Alzheimer's disease (AD) is the most common form of dementia. However, the etiopathogenesis of this devastating disease is not fully understood. Recent studies in rodents suggest that alterations in ...the gut microbiome may contribute to amyloid deposition, yet the microbial communities associated with AD have not been characterized in humans. Towards this end, we characterized the bacterial taxonomic composition of fecal samples from participants with and without a diagnosis of dementia due to AD. Our analyses revealed that the gut microbiome of AD participants has decreased microbial diversity and is compositionally distinct from control age- and sex-matched individuals. We identified phylum- through genus-wide differences in bacterial abundance including decreased Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium in the microbiome of AD participants. Furthermore, we observed correlations between levels of differentially abundant genera and cerebrospinal fluid (CSF) biomarkers of AD. These findings add AD to the growing list of diseases associated with gut microbial alterations, as well as suggest that gut bacterial communities may be a target for therapeutic intervention.
Brain changes associated with Alzheimer's disease (AD) begin decades before disease diagnosis. While β-amyloid plaques and neurofibrillary tangles are defining features of AD, neuronal loss and ...synaptic pathology are closely related to the cognitive dysfunction. Brain imaging methods that are tuned to assess degeneration of myelinated nerve fibers in the brain (collectively called white matter) include diffusion tensor imaging (DTI) and related techniques, and are expected to shed light on disease-related loss of structural connectivity. Participants (N = 70, ages 47-76 years) from the Wisconsin Registry for Alzheimer's Prevention study underwent DTI and hybrid diffusion imaging to determine a free-water elimination (FWE-DTI) model. The study assessed the extent to which preclinical AD pathology affects brain white matter. Preclinical AD pathology was determined using cerebrospinal fluid (CSF) biomarkers. The sample was enriched for AD risk (APOE ε4 and parental history of AD). AD pathology assessed by CSF analyses was significantly associated with altered microstructure on both DTI and FWE-DTI. Affected regions included frontal, parietal, and especially temporal white matter. The f-value derived from the FWE-DTI model appeared to be the most sensitive to the relationship between the CSF AD biomarkers and microstructural alterations in white matter. These findings suggest that white matter degeneration is an early pathological feature of AD that may have utility both for early disease detection and as outcome measures for clinical trials. More complex models of microstructural diffusion properties including FWE-DTI may provide increased sensitivity to early brain changes associated with AD over standard DTI.
Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for ...Alzheimer's disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease.
In this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer's clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein).
CSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ
) and neuronal degeneration (total tau and neurofilament light chain protein).
These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.
Objectives
To evaluate the associations between sensory impairments and 10‐year risk of cognitive impairment.
Design
The Epidemiology of Hearing Loss Study (EHLS), a longitudinal, population‐based ...study of aging in the Beaver Dam, Wisconsin community. Baseline examinations were conducted in 1993 and follow‐up examinations have been conducted every 5 years.
Setting
General community.
Participants
EHLS members without cognitive impairment at EHLS‐2 (1998–2000). There were 1,884 participants (mean age 66.7) with complete EHLS‐2 sensory data and follow‐up information.
Measurements
Cognitive impairment was defined as a Mini‐Mental State Examination score of <24 or history of dementia or Alzheimer's disease. Hearing impairment was a pure‐tone average of hearing thresholds (0.5, 1, 2, 4 kHz) of >25 dB hearing level in either ear, visual impairment was a Pelli‐Robson contrast sensitivity of <1.55 log units in the better eye, and olfactory impairment was a San Diego Odor Identification Test score of <6.
Results
Hearing, visual, and olfactory impairment were independently associated with cognitive impairment risk (hearing: hazard ratio (HR) = 1.90, 95% confidence interval (CI) = 1.11–3.26; vision: HR = 2.05, 95% CI = 1.24–3.38; olfaction: HR = 3.92, 95% CI = 2.45–6.26)). Nevertheless, 85% of participants with hearing impairment, 81% with visual impairment, and 76% with olfactory impairment did not develop cognitive impairment during follow‐up.
Conclusion
The relationship between sensory impairment and cognitive impairment was not unique to one sensory system, suggesting that sensorineural health may be a marker of brain aging. The development of a combined sensorineurocognitive measure may be useful in uncovering mechanisms of healthy brain aging.
This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the ...Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.
Introduction
This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared ...biomarkers across groups defined by clinical diagnosis and pTau181/Aβ42 status (+/−) and explored their value in predicting cognition.
Methods
CSF biomarkers amyloid beta (Aβ)42, pTau181, tTau, Aβ40, neurogranin, neurofilament light (NfL), α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation SD = 9.0; 50 with dementia; 54 with mild cognitive impairment MCI, 616 unimpaired).
Results
Neurodegeneration and glial activation biomarkers were elevated in pTau181/Aβ42+ MCI/dementia participants relative to all pTau181/Aβ42‐ participants. Neurodegeneration biomarkers increased with clinical severity among pTau181/Aβ42+ participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance.
Discussion
The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages.
Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We ...investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer's disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n = 173). CSF samples were analyzed for markers of AD pathology (Aβ42, phosphorylated tau p-tau, sAβPPβ) or neuronal damage (total tau; neurofilament light chain) (n = 147). Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1β levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1β, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF Aβ42. Higher CSF sAβPPβ levels were associated with higher plasma markers only (IL-8; MCP-1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1β were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF Aβ42 modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage.
The prevalence of Alzheimer's disease (AD) is increasing rapidly, heightening the importance of finding effective preventive therapies for this devastating disease. Midlife vascular risk factors, ...including type 2 diabetes mellitus (T2DM), have been associated with increased risk of AD decades later and may serve as targets for AD prevention. Studies to date suggest that T2DM and hyperinsulinemia increase risk for AD, possibly through their effects on amyloid-beta metabolism and cerebrovascular dysfunction - two early findings in preclinical AD pathology. This paper reviews the evidence supporting a relationship between T2DM, hyperinsulinemia, and diabetic dyslipidemia on the development of AD, discusses DM treatment trials and their preliminary results on cognitive function, and proposes some strategies for optimizing future AD prevention trial design.
To examine whether engagement in physical activity might favorably alter the age-dependent evolution of Alzheimer disease (AD)-related brain and cognitive changes in a cohort of at-risk, ...late-middle-aged adults.
Three hundred seventeen enrollees in the Wisconsin Registry for Alzheimer's Prevention underwent T1 MRI; a subset also underwent (11)C-Pittsburgh compound B-PET (n = 186) and (18)F-fluorodeoxyglucose-PET (n = 152) imaging. Participants' responses on a self-report measure of current physical activity were used to classify them as either physically active or physically inactive based on American Heart Association guidelines. They also completed a comprehensive neuropsychological battery. Covariate-adjusted regression analyses were used to test whether the adverse effect of age on imaging and cognitive biomarkers was modified by physical activity.
There were significant age × physical activity interactions for β-amyloid burden (p = 0.014), glucose metabolism (p = 0.015), and hippocampal volume (p = 0.025) such that, with advancing age, physically active individuals exhibited a lesser degree of biomarker alterations compared with the physically inactive. Similar age × physical activity interactions were also observed on cognitive domains of Immediate Memory (p = 0.042) and Visuospatial Ability (p = 0.016). In addition, the physically active group had higher scores on Speed and Flexibility (p = 0.002) compared with the inactive group.
In a middle-aged, at-risk cohort, a physically active lifestyle is associated with an attenuation of the deleterious influence of age on key biomarkers of AD pathophysiology. However, because our observational, cross-sectional design cannot establish causality, randomized controlled trials/longitudinal studies will be necessary for determining whether midlife participation in structured physical exercise forestalls the development of AD and related disorders in later life.
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