Markers Of Alzheimer's Disease Research Articles

Melatonin improves cognitive function by suppressing endoplasmic reticulum stress and promoting synaptic plasticity during chronic cerebral hypoperfusion in rats

Chronic cerebral hypoperfusion (CCH) is the most common cause of cognitive impairment, which is commonly found in Alzheimer’s disease (AD) and vascular dementia (VaD). Recently, studies have demonstrated that melatonin is an effective treatment in various neurodegenerative diseases. In this study, we aimed to investigate the effects of melatonin on CCH-induced AD pathology, endoplasmic reticulum (ER) stress, and synaptic plasticity, all of which are correlated with the activation of oxidative stress, apoptosis, and cognitive impairment. CCH was induced in male Wistar rats by bilateral common carotid artery occlusion (2VO). After surgery, rats were treated with melatonin (10 mg/kg) or piracetam (600 mg/kg) by oral gavage once a day for 4 weeks. At the end of the experiment, all rats were assessed for memory impairment by using the Morris water maze test. Subsequently, rats were sacrificed, and brains were removed to determine the levels of beta-amyloid (Aβ), malondialdehyde (MDA); the acetylcholinesterase (AChE) activity; subjected to terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL); and subjected to western blotting of proteins related to memory, AD pathology, oxidative stress, ER stress, and apoptosis. Melatonin alleviated brain injury during 2VO induction, as revealed by decreased the expression of AD markers, attenuated oxidative stress, suppressed the expression of proteins related to ER stress, apoptosis, and stimulated the expression of the synaptic markers resulting in promoted cognitive function. Therefore, our data demonstrated that melatonin ameliorated cognitive impairment in the 2VO model, and these beneficial effects were associated with reduction in oxidative stress, ER stress, and apoptosis.

Personality Impact on Alzheimer's Disease - Signature and Vascular Imaging Markers: A PET-MRI Study.

Several studies postulated that personality is an independent determinant of cognitive trajectories in old age. This study explores the impact of personality on widely used Alzheimer's disease (AD) and vascular imaging markers. We examined the association between personality and three classical AD imaging markers (centiloid-based-amyloid load, MRI volumetry in hippocampus, and media temporal lobe atrophy), and two vascular MRI parameters (Fazekas score and number of cortical microbleeds) assessed at baseline and upon a 54-month-follow-up. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify predictors of imaging markers including sex, personality factors, presence of APOE ɛ4 allele and cognitive evolution over time. Cortical GM volumes were negatively associated with higher levels of Conscientiousness both at baseline and follow-up. In contrast, higher scores of Openness were related to better preservation of left hippocampal volumes in these two time points and negatively associated with medial temporal atrophy at baseline. Amyloid load was not affected by personality factors. Cases with higher Extraversion scores displayed higher numbers of cortical microbleeds at baseline. Personality impact on brain morphometry is detected only in some among the routinely used imaging markers. The most robust associations concern the positive role of high levels of Conscientiousness and Openness on AD-signature MRI markers. Higher extraversion levels are associated with increased vulnerability to cortical microbleeds pointing to the fact that the socially favorable traits may have a detrimental effect on brain integrity in old age.

Germacrone alleviates okadaic acid-induced neurotoxicity in PC12 cells via M1 muscarinic receptor-mediated Galphaq (Gq)/phospholipase C beta (PLCβ)/ protein kinase C (PKC) signaling

ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disorder with prominent individual morbidity and mortality among elderly people. Germacrone (Germ) has been reported to exert dominant protective roles in multiple human diseases, and neurological diseases are also included. The intention of this paper is to determine the impacts of Germ on okadaic acid (OA)-treated PC12 cells and confirm the hidden regulatory mechanism. First, PC12 cells were induced by OA in the absence or presence of Germ. Cell counting kit-8 assay was to monitor cell proliferation. Western blot was to test the protein levels of cholinergic muscarinic M1 receptor (CHRM1), Galphaq (Gq), phospholipase C beta (PLCβ) and protein kinase C (PKC). The levels of reactive oxygen species (ROS) and other oxidative stress markers were evaluated using corresponding kits. ELISA was used to estimate the levels of AD markers. RT-qPCR was used to examine the mRNA levels of beta-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1) and apolipoprotein E (APOE). The results uncovered that Germ enhanced the proliferation of OA-insulted PC12 cells, elevated the protein level of CHRM1 and activated the Gq/PLCβ/PKC signaling. Moreover, after OA-induced PC12 cells were administered with Germ, insufficiency of CHRM1 impeded cell proliferation, enhanced oxidative stress and neuron injury and inactivated the Gq/PLCβ/PKC signaling. Furthermore, the addition of Gq inhibitor UBO-QIC, PLCβ inhibitor U73122 or PKC inhibitor Go6983 reversed the enhanced proliferation, the reduced oxidative stress and neuron injury in OA-treated PC12 cells caused by Germ. Collectively, Germ modulated M1 muscarinic receptor-mediated Gq/PLCβ/PKC signaling, thereby alleviating OA-induced PC12 cell injury.

Blood mRNA Expression in Alzheimer's Disease and Dementia With Lewy Bodies

The objective of this study was to investigate the expression of genes in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), both at the mild cognitive impairment (MCI) and dementia stages, to improve our understanding of disease pathophysiology and investigate the potential for diagnostic and prognostic biomarkers based on mRNA expression. Cross-sectional observational study. University research center. People with MCI with Lewy bodies (MCI-LB, n=55), MCI-AD (n=19), DLB (n=38), AD (n=24) and a cognitively unimpaired comparison group (n=28). Ribonucleic acid sequencing of whole blood. Differentially expressed genes (DEGs) were identified and gene set enrichment analysis was carried out. Compared with the cognitively unimpaired group, there were 22 DEGs in MCI-LB/DLB and 61 DEGs in MCI-AD/AD. DEGS were also identified when comparing the two disease groups. Expression of ANP32A was associated with more rapid cognitive decline in MCI-AD/AD. Gene set enrichment analysis identified downregulation in gene sets including MYC targets and oxidative phosphorylation in MCI-LB/DLB; upregulation of immune and inflammatory responses in MCI-AD/AD; and upregulation of interferon-α and -γ responses in MCI-AD/AD compared with MCI-LB/DLB. This study identified multiple DEGs in MCI-LB/DLB and MCI-AD/AD. One of these DEGs, ANP32A, may be a prognostic marker in AD. Genes related to mitochondrial function were downregulated in MCI-LB/DLB. Previously reported upregulation of genes associated with inflammation and immune responses in MCI-AD/AD was confirmed in this cohort. Differences in interferon responses between MCI-AD/AD and MCI-LB/DLB suggest that there are key differences in peripheral immune responses between these diseases.

Cerebrospinal fluid neurofilament light chain is a marker of aging and white matter damage

BackgroundCerebrospinal fluid (CSF) neurofilament light chain (NfL) reflects neuro-axonal damage and is increasingly used to evaluate disease progression across neurological conditions including Alzheimer disease (AD). However, it is unknown how NfL relates to specific types of brain tissue. We sought to determine whether CSF NfL is more strongly associated with total gray matter, white matter, or white matter hyperintensity (WMH) volume, and to quantify the relative importance of brain tissue volume, age, and AD marker status (i.e., APOE genotype, brain amyloidosis, tauopathy, and cognitive status) in predicting CSF NfL. Methods419 participants (Clinical Dementia Rating [CDR] Scale > 0, N = 71) had CSF, magnetic resonance imaging (MRI), and neuropsychological data. A subset had amyloid positron emission tomography (PET) and tau PET. Pearson correlation analysis was used to determine the association between CSF NfL and age. Multiple regression was used to determine which brain volume (i.e., gray, white, or WMH volume) most strongly associated with CSF NfL. Stepwise regression and dominance analyses were used to determine the individual contributions and relative importance of brain volume, age, and AD marker status in predicting CSF NfL. ResultsCSF NfL increased with age (r = 0.59, p < 0.001). Elevated CSF NfL was associated with greater total WMH volume (p < 0.001), but not gray or white matter volume (p's > 0.05) when considered simultaneously. Age and WMH volume were consistently more important (i.e., have greater R2 values) than AD markers when predicting CSF NfL. ConclusionsCSF NfL is a non-specific marker of aging and white matter integrity with limited sensitivity to specific markers of AD. CSF NfL likely reflects processes associated with cerebrovascular disease.

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer's Disease.

Background: Despite research on the molecular bases of Alzheimer’s disease (AD), effective therapies against its progression are still needed. Recent studies have shown direct links between AD progression and neurovascular dysfunction, highlighting it as a potential target for new therapeutics development. In this work, we screened and evaluated the inhibitory effect of natural compounds from native Peruvian plants against tau protein, amyloid beta, and angiotensin II type 1 receptor (AT1R) pathologic AD markers. Methods: We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation (MD), and MM/GBSA estimation, to identify metabolites from Peruvian plants with inhibitory properties, and compared them to nicotinamide, telmisartan, and grapeseed extract drugs in clinical trials. Results: Our results demonstrated the increased bioactivity of three plants’ metabolites against tau protein, amyloid beta, and AT1R. The MD simulations indicated the stability of the AT1R:floribundic acid, amyloid beta:rutin, and tau:brassicasterol systems. A polypharmaceutical potential was observed for rutin due to its high affinity to AT1R, amyloid beta, and tau. The metabolite floribundic acid showed bioactivity against the AT1R and tau, and the metabolite brassicasterol showed bioactivity against the amyloid beta and tau. Conclusions: This study has identified molecules from native Peruvian plants that have the potential to bind three pathologic markers of AD.

Editors' Note: Cognitive Activity and Onset Age of Incident Alzheimer Disease Dementia

In their prospective observational cohort study, Dr. Wilson et al. explored the relationship between cognitive activity and incident dementia among consecutive elderly patients from the Rush Memory and Aging Project. The investigators hypothesized that self-reported higher levels of cognitive activity such as reading would be associated with older age of dementia onset in patients with clinical Alzheimer disease (AD). Of the 1903 included patients, 457 (24%) developed possible or probable AD over a mean of 6.8 years (±4.6) of follow-up. In the primary analysis, higher cognitive activity was independently associated with later dementia onset in the accelerated failure time model (estimate 0.026, 95% CI 0.013–0.039). This relationship persisted in multiple other exploratory models, including a model that accounted for sex and educational level, a model which adjusted for early-life cognitive activity (which bore no independent association with dementia), and a model excluding patients with possible AD from outcome events. When the top 10th percentile of patients with high cognitive activity were compared with the bottom 10th percentile, patients in the top 10th percentile developed dementia at a mean of 5 years later (93.6 vs 88.6 years). Dr. Krauss suggests that the hypothesized direction of the association (more cognitive activity → delay in dementia diagnosis) may possibly be reversed and that the low level of cognitive activity in late life may be an early sign of dementia. In an attempt to disprove this alternative hypothesis, the investigators analyzed the relationship between cognitive activity with markers of AD at enrollment and found no association. The authors agree with Dr. Krauss that their study cannot fully disprove the reverse causality hypothesis; however, these data complement previous research that continues to build the argument for an important relationship between cognitive activity and the subsequent symptoms of dementia. In their prospective observational cohort study, Dr. Wilson et al. explored the relationship between cognitive activity and incident dementia among consecutive elderly patients from the Rush Memory and Aging Project. The investigators hypothesized that self-reported higher levels of cognitive activity such as reading would be associated with older age of dementia onset in patients with clinical Alzheimer disease (AD). Of the 1903 included patients, 457 (24%) developed possible or probable AD over a mean of 6.8 years (±4.6) of follow-up. In the primary analysis, higher cognitive activity was independently associated with later dementia onset in the accelerated failure time model (estimate 0.026, 95% CI 0.013–0.039). This relationship persisted in multiple other exploratory models, including a model that accounted for sex and educational level, a model which adjusted for early-life cognitive activity (which bore no independent association with dementia), and a model excluding patients with possible AD from outcome events. When the top 10th percentile of patients with high cognitive activity were compared with the bottom 10th percentile, patients in the top 10th percentile developed dementia at a mean of 5 years later (93.6 vs 88.6 years). Dr. Krauss suggests that the hypothesized direction of the association (more cognitive activity → delay in dementia diagnosis) may possibly be reversed and that the low level of cognitive activity in late life may be an early sign of dementia. In an attempt to disprove this alternative hypothesis, the investigators analyzed the relationship between cognitive activity with markers of AD at enrollment and found no association. The authors agree with Dr. Krauss that their study cannot fully disprove the reverse causality hypothesis; however, these data complement previous research that continues to build the argument for an important relationship between cognitive activity and the subsequent symptoms of dementia.

Author Response: Cognitive Activity and Onset Age of Incident Alzheimer Disease Dementia

We appreciate the interest in our research.1 In the cohort study of older persons who developed incident Alzheimer disease (AD), we found that a lower level of cognitive activity was associated with earlier age of dementia onset.1 According to the reverse-causality hypothesis, a low level of cognitive activity is not a risk factor for AD but an early sign of the disease. As a test of this hypothesis, we computed the correlations of cognitive activity at the time of study enrollment with markers of AD and related dementias from a postmortem neuropathologic examination. These correlations were not significant, which we concluded provided no support for the reverse-causality hypothesis.

Trait Mindfulness Is Associated With Less Amyloid, Tau, and Cognitive Decline in Individuals at Risk for Alzheimer’s Disease

BackgroundMindfulness, defined as nonjudgmental awareness of the present moment, has been associated with an array of mental and physical health benefits. Mindfulness may also represent a protective factor for Alzheimer’s disease (AD). Here, we tested the potential protective effect of trait mindfulness on cognitive decline and AD pathology in older adults at risk for AD dementia. MethodsMeasures of trait mindfulness, longitudinal cognitive assessments, and amyloid-β (Aβ) and tau positron emission tomography scans were collected in 261 nondemented older adults with a family history of AD dementia from the PREVENT-AD (Pre-symptomatic Evaluation of Experimental or Novel Treatments for AD) observational cohort study. Multivariate partial least squares analyses were used to examine relationships between combinations of different facets of trait mindfulness and 1) cognitive decline, 2) Aβ, and 3) tau. ResultsHigher levels of mindful nonjudgment, describing, and nonreactivity were associated with less cognitive decline in attention, global cognition, and immediate and delayed memory. Higher levels of mindful nonjudgment and nonreactivity were related to less Aβ positron emission tomography signal in bilateral medial and lateral temporoparietal and frontal regions. Higher levels of mindful acting with awareness, describing, nonjudgment, and nonreactivity were associated with less tau positron emission tomography signal in bilateral medial and lateral temporal regions. ConclusionsTrait mindfulness was associated with less cognitive decline and less Aβ and tau in the brain in older adults at risk for AD dementia. Longitudinal studies examining the temporal relationship between trait mindfulness and AD markers, along with mindfulness intervention studies, will be important for further clarifying the potential protective benefits of mindfulness on AD risk.

Small Heat Shock Protein 22 Improves Cognition and Learning in the Tauopathic Brain.

The microtubule-associated protein tau pathologically accumulates and aggregates in Alzheimer’s disease (AD) and other tauopathies, leading to cognitive dysfunction and neuronal loss. Molecular chaperones, like small heat-shock proteins (sHsps), can help deter the accumulation of misfolded proteins, such as tau. Here, we tested the hypothesis that the overexpression of wild-type Hsp22 (wtHsp22) and its phosphomimetic (S24,57D) Hsp22 mutant (mtHsp22) could slow tau accumulation and preserve memory in a murine model of tauopathy, rTg4510. Our results show that Hsp22 protected against deficits in synaptic plasticity and cognition in the tauopathic brain. However, we did not detect a significant change in tau phosphorylation or levels in these mice. This led us to hypothesize that the functional benefit was realized through the restoration of dysfunctional pathways in hippocampi of tau transgenic mice since no significant benefit was measured in non-transgenic mice expressing wtHsp22 or mtHsp22. To identify these pathways, we performed mass spectrometry of tissue lysates from the injection site. Overall, our data reveal that Hsp22 overexpression in neurons promotes synaptic plasticity by regulating canonical pathways and upstream regulators that have been characterized as potential AD markers and synaptogenesis regulators, like EIF4E and NFKBIA.

Cerebrospinal Fluid Biomarkers, Brain Structural and Cognitive Performances Between Normotensive and Hypertensive Controlled, Uncontrolled and Untreated 70-Year-Old Adults.

Background: Hypertension is an important risk factor for Alzheimer’s disease (AD). The pathophysiological mechanisms underlying the relationship between AD and hypertension are not fully understood, but they most likely involve microvascular dysfunction and cerebrovascular pathology. Although previous studies have assessed the impact of hypertension on different markers of brain integrity, no study has yet provided a comprehensive comparison of cerebrospinal fluid (CSF) biomarkers and structural brain differences between normotensive and hypertensive groups in a single and large cohort of older adults in relationship to cognitive performances.Objective: The aim of the present work was to investigate the differences in cognitive performances, CSF biomarkers and magnetic resonance imaging (MRI) of brain structure between normotensive, controlled hypertensive, uncontrolled hypertensive, and untreated hypertensive older adults from the Gothenburg H70 Birth Cohort Studies.Methods: As an indicator of vascular brain pathology, we measured white matter hyperintensities (WMHs), lacunes, cerebral microbleeds, enlarged perivascular space (epvs), and fractional anisotropy (FA). To assess markers of AD pathology/neurodegeneration, we measured hippocampal volume, temporal cortical thickness on MRI, and amyloid-β42, phosphorylated tau, and neurofilament light protein (NfL) in cerebrospinal fluid. Various neuropsychological tests were used to assess performances in memory, attention/processing speed, executive function, verbal fluency, and visuospatial abilities.Results: We found more white matter pathology in hypertensive compared to normotensive participants, with the highest vascular burden in uncontrolled participants (e.g., lower FA, more WMHs, and epvs). No significant difference was found in any MRI or CSF markers of AD pathology/neurodegeneration when comparing normotensive and hypertensive participants, nor among hypertensive groups. No significant difference was found in most cognitive functions between groups.Conclusion: Our results suggest that good blood pressure control may help prevent cerebrovascular pathology. In addition, hypertension may contribute to cognitive decline through its effect on cerebrovascular pathology rather than AD-related pathology. These findings suggest that hypertension is associated with MRI markers of vascular pathology in the absence of a significant decline in cognitive functions.

Blood Circulatory Level of Seven Sirtuins in Alzheimer's Disease: Potent Biomarker Based on Translational Research.

Alzheimer's disease (AD) is an accelerating neurodegenerative disorder. Dysfunction of mitochondria and oxidative stress contributes to the pathogenesis of AD. Sirtuins play a role in this pathway and can be a potential marker to study neurodegenerative changes. This study evaluated serum levels of all seven sirtuin (SIRT1-SIRT7) proteins in three study groups: AD, mild cognitive impairment (MCI) and geriatric control (GC) by surface plasmon resonance (SPR) technique. Further, it was validated by the Western blot experiment. ROC analysis was performed to differentiate the study group based on the concentration of serum SIRT proteins. Out of seven sirtuins, serum SIRT1, SIRT3 and SIRT6 levels (mean ± SD) were significantly decreased in AD (1.65 ± 0.56, 3.15 ± 0.28, 3.36 ± 0.32ng/µl), compared to MCI (2.17 ± 0.39, 3.60 ± 0.51, 3.73 ± 0.48ng/µl) and GC (2.84 ± 0.47, 4.55 ± 0.48, 4.65 ± 0.55ng/µl). ROC analysis showed the cut-off value with high sensitivity and specificity for cognitive impairment (AD and MCI). The concentration declined significantly with the disease progression. No specific difference was observed in the case of other SIRTs between the study groups. This study reveals an inverse relation of serum SIRT1, SIRT3 and SIRT6 concentration with AD. ROC analysis showed that these serum proteins have greater accuracy in diagnosing of AD. This is the first report of estimation of all seven serum sirtuins and the clinical relevance of SIRT3 and SIRT6 as serum protein markers for AD.

The relationship between Alzheimer's-related brain atrophy patterns and sleep macro-architecture.

Sleep is increasingly recognized as a major risk factor for neurodegenerative disorders such as Alzheimer's disease (AD). Using an magnetic resonance imaging (MRI)-based AD score based on clinical data from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) case-control cohort, we investigated the associations between polysomnography-based sleep macro-architecture and AD-related brain atrophy patterns in 712 pre-symptomatic, healthy subjects from the population-based Study of Health in Pomerania. We identified a robust inverse association between slow-wave sleep and the AD marker (estimate: -0.019; 95% confidence interval: -0.03 to -0.0076; false discovery rate [FDR]=0.0041), as well as with gray matter (GM) thicknesses in typical individual cortical AD-signature regions. No effects were identified regarding rapid eye movement or non-rapid eye movement (NREM) stage 2 sleep, and NREM stage 1 was positively associated with GM thickness, mainly in the prefrontal cortical regions. There is a cross-sectional relationship between AD-related neurodegenerative patterns and the proportion of sleep spent in slow-wave sleep.

Isoorientin Affects Markers of Alzheimer's Disease via Effects on the Oral and Gut Microbiota in APP/PS1 Mice

BackgroundThere is growing evidence of strong associations between the pathogenesis of Alzheimer's disease (AD) and dysbiotic oral and gut microbiota. Recent studies demonstrated that isoorientin (ISO) is anti-inflammatory and alleviates markers of AD, which were hypothesized to be mediated by the oral and gut microbiota. ObjectivesWe studied the effects of oral administration of ISO on AD-related markers and the oral and gut microbiota in mice. MethodsEight-month-old amyloid precursor protein/presenilin-1 (AP) transgenic male mice were randomly allocated to 3 groups of 15 mice each: vehicle (AP) alone or with a low dose of ISO (AP + ISO-L; 25 mg/kg) or a high dose of ISO (AP + ISO-H; 50 mg/kg). Age-matched wild-type (WT) C57BL/6 male littermates were used as controls. The 4 groups were treated intragastrically with ISO or sterilized ultrapure water for 2 months. AD-related markers in the brain, serum, colon, and liver were analyzed with immunohistochemical and histochemical staining, Western blotting, and ELISA. Oral and gut microbiotas were analyzed using 16S ribosomal RNA gene sequencing. ResultsThe high-dose ISO treatment significantly decreased amyloid beta 42–positive deposition by 38.1% and 45.2% in the cortex and hippocampus, respectively, of AP mice (P < 0.05). Compared with the AP group, both ISO treatments reduced brain phospho-Tau, phosphor-p65, phosphor–inhibitor of NF-κB, and brain and serum LPS and TNF-α by 17.9%–72.5% and increased brain and serum IL-4 and IL-10 by 130%–210% in the AP + ISO-L and AP + ISO-H groups (P < 0.05). Abundances of 26, 25, and 23 microbial taxa in oral, fecal and cecal samples, respectively, were increased in both the AP + ISO-L and AP + ISO-H groups relative to the AP group [linear discriminant analysis (LDA) >3.0; P < 0.05]. Gram-negative bacteria, Alteromonas, Campylobacterales, and uncultured Bacteroidales bacterium were positively correlated (rho = 0.28–0.59; P < 0.05) with the LPS levels and responses of inflammatory cytokines. ConclusionsThe microbiota-gut-brain axis is a potential mechanism by which ISO reduces AD-related markers in AP mice.

Age differences in the association between sleep and Alzheimer's disease biomarkers in the EPAD cohort.

We aimed to determine the independent association between sleep quality and Alzheimer's disease (AD) biomarkers, and whether the associations differ with age. We included 1240 individuals aged ≥50, without dementia from the European Prevention of Alzheimer's Disease v1500.0 dataset. Linear regression was used to examine Pittsburgh Sleep Quality Index (PSQI) scores against cerebrospinal fluid (CSF) phosphorylated tau/β-amyloid ratio (p-tau/Aβ42) for the entire sample and via age tertiles. Models controlled for demographic, clinical, genetic, vascular, and neuroimaging variables. For the youngest age tertile, shorter sleep duration and higher sleep efficiency were associated with greater p-tau/Aβ42 ratio. For the oldest tertile, longer sleep latency was associated with greater p-tau/Aβ42. Differential relationships between sleep and AD pathology depend on age. Short sleep duration and sleep efficiency are relevant in middle age whereas time taken to fall asleep is more closely linked to AD biomarkers in later life. This study shows age differences in the link between sleep and AD biomarkers.Shorter sleep was associated with greater p-tau/Aβ42 ratio in middle age.The association was independent of genetic, vascular, and neuroimaging markers of AD.

Comparative study of rivastigmine and galantamine on the transgenic Drosophila model of Alzheimer's disease

Alzheimer's Disease (AD) is characterized as a progressive neurodegenerative disease most commonly associated with memory deficits and cognitive decline. The formation of amyloid plaques and neurofibrillary tangles are important pathological markers of AD. The accumulation of amyloid plaques and neurofibrillary tangles leads to the loss of neurons including the cholinergic neurons thus decreasing the levels of acetylcholine (a neurotransmitter). To reduce the AD symptoms cholinesterase inhibitors are widely used to decrease the hydrolysis of acetylcholine released from presynaptic neurons. In the present study we have studied the effect of rivastigmine and galantamine (commonly used cholinesterase inhibitors) on the transgenic Drosophila model of AD expressing human Aβ-42 in the neurons. The effect of similar doses of rivastigmine and galantamine (i.e. 0.1,1 and 10 ​mM) was studied on the climbing ability, lifespan, oxidative stress markers, caspase 9 and 3, acetylcholinesterase activity and on the formation of Aβ-42 aggregates. The results suggest that the rivastigmine is more potent in reducing the oxidative stress and improving climbing ability of AD flies. Both the drugs were found to be effective in increasing the lifespan of AD flies. Galantamine was found to be a more potent inhibitor of acetylcholinesterase compared to rivastigmine. Galantamine prevents the formation of Aβ-42 aggregates more effectively compared to rivastigmine.

The Cause of Alzheimer's Disease: The Theory of Multipathology Convergence to Chronic Neuronal Stress.

The field of Alzheimer’s disease (AD) research critically lacks an all-inclusive etiology theory that would integrate existing hypotheses and explain the heterogeneity of disease trajectory and pathologies observed in each individual patient. Here, we propose a novel comprehensive theory that we named: the multipathology convergence to chronic neuronal stress. Our new theory reconsiders long-standing dogmas advanced by previous incomplete theories. Firstly, while it is undeniable that amyloid beta (Aβ) is involved in AD, in the seminal stage of the disease Aβ is unlikely pathogenic. Instead, we hypothesize that the root cause of AD is neuronal stress in the central nervous system (CNS), and Aβ is expressed as part of the physiological response to protect CNS neurons from stress. If there is no return to homeostasis, then Aβ becomes overexpressed, and this includes the generation of longer forms that are more toxic and prone to oligomerization. Secondly, AD etiology is plausibly not strictly compartmentalized within the CNS but may also result from the dysfunction of other physiological systems in the entire body. This view implies that AD may not have a single cause, but rather needs to be considered as a spectrum of multiple chronic pathological modalities converging to the persistent stressing of CNS neurons. These chronic pathological modalities, which include cardiovascular disease, metabolic disorders, and CNS structural changes, often start individually, and over time combine with other chronic modalities to incrementally escalate the amount of stress applied to CNS neurons. We present the case for considering Aβ as a marker of neuronal stress in response to hypoxic, toxic, and starvation events, rather than solely a marker of AD. We also detail numerous human chronic conditions that can lead to neuronal stress in the CNS, making the link with co-morbidities encountered in daily clinical AD practice. Finally, we explain how our theory could be leveraged to improve clinical care for AD and related dementia in personalized medicine paradigms in the near future.

Memory-driven eye movements prospectively predict dementia in people at risk of Alzheimer's disease.

Oculomotor behaviors linked to cognitive performance revealed neurocognitive features of Alzheimer's disease (AD) that can enhance the accuracy of its assessment and diagnosis. A sample of 107 participants (i.e., 65 mild cognitive impairment [MCI] and 42 controls) were recruited and followed up for 40 months. At baseline, they underwent assessment with the ViewMind digital biomarker, which draws cognitive-related patterns of eye movement while people perform the visual short-term memory binding task. Baseline data predicted that 36 patients with MCI would progress to the AD clinical syndrome (ADS Progressing). The remaining 29 MCI patients were predicted to remain as MCI or progress to other forms of dementia. After 40 months of follow-up, 94% of ADS Progressing patients had received a diagnosis of dementia, whereas none of the non-ADS Progressing had. The analysis of eye movement behavior combined with cognitive markers for AD can effectively predict progression to ADS among patients with MCI.

Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan

The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer’s disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20–81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37–72 years of age), the developmental ABCD study (N = 10 283; 9–11 years of age), and a middle-aged sample (N = 339; 40–65 years of age). Hippocampal volume, brain amyloid-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aβ plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF Aβ42 (FDR-corrected p = 6.9x10-2), and lower ratios of Aβ42 to Aβ40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF Aβ42 to Aβ40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers. ConclusionThe inverse correlation between APOEε 4 and blood CRP levels existed before any pathological AD biomarker was observed, and only in the low CRP level range. Thus, we suggest to investigate whether APOEε 4 can confer risk by being associated with a lower inflammatory response to daily exposures, possibly leading to greater accumulation of low-grade inflammatory stress throughout life. A lifespan perspective is needed to understand this relationship concerning risk of developing AD.

Therapeutic Effects of Hydrogen Gas Inhalation on Trimethyltin-Induced Neurotoxicity and Cognitive Impairment in the C57BL/6 Mice Model.

Oxidative stress (OS) is one of the causative factors in the pathogenesis of various neurodegenerative diseases, including Alzheimer’s disease (AD) and cognitive dysfunction. In the present study, we investigated the effects of hydrogen (H2) gas inhalation in trimethyltin (TMT)-induced neurotoxicity and cognitive dysfunction in the C57BL/6 mice. First, mice were divided into the following groups: mice without TMT injection (NC), TMT-only injection group (TMT only), TMT injection + lithium chloride-treated group as a positive control (PC), and TMT injection + 2% H2 inhalation-treated group (H2). The TMT injection groups were administered a single dosage of intraperitoneal TMT injection (2.6 mg/kg body weight) and the H2 group was treated with 2% H2 for 30 min once a day for four weeks. Additionally, a behavioral test was performed with Y-maze to test the cognitive abilities of the mice. Furthermore, multiple OS- and AD-related biomarkers such as reactive oxygen species (ROS), nitric oxide (NO), calcium (Ca2+), malondialdehyde (MDA), glutathione peroxidase (GPx), catalase, inflammatory cytokines, apolipoprotein E (Apo-E), amyloid β (Aβ)-40, phospho-tau (p-tau), Bcl-2, and Bcl-2- associated X (Bax) were investigated in the blood and brain. Our results demonstrated that TMT exposure alters seizure and spatial recognition memory. However, after H2 treatment, memory deficits were ameliorated. H2 treatment also decreased AD-related biomarkers, such as Apo-E, Aβ-40, p-tau, and Bax and OS markers such as ROS, NO, Ca2+, and MDA in both serum and brain. In contrast, catalase and GPx activities were significantly increased in the TMT-only group and decreased after H2 gas treatment in serum and brain. In addition, inflammatory cytokines such as granulocyte colony-stimulating factors (G-CSF), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) were found to be significantly decreased after H2 treatment in both serum and brain lysates. In contrast, Bcl-2 and vascular endothelial growth factor (VEGF) expression levels were found to be enhanced after H2 treatment. Taken together, our results demonstrated that 2% H2 gas inhalation in TMT-treated mice exhibits memory enhancing activity and decreases the AD, OS, and inflammatory-related markers. Therefore, H2 might be a candidate for repairing neurodegenerative diseases with cognitive dysfunction. However, further mechanistic studies are needed to fully clarify the effects of H2 inhalation on TMT-induced neurotoxicity and cognitive dysfunction.