Search

Midlife cardiometabolic risk factors are associated with an increased risk of Alzheimer’s dementia (AD). Moderate calorie restriction (CR) in healthy, non-obese young and middle-aged adults improves cardiometabolic risk factors. Plasma concentrations of amyloid β oligomers (Aβ-42 and Aβ-40) and total tau are emerging biomarkers of AD pathology. Our objective was to determine the impact of two years of CR in healthy young and middle-aged adults on Aβ-42, Aβ-40, and total tau in the Comprehensive Assessment of Long term Effects of Reducing Intake of Energy (CALERIE) Study. Participants were randomized 2:1 to 24 months of CR (prescribed as 25% reduction in baseline calorie requirements) versus an ad libitum (AL) diet. We quantified plasma Aβ-42, Aβ-40, and total tau using the ultrasensitive single molecule array (SIMOA) technology at baseline and two years in a subset of CALERIE (N=133). We used linear regression to evaluate the impact of CR, including age, sex, and presence/absence of the APOE-ε4 risk allele as covariates. We hypothesized that there would be differential CR effects based on APOE-ε4 carrier status; to test this, we included an interaction term. As compared to AL, there was a trend towards decreased Aβ-40, controlling for age, baseline Aβ-40 concentrations, and APOE-ε4 carrier status (β=-12.59, 95% CI[-27.14, 1.96], p=0.093) with 12% (average achieved) CR. The CR*APOE-ε4 carrier status interaction term was significant at a pre-defined threshold of p

Early, accurate diagnosis of Alzheimer disease (AD) is essential but remains challenging. Neuropathological hallmarks of AD are β-amyloid neuritic plaques and tau protein neurofibrillary tangles. 18F-Florbetapir is one of several available PET tracers for imaging cortical fibrillary β-amyloid plaques. 18F-Flortaucipir PET was recently approved for evaluating the distribution and density of aggregated neurofibrillary tangles. We present cases of mild cognitive impairment or suspected AD to depict the nuances of flortaucipir distribution and scan interpretation as well as how combined information from amyloid and tau PET may help with differential diagnosis and prognosis.

In mild cognitive impairment (MCI) due to Alzheimer disease (AD), also known as prodromal AD, there is evidence for a pathologic shortage of uridine, choline, and docosahexaenoic acid [DHA]), which are key nutrients needed by the brain. Preclinical and clinical evidence shows the importance of nutrient bioavailability to support the development and maintenance of brain structure and function in MCI and AD. Availability of key nutrients is limited in MCI, creating a distinct nutritional need for uridine, choline, and DHA. Evidence suggests that metabolic derangements associated with ageing and disease-related pathology can affect the body’s ability to generate and utilize nutrients. This is reflected in lower levels of nutrients measured in the plasma and brains of individuals with MCI and AD dementia, and progressive loss of cognitive performance. The uridine shortage cannot be corrected by normal diet, making uridine a conditionally essential nutrient in affected individuals. It is also challenging to correct the choline shortfall through diet alone, because brain uptake from the plasma significantly decreases with ageing. There is no strong evidence to support the use of single-agent supplements in the management of MCI due to AD. As uridine and choline work synergistically with DHA to increase phosphatidylcholine formation, there is a compelling rationale to combine these nutrients. A multinutrient enriched with uridine, choline, and DHA developed to support brain function has been evaluated in randomized controlled trials covering a spectrum of dementia from MCI to moderate AD. A randomized controlled trial in subjects with prodromal AD showed that multinutrient intervention slowed brain atrophy and improved some measures of cognition. Based on the available clinical evidence, nutritional intervention should be considered as a part of the approach to the management of individuals with MCI due to AD, including adherence to a healthy, balanced diet, and consideration of evidence-based multinutrient supplements.

Background: Previous studies have demonstrated that aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet can improve neurocognition. However, the mechanisms by which lifestyle improves neurocognition have not been widely studied. We examined the associations between changes in metabolic, neurotrophic, and inflammatory biomarkers with executive functioning among participants from the Exercise and Nutritional Interventions for Neurocognitive Health Enhancement (ENLIGHTEN) trial. Objective: To examine the association between changes in metabolic function and neurocognition among older adults with cognitive impairment, but without dementia (CIND) participating in a comprehensive lifestyle intervention. Methods: ENLIGHTEN participants were randomized using a 2×2 factorial design to receive AE, DASH, both AE+DASH, or a health education control condition (HE) for six months. Metabolic biomarkers included insulin resistance (homeostatic model assessment [HOMA-IR]), leptin, and insulin-like growth factor (IGF-1); neurotrophic biomarkers included brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF); and inflammatory biomarkers included interleukin-6 (IL-6) and C-Reactive Protein (CRP). Results: Participants included 132 sedentary older adults (mean age = 65 [SD = 7]) with CIND. Results demonstrated that both AE (d = 0.48, p = 0.015) and DASH improved metabolic function (d = 0.37, p = 0.039), without comparable improvements in neurotrophic or inflammatory biomarkers. Greater improvements in metabolic function, including reduced HOMA-IR (B = –2.3 [–4.3, –0.2], p = 0.033) and increased IGF-1 (B = 3.4 [1.2, 5.7], p = 0.004), associated with increases in Executive Function. Conclusion: Changes in neurocognition after lifestyle modification are associated with improved metabolic function.

ObjectivesWe assessed the relationship between the Patient Health Questionnaire-9 (PHQ-9) at intake and other measurements intended to assess biological factors, markers of disease and health status.Design, setting and participantsWe performed a cross-sectional analysis of 2365 participants from the Baseline Health Study, a prospective cohort of adults selected to represent major demographic groups in the USA. Participants underwent deep phenotyping on demographic, clinical, laboratory, functional and imaging findings.ImportanceDespite extensive research on the clinical implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and other measures of health and disease; we sought to better understand this relationship.InterventionsNone.Main outcomes and measuresCross-sectional measures of medical illnesses, gait, balance strength, activities of daily living, imaging and laboratory tests.ResultsCompared with lower PHQ-9 scores, higher scores were associated with female sex (46.9%–66.7%), younger participants (53.6–42.4 years) and compromised physical status (higher resting heart rates (65 vs 75 bpm), larger body mass index (26.5–30 kg/m2), greater waist circumference (91–96.5 cm)) and chronic conditions, including gastro-oesophageal reflux disease (13.2%–24.7%) and asthma (9.5%–20.4%) (pConclusionsOur study highlights how: (1) even subthreshold depressive symptoms (measured by PHQ-9) may be indicative of several individual- and population-level concerns that demand more attention; and (2) depression should be considered a comorbidity in common disease.Trial registration numberNCT03154346.

ObjectiveTo investigate the association of triglyceride (TG) principal component scores with Alzheimer disease (AD) and the amyloid, tau, neurodegeneration, and cerebrovascular disease (A/T/N/V) biomarkers for AD.MethodsSerum levels of 84 TG species were measured with untargeted lipid profiling of 689 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including 190 cognitively normal older adults (CN), 339 with mild cognitive impairment (MCI), and 160 with AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [18F]fluorodeoxyglucose-PET) were assessed with a generalized linear model approach. In both cases, the Bonferroni method of adjustment was used to correct for multiple comparisons.ResultsThe 84 TGs yielded 9 principal components, 2 of which, consisting of long-chain, polyunsaturated fatty acid–containing TGs (PUTGs), were significantly associated with MCI and AD. Lower levels of PUTGs were observed in MCI and AD compared to CN. PUTG principal component scores were also significantly associated with hippocampal volume and entorhinal cortical thickness. In participants carrying the APOE ε4 allele, these principal components were significantly associated with CSF β-amyloid1–42 values and entorhinal cortical thickness.ConclusionThis study shows that PUTG component scores were significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE ε4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.

Late-onset Alzheimer’s disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine., Sex and the APOE ε4 genotype are important risk factors for late-onset Alzheimer’s disease. In the current study, the authors investigate how sex and APOE ε4 genotype modify the association between Alzheimer’s disease biomarkers and metabolites in serum.

BACKGROUND Greater body weight has been associated impairments in neurocognition and greater dementia risk, although the mechanisms linking weight and neurocognition have yet to be adequately delineated. OBJECTIVE To examine metabolic mechanisms underlying the association between obesity and neurocognition. METHODS We conducted a secondary analysis of weight, neurocognition, and the potentially mediating role of metabolic and inflammatory biomarkers among 160 participants from the ENLIGHTEN trial of vascular cognitive impairment, no dementia (CIND). Neurocognition was assessed using a 45-minute assessment battery assessing Executive Function, Verbal and Visual Memory. We considered three metabolic biomarkers: insulin resistance (homeostatic model assessment [HOMA-IR]), plasma leptin, and insulin-like growth factor (IGF-1). Inflammation was assessed using C-reactive protein. Multiple regression analyses were used. RESULTS Participants included 160 sedentary older adults with CIND. Participants tended to be overweight or obese (mean BMI = 32.5 [SD = 4.8]). Women exhibited higher BMI (p = 0.043), CRP (p

BackgroundThe General Anxiety Disorder-7 (GAD-7) questionnaire is a standard tool used for screening and follow-up of patients with Generalized Anxiety Disorder (GAD). Although it is generally accepted that anxiety correlates with clinical and psychosocial stressors, precise quantitative data is limited on the relations among GAD-7, traditional biomarkers, and other measures of health. Even less is known about how GAD-7 relates to race, ethnicity, and socioeconomic status (SES).We determined how multiple demographic and socioeconomic data correlate with the participants’ GAD-7 results when compared with laboratory, physical function, clinical, and other biological markers.MethodsThe Project Baseline Health Study (BHS) is a prospective cohort of adults representing several populations in the USA. We analyzed a deeply phenotyped group of 2502 participants from that study. Measures of interest included: clinical markers or history of medical diagnoses; physical function markers including gait, grip strength, balance time, daily steps, and echocardiographic parameters; psychometric measurements; activities of daily living; socioeconomic characteristics; and laboratory results.ResultsHigher GAD-7 scores were associated with female sex, younger age, and Hispanic ethnicity. Measures of low SES were also associated with higher scores, including unemployment, income ≤$25,000, and ≤12 years of education. After adjustment for 166 demographic, clinical, laboratory, and symptom characteristics, unemployment and overall higher SES risk scores were highly correlated with anxiety scores. Protective factors included Black race and older age.LimitationsCorrelations identified in this cross-sectional study cannot be used to infer causal relationships; further, we were not able to account for possible use of anxiety treatments by study participants.ConclusionsThese findings highlight the importance of understanding anxiety as a biopsychosocial entity. Clinicians and provider organizations need to consider both the physical manifestations of the disorder and their patients’ social determinants of health when considering treatment pathways and designing interventions.

With the explosive growth of biomarker data in Alzheimer’s disease (AD) clinical trials, numerous mathematical models have been developed to characterize disease-relevant biomarker trajectories over time. While some of these models are purely empiric, others are causal, built upon various hypotheses of AD pathophysiology, a complex and incompletely understood area of research. One of the most challenging problems in computational causal modeling is using a purely data-driven approach to derive the model’s parameters and the mathematical model itself, without any prior hypothesis bias. In this paper, we develop an innovative data-driven modeling approach to build and parameterize a causal model to characterize the trajectories of AD biomarkers. This approach integrates causal model learning, population parameterization, parameter sensitivity analysis, and personalized prediction. By applying this integrated approach to a large multicenter database of AD biomarkers, the Alzheimer’s Disease Neuroimaging Initiative, several causal models for different AD stages are revealed. In addition, personalized models for each subject are calibrated and provide accurate predictions of future cognitive status.

Gut-microbiome-inflammation interactions have been linked to neurodegeneration in Alzheimer’s disease (AD) and other disorders. We hypothesized that treatment with rifaximin, a minimally absorbed gut-specific antibiotic, may modify the neurodegenerative process by changing gut flora and reducing neurotoxic microbial drivers of inflammation. In a pilot, open-label trial, we treated 10 subjects with mild to moderate probable AD dementia (MMSE = 17 ± 3) with rifaximin for 3 months. Treatment was associated with a significant reduction in serum neurofilament-light levels (p Research in ContextSystematic ReviewPubMed reviews showed emerging evidence for gut-microbiome-inflammation links in Alzheimer’s disease (AD).InterpretationOur pilot study revealed that rifaximin, a minimally absorbed, gut-specific antibiotic, reduced surrogate markers of neurodegeneration while increasing, potentially beneficial, microbiota in phylum Firmicutes. These data provide initial support to the hypothesis that microbiome related products may play a role in neurodegenerative disorders.Future DirectionsWe plan to conduct additional human and pre-clinical studies to confirm these findings and determine the potential of rifaximin as a therapeutic for AD.

Digital cognitive tests offer several potential advantages over established paper-pencil tests but have not yet been fully evaluated for the clinical evaluation of mild cognitive impairment. The NeuroCognitive Performance Test (NCPT) is a web-based, self-directed, modular battery intended for repeated assessments of multiple cognitive domains. Using a sample of 101 MCI subjects, we report in this study that the NCPT composite is significantly correlated with both a composite measure of established tests (r=0.77, p

INTRODUCTIONEmbedding single-omics disease associations into the wider context of multi-level molecular changes in Alzheimer’s disease (AD) remains one central challenge in AD research.METHODSResults from numerous AD-specific omics studies from AMP-AD, NIAGADS, and other initiatives were integrated into a comprehensive network resource and complemented with molecular associations from large-scale population-based studies to provide a global view on AD.RESULTSWe present the AD Atlas, an online resource (www.adatlas.org) integrating over 20 large studies providing disease-relevant information on 20,353 protein-coding genes, 8,615 proteins, 997 metabolites and 31 AD-related phenotypes. Multiple showcases demonstrate the utility of this resource for contextualization of AD research results and subsequent downstream analyses, such as drug repositioning approaches.DISCUSSIONBy providing a global view on multi-omics results through a user-friendly interface, the AD Atlas enables the formulation of molecular hypotheses and retrieval of clinically relevant insights that can be validated in follow-up analyses or experiments.

Background Depression (DEP) and cognitive impairment (CI) share etiological risk factors, anatomical underpinnings, and interact to produce deleterious treatment outcomes. Both DEP and CI exhibit altered patterns of cortical thickness which may impact the course of antidepressant treatment, though inconsistencies in directionality and affected brain regions have been reported. In this study, we examined the relationship between cortical thickness and treatment outcome in older adults with comorbid DEP-CI. Methods 55 patients with DEP-CI received baseline MRI scans as part of a larger clinical trial at NYSPI/Columbia University Medical Center and Duke University Medical Center. Mood was assessed using the Hamilton Depression Rating Scale. Patients received open antidepressant treatment for 8 weeks followed by another 8 weeks of the same medication or switch to another antidepressant for a total of 16 weeks. Cortical thickness was extracted using an automated brain segmentation program (FreeSurfer). Vertex-wise analyses evaluated the relationship between cortical thickness and treatment outcome. Results Remitters exhibited diffuse clusters of greater cortical thickness and reduced cortical thickness compared to non-remitters. Thicker baseline middle frontal gyrus most consistently predicted greater likelihood and faster rate of remission. White matter hyperintensities and hippocampal volume were not associated with antidepressant treatment outcome. Limitations MRI was conducted at baseline only and sample size was small. Discussion Cortical thickness predicts treatment remission and magnitude of early improvement. Results indicate that individuals with DEP-CI exhibit unique patterns of structural abnormalities compared to their depressed peers without CI that have consequences for their recovery with antidepressant treatment.

Dysregulation of sphingomyelin (SM) and ceramide metabolism have been implicated in Alzheimer’s Disease (AD). Genome-wide and transcriptome wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with AD. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. Evaluation of peripheral lipidomic profiles is useful in providing perspective on metabolic dysregulation in preclinical and clinical AD states. In this study, we focused on the sphingolipid pathway and carried out multi-omic analyses to identify central and peripheral metabolic changes in AD patients and correlate them to imaging features and cognitive performance in amyloidogenic mouse models. Our multi-omic approach was based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on 1708 context-specific metabolic networks to identify differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in SM pathway with AD pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in AD; (e) metabolite genome-wide association studies (mGWAS) to define receptors within pathway as potential drug target. Our findings from complementary approaches suggested that depletion of S1P compensated for AD cellular pathology, likely by upregulating the SM pathway, suggesting that modulation of S1P signaling may have protective effects in AD. We tested this hypothesis in APP/PS1 mice and showed that prolonged exposure to fingolimod, an S1P signaling modulator approved for treatment of multiple sclerosis, alleviated the cognitive impairment in mice. Our multi-omic approach identified potential targets in the SM pathway and suggested modulators of S1P metabolism as possible candidates for AD treatment.

Background Interactions between the gut microbiota, microglia, and aging may modulate Alzheimer’s disease (AD) pathogenesis but the precise nature of such interactions is not known. Methods We developed an integrated multi-dimensional, knowledge-driven, systems approach to identify interactions among microbial metabolites, microglia, and AD. Publicly available datasets were repurposed to create a multi-dimensional knowledge-driven pipeline consisting of an integrated network of microbial metabolite–gene–pathway–phenotype (MGPPN) consisting of 34,509 nodes (216 microbial metabolites, 22,982 genes, 1329 pathways, 9982 mouse phenotypes) and 1,032,942 edges. Results We evaluated the network-based ranking algorithm by showing that abnormal microglia function and physiology are significantly associated with AD pathology at both genetic and phenotypic levels: AD risk genes were ranked at the top 6.4% among 22,982 genes, P < 0.001. AD phenotypes were ranked at the top 11.5% among 9982 phenotypes, P < 0.001. A total of 8094 microglia–microbial metabolite–gene–pathway–phenotype–AD interactions were identified for top-ranked AD-associated microbial metabolites. Short-chain fatty acids (SCFAs) were ranked at the top among prioritized AD-associated microbial metabolites. Through data-driven analyses, we provided evidence that SCFAs are involved in microglia-mediated gut–microbiota–brain interactions in AD at both genetic, functional, and phenotypic levels. Conclusion Our analysis produces a novel framework to offer insights into the mechanistic links between gut microbial metabolites, microglia, and AD, with the overall goal to facilitate disease mechanism understanding, therapeutic target identification, and designing confirmatory experimental studies.

The most common screening tool for depression is the Patient Health Questionnaire-9 (PHQ-9). Despite extensive research on the clinical and behavioral implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and social determinants of health and disease.To assess the relationship between the PHQ-9 at intake and other measurements intended to assess social determinants of health.Cross-sectional analyses of 2502 participants from the Baseline Health Study (BHS), a prospective cohort of adults selected to represent major demographic groups in the US; participants underwent deep phenotyping on demographic, socioeconomic, clinical, laboratory, functional, and imaging findings.None.Cross-sectional measures of clinical and socioeconomic status (SES).In addition to a host of clinical and biological factors, higher PHQ-9 scores were associated with female sex, younger participants, people of color, and Hispanic ethnicity. Multiple measures of low SES, including less education, being unmarried, not currently working, and lack of insurance, were also associated with higher PHQ-9 scores across the entire spectrum of PHQ-9 scores. A summative score of SES, which was the 6th most predictive factor, was associated with higher PHQ-9 score after adjusting for 150 clinical, lab testing, and symptomatic characteristics.Our findings underscore that depression should be considered a comorbidity when social determinants of health are addressed, and both elements should be considered when designing appropriate interventions.

ObjectiveTo characterize the global physician community’s opinions on the use of digital tools for COVID-19 public health surveillance and self-surveillance.MethodsCross-sectional, random, stratified survey done on Sermo, a physician networking platform, between September 9-15, 2020. We aimed to sample 1,000 physicians divided among the USA, EU, and rest of the world. The survey questioned physicians on the risk-benefit ratio of digital tools, as well as matters of data privacy and trust.ResultsThe survey was completed by 1004 physicians with a mean (SD) age of 49.14 (12) years. Enthusiasm was highest for self-monitoring smart watches (66%) and contact tracing apps (66%) and slightly lower (48-56%) for other tools. Trust was highest for health providers (68%) and lowest for technology companies (30%). Most respondents (69.8%) felt that loosening privacy standards to fight the pandemic would lead to misuse of privacy in the future.ConclusionThe survey provides foundational insights about how physicians think of surveillance. Collaborations between public health and technology researchers to strengthen evidence of effectiveness and build public trust may be useful.

Using flortaucipir, Pontecorvo et al. reveal an increase in cortical tau over 18 months in Aβ+ but not Aβ- subjects, and an association between baseline tau and the magnitude of changes in tau and cognitive performance. The abundance and distribution of tau may influence both tau spreading and cognitive decline., The advent of tau-targeted PET tracers such as flortaucipir (18F) (flortaucipir, also known as 18F-AV-1451 or 18F-T807) have made it possible to investigate the sequence of development of tau in relationship to age, amyloid-β, and to the development of cognitive impairment due to Alzheimer’s disease. Here we report a multicentre longitudinal evaluation of the relationships between baseline tau, tau change and cognitive change, using flortaucipir PET imaging. A total of 202 participants 50 years old or older, including 57 cognitively normal subjects, 97 clinically defined mild cognitive impairment and 48 possible or probable Alzheimer’s disease dementia patients, received flortaucipir PET scans of 20 min in duration beginning 80 min after intravenous administration of 370 MBq flortaucipir (18F). On separate days, subjects also received florbetapir amyloid PET imaging, and underwent a neuropsychological test battery. Follow-up flortaucipir scans and neuropsychological battery assessments were also performed at 9 and 18 months. Fifty-five amyloid-β+ and 90 amyloid-β− subjects completed the baseline and 18-month study visits and had valid quantifiable flortaucipir scans at both time points. There was a statistically significant increase in the global estimate of cortical tau burden as measured by standardized uptake value ratio (SUVr) from baseline to 18 months in amyloid-β+ but not amyloid-β− subjects (least squared mean change in flortaucipir SUVr : 0.0524 ± 0.0085, P < 0.0001 and 0.0007 ± 0.0024 P = 0.7850, respectively), and a significant association between magnitude of SUVr increase and baseline tau burden. Voxel-wise evaluations further suggested that the regional pattern of change in flortaucipir PET SUVr over the 18-month study period (i.e. which regions exhibited the greatest change) also varied as a function of baseline global estimate of tau burden. In subjects with lower global SUVr, temporal lobe regions showed the greatest flortaucipir retention, whereas in subjects with higher baseline SUVr, parietal and frontal regions were increasingly affected. Finally, baseline flortaucipir and change in flortaucipir SUVr were both significantly (P < 0.0001) associated with changes in cognitive performance. Taken together, these results provide a preliminary characterization of the longitudinal spread of tau in Alzheimer’s disease and suggest that the amount and location of tau may have implications both for the spread of tau and the cognitive deterioration that may occur over an 18-month period.

ObjectiveTo determine the independent and additive effects of aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet on executive functioning in adults with cognitive impairments with no dementia (CIND) and risk factors for cardiovascular disease (CVD).MethodsA 2-by-2 factorial (exercise/no exercise and DASH diet/no DASH diet) randomized clinical trial was conducted in 160 sedentary men and women (age >55 years) with CIND and CVD risk factors. Participants were randomly assigned to 6 months of AE, DASH diet nutritional counseling, a combination of both AE and DASH, or health education (HE). The primary endpoint was a prespecified composite measure of executive function; secondary outcomes included measures of language/verbal fluency, memory, and ratings on the modified Clinical Dementia Rating Scale.ResultsParticipants who engaged in AE (d = 0.32, p = 0.046) but not those who consumed the DASH diet (d = 0.30, p = 0.059) demonstrated significant improvements in the executive function domain. The largest improvements were observed for participants randomized to the combined AE and DASH diet group (d = 0.40, p = 0.012) compared to those receiving HE. Greater aerobic fitness (b = 2.3, p = 0.049), reduced CVD risk (b = 2.6, p = 0.042), and reduced sodium intake (b = 0.18, p = 0.024) were associated with improvements in executive function. There were no significant improvements in the memory or language/verbal fluency domains.ConclusionsThese preliminary findings show that AE promotes improved executive functioning in adults at risk for cognitive decline.ClinicalTrials.gov identifierNCT01573546.Classification of evidenceThis study provides Class I evidence that for adults with CIND, AE but not the DASH diet significantly improves executive functioning.

BackgroundRisk perception, influenced and biased by multiple factors, can affect behavior.ObjectiveTo assess the variability of physician perceptions of catching COVID-19.DesignCross sectional, random stratified sample of physicians registered with Sermo, a global networking platform open to verified and licensed physicians.Main outcome measuresThe survey asked: “What is your likelihood of catching COVID-19 in the next three months?” The physicians were asked to give their best estimate as an exact percentage.ResultsThe survey was completed by 1004 physicians (40 countries, 67 specialties, 49% frontline [e.g. ER, infectious disease, internal medicine]) with a mean (SD) age of 49.14 (12) years. Mean (SD) self-risk estimate was 32.3% ± 26% with a range from 0% to 100% (Figure 1a). Risk estimates were higher in younger (ConclusionsTo our knowledge, this is the first global study to document physician risk perceptions for catching COVID-19 and how it is impacted by age, gender, practice specialty and geography. Accurate calibration of risk perception is vital since both over- and underestimation of risk could impact physician behavior and have implications for public health.

Among the non-pharmacological methods under development for maintaining cognitive function across the lifespan is computerized cognitive training (CCT). There has been considerable interest in using CCT to slow or remediate age-related cognitive decline, both normal and pathological. Toward these ends, it would be useful to know how the effects of CCT on cognitive function vary over the course of normal cognitive aging. Are there changes in either 1) the overall efficacy of CCT or 2) which cognitive faculties are affected? To address these two questions, we reanalyzed results from a large online study by Hardy et al. (1) of 4,715 adults between 18 and 80 that examined effects of CCT on both a neuropsychological test battery and self-reported ratings of cognition and affect in daily living. Combined across all participants, Hardy et al. found greater improvement on both types of assessment following 10 weeks of CCT with the commercial program Lumosity, as compared to practice with a control activity involving computerized crossword puzzles. The present study compared the size of these effects on the older (50–80) and younger (18–49) participants. To address the question of overall efficacy, we examined CCT effects (treatment minus control) on overall performance of the test battery and mean rating. No significant difference on either measure was found between the two age cohorts. To address the question of whether the same magnitude of overall effects on both age cohorts was due to equivalent effects on the same set of underlying cognitive functions, we examined the patterns of CCT effects across individual subtests and rated items. These patterns did not differ significantly between the two age cohorts. Our findings suggest that benefits from CCT can occur to a similar degree and in a similar way across an extended part of the adult lifespan. Moreover, the overall effects of CCT delivered over the internet were of the same small to medium size as those typically found in the lab or clinic. Besides improving access and reducing the cost of CCT for older adults, delivery over the internet makes long-term training more practicable, which could potentially yield larger benefits.

Metabolomics in the Alzheimer’s Disease Neuroimaging Initiative cohort provides a powerful tool for mapping biochemical changes in Alzheimer’s disease, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-β deposition in Alzheimer’s disease. We examined 140 serum metabolites and their associations with brain amyloid-β deposition, cognition and conversion from mild cognitive impairment to Alzheimer’s disease in the Alzheimer’s Disease Neuroimaging Initiative. Processed [18F] Florbetapir PET images were used to perform a voxel-wise statistical analysis of the effect of metabolite levels on amyloid-β accumulation across the whole brain. We performed a multivariable regression analysis using age, sex, body mass index, apolipoprotein E ε4 status and study phase as covariates. We identified nine metabolites as significantly associated with amyloid-β deposition after multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-β accumulation and higher memory scores. However, higher levels of seven phosphatidylcholines (lysoPC a C18:2, PC aa C42:0, PC ae C42:3, PC ae C44:3, PC ae C44:4, PC ae C44:5 and PC ae C44:6) were associated with increased brain amyloid-β deposition. In addition, higher levels of PC ae C44:4 were significantly associated with lower memory and executive function scores and conversion from mild cognitive impairment to Alzheimer’s disease dementia. Our findings suggest that dysregulation of peripheral phosphatidylcholine metabolism is associated with earlier pathological changes noted in Alzheimer’s disease as measured by brain amyloid-β deposition as well as later clinical features including changes in memory and executive functioning. Perturbations in phosphatidylcholine metabolism may point to issues with membrane restructuring leading to the accumulation of amyloid-β in the brain. Additional studies are needed to explore whether these metabolites play a causal role in the pathogenesis of Alzheimer’s disease or if they are biomarkers for systemic changes during preclinical phases of the disease., Nho et al. report that serum-based metabolites are associated with brain amyloid-β deposition, cognition and disease progression from mild cognitive impairment to Alzheimer’s disease in a large cohort of older adults. Results suggest that dysregulation of very long chain peripheral phospholipid metabolism is associated with earlier pathological changes in Alzheimer’s disease., Graphical Abstract Graphical Abstract

IntroductionCOVID-19 immunity passports could protect the right to free movement, but critics worry about insufficient evidence, privacy, fraud, and discrimination. We aimed to characterize the global physician community’s opinion regarding immunity passports.MethodsCross sectional, random stratified sample of physicians registered with Sermo, a global networking platform open to verified and licensed physicians. The survey aimed to sample 1,000 physicians divided among the USA, EU and rest of the world. The survey question on immunology asked physicians to offer their insights into whether we know enough about COVID-19 immunity and its duration to offer immunity passports at the present time.ResultsThe survey was completed by 1004 physicians (67 specialties, 40 countries, 49% frontline specialties) with a mean (SD) age of 49.14 (12) years. Overall, 52% answered NO, 17% were UNCERTAIN, and 31% answered YES (P ConclusionOur findings suggest a current lack of support among physicians for immunity passports. It is hoped that ongoing research and vaccine trials will provide further clarity.

Sex differences in Alzheimer's disease (AD) are not well understood.We performed sex-specific analyses of AD and annualized cognitive decline with clinical and blood biomarker data in participants 60+ years old in the community-based longitudinal Framingham Heart Study Offspring Cohort (During 11 years of follow-up, women were 96% more likely than men to be diagnosed with clinical AD dementia after adjusting for age and education in the younger age group 60 to 70 years (Our study suggests that both early life and later-life pathological factors may contribute to potential sex differences in incident AD.

Background: There is a need to more fully characterize financial capacity losses in the preclinical and prodromal stages of Alzheimer’s disease (AD) and their pathological substrates. Objectives: To test the association between financial skills and cortical β-amyloid deposition in aging and subjects at risk for AD. Design: Cross-sectional analyses of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-3) study conducted across 50 plus sites in the US and Canada. Setting: Multicenter biomarker study. Participants: 243 subjects (144 cognitively normal, 79 mild cognitive impairment [MCI], 20 mild AD). Measurements: 18F-Florbetapir brain PET scans to measure global cortical β-amyloid deposition (SUVr) and the Financial Capacity Instrument Short Form (FCI-SF) to evaluate an individual’s financial skills in monetary calculation, financial concepts, checkbook/register usage, and bank statement usage. There are five sub scores and a total score (range of 0–74) with higher scores indicating better financial skill. Results: FCI-SF total score was significantly worse in MCI [Cohen’s d= 0.9 (95%CI: 0.6-1.2)] and AD subjects [Cohen’s d=3.1(CI: 2.5-3.7)] compared to normals. Domain scores and completion times also showed significant difference. Across all subjects, higher cortical β-amyloid SUVr was significantly associated with worse FCI-SF total score after co-varying for age, education, and cognitive score [Cohen’s f2=0.751(CI: 0.5-1.1)]. In cognitively normal subjects, after covarying for age, gender, and education, higher β -amyloid PET SUVr was associated with longer task completion time [Cohen’s f2=0.198(CI: 0.06-0.37)]. Conclusion: Using a multicenter study sample, we document that financial capacity is impaired in the prodromal and mild stages of AD and that such impairments are, in part, associated with the extent of cortical β-amyloid deposition. In normal aging, β-amyloid deposition is associated with slowing of financial tasks. These data confirm and extend prior research highlighting the utility of financial capacity assessments in at risk samples.

BackgroundThe potential for machine learning to disrupt the medical profession is the subject of ongoing debate within biomedical informatics.ObjectiveThis study aimed to explore psychiatrists’ opinions about the potential impact innovations in artificial intelligence and machine learning on psychiatric practiceMethodsIn Spring 2019, we conducted a web-based survey of 791 psychiatrists from 22 countries worldwide. The survey measured opinions about the likelihood future technology would fully replace physicians in performing ten key psychiatric tasks. This study involved qualitative descriptive analysis of written responses (“comments”) to three open-ended questions in the survey.ResultsComments were classified into four major categories in relation to the impact of future technology on: (1) patient-psychiatrist interactions; (2) the quality of patient medical care; (3) the profession of psychiatry; and (4) health systems. Overwhelmingly, psychiatrists were skeptical that technology could replace human empathy. Many predicted that ‘man and machine’ would increasingly collaborate in undertaking clinical decisions, with mixed opinions about the benefits and harms of such an arrangement. Participants were optimistic that technology might improve efficiencies and access to care, and reduce costs. Ethical and regulatory considerations received limited attention.ConclusionsThis study presents timely information on psychiatrists’ views about the scope of artificial intelligence and machine learning on psychiatric practice. Psychiatrists expressed divergent views about the value and impact of future technology with worrying omissions about practice guidelines, and ethical and regulatory issues.

Sex differences in Alzheimer’s disease (AD) biology and progression are not yet fully characterized. The goal of this study is to examine the effect of sex on cognitive progression in subjects with high likelihood of mild cognitive impairment (MCI) due to Alzheimer’s and followed up to 10 years in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cerebrospinal fluid total-tau and amyloid-beta (Aβ42) ratio values were used to sub-classify 559 MCI subjects (216 females, 343 males) as having “high” or “low” likelihood for MCI due to Alzheimer’s. Data were analyzed using mixed-effects models incorporating all follow-ups. The worsening from baseline in Alzheimer’s Disease Assessment Scale-Cognitive score (mean, SD) (9 ± 12) in subjects with high likelihood of MCI due to Alzheimer’s was markedly greater than that in subjects with low likelihood (1 ± 6, p p = 0.006). Our findings highlight the need to further investigate these findings in other populations and develop sex specific timelines for Alzheimer’s disease progression.

The rapid growth of mobile phones, automated speech recognizing personal assistants, and internet access among the elderly provides new opportunities for incorporating such technologies into clinical research and personalized medical care. Alzheimer’s disease is a good test case given the need for early detection, the high rate of clinical trial failures, the need to more efficiently recruit patients for trials, and the need for sensitive and ecologically valid trial outcomes.

Key Points Question Can noninvasive, wrist-worn wearable devices detect acute viral respiratory infection and predict infection severity before symptom onset? Findings In a cohort study of 31 participants inoculated with H1N1 and 18 participants with rhinovirus, infection detection and severity prediction models trained using data on wearable devices were able to distinguish between infection and noninfection with 92% accuracy for H1N1 and 88% accuracy for rhinovirus and were able to distinguish between mild and moderate infection 24 hours prior to symptom onset with 90% accuracy for H1N1 and 89% accuracy for rhinovirus. Meaning This study suggests that the use of wearable devices to identify individuals with presymptomatic acute viral respiratory infection is feasible; because wearable devices are common in the general population, using them for infection screening may help limit the spread of contagion., Importance Currently, there are no presymptomatic screening methods to identify individuals infected with a respiratory virus to prevent disease spread and to predict their trajectory for resource allocation. Objective To evaluate the feasibility of using noninvasive, wrist-worn wearable biometric monitoring sensors to detect presymptomatic viral infection after exposure and predict infection severity in patients exposed to H1N1 influenza or human rhinovirus. Design, Setting, and Participants The cohort H1N1 viral challenge study was conducted during 2018; data were collected from September 11, 2017, to May 4, 2018. The cohort rhinovirus challenge study was conducted during 2015; data were collected from September 14 to 21, 2015. A total of 39 adult participants were recruited for the H1N1 challenge study, and 24 adult participants were recruited for the rhinovirus challenge study. Exclusion criteria for both challenges included chronic respiratory illness and high levels of serum antibodies. Participants in the H1N1 challenge study were isolated in a clinic for a minimum of 8 days after inoculation. The rhinovirus challenge took place on a college campus, and participants were not isolated. Exposures Participants in the H1N1 challenge study were inoculated via intranasal drops of diluted influenza A/California/03/09 (H1N1) virus with a mean count of 106 using the median tissue culture infectious dose (TCID50) assay. Participants in the rhinovirus challenge study were inoculated via intranasal drops of diluted human rhinovirus strain type 16 with a count of 100 using the TCID50 assay. Main Outcomes and Measures The primary outcome measures included cross-validated performance metrics of random forest models to screen for presymptomatic infection and predict infection severity, including accuracy, precision, sensitivity, specificity, F1 score, and area under the receiver operating characteristic curve (AUC). Results A total of 31 participants with H1N1 (24 men [77.4%]; mean [SD] age, 34.7 [12.3] years) and 18 participants with rhinovirus (11 men [61.1%]; mean [SD] age, 21.7 [3.1] years) were included in the analysis after data preprocessing. Separate H1N1 and rhinovirus detection models, using only data on wearble devices as input, were able to distinguish between infection and noninfection with accuracies of up to 92% for H1N1 (90% precision, 90% sensitivity, 93% specificity, and 90% F1 score, 0.85 [95% CI, 0.70-1.00] AUC) and 88% for rhinovirus (100% precision, 78% sensitivity, 100% specificity, 88% F1 score, and 0.96 [95% CI, 0.85-1.00] AUC). The infection severity prediction model was able to distinguish between mild and moderate infection 24 hours prior to symptom onset with an accuracy of 90% for H1N1 (88% precision, 88% sensitivity, 92% specificity, 88% F1 score, and 0.88 [95% CI, 0.72-1.00] AUC) and 89% for rhinovirus (100% precision, 75% sensitivity, 100% specificity, 86% F1 score, and 0.95 [95% CI, 0.79-1.00] AUC). Conclusions and Relevance This cohort study suggests that the use of a noninvasive, wrist-worn wearable device to predict an individual’s response to viral exposure prior to symptoms is feasible. Harnessing this technology would support early interventions to limit presymptomatic spread of viral respiratory infections, which is timely in the era of COVID-19., This cohort study evaluates the feasibility of using noninvasive, wrist-worn wearable devices to detect presymptomatic viral infection after exposure and predict infection severity in patients exposed to H1N1 influenza or human rhinovirus.

IMPORTANCE: Flortaucipir positron emission tomography (PET) scans, rated with a novel, US Food and Drug Administration–approved, clinically applicable visual interpretation method, provide valuable information regarding near-term clinical progression of patients with Alzheimer disease (AD) or mild cognitive impairment (MCI). OBJECTIVE: To evaluate the association between flortaucipir PET visual interpretation and patients’ near-term clinical progression. DESIGN/SETTING/PARTICIPANTS: Two prospective, open-label, longitudinal studies were conducted from December 2014 to September 2019. Study 1 screened 298 patients and enrolled 160 participants who had a flortaucipir scan at baseline visit. Study 2 selected 205 participants from the AMARANTH trial, which was terminated after futility analysis. Out of the 2218 AMARANTH participants, 424 had a flortaucipir scan around randomization, but 219 did not complete 18-month clinical dementia rating (CDR) assessments and thus were excluded. In both studies, all participants were diagnosed as clinically impaired, and they were longitudinally followed up for approximately 18 months after baseline. MAIN OUTCOMES AND MEASURES: Flortaucipir scans were rated as either advanced or nonadvanced AD pattern using a predetermined visual interpretation method. The CDR sum of box (CDR-SB) score was used as primary clinical end point measurement in both studies. RESULTS: Of the 364 study participants who had readable scans, 48% were female (n = 174 of 364), and the mean (SD) age was 71.8 (8.7) years. Two hundred forty participants were rated as having an advanced AD pattern. At 18 months follow-up, 70% of those with an advanced AD pattern (n = 147 of 210) had 1 point or more increase in CDR-SB, an event predefined as clinically meaningful deterioration. In contrast, only 46% of those with a nonadvanced AD pattern scan (n = 48 of 105) experienced the same event (risk ratio [RR], 1.40; 95% CI, 1.11-1.76; P = .005). The adjusted mean CDR-SB changes were 2.28 and 0.98 for advanced and nonadvanced AD pattern groups, respectively (P

Objective The aim of the study was to determine the relationship of lifestyle factors and neurocognitive functioning in older adults with vascular risk factors and cognitive impairment, no dementia (CIND). Methods One hundred sixty adults (M [SD] = 65.4 [6.8] years) with CIND completed neurocognitive assessments of executive function, processing speed, and memory. Objective measures of physical activity using accelerometry, aerobic capacity determined by exercise testing, and dietary habits quantified by the Food Frequency Questionnaire and 4-Day Food Diary to assess adherence to the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets were obtained to assess direct effects with neurocognition. Potential indirect associations of high-sensitivity C-reactive protein and the Framingham Stroke Risk Profile also were examined. Results Greater aerobic capacity (β = 0.24) and daily physical activity (β = 0.15) were associated with better executive functioning/processing speed and verbal memory (βs = 0.24; 0.16). Adherence to the DASH diet was associated with better verbal memory (β = 0.17). Greater high-sensitivity C-reactive protein (βs = -0.14; -0.21) and Framingham Stroke Risk Profile (β = -0.18; -0.18) were associated with poorer executive functioning/processing speed and verbal memory. Greater stroke risk partially mediated the association of aerobic capacity with executive functioning/processing speed, and verbal memory and greater inflammation partially mediated the association of physical activity and aerobic fitness, with verbal memory. Conclusions Higher levels of physical activity, aerobic fitness, and adherence to the DASH diet are associated with better neurocognitive performance in adults with CIND. These findings suggest that the adoption of healthy lifestyle habits could reduce the risk of neurocognitive decline in vulnerable older adults. Clinical trial registration NCT01573546.

Aims: To evaluate the impact of amyloid PET imaging on diagnosis and patient management in a multicenter, randomized, controlled study. Methods: Physicians identified patients seeking a diagnosis for mild cognitive impairment or dementia, possibly due to Alzheimer disease (AD), and recorded a working diagnosis and a management plan. The patients underwent florbetapir PET scanning and were randomized to either immediate or delayed (1-year) feedback regarding amyloid status. At the 3-month visit, the physician updated the diagnosis and recorded a summary of the actual patient management since the post-scan visit. The study examined the impact of immediate versus delayed feedback on patient diagnosis/management at 3 and 12 months. Results: A total of 618 subjects were randomized (1:1) to immediate or delayed feedback arms, and 602 subjects completed the 3-month primary endpoint visit. A higher proportion of patients in the immediate feedback arm showed a change in diagnosis compared to the controls (32.6 vs. 6.4%; p = 0.0001). Similarly, a higher proportion of patients receiving immediate feedback had a change in management plan (68 vs. 55.5%; p < 0.002), mainly driven by changes in AD medication. Specifically, acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001). These between-group differences persisted until the 12-month visit. Conclusion: Knowledge of the amyloid status affects the diagnosis and alters patient management.

IntroductionPrevious studies evaluating the association between clinically diagnosed Alzheimer's disease (AD) and age-related macular degeneration (AMD) have generated conflicting results. This study is the first to assess whether AMD prevalence is higher in AD patients than non-AD controls by using histopathology to definitively diagnose AD.MethodsThis was a retrospective case-control study utilizing diagnostic information extracted from autopsy reports of patients age 75 and above, including 115 with a neuropathological diagnosis of AD and 57 age-matched normal controls.ResultsThe rate of AMD was not significantly higher in AD cases (53.0%) than in controls (59.6%) (z = 0.820, p = 0.794). AMD severity as determined by Sarks score was similar between AD patients and controls (χ2 = 2.96, p = 0.706). There was also no significant association between Braak stage of AD severity and AMD (χ2 = 4.55, p = 0.602).DiscussionNo significant effect of AD diagnosis or pathologic severity on AMD comorbidity was found, suggesting that any shared mechanisms between AMD and AD may be nondeterministic.

IntroductionMild cognitive impairment (MCI) is common in older adults and represents a high-risk group for progression to Alzheimer’s disease (AD). Medication trials in MCI have generally failed, but new discoveries with brain plasticity in ageing have led to the study of cognitive training as a potential treatment to improve cognitive abilities. Computerised cognitive training (CCT) involves computerised cognitive exercises that target specific cognitive abilities and neural networks to potentially improve cognitive functioning through neuroplasticity.Methods and analysisIn a two-site study (New York State Psychiatric Institute/Columbia University Medical Center and Duke University Medical Center), we will randomise 100 patients with MCI (Wechsler Memory Scale-III Logical Memory II score 0–11; Folstein Mini Mental State Examination ≥23) to home-based CCT (suite of exercises: memory, matching, spatial recognition, processing speed) or a home-based active control condition (computerised crossword puzzle training (CPT)) with 12 weeks of intensive training followed by regular booster sessions up to 78 weeks. All patients will receive standard neuropsychological and functional assessments in clinic as well as structural/functional brain MRI scans at study entry and endpoint. We will test if CCT, versus CPT, leads to improved cognitive functioning, transfers to functional ability and tasks of everyday life and impacts hippocampal volume changes and changes in the default mode network of the brain measured by resting-state functional MRI.Ethics and disseminationThe study will be conducted following ethics approval and written informed consent will be obtained from all subjects. Study results will be disseminated via publication, clinicaltrials.gov, media and conference presentations. This will be the first controlled long-term trial to evaluate the effects of home-based CCT versus computerised CPT on cognitive abilities and functional measures and neural outcomes as determined by MRI indices in patients with MCI. Positive results from trial may support further development of home-based CCT.Trial registration numberClinicalTrials.gov identifier (NCT03205709).

OBJECTIVES To evaluate the longer term changes in executive functioning among participants with cardiovascular disease (CVD) risk factors and cognitive impairments with no dementia (CIND) randomized to a diet and exercise intervention. DESIGN A 2 (Exercise) × 2 (Dietary Approaches to Stop Hypertension [DASH] eating plan) factorial randomized clinical trial. SETTING Academic tertiary care medical center. PARTICIPANTS Volunteer sample of 160 older sedentary adults with CIND and at least one additional CVD risk factor enrolled in the ENLIGHTEN trial between December 2011 and March 2016. INTERVENTIONS Six months of aerobic exercise (AE), DASH diet counseling, combined AE + DASH, or health education (HE) controls. MEASUREMENTS Neurocognitive battery recommended by the Neuropsychological Working Group for Vascular Cognitive Disorders including measures of executive function, memory, and language/verbal fluency. Secondary outcomes included the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Six-Minute Walk Distance (6MWD), and CVD risk including blood pressure, body weight, and CVD medication burden. RESULTS Despite discontinuation of lifestyle changes, participants in the exercise groups retained better executive function 1 year post-intervention (P = .041) compared with non-exercise groups, with a similar, albeit weaker, pattern in the DASH groups (P = .054), without variation over time (P's > .867). Participants in the exercise groups also achieved greater sustained improvements in 6MWD compared with non-Exercise participants (P

BackgroundAlzheimer’s disease (AD) is a major public health concern and there is an urgent need to better understand its complex biology and develop effective therapies. AD progression can be tracked in patients though validated imaging and spinal fluid biomarkers of pathology and neuronal loss. We still, however, lack a coherent quantitative model that explains how these biomarkers interact and evolve over time. Such a model could potentially help identify the major drivers of disease in individual patients and simulate response to therapy prior to entry in clinical trials. A current theory of AD biomarker progression, known as the dynamic biomarker cascade model, hypothesizes AD biomarkers evolve in a sequential, but temporally overlapping manner. A computational model incorporating assumptions about the underlying biology of this theory and its variations would be useful to test and refine its accuracy with longitudinal biomarker data from clinical trials.MethodsWe implemented a causal model to simulate time-dependent biomarker data under the descriptive assumptions of the dynamic biomarker cascade theory. We modeled pathologic biomarkers (beta-amyloid and tau), neuronal loss biomarkers and cognitive impairment as non-linear first order ordinary differential equations (ODEs) to include amyloid-dependent and non-dependent neurodegenerative cascades. We tested the feasibility of the model by adjusting its parameters to simulate three specific natural history scenarios in early-onset autosomal dominant AD and late-onset AD, and determine whether computed biomarker trajectories agreed with current assumptions of AD biomarker progression. We also simulated the effects of anti-amyloid therapy in late-onset AD.ResultsThe computational model of early-onset AD demonstrated the initial appearance of amyloid, followed by biomarkers of tau and neurodegeneration, followed by onset of cognitive decline based on cognitive reserve, as predicted by prior literature. Similarly, the late-onset AD computational models demonstrated the first appearance of amyloid or non-amyloid-related tauopathy, depending on the magnitude of comorbid pathology, and also closely matched the biomarker cascades predicted by prior literature. Forward simulation of anti-amyloid therapy in symptomatic late-onset AD failed to demonstrate any slowing in progression of cognitive decline, consistent with prior failed clinical trials in symptomatic patients.ConclusionWe have developed and computationally implemented a mathematical causal model of the dynamic biomarker cascade theory in AD. We demonstrate the feasibility of this model by simulating biomarker evolution and cognitive decline in early and late-onset natural history scenarios, as well as in a treatment scenario targeted at core AD pathology. Models resulting from this causal approach can be further developed and refined using patient data from longitudinal biomarker studies, and may in the future play a key role in personalizing approaches to treatment.

IntroductionIncreasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD).MethodsSerum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing.ResultsIn AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles.ConclusionWe report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.

Summary Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline., Graphical Abstract, Highlights Altered cholesterol and bile acid metabolism linked to Alzheimer disease (AD) Evidence for alternative bile acid pathway genes expression in post-mortem brains Metabolomics analysis shows secondary bile acids associated with cognitive decline Genome-scale metabolic networks of brain regions identify reactions linked to AD, Baloni et al. use a systems biology approach to identify alterations in cholesterol and bile acid metabolism in Alzheimer disease (AD). Expression of alternative bile acid and neural cholesterol clearance pathway along with transporters of taurine and bile acids suggest the role of the gut-brain axis in AD.