered in the brain in dementia. We found that lower serum levels of 7α-hydroxycholesterol (7α-OHC) and primary BAs were associated with higher brain amyloid deposition, faster WML accumulation, and faster brain atrophy mainly in males. Consistent with this finding, we observed a sex difference in the association between use of BAS and risk of VaD. We found that primary BAs were detectable in the brain, and levels of gene expression of BA receptors were altered in AD mainly in males. What do these findings mean? Our findings suggest that cholesterol catabolism and BA synthesis may impact dementia progression through sex-specific effects on signaling pathways in the brain. These results set the stage for experimental studies to test whether BA signaling in the brain may be a novel therapeutic target in dementia.

Summary With the advent of continuous health monitoring with wearable devices, users now generate their unique streams of continuous data such as minute-level step counts or heartbeats. Summarizing these streams via scalar summaries often ignores the distributional nature of wearable data and almost unavoidably leads to the loss of critical information. We propose to capture the distributional nature of wearable data via user-specific quantile functions (QF) and use these QFs as predictors in scalar-on-quantile-function-regression (SOQFR). As an alternative approach, we also propose to represent QFs via user-specific L-moments, robust rank-based analogs of traditional moments, and use L-moments as predictors in SOQFR (SOQFR-L). These two approaches provide two mutually consistent interpretations: in terms of quantile levels by SOQFR and in terms of L-moments by SOQFR-L. We also demonstrate how to deal with multi-modal distributional data via Joint and Individual Variation Explained using L-moments. The proposed methods are illustrated in a study of association of digital gait biomarkers with cognitive function in Alzheimers disease. Our analysis shows that the proposed methods demonstrate higher predictive performance and attain much stronger associations with clinical cognitive scales compared to simple distributional summaries.

Introduction Few studies have explored whether gait measured continuously within a community setting can identify individuals with Alzheimer's disease (AD). This study tests the feasibility of this method to identify individuals at the earliest stage of AD. Methods Mild AD (n = 38) and cognitively normal control (CNC; n = 48) participants from the University of Kansas Alzheimer's Disease Center Registry wore a GT3x+ accelerometer continuously for 7 days to assess gait. Penalized logistic regression with repeated five‐fold cross‐validation followed by adjusted logistic regression was used to identify gait metrics with the highest predictive performance in discriminating mild AD from CNC. Results Variability in step velocity and cadence had the highest predictive utility in identifying individuals with mild AD. Metrics were also associated with cognitive domains impacted in early AD. Discussion Continuous gait monitoring may be a scalable method to identify individuals at‐risk for developing dementia within large, population‐based studies.

Cytokine signaling, including tumor necrosis factor (TNF) and interleukin (IL)-6, through the Janus-kinase (JAK)-signal transducer and activator of transcription pathway, was hypothesized to attenuate the risk of Alzheimer disease and related dementia (ADRD) in the Drug Repurposing for Effective Alzheimer Medicines (DREAM) initiative based on multiomics phenotyping.To evaluate the association between treatment with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept and risk of incident ADRD.This cohort study was conducted among US Medicare fee-for-service patients with rheumatoid arthritis aged 65 years and older from 2007 to 2017. Patients were categorized into 3 cohorts based on initiation of tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors compared with a common comparator abatacept (a T-cell activation inhibitor). Analyses were conducted from August 2020 to August 2021.The main outcome was onset of ADRD based on diagnosis codes evaluated in 4 alternative analysis schemes: (1) an as-treated follow-up approach, (2) an as-started follow-up approach incorporating a 6-month induction period, (3) incorporating a 6-month symptom to diagnosis period to account for misclassification of ADRD onset, and (4) identifying ADRD through symptomatic prescriptions and diagnosis codes. Hazard ratios (HRs) with 95% CIs were calculated from Cox proportional hazard regression after adjustment for 79 preexposure characteristics through propensity score matching.After 1:1 propensity score matching to patients using abatacept, a total of 22 569 propensity score-matched patient pairs, including 4224 tofacitinib pairs (mean [SD] age 72.19 [5.65] years; 6945 [82.2%] women), 6369 tocilizumab pairs (mean [SD] age 72.01 [5.46] years; 10 105 [79.4%] women), and 11 976 TNF inhibitor pairs (mean [SD] age 72.67 [5.91] years; 19 710 [82.3%] women), were assessed. Incidence rates of ADRD varied from 2 to 18 per 1000 person-years across analyses schemes. There were no statistically significant associations of ADRD with tofacitinib (analysis 1: HR, 0.90 [95% CI, 0.55-1.51]; analysis 2: HR, 0.78 [95% CI, 0.53-1.13]; analysis 3: HR, 1.29 [95% CI, 0.72-2.33]; analysis 4: HR, 0.50 [95% CI, 0.21-1.20]), tocilizumab (analysis 1: HR, 0.82 [95% CI, 0.55-1.21]; analysis 2: HR, 1.05 [95% CI, 0.81-1.35]; analysis 3: HR, 1.21 [95% CI, 0.75-1.96]; analysis 4: HR, 0.78 [95% CI, 0.44-1.39]), or TNF inhibitors (analysis 1: HR, 0.93 [95% CI, 0.72-1.20]; analysis 2: HR, 1.02 [95% CI, 0.86-1.20]; analysis 3: HR, 1.13 [95% CI, 0.86-1.48]; analysis 4: 0.90 [95% CI, 0.60-1.37]) compared with abatacept. Results from prespecified subgroup analysis by age, sex, and baseline cardiovascular disease were consistent except in patients with cardiovascular disease, for whom there was a potentially lower risk of ADRD with TNF inhibitors vs abatacept, but only in analyses 2 and 4 (analysis 1: HR, 0.76 [95% CI, 0.50-1.16]; analysis 2: HR, 0.74 [95% CI, 0.56-0.99]; analysis 3: HR, 1.03 [95% CI, 0.65-1.61]; analysis 4: HR, 0.45 [95% CI, 0.21-0.98]).This cohort study did not find any association of risk of ADRD in patients treated with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept.

Neuroimaging and fluid biomarkers have revolutionized the way we define Alzheimer’s disease (AD), identify at-risk individuals, diagnose those with symptoms, and may eventually enable us to treat patients in the earliest stages of the disease. We review advances in imaging the principal pathological hallmarks and functional perturbations in the AD brain and map progress in identifying cerebrospinal fluid and blood biomarkers of AD. Together, these modalities have provided invaluable insights into the evolution of AD decades before the onset of cognitive impairment. While they have been rapidly adopted into clinical settings, the evidence base for this remains contested. However, the clear value of neuroimaging and fluid biomarkers is in their relevance to clinical trials and the recruitment of individuals who perceive themselves to be at sufficiently high risk to warrant joining research studies testing experimental AD treatments. This marks a paradigm shift in our efforts to overcome one of the global public health challenges of our time.

[This corrects the article DOI: 10.1371/journal.pmed.1003012.].

BACKGROUND An epistatic interaction between the ɛ4 allele of apolipoprotein E (APOEɛ4) gene and the K-variant of butyrylcholinesterase (BCHE-K) genes has been previously reported to increase risk of Alzheimer's disease (AD). However, these observations were largely from case-control studies with small sample sizes. OBJECTIVE To examine the interaction between APOEɛ4 and BCHE-K on: 1) the risk of incident AD and 2) rates of change in brain volumes and cognitive performance during the preclinical stages of AD in a prospective cohort study. METHODS The study sample for survival analysis included 691 Caucasian participants (age at baseline, 58.4±9.9 years; follow-up time,16.9±9.7 years) from the Baltimore Longitudinal Study of Aging. The neuroimaging sample included 302 participants with 1,388 magnetic resonance imaging (MRI) scans. Cognitive performance was assessed in 703 participants over 4,908 visits. RESULTS A total of 122 diagnoses (79 AD, 43 mild cognitive impairment [MCI]) were identified. Participants with both APOEɛ4 and BCHE-K variants had a 3.7-fold greater risk of AD (Hazard ratio [HR] 95% CI=1.99-6.89, p

Rapid lifestyle and dietary changes have contributed to a rise in the global prevalence of metabolic syndrome (MetS), which presents a potential healthcare crisis, owing to its association with an increased burden of multiple cardiovascular and neurological diseases. Prior work has identified the role that genetic, lifestyle, and environmental factors can play in the prevalence of MetS. Metabolomics is an important tool to study alterations in biochemical pathways intrinsic to the pathophysiology of MetS. We undertook a metabolomic study of MetS in serum samples from two ethnically distinct, well-characterized cohorts&mdash, the Baltimore Longitudinal Study of Aging (BLSA) from the U.S. and the Tsuruoka Metabolomics Cohort Study (TMCS) from Japan. We used multivariate logistic regression to identify metabolites that were associated with MetS in both cohorts. Among the top 25 most significant (lowest p-value) metabolite associations with MetS in each cohort, we identified 18 metabolites that were shared between TMCS and BLSA, the majority of which were classified as amino acids. These associations implicate multiple biochemical pathways in MetS, including branched-chain amino acid metabolism, glutathione production, aromatic amino acid metabolism, gluconeogenesis, and the tricarboxylic acid cycle. Our results suggest that fundamental alterations in amino acid metabolism may be central features of MetS.

Background There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. Methods and findings We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators. Conclusions In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD., Uma Mahajan and coworkers study metabolic perturbations in specific brain regions in Alzheimer disease., Author summary Why was this study done? A growing body of evidence suggests that Alzheimer disease (AD) may be associated with dysregulation of multiple metabolic pathways, and identifying novel molecular targets underlying AD pathogenesis is essential for developing effective AD treatments. Past studies have shown that abnormalities in choline-related biochemical pathways may be associated with AD pathogenesis, specifically the transmethylation, polyamine synthesis/catabolism and related pathways. Our study tested the hypothesis that dysregulation of choline-related biochemical pathways in the brain is associated with AD pathogenesis; we examined metabolites within biochemical reactions linked to transmethylation and polyamine synthesis/catabolism. What did the researchers do and find? We performed quantitative and targeted metabolomics on brain tissue samples (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) and transcriptomics from Gene Expression Omnibus data (entorhinal cortex [AD: n = 25; CN: n = 52] and hippocampus [AD: n = 29; CN: n = 56]) to identify aberrations across 6 biochemical reactions linked to the transmethylation and polyamine pathways: methionine cycle, transsulfuration and glutathione synthesis, polyamine synthesis and catabolism, urea cycle, glutamate-aspartate metabolism, and neurotransmitter metabolism. We found significant metabolite alterations associated with AD mainly in the inferior temporal gyrus (ITG) across all pathways tested, as well as associations between metabolite concentrations and severity of AD pathology. Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. What do these findings mean? Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to severity of AD pathology and the expression of clinical symptoms. This study adds to a comprehensive understanding of the metabolic basis of AD pathogenesis and provides insights into novel targets for disease-modifying therapies. The cross-sectional nature of the study limits our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression.

Introduction Biomarker discovery of dementia and cognitive impairment is important to gather insight into mechanisms underlying the pathogenesis of these conditions. Methods In 997 adults from the InCHIANTI study, we assessed the association of 1301 plasma proteins with dementia and cognitive impairment. Validation was conducted in two Alzheimer's disease (AD) case‐control studies as well as endophenotypes of AD including cognitive decline, brain amyloid burden, and brain volume. Results We identified four risk proteins that were significantly associated with increased odds (peptidase inhibitor 3 (PI3), trefoil factor 3 (TFF3), pregnancy associated plasma protein A (PAPPA), agouti‐related peptide (AGRP)) and two protective proteins (myostatin (MSTN), integrin aVb5 (ITGAV/ITGB5)) with decreased odds of baseline cognitive impairment or dementia. Of these, four proteins (MSTN, PI3, TFF3, PAPPA) were associated cognitive decline in subjects that were cognitively normal at baseline. ITGAV/ITGB5 was associated with lower brain amyloid burden, MSTN and ITGAV/ITGB5 were associated with larger brain volume and slower brain atrophy, and PI3, PAPPA, and AGRP were associated with smaller brain volume and/or faster brain atrophy. Discussion These proteins may be useful as non‐invasive biomarkers of dementia and cognitive impairment.

Drug discovery for disease‐modifying therapies for Alzheimer's disease and related dementias (ADRD) based on the traditional paradigm of experimental animal models has been disappointing. We describe the rationale and design of the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, an innovative multidisciplinary alternative to traditional drug discovery. First, we use a systems biology perspective in the "hypothesis generation" phase to identify metabolic abnormalities that may either precede or interact with the accumulation of ADRD neuropathology, accelerating the expression of clinical symptoms of the disease. Second, in the "hypothesis refinement" phase we propose use of large patient cohorts to test whether drugs approved for other indications that also target metabolic drivers of ADRD pathogenesis might alter the trajectory of the disease. We emphasize key challenges in population‐based pharmacoepidemiologic studies aimed at quantifying the association between medication use and ADRD onset and outline robust causal inference principles to safeguard against common pitfalls. Candidate ADRD treatments emerging from this approach will hold promise as plausible disease‐modifying therapies for evaluation in randomized controlled trials.

Alzheimer's disease (AD) is an incurable neurodegenerative disease that is more prevalent in women. The increased risk of AD in women is not well understood. It is well established that there are sex differences in metabolism and that metabolic alterations are an early component of AD. We utilized a cross-species approach to evaluate conserved metabolic alterations in the serum and brain of human AD subjects, two AD mouse models, a human cell line, and two Caenorhabditis elegans AD strains. We found a mitochondrial complex I-specific impairment in cortical synaptic brain mitochondria in female, but not male, AD mice. In the hippocampus, Polβ haploinsufficiency caused synaptic complex I impairment in male and female mice, demonstrating the critical role of DNA repair in mitochondrial function. In non-synaptic, glial-enriched, mitochondria from the cortex and hippocampus, complex II-dependent respiration increased in female, but not male, AD mice. These results suggested a glial upregulation of fatty acid metabolism to compensate for neuronal glucose hypometabolism in AD. Using an unbiased metabolomics approach, we consistently observed evidence of systemic and brain metabolic remodeling with a shift from glucose to lipid metabolism in humans with AD, and in AD mice. We determined that this metabolic shift is necessary for cellular and organismal survival in C. elegans, and human cell culture AD models. We observed sex-specific, systemic, and brain metabolic alterations in humans with AD, and that these metabolite changes significantly correlate with amyloid and tau pathology. Among the most significant metabolite changes was the accumulation of glucose-6-phosphate in AD, an inhibitor of hexokinase and rate-limiting metabolite for the pentose phosphate pathway (PPP). Overall, we identified novel mechanisms of glycolysis inhibition, PPP, and tricarboxylic acid cycle impairment, and a neuroprotective augmentation of lipid metabolism in AD. These findings support a sex-targeted metabolism-modifying strategy to prevent and treat AD.

While Alzheimer’s disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association is unclear. Using a novel, 3-step study design we examined the role of cholesterol catabolism in dementia by testing whether 1) the synthesis of the primary cholesterol breakdown products (bile acids (BA)) were associated with neuroimaging markers of dementia; 2) pharmacological modulation of BAs alters dementia risk; and 3) brain BA concentrations and gene expression were associated with AD. We found that higher serum concentrations of BAs are associated with lower brain amyloid deposition, slower WML accumulation, and slower brain atrophy in males. Opposite effects were observed in females. Modulation of BA levels alters risk of incident VaD in males. Altered brain BA signaling at the metabolite and gene expression levels occurs in AD. Dysregulation of peripheral cholesterol catabolism and BA synthesis may impact dementia pathogenesis through signaling pathways in the brain.

Introduction It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis. Methods Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, we measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose. Results Higher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations. Discussion Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms.

Purpose Regular physical activity is a key component of healthy aging, but few older adults meet physical activity guidelines. Poor aging expectations can contribute to this lack of activity, since negative stereotypes about the aging process can be internalized and affect physical performance. Although prior cross-sectional studies have shown that physical activity and aging expectations are associated, less is known about this association longitudinally, particularly among traditionally underrepresented groups. It is also unclear whether different domains of aging expectations are differentially associated with physical activity. Design and Methods The number of minutes/week of physical activity in which Baltimore Experience Corps Trial participants (N = 446; 92.6% African American) engaged were measured using the CHAMPS questionnaire, while their aging expectations were measured using the ERA-12 survey. Linear mixed effects models assessed the association between physical activity and aging expectations over 2 years, both in full and sex-stratified samples. Separate models were also fit for different ERA-12 domains. Results We found that higher overall expectations regarding aging are associated with higher engagement in moderate- to high-intensity physical activity over a 2-year period of time for women only. When the ERA-12 domains were examined separately, only the physical domain was associated with physical activity, both in women and overall. Implications Low expectations regarding physical aging may represent a barrier to physical activity for older adults. Given that most older adults do not meet recommended physical activity guidelines, identifying factors that improve aging expectations may be a way to increase physical activity levels in aging populations.

We thank Wolff-Hughes and colleagues for their thoughtful response (Wolff-Hughes et al., 2017) to our recently published findings (Varma et al., 2017). Wolff-Hughes et al. correctly indicate that our findings, which model physical activity (PA) over the lifespan using total log-transformed activity counts (TLAC) as a proxy measure for total volume of PA, are inconsistent with their findings (Wolff-Hughes et al., 2014; Wolff-Hughes et al., 2015) that use total (non-transformed) activity counts (TAC). The main issue is whether TLAC or TAC is the most appropriate measure of total volume of PA. We argue that 1) TAC most closely reflects moderate-to-vigorous PA (MVPA) while TLAC most closely reflects light-intensity PA (LiPA); and propose 2) TAC(λ) as a unifying measure to appropriately capture total volume of PA.

Hippocampal atrophy is a hallmark of Alzheimer's disease pathology, and a target biomarker region for testing intervention efficacy. Over the last few decades, a growing body of evidence from animal and human models suggests that physical activity (PA) is associated with structural benefits to the hippocampus in older adults. Very few human studies, however have explored hippocampal sub-regional specificity of PA; this is significant considering that sub-regions of the hippocampus are associated with distinct cognitive tasks and are differentially affected by disease pathology. This study used objective and self-reported measures of daily walking activity and exercise, and surface-based regional shape analysis using high-field hippocampal sub-regional partitions to explore sub-region specific hippocampal associations in a sample of nondemented, community-dwelling older adults at elevated sociodemographic risk for cognitive decline. Vertex-wise surface areas, which may be more sensitive than global volume measures, were calculated using shape diffeomorphometry, and PA was assessed using step activity monitors and PA questionnaires. We found that daily walking activity in a participant's environment was associated in cross-section mainly with larger surface areas of the subiculum in women. Associations remained significant when controlling for self-reported exercise. Prior studies have found that PA related to exercise and aerobic fitness may be most closely associated with the anterior hippocampus, particularly the dentate gyrus of the hippocampus. These novel findings are the first, to our knowledge, in human models to suggest that PA related to navigation that may not reach the level of moderate-intensity exercise may be associated with specific sub-regions of the hippocampus. These findings underscore the importance of better understanding the independent and related biological mechanisms and pathways by which increasing exercise as well as non-exercise, lifestyle PA may influence structural brain health. © 2016 Wiley Periodicals, Inc.

Introduction Older adults with a high number of chronic conditions and who live in environments that do not promote physical activity have great difficulty initiating and adhering to exercise programs. Novel lifestyle activity interventions that can effectively increase physical activity may address disparities in health in these populations. This study evaluates the effects of the Baltimore Experience Corps program, a community-based volunteer program, on walking activity in older adults. Methods The Baltimore Experience Corps Trial is a sex-stratified RCT that recruited participants from 2006 to 2009. Older adult participants aged ≥60 years ( n =123) were from a nested objective physical activity trial within the larger Baltimore Experience Corps Trial. Participants randomized to the intervention group were placed as volunteers within the Baltimore public school system for 2 years. The primary study outcome was objectively measured total amount of walking activity measured in steps/day. Differences between intervention and control groups were measured at 12 and 24 months using linear mixed effects models. Data were analyzed in 2014. Results At 24 months, women, but not men, in the intervention group showed an increased amount of walking activity, averaging 1,500.3 (95% CI=77.6, 2,922.9) greater steps/day compared with the control group. Women in the control group showed a decline of 1,191.6 (95% CI=–2243.7, –139.5) steps/day at 24 months compared to baseline. Conclusions A community-based volunteer intervention increased walking activity among older women, who were at elevated risk for both inactivity and adverse health outcomes. Trial registration This study is registered at www.clinicaltrials.gov NCT00380562.

ObjectivesNumerous studies show benefits of mid- and late-life activity on neurocognitive health. Yet, few studies have examined how engagement in enriching activities during childhood, when the brain is most plastic, may confer long-term neurocognitive benefits that may be especially important to individuals raised in low-income settings. We examined associations between enriching early-life activities (EELAs) and hippocampal and amygdala volumes in a sample of predominantly African-American, community-dwelling older adults. We further assessed whether these associations were independent of current activity engagement.MethodsNinety participants from the baseline Brain Health Substudy of the Baltimore Experience Corps Trial (mean age: 67.4) completed retrospective activity inventories and an magnetic resonance imaging scan. Volumes were segmented using FreeSurfer.ResultsEach additional EELA was associated with a 2.3% (66.6 mm3) greater amygdala volume after adjusting for covariates. For men, each additional EELA was associated with a 4.1% (278.9 mm3) greater hippocampal volume. Associations were specific to these regions when compared with the thalamus, used as a control region.DiscussionEnriching lifestyle activities during an important window of childhood brain development may be a modifiable factor that impacts lifelong brain reserve, and results highlight the importance of providing access to such activities in historically underserved populations.

Background Emerging evidence suggests a possible role of the renin angiotensin system in the pathophysiologic process of Alzheimer's disease, of which angiotensin converting enzyme-1 (ACE-1) and angiotensin II (ANGII) are important proteins. Few studies evaluated associations between blood ACE-1 and none between ANGII levels, and cognition. Objective Our pilot study was aimed to examine associations between blood ACE-1 and ANG II levels and cognitive function in non-demented participants at baseline and over a 1-year period. Methods 56 participants were included from the Brain Health Substudy of the Baltimore Experience Corps Study. Linear regression analysis, adjusting for confounders, was used to determine associations between baseline ACE-1 and ANGII, and baseline and 1-year follow-up measures of psychomotor and processing speed, executive function, verbal learning memory and working memory, and whether these associations were mediated by blood pressure. Results Participants were predominantly female (75%), African-American (93%), with mean age of 67.8 years and education of 14.3 years. There were no associations between baseline ACE-1 or ANGII levels and cognitive function; however, there were significant association between baseline ACE-1 levels and 1-year follow-up Trail Making Test, Part A (β= 0.003, p = 0.04) and Digit Span (β= -0.001, p = 0.02). Conclusions In this cognitively intact sample, elevated ACE-1 levels were associated with worse processing speed and working memory after 1 year. Findings from this pilot study suggest that changes in the RAS are associated with alterations in cognitive function warranting further assessment of the role of RAS in neurodegenerative disorders.

Background The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. Methods and findings Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and “asymptomatic Alzheimer’s disease” (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes—sphingolipids and glycerophospholipids—that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer’s Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer’s Disease [EASE-AD]). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio [HR] = 4.430, 95% confidence interval [CI] = 1.703–11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516–7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373–9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047–4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples. Conclusions We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD., Using quantitative and targeted metabolomics, Vijay Varma and colleagues identified metabolites for which brain tissue levels were associated with Alzheimer disease (AD) neuropathology and blood concentrations were associated with AD progression in prodromal and preclinical stages., Author summary Why was this study done? Metabolomics, which measures the biochemical products of cell processes, can be used to measure alterations in biochemical pathways related to AD. Several recent studies have applied metabolomics to explore potential blood biomarkers for Alzheimer disease (AD). Prior blood biomarker studies have not linked signals in the blood to those in the brain and have relied mainly on discriminating between AD/mild cognitive impairment (MCI) and control samples. These study designs ignore the long preclinical prodrome of AD and do not provide biological insights into the evolution of AD pathology in the brain and eventual development of clinical symptoms. Our study was designed to link alterations in metabolite signals in the brain to those in the blood, explore how those alterations were associated with distinct endophenotypes of AD, and identify the key biological pathways implicated. What did the research do and find? We used quantitative and targeted metabolomics assays on brain tissue samples (N = 44) and machine-learning methods to identify a brain metabolite signature of AD, i.e., a 26-metabolite panel that discriminated AD and control samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed the same 26 metabolites in blood from two longitudinal cohorts that represent prodromal (Alzheimer’s Disease Neuroimaging Initiative [ADNI], N = 767) and preclinical (Baltimore Longitudinal Study of Aging [BLSA], N = 207) AD and tested their associations with MRI measures, CSF biomarkers, risk of conversion to incident AD, and cognitive performance. We found that higher blood concentrations of sphingolipid species were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. These metabolites map to several biologically relevant pathways in AD, including tau phosphorylation, Aβ metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. What do these findings mean? Our study design represents a novel approach for identifying markers of disease progression in AD and potential avenues for therapeutic intervention. Perturbations in sphingolipid metabolism are consistently associated with preclinical and prodromal AD, as well as with AD pathology at autopsy, providing compelling evidence for their significant role in AD pathogenesis.

Behavioural interventions to prevent and delay dementia onset and progression are on the rise. Physical, sensory, electrical, and multimodal lifestyle activity may impact cognitive and brain health in multiple ways that impact directly or indirectly the neuropathology and clinical symptoms of Alzheimer’s disease and dementias. Many of these programmes are scalable through existing clinical settings and community infrastructure, including schools, community and retirement centres, religious institutions, and other public and private non-profit organizations. At the same time, much remains to be learned about the specific physical and lifestyle activities that contribute to cognitive health or offer resilience to pathology, and the limits of their effectiveness. An important objective for these studies will be to explore the additive and interactive effects of different interventions, both behavioural and pharmacologic.

Purpose of the study The goal of the study was to examine barriers and facilitators to clinical research participation among African Americans, as well as recommendations for overcoming these. Design and methods Eight focus groups were conducted consisting of 64 individuals. These focus groups targeted 2 groups of individuals: (a) community members, including both individuals involved in research and individuals not involved in research, and (b) community leaders, including clergy, community health care providers and service providers who may influence decisions to participate in research. Results Among participants in both groups, the most common barriers to participation included fear and mistrust of research due to multiple factors, such as a lack of information about research and prevailing knowledge of historical occurrences. Facilitators to research participation included intrinsic factors, such as a desire to help others, and extrinsic factors, such as familiarity with the research recruiter. The focus groups also directly engaged participants in discussions of strategies that might improve recruitment, such as the importance of providing personal stories that enable community members to understand the potential benefits of research. Implications Findings from these focus groups address the mandate from funding agencies that emphasize the importance of including racially diverse populations in clinical research studies, and offer potential solutions for increasing the recruitment and retention of minority participants.

Hippocampal atrophy is associated with memory impairment and dementia and serves as a key biomarker in the preclinical stages of Alzheimer's disease. Physical activity, one of the most promising behavioral interventions to prevent or delay cognitive decline, has been shown to be associated with hippocampal volume; specifically increased aerobic activity and fitness may have a positive effect on the size of the hippocampus. The majority of older adults, however, are sedentary and have difficulty initiating and maintaining exercise programs. A modestly more active lifestyle may nonetheless be beneficial. This study explored whether greater objectively measured daily walking activity was associated with larger hippocampal volume. We additionally explored whether greater low-intensity walking activity, which may be related to leisure-time physical, functional, and social activities, was associated with larger hippocampal volume independent of exercise and higher-intensity walking activity. Segmentation of hippocampal volumes was performed using Functional Magnetic Resonance Imaging of the Brain's Software Library (FSL), and daily walking activity was assessed using a step activity monitor on 92, nondemented, older adult participants. After controlling for age, education, body mass index, cardiovascular disease risk factors, and the Mini Mental State Exam, we found that a greater amount, duration, and frequency of total daily walking activity were each associated with larger hippocampal volume among older women, but not among men. These relationships were specific to hippocampal volume, compared with the thalamus, used as a control brain region, and remained significant for low-intensity walking activity, independent of moderate- to vigorous-intensity activity and self-reported exercise. This is the first study, to our knowledge, to explore the relationship between objectively measured daily walking activity and hippocampal volume in an older adult population. Findings suggest the importance of examining whether increasing nonexercise, lifestyle physical activities may produce measurable cognitive benefits and affect hippocampal volume through molecular pathways unique to those related to moderate-intensity exercise.

We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.