Individuals with prevalent hypertension are at an increased risk of developing dementia and tend to exhibit lower cognitive function. However, the magnitude of cognitive change following the onset of new hypertension remains uncertain. A cohort of 7949 adults aged 45 and older without hypertension at baseline was followed prospectively for 7 years. Cognitive assessments were conducted initially (wave 1) and at least once between wave 2 (2013) and wave 4 (2018). Cognitive function was evaluated using a global cognition score, derived as a composite measure from four distinct cognitive tests. Linear mixed-effects models were employed to estimate the changes in cognitive function at the onset of hypertension (intercept change) and the subsequent rate of cognitive decline (slope change) over the follow-up period. The models accounted for pre-hypertension cognitive trajectories and participant-specific factors, with interaction terms included for antihypertensive medication, age and educational level. Of the 7949 participants, 1993 (25.07%, mean age 58.8 ± 8.84 years, 48.0% male) developed new-onset hypertension. Both groups-those without hypertension and those with new-onset hypertension-experienced annual cognitive decline during the follow-up period. The onset of hypertension was not associated with an acute decrease in global cognition or performance on the four cognitive tests. However, after the onset of hypertension, participants exhibited a statistically significant accelerated decline in global cognition (- 0.029 SD/year; 95% CI - 0.043 to - 0.015; p < 0.001), attention and calculation (- 0.022 SD/year; 95% CI - 0.040 to - 0.004; p = 0.017), and orientation (- 0.022 SD/year; 95% CI - 0.038 to - 0.005; p = 0.010). No significant changes were observed in episodic memory (- 0.009 SD/year; 95% CI - 0.028 to 0.010; p = 0.346) or visuospatial abilities (- 0.013 SD/year; 95% CI - 0.032 to 0.006; p = 0.185). Interaction analyses indicated that the use of antihypertensive medication, age, and educational level moderated the extent of global cognitive decline post-hypertension onset. The onset of new hypertension was not associated with an immediate decline in cognitive function compared to individuals without hypertension. However, it was linked to more rapid declines in global cognition, orientation, and attention and calculation abilities over time. These findings underscore the potential importance of hypertension prevention for maintaining long-term brain health.

Alzheimer's Disease (AD) patients often show brain and cardiac malfunction. AD represents a leading cause of morbidity and mortality worldwide, but the demand for effective treatment for AD is far from being met. This is primarily because AD pathogenesis, including brain-heart interaction, is poorly understood. Proteasome functional insufficiency is implicated in AD; as such, proteasome enhancement promises a potentially new strategy to treat AD. The proteasome can be activated by protein kinase A (PKA) via selectively phosphorylating Ser14-RPN6/PSMD11 (p-S14-RPN6); however, whether p-S14-RPN6 is altered and what role p-S14-RPN6 plays in AD remain unclear. Hence, this study was conducted to address these critical gaps. We found that genetic blockade of the homeostatic p-S14-Rpn6 via germline knock-in of Rpn6 S14A (referred to as S14A) significantly reduced proteasome activities in the cerebral cortex but did not discernibly impair learning and memory function in 4-month-old mice or cause cardiac dysfunction before 12 months of age. Increases in Ser14-phosphorylated Rpn6 in the cerebral cortex and markedly elevated Aβ proteins in the myocardium were observed in young 5XFAD mice, a commonly used AD model. When introduced into the 5XFAD mice, S14A significantly aggravated the learning and memory deficits as revealed by the radial arm water maze tests and accelerated cardiac malfunction as measured by serial echocardiography in the same cohort of 5XFAD mice. Thus, the present study establishes for the first time that homeostatic activation of 26S proteasomes by basal p-S14-RPN6 or PKA activity protects against both the brain and heart malfunction in the 5XFAD mice.

We report a case of dual amyloidosis with Alzheimer's disease and wild-type transthyretin (ATTRwt) amyloidosis. A 76-year-old man with Alzheimer's disease was referred for anti-amyloid-β therapy with lecanemab. He also had symptoms of congestive heart failure and a history of carpal tunnel syndrome, cubital tunnel syndrome, and lumbar spinal stenosis; raising Technetium-99m pyrophosphate myocardial scintigraphy showed abnormal uptake, and histopathologic examination revealed transthyretin (TTR) amyloid deposition in both myocardial and gastrointestinal biopsy specimens. Genetic testing for the TTR gene revealed no variants. The diagnosis of ATTRwt amyloidosis was confirmed, and treatment with a TTR tetramer stabilizer, tafamidis, was initiated. Alzheimer's disease of the brain and ATTRwt amyloidosis of the heart are both representative amyloidoses associated with aging. To date, there are no reported cases of dual amyloidosis other than autopsy cases, but considering the high prevalence of both diseases, it is plausible that a significant number of elderly individuals may suffer from both diseases simultaneously but are underdiagnosed. In recent years, disease-modifying drugs effective against both diseases have become available, making early diagnosis increasingly important.

Heart failure is associated with progressive reduction in cerebral blood flow and neurodegenerative changes leading to cognitive decline. The glymphatic system is crucial for the brain's waste removal, and its dysfunction is linked to neurodegeneration. In this study, we used a mouse model of heart failure, induced by myocardial infarction, to investigate the effects of heart failure with reduced ejection fraction on the brain's glymphatic function. Using dynamic contrast-enhanced MRI and high-resolution fluorescence microscopy, we found increased solute influx from the CSF spaces to the brain, i.e. glymphatic influx, at 12 weeks post-myocardial infarction. Two-photon microscopy revealed that cerebral arterial pulsatility, a major driver of the glymphatic system, was potentiated at this time point, and could explain this increase in glymphatic influx. However, clearance of proteins from the brain parenchyma did not increase proportionately with influx, while a relative increase in brain parenchyma volume was found at 12 weeks post-myocardial infarction, suggesting dysregulation of brain fluid dynamics. Additionally, our results showed a correlation between brain clearance and cerebral blood flow. These findings highlight the role of cerebral blood flow as a key regulator of the glymphatic system, suggesting its involvement in the development of brain disorders associated with reduced cerebral blood flow. This study paves the way for future investigations into the effects of cardiovascular diseases on the brain's clearance mechanisms, which may provide novel insights into the prevention and treatment of cognitive decline.

Alzheimer's disease (AD) is the most common cause of dementia and represents 75% of all dementia types. AD neuropathology is due to the progressive deposition of extracellular amyloid-beta (Aβ) peptide and intracellular hyperphosphorylated tau protein. The accumulated Aβ forms amyloid plaques, while the hyperphosphorylated tau protein forms neurofibrillary tangles (NFTs). Both amyloid plaques and NFTs are hallmarks of AD neuropathology. The fundamental mechanism involved in the pathogenesis of AD is still elusive, although Aβ is the more conceivable theory. Aβ-induced neurodegeneration and associated neuroinflammation, oxidative stress, endoplasmic reticulum stress (ER), and mitochondrial dysfunction contribute to the development of cognitive impairment and dementia. Of note, Aβ is not only originated from the brain but also produced peripherally and, via the blood-brain barrier (BBB), can accumulate in the brain and result in the development of AD. It has been shown that cardiometabolic conditions such as obesity, type 2 diabetes (T2D), and heart failure (HF) are regarded as possible risk factors for the development of AD and other types of dementia, such as vascular dementia. HF-induced chronic cerebral hypoperfusion, oxidative stress, and inflammation can induce the development and progression of AD. Interestingly, AD is regarded as a systemic disease that causes systemic inflammation and oxidative stress, which in turn affects peripheral organs, including the heart. Aβ through deranged BBB can be transported into the systemic circulation from the brain and accumulated in the heart, leading to the development of HF. These findings suggest a close relationship between AD and HF. However, the exact mechanism of AD-induced HF is not fully elucidated. Therefore, this review aims to discuss the link between AD and the risk of HF regarding the potential role of Aβ in the pathogenesis of HF.

Multimorbidity is associated with increased risk of dementia, but previous estimation of the joint contribution of constituent conditions to dementia incidence did not model additive contributions or temporal proximity in the sequential onset of conditions.

Data were analyzed from 9944 Health and Retirement Study participants and Medicare fee-for-service beneficiaries, ages 68-99, without Alzheimer's disease and related dementias (ADRD) at baseline, from 1998-2016. ADRD and chronic condition were encoded using validated claims algorithms. We estimated the absolute contribution of eight conditions to ADRD with the longitudinal extension of the average attributable fraction (LE-AAF).

Hypertension, acute myocardial infarction, atrial fibrillation, diabetes, heart failure, ischemic heart disease, stroke, and arthritis additively accounted for 71.8% (95% confidence interval [CI]: 62.9%-79.1%) of ADRD incident cases based on LE-AAF.

Our findings suggest that multimorbidity plays a pivotal role in ADRD incidence. Targeting constituents of a cardiovascular path to dementia may contribute most to lowering dementia risk.

Most dementia cases (71.8%) were attributable to eight chronic conditions. Hypertension was the largest contributor to dementia risk. Confidence intervals were smallest for constituents of a cardiovascular path to dementia. Longitudinal extension of the average attributable fractions (LE-AAFs) explicitly consider longitudinal patterns of comorbidities. Acute myocardial infarction did not contribute significantly to dementia incidence.

Alzheimer's disease (AD) is a widespread neurodegenerative disease, often accompanied by multiple comorbidities, significantly increasing the risk of death for patients. The age adjusted Charlson Comorbidity Index (aCCI) is an important clinical tool for measuring the burden of comorbidities in patients, closely related to mortality and prognosis. This study aims to use the MIMIC-V database and various regression and machine learning models to screen and validate features closely related to aCCI, providing a theoretical basis for personalized management of AD patients.

The research data is sourced from the MIMIC-V database, which contains detailed clinical information of AD patients. Multiple logistic regression, LASSO regression, random forest, Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost) models were used to screen for feature factors significantly correlated with aCCI. By comparing model performance, evaluating the classification ability and prediction accuracy of each method, and ultimately selecting the best model to construct a regression model and a nomogram. The model performance is evaluated through classification accuracy, net benefit, and robustness. The feature selection results were validated by regression analysis.

Multiple models have performed well in classifying aCCI patients, among which the model constructed using LASSO regression screening feature factors has the best performance, with the highest classification accuracy and net benefit. LASSO regression identified the following 11 features closely related to aCCI: age, respiratory rate, base excess, glucose, red blood cell distribution width (RDW), alkaline phosphatase (ALP), whole blood potassium, hematocrit (HCT), phosphate, creatinine, and mean corpuscular hemoglobin (MCH). The column chart constructed based on these feature factors enables intuitive prediction of patients with high aCCI probability, providing a convenient clinical tool.

The results of this study indicate that the features screened by LASSO regression have the best predictive performance and can significantly improve the predictive ability of aCCI related comorbidities in AD patients. The column chart constructed based on this feature factor provides theoretical guidance for personalized management and precise treatment of AD patients.

Heart failure (HF) frequently suffers from brain abnormalities and cognitive impairments. This study aims to investigate brain structure and function alteration in patients with chronic HF. This retrospective study included 49 chronic HF and 49 health controls (HCs). Voxel-based morphometry was conducted on structural MRI to quantify gray matter volume (GMV), and functional connectivity (FC) was assessed with seed-based analysis using resting-state fMRI. White matter microstructure integrity was also evaluated through tract-based spatial statistics employing DTI. Correlations between multimodal MRI features and cognitive performance were further investigated in patients with chronic HF. Patients with chronic HF exhibited significantly reduced regional GMV, white matter microstructure injury (Family wise error correction, p＜0.05), and decreased FC in multiple brain regions involved in cognition, sensorimotor, visual function (Gaussian random field correction, voxel level p＜0.0001 and cluster-level p＜0.01). There was no observed increases in GMV or FC compared with HCs. Decreased GMV showed positive correlations with cognitive performance (r = 0.025-0.577, p = 0.025-0.001), while decreased fractional anisotropy was negatively correlated with anxiety scores (r = -0.339, p = 0.040) in patients with chronic HF. This study revealed that patients with chronic HF exhibited brain structure injury affecting gray matter and white matter, as well as FC abnormalities of brain regions responsible for cognition, sensorimotor and visual function. These findings suggest GMV could serve as a neuroimaging biomarker for cognitive impairments and a potential target for neuroprotective therapies in patients with chronic HF.

Alzheimer's disease (AD) is well known among the elderly and has a profound impact on both patients and their families. Increasing research indicates that AD is a systemic disease, with a strong connection to cardiovascular disease. They share common genetic factors, such as mutations in the presenilin (PS1 and PS2) and the apolipoprotein E (APOE) genes. Cardiovascular conditions can lead to reduced cerebral blood flow and increased oxidative stress. These factors contribute to the accumulation of Aβ plaques and the formation of abnormal tau protein tangles, which are both key pathological features of AD. Additionally, Aβ deposits and abnormal protein responses have been observed in cardiomyocytes as well as in peripheral tissues. The toxic Aβ deposition intensifies damage to the microvascular structure associated with blood-brain barrier disruption and the initiation of neuroinflammation, which may accelerate the onset of neurocognitive deficits and cardiovascular dysfunction. Thus, we discuss the main mechanisms linking AD and cardiac dysfunction to enhance our understanding of these conditions. Ultimately, insights into the brain-heart axis may help us develop effective treatment strategies in the future.

Atrial fibrillation and heart failure have both been suggested to increase stroke and dementia risk. However, in observational studies, reversed causation and unmeasured confounding may occur. To mitigate these issues, this study aims to investigate if higher genetic risk for atrial fibrillation and heart failure increases dementia and stroke risk. Data were obtained from the population-based Gothenburg H70 Birth Cohort Studies in Sweden. Participants (N = 984) were born in 1930 with baseline examinations at age 70, 75, 79 or 85 and follow-ups until age 88-89. Polygenic risk scores at the 5 × 10-8, 1 × 10-5, 1 × 10-3 and 1 × 10-1 thresholds were generated for atrial fibrillation and heart failure. Stroke was diagnosed based on self-reports, close-informant interviews, and the National Patient Register. Dementia was diagnosed based on neuropsychiatric examinations, close-informant interviews, and the National Patient Register. Cox regression analyses were performed, adjusted for sex, age at baseline and the first five principal components to correct for population stratification. Those within the highest atrial fibrillation-polygenic risk score tertile had a 1.5 (95% CI 1.09-2.03) increased risk of dementia (at the 1 × 10-5 threshold) and a 1.5 (95% CI 1.07-2.03) increased risk of stroke (at the 1 × 10-3 threshold) compared to the lowest tertile. Those within the highest heart failure-polygenic risk score tertile had a 1.6 (95% CI 1.19-2.27) increased risk of dementia (at the 5 × 10-8 threshold), but no increased risk of stroke (HR 1.2; 95% CI 0.83-1.60 at the 1 × 10-5 threshold), compared to the lowest tertile. When analysing the polygenic risk scores as a continuous variable, the associations were in the same direction, although weaker. This study, investigating genetic risk of atrial fibrillation and heart failure in relation to stroke and dementia, supports the increasing body of evidence suggesting that atrial fibrillation is associated with both stroke and dementia risk. Whether heart failure increases dementia risk is less established, but the present study found that genetic risk of heart failure increased dementia risk. The finding that genetic risk for heart failure did not increase stroke risk needs to be interpreted with caution, as it may be due to a lack of statistical power. There are guidelines on how to best treat atrial fibrillation to prevent stroke, but more knowledge is needed on how to treat atrial fibrillation and heart failure to prevent dementia.

Alzheimer's disease (AD) poses a significant worldwide health challenge, requiring novel approaches for improved models and treatment development. This comprehensive review emphasises the systematic development and improvement of a biomimetic brain environment to address the shortcomings of existing AD models and enhance the efficiency of screening potential drug treatments. We identify drawbacks in traditional models and emphasise the necessity for more physiologically accurate systems through an in-depth analysis of current literature. This review aims to study the development of an advanced AD model that accurately replicates key AD pathophysiological aspects using cutting-edge biomaterials and microenvironment design. Incorporating biomolecular elements like Tau proteins and beta-amyloid (Aβ) plaques improve the accuracy of illustrating disease mechanisms. The expected results involve creating a solid foundation for high-throughput screening with enhanced scalability, translational significance, and the possibility of speeding up drug discovery. Thus, this review fills the gaps in AD modelling and shows potential for creating precise and efficient drug treatments for AD.

Cardiovascular disease (CVD) and Alzheimer's disease (AD) are two diseases highly prevalent in the aging population and often co-occur. The exact relationship between the two diseases is uncertain, though epidemiological studies have demonstrated that CVDs appear to increase the risk of AD and vice versa. This scoping review aims to examine the current identified overlapping genetics between CVDs and AD at the individual gene level and at the shared pathway level.

Following PRISMA-ScR guidelines for a scoping review, we searched the PubMed and Scopus databases from 1990 to October 2024 for articles that involved (1) CVDs, (2) AD, and (3) used statistical methods to parse genetic relationships.

Our search yielded 2918 articles, of which 274 articles passed screening and were organized into two main sections: (1) evidence of shared genetic risk; and (2) shared mechanisms. The genes APOE, PSEN1, and PSEN2 reportedly have wide effects across the AD and CVD spectrum, affecting both cardiac and brain tissues. Mechanistically, changes in three main pathways (lipid metabolism, blood pressure regulation, and the breakdown of the blood-brain barrier (BBB)) contribute to subclinical and etiological changes that promote both AD and CVD progression. However, genetic studies continue to be limited by the availability of longitudinal data and lack of cohorts that are representative of diverse populations.

Highly penetrant familial genes simultaneously increase the risk of CVDs and AD. However, in most cases, sets of dysregulated genes within larger-scale mechanisms, like changes in lipid metabolism, blood pressure regulation, and BBB breakdown, increase the risk of both AD and CVDs and contribute to disease progression.

Alzheimer's disease (AD) prevalence has increased in the last century which can be attributed to increased lifespan, but environment is also important. Exposure to artificial light at night is one environmental factor that may influence AD.

This study evaluated the relationship between outdoor nighttime light exposure and AD prevalence in the United States using satellite acquired outdoor nighttime light intensity and Medicare data.

Higher outdoor nighttime light was associated with higher prevalence of AD. While atrial fibrillation, diabetes, hyperlipidemia, hypertension, and stroke were associated more strongly with AD prevalence than nighttime light intensity, nighttime light was more strongly associated with AD prevalence than alcohol abuse, chronic kidney disease, depression, heart failure, and obesity. Startlingly, nighttime light exposure more strongly associated with AD prevalence in those under the age of 65 than any other disease factor examined.

These data suggest light exposure at night may influence AD, but additional studies are needed.

Advancements in modern medicine have extended human lifespan, but they have also led to an increase in age-related diseases such as Alzheimer's disease (AD) and atherosclerosis (AS). Growing research evidence indicates a close connection between these two conditions.

We downloaded four gene expression datasets related to AD and AS from the Gene Expression Omnibus (GEO) database (GSE33000, GSE100927, GSE44770, and GSE43292) and performed differential gene expression (DEGs) analysis using the R package "limma". Through Weighted gene correlation network analysis (WGCNA), we selected the gene modules most relevant to the diseases and intersected them with the DEGs to identify crosstalk genes (CGs) between AD and AS. Subsequently, we conducted functional enrichment analysis of the CGs using DAVID. To screen for potential diagnostic genes, we applied the least absolute shrinkage and selection operator (LASSO) regression and constructed a logistic regression model for disease prediction. We established a protein-protein interaction (PPI) network using STRING (https://cn.string-db.org/) and Cytoscape and analyzed immune cell infiltration using the CIBERSORT algorithm. Additionally, NetworkAnalyst (http://www.networkanalyst.ca) was utilized for gene regulation and interaction analysis, and consensus clustering was employed to determine disease subtypes. All statistical analyses and visualizations were performed using various R packages, with a significance level set at p<0.05.

Through intersection analysis of disease-associated gene modules identified by DEGs and WGCNA, we identified a total of 31 CGs co-existing between AD and AS, with their biological functions primarily associated with immune pathways. LASSO analysis helped us identify three genes (C1QA, MT1M, and RAMP1) as optimal diagnostic CGs for AD and AS. Based on this, we constructed predictive models for both diseases, whose accuracy was validated by external databases. By establishing a PPI network and employing four topological algorithms, we identified four hub genes (C1QB, CSF1R, TYROBP, and FCER1G) within the CGs, closely related to immune cell infiltration. NetworkAnalyst further revealed the regulatory networks of these hub genes. Finally, defining C1 and C2 subtypes for AD and AS respectively based on the expression profiles of CGs, we found the C2 subtype exhibited immune overactivation.

This study utilized gene expression matrices and various algorithms to explore the potential links between AD and AS. The identification of CGs revealed interactions between these two diseases, with immune and inflammatory imbalances playing crucial roles in their onset and progression. We hope these findings will provide valuable insights for future research on AD and AS.

Digital PET/CT systems with a long axial field of view have become available and are emerging as the current state of the art. These new camera systems provide wider anatomic coverage, leading to major increases in system sensitivity. Preliminary results have demonstrated improvements in image quality and quantification, as well as substantial advantages in tracer kinetic modeling from dynamic imaging. These systems also potentially allow for low-dose examinations and major reductions in acquisition time. Thereby, they hold great promise to improve PET-based interrogation of cardiac physiology and biology. Additionally, the whole-body coverage enables simultaneous assessment of multiple organs and the large vascular structures of the body, opening new opportunities for imaging systemic mechanisms, disorders, or treatments and their interactions with the cardiovascular system as a whole. The aim of this perspective document is to debate the potential applications, challenges, opportunities, and remaining challenges of applying PET/CT with a long axial field of view to the field of cardiovascular disease.

Alzheimer's disease (AD) prevalence has increased in the last century which can be attributed to increased lifespan, but environment is also important. This study evaluated the relationship between outdoor nighttime light exposure and AD prevalence in the United States. Higher outdoor nighttime light was associated with higher prevalence of AD. While atrial fibrillation, diabetes, hyperlipidemia, hypertension, and stroke were associated more strongly with AD prevalence than nighttime light intensity, nighttime light was more strongly associated with AD prevalence than alcohol abuse, chronic kidney disease, depression, heart failure, and obesity. Startlingly, nighttime light exposure more strongly associated with AD prevalence in those under the age of 65 than any other disease factor examined. These data indicate a need to investigate how nighttime light exposure influences AD pathogenesis.

Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein-based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration.

In 706 cognitively normal adults, we examined whether 14 protein-based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma-based biomarkers of AD pathology (amyloid-β [Aβ]42/40 , tau phosphorylated at threonine-181 [pTau-181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aβ and tau. In a separate cohort (n = 11,285), we examined whether protein-based health indicators associated with neurodegeneration also predict 25-year dementia risk.

Greater protein-based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aβ42/40 and higher pTau-181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau-181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aβ42/40 , pTau-181, NfL, and GFAP levels, respectively. Only protein-based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25-year dementia risk, even among those without clinically defined cardiovascular disease.

Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260-273.

Age-related changes in aortic biomechanics can impact the brain by reducing blood flow and increasing pulsatile energy transmission. Clinical studies have shown that impaired cardiac function in patients with heart failure is associated with cognitive impairment. Although previous studies have attempted to elucidate the complex relationship between age-associated aortic stiffening and pulsatility transmission to the cerebral network, they have not adequately addressed the effect of interactions between aortic stiffness and left ventricle (LV) contractility (neither on energy transmission nor on brain perfusion). In this study, we use a well-established and validated one-dimensional blood flow and pulse wave computational model of the circulatory system to address how age-related changes in cardiac function and vasculature affect the underlying mechanisms involved in the LV-aorta-brain hemodynamic coupling. Our results reveal how LV contractility affects pulsatile energy transmission to the brain, even with preserved cardiac output. Our model demonstrates the existence of an optimal heart rate (near the normal human heart rate) that minimizes pulsatile energy transmission to the brain at different contractility levels. Our findings further suggest that the reduction in cerebral blood flow at low levels of LV contractility is more prominent in the setting of age-related aortic stiffening. Maintaining optimal blood flow to the brain requires either an increase in contractility or an increase in heart rate. The former consistently leads to higher pulsatile power transmission, and the latter can either increase or decrease subsequent pulsatile power transmission to the brain.NEW & NOTEWORTHY We investigated the impact of major aging mechanisms of the arterial system and cardiac function on brain hemodynamics. Our findings suggest that aging has a significant impact on heart-aorta-brain coupling through changes in both arterial stiffening and left ventricle (LV) contractility. Understanding the underlying physical mechanisms involved here can potentially be a key step for developing more effective therapeutic strategies that can mitigate the contributions of abnormal LV-arterial coupling toward neurodegenerative diseases and dementia.

The recent advent of positron emission tomography (PET) scanners that can image the entire human body opens up intriguing possibilities for cardiovascular research and future clinical applications. These new systems permit radiotracer kinetics to be measured in all organs simultaneously. They are particularly well suited to study cardiovascular disease and its effects on the entire body. They could also play a role in quantitatively measuring physiologic, metabolic, and immunologic responses in healthy individuals to a variety of stressors and lifestyle interventions, and may ultimately be instrumental for evaluating novel therapeutic agents and their molecular effects across different tissues. In this review, we summarize recent progress in PET technology and methodology, discuss several emerging cardiovascular applications for total-body PET, and place this in the context of multiorgan and systems medicine. Finally, we discuss opportunities that will be enabled by the technology, while also pointing to some of the challenges that still need to be addressed.

Fatigue is a common symptom in neurodegenerative diseases and is associated with decreased cognitive performances. A full knowledge of the causes and physiopathological pathways leading to fatigue in Alzheimer's disease could help treating this symptom and obtain positive effects on cognitive functions.

To provide an overview of the clinical conditions and the biological mechanisms leading to fatigue in Alzheimer's disease patients. To review the recent advances on fatigue management and describe the landscape of future possibilities.

We performed a narrative review including all type of studies (e.g. cross-sectional and longitudinal analysis, reviews, clinical trials).

We found very few studies considering the symptom fatigue in Alzheimer's disease patients. Populations, designs, and objectives varied across studies rendering comparability across studies difficult to perform. Results from cross-sectional and longitudinal analysis suggest that the amyloid cascade may be involved in the pathogenesis of fatigue and that fatigue may be a prodromal manifestation of Alzheimer's disease. Fatigue and neurodegeneration of Alzheimer's disease could share common brain signatures (i.e. hippocampal atrophy and periventricular leukoaraiosis). Some mechanisms of aging (i.e. inflammation, mitochondrial dysfunction, telomere shortening) may be proposed to play a common underlying role in Alzheimer's disease neurodegeneration and muscle fatigability. Considering treatments, donepezil has been found to reduce cognitive fatigue in a 6-week randomized controlled study. Fatigue is frequently reported as an adverse event in patients treated by anti-amyloid agents in clinical trials.

The literature is actually inconclusive about the main causes of fatigue in Alzheimer's disease individuals and its potential treatments. Further research is needed to disentangle the role of several components such as comorbidities, depressive symptoms, iatrogenic factors, physical decline and neurodegeneration itself. Given the clinical relevance of this symptom, it seems to be important to systematically assess fatigue by validated tools in Alzheimer's disease clinical trials.

There is an expanding body of literature implicating heart disease and stroke as risk factors for Alzheimer's disease (AD). Hawaii is one of the six majority-minority states in the United States and has significant racial health disparities. The Native-Hawaiians/Pacific-Islander (NHPI) population is well-known as a high-risk group for a variety of disease conditions.

We explored the association of cardiovascular disease with AD development based on the Hawaii Medicare data, focusing on racial disparities.

We utilized nine years of Hawaii Medicare data to identify subjects who developed heart failure (HF), ischemic heart disease (IHD), atrial fibrillation (AF), acute myocardial infarction (AMI), stroke, and progressed to AD, using multistate models. Propensity score-matched controls without cardiovascular disease were identified to compare the risk of AD after heart disease and stroke. Racial/Ethnic differences in progression to AD were evaluated, accounting for other risk factors.

We found increased risks of AD for AF, HF, IHD, and stroke. Socioeconomic (SE) status was found to be critical to AD risk. Among the low SE group, increased AD risks were found in NHPIs compared to Asians for all conditions selected and compared to whites for HF, IHD, and stroke. Interestingly, these observations were found reversed in the higher SE group, showing reduced AD risks for NHPIs compared to whites for AF, HF, and IHD, and to Asians for HF and IHD.

NHPIs with poor SE status seems to be mostly disadvantaged by the heart/stroke and AD association compared to corresponding whites and Asians.

The average age at onset of heart failure (HF) shows a progressive decrease in recent years; however, the association between age at onset of HF and risk of subsequent dementia remains undetermined.

The study sought to examine whether younger onset age of HF is associated with a higher risk of incident dementia.

Individual-level data from the UK Biobank cohort study were analyzed in the present study. Cox regression models and the propensity score matching method were used to analyze the associations of HF and its onset age with subsequent all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD).

Compared with 442,791 participants without HF, those with HF had a higher risk of all-cause dementia (HR: 1.14). Among 14,413 participants with HF, multivariable-adjusted HRs for all-cause dementia, AD, and VD were 1.18, 1.64, and 1.27, respectively, per 10-year decrease in age at HF onset. The propensity score matching analyses found that the strength of association between HF and all-cause dementia increased with decreasing onset age of HF (≥75 years, HR: 1.05; 65-74 years, HR: 1.10; <65 years, HR: 1.67) after multivariable adjustment. Similarly, participants with onset age of HF <65 years had the greatest HRs for incident AD and VD, compared with their matched control subjects.

Younger age at HF onset was associated with increased risk of dementia. Individuals with an onset age of HF before 65 years of age may represent a particularly vulnerable population for dementia irrespective of subtypes and need careful monitoring and timely intervention to attenuate subsequent risk of incident dementia.

Late-onset Alzheimer's disease (LOAD) is the most frequent cause of dementia in older persons. Subjects affected by type 2 diabetes mellitus (T2DM) are at higher risk of vascular disease, cognitive decline, and dementia. LOAD has many characteristics shared with impaired insulin signaling pathways, and substantial evidence has demonstrated a pivotal role in dysregulated glucose metabolism in its pathogenesis. Recent studies have shown that some anti-diabetic drugs, other than regulating the metabolism of peripheral tissues, can also modulate the brain's metabolism, reduce inflammation, and have a direct neuroprotective effect. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a newer class with many pleiotropic effects that may have strong neuroprotective potential. After a summary of the principal "anti-diabetic" drugs acting as suitable candidates in treating LOAD, this narrative review explored the potential role of SGLT2i on cognition from pre-clinical to clinical studies.

(1) Background: Assessment of cognitive function is not routine in cardiac patients, and knowledge on the subject remains limited. The aim of this study was to assess post-myocardial infarction (MI) cognitive functioning in order to determine the frequency of cognitive impairment (CI) and to identify factors that may influence it. (2) Methods: A prospective study included 468 patients hospitalized for MI. Participants were assessed twice: during the first hospitalization and 6 months later. The Mini-Mental State Examination was used to assess the occurrence of CI. (3) Results: Cognitive dysfunction based on the MMSE was found in 37% (N-174) of patients during the first hospitalization. After 6 months, the prevalence of deficits decreased significantly to 25% (N-91) (p < 0.001). Patients with CI significantly differed from those without peri-infarction deficits in the GFR, BNP, ejection fraction and SYNTAX score, while after 6 months, significant differences were observed in LDL and HCT levels. There was a high prevalence of non-cognitive mental disorders among post-MI patients. (4) Conclusions: There is a high prevalence of CI and other non-cognitive mental disorders, such as depression, sleep disorders and a tendency to aggression, among post-MI patients. The analysis of the collected material indicates a significant impact of worse cardiac function expressed as EF and BNP, greater severity of coronary atherosclerosis expressed by SYNTAX results, and red blood cell parameters and LDL levels on the occurrence of CI in the post-MI patient population.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cerebral amyloid β (Aβ) deposition and tau pathology. The AD-mediated degeneration of the brain neuro-signaling pathways, together with a potential peripheral amyloid accumulation, may also result in the derangement of the peripheral nervous system, culminating in detrimental effects on other organs, including the heart. However, whether and how AD pathology modulates cardiac function, neurotrophins, innervation, and amyloidosis is still unknown. Here, we report for the first time that cardiac remodeling, amyloid deposition, and neuro-signaling dysregulation occur in the heart of Tg2576 mice, a widely used model of AD and cerebral amyloidosis.

Echocardiographic analysis showed significant deterioration of left ventricle function, evidenced by a decline of both ejection fraction and fraction shortening percentage in 12-month-old Tg2576 mice compared to age-matched WT littermates. Tg2576 mice hearts exhibited an accumulation of amyloid aggregates, including Aβ, an increase in interstitial fibrosis and severe cardiac nervous system dysfunction. The transgenic mice also showed a significant decrease in cardiac nerve fiber density, including both adrenergic and regenerating nerve endings. This myocardial denervation was accompanied by a robust reduction in NGF and BDNF protein expression as well as GAP-43 expression (regenerating fibers) in both the brain and heart of Tg2576 mice. Accordingly, cardiomyocytes and neuronal cells challenged with Aβ oligomers showed significant downregulation of BDNF and GAP-43, indicating a causal effect of Aβ on the loss of cardiac neurotrophic function.

Overall, this study uncovers possible harmful effects of AD on the heart, revealing cardiac degeneration induced by Aβ through fibrosis and neuro-signaling pathway deregulation for the first time in Tg2576 mice. Our data suggest that AD pathology can cause deleterious effects on the heart, and the peripheral neurotrophic pathway may represent a potential therapeutic target to limit these effects.

The functions of the glymphatic system include clearance of the metabolic waste and modulation of the water transport in the brain, and it forms a brain-wide fluid network along with cerebrospinal fluid (CSF) and interstitial fluid (ISF). The glymphatic pathway consists of periarterial influx of CSF, astrocyte-mediated interchange between ISF and CSF supported by aquaporin-4 (AQP4) on the endfeet of astrocyte around the periarterioles, and perivenous efflux of CSF. Finally, CSF is absorbed by the arachnoid granules or flows into the cervical lymphatic vessels. There is growing evidence from animal experiments that the glymphatic system dysfunction is involved in many neurological disorders, such as Alzheimer's disease, stroke, epilepsy, traumatic brain injury and meningitis. In this review, we summarize the latest progress on the glymphatic system and its driving factors, as well as changes in the glymphatic pathway in different neurological diseases. We significantly highlight the likely therapeutic approaches for glymphatic pathway in neurological diseases, and the importance of AQP4 and normal sleep architecture in this process.

The NCD cohort study RIFADE (RIsk FActors of DEmentia) investigates the interaction of risk factors and neurocognitive disorders (NCDs) due to Alzheimer's disease (NCD-AD) and NCD of vascular type (NCD-vascular). Retrospective recruitment referred to a period from 2007 to 2018 in a single centre. In addition to the baseline visit, follow-up visits took place at 3, 6, 12 months followed by yearly visits. Visit times varied in part depending on adherence. The study also comprises an EEG bank and a bank with cerebral MRI (c-MRI).

Inclusion criteria were broad in order to cover a wide range of patterns of NCD. At baseline, patients underwent a large panel of assessments, e.g. including clinical history, diagnostic evaluation for NCD according to DSM-IV and NINDS AIREN criteria, a cognitive test battery including the DemTect, the clock drawing test and the Instrumental-Activities-of-Daily-Living-scale of Lawton and Brodie, EEG and c-MRI. At each follow-up visit, cognitive tests were repeated, in most cases also EEGs and in some cases c-MRIs. Numerous risk factors (RF) including vascular RF, atrial fibrillation, heart failure, sleep apnoea and lifestyle factors such as sedentary lifestyle, low cognitive style and smoking were evaluated for presence and for correction status at each visit, and modulation of uncorrected RF was initiated.

Overall, 126 subjects with a clinical diagnosis of NCD were included (52% female, mean age 71 ± 10.6 years (range 35e86)), number of follow-up visits per subject 2.9 ± 2.4, observation time per subject 3.4 ± 2.8 years). Of these, 55/28/17% presented with the clinical stages subjective cognitive decline (SCD)/mild cognitive impairment (MCI)/dementia (major NCD). Clinical diagnoses, retrospectively re-evaluated according to DSM-5, were 5/21/68/6% Alzheimer´s disease (NCD-AD)/vascular NCD (NCD-vascular) / mixed NCD (NCD-AD + NCD-vascular)/unspecified NCD. First longitudinal results revealed a mean DemTect score at baseline 12.6 ± 4.2 vs last visit 12.0 ± 4.8 (p = 0.08) and a clock drawing test score at baseline 1.9 ± 1.3 vs last visit 2.3 ± 1.5 (p < 0.0001). Of all subjects with MCI or major NCD (n = 57), 19 improved in the clinical stage from baseline to last visit (33.3%). Sixteen subjects progressed from SCD or MCI (n = 104) to major NCD (15.4%).

The German NCD cohort RIFADE comprises patients with all clinical stages of NCD. A considerable subgroup improved in clinical stage. Further analysis is needed to answer the question of whether modulation of multiple risk factors provides a favourable effect on cognitive outcome in NCD.

Aging plays a major role in neurodegenerative disorders such as Alzheimer's disease, and impacts neuronal loss. Olfactory dysfunction can be an early alteration heralding the presence of a neurodegenerative disorder in aging. Studying alterations in olfaction-related brain regions might help detection of neurodegenerative diseases at an earlier stage as well as protect individuals from any danger caused by loss of sense of smell.

To assess the effect of age and sex on olfactory cortex volume in cognitively healthy participants.

Neurologically healthy participants were divided in three groups based on their age: young (20-35 years; n = 53), middle-aged (36-65 years; n = 66) and older (66-85 years; n = 95). T1-weighted MRI scans acquired at 1.5 T were processed using SPM12. Smoothed images were used to extract the volume of olfactory cortex regions.

ANCOVA analyses showed significant differences in volume between age groups in the olfactory cortex (p ≤ 0.0001). In women, neuronal loss started earlier than in men (in the 4th decade of life), while in men more substantial neuronal loss in olfactory cortex regions was detected only later in life.

Data indicate that age-related reduction in the volume of the olfactory cortex starts earlier in women than in men. The findings suggest that volume changes in olfaction-related brain regions in the aging population deserve further attention as potential proxies of increased risk of neurodegenerative diseases.

Neuroinflammation is a devastating predisposing factor for Alzheimer's disease (AD). A number of clinical findings have reported peripheral disorders among AD patients. Amyloid beta (Aβ) is a toxic physiological aggregate that serves as a triggering factor for hepatic and cardiac disorders related to neurotoxicity. As a drawback of Aβ excessive accumulation in the brain, part of Aβ is believed to readily cross the blood-brain barrier (BBB) into the peripheral circulation resulting in serious inflammatory and toxic cascades acting as a direct bridge to cardiac and hepatic pathophysiology. The main aim is to find out whether neuroinflammation-related AD may result in cardiac and liver dysfunctions. Potential therapeutic interventions are also suggested to alleviate AD's cardiac and hepatic defects. Male rats were divided into: control group I, lipopolysaccharide (LPS)-neuroinflammatory-induced group II, LPS-neuroinflammatory-induced group treated with sodium hydrogen sulphide donor (NaHS) (group III), and LPS-neuroinflammatory-induced group treated with mesenchymal stem cells (MSCs) (group IV). Behavior and histopathological studies were conducted in addition to the estimation of different biological biomarkers. It was revealed that the increased toxic Aβ level in blood resulted in cardiac and hepatic malfunctions as a drawback of exaggerated inflammatory cascades. The administration of NaHS and MSCs proved their efficiency in combating neuroinflammatory drawbacks by hindering cardiac and hepatic dysfunctions. The consistent direct association of decreased heart and liver functions with increased Aβ levels highlights the direct involvement of AD in other organ complications. Thereby, these findings will open new avenues for combating neuroinflammatory-related AD and long-term asymptomatic toxicity.

Alzheimer's disease (AD) is a complex neurodegenerative disease. There is epidemiological evidence that heart failure (HF) patients are at higher risk of developing AD, and the impact of sacubitril/valsartan, the first angiotensin receptor-neprilysin inhibitor (ARNI) approved for HF, on cognitive functions is still controversial. To investigate the effect of sacubitril/valsartan on cognitive functions in colchicine-induced AD rat model. Forty adult male Wistar rats were equally allocated into four groups (each of 10 rats): Group I: normal control, Group II: intracerebroventricular injection of colchicine (15 μg/5 μl/bilaterally), Group III: colchicine (15 μg/5 μl/bilaterally, icv) + oral sacubitril/valsartan (100 mg/kg/day) for 25 days, and Group IV: colchicine (15 μg/5 μl/bilaterally, icv) + oral valsartan (50 mg/kg/day) for 25 days. Behavioral assessment was done using Morris water maze and passive avoidance tasks. Biochemically, β-amyloid (1-40 and 1-42) peptides, oxidative stress (malondialdehyde and superoxide dismutase) and inflammatory (tumor necrosis factor-alpha) parameters were measured in hippocampus and prefrontal cortex. Sacubitril/valsartan exaggerated colchicine-induced cognitive impairment in both Morris water maze and passive avoidance tasks and was associated with significant increase in β-amyloid accumulation, oxidative stress, and inflammation versus valsartan. Sacubitril/valsartan caused deleterious effect on cognitive impairment and biochemical alterations in colchicine-induced AD rat model. Hence, special caution should be taken following long-term intake of ARNI on cognitive functions.

This study aimed to examine the association between cardiopulmonary function, health-related quality of life (HRQOL) and cognitive function among nursing home residents aged 80 years and over.

A nursing home-based, cross-sectional study was implemented among 677 aged over 80 years in Shanghai, China. A total of 197 participants underwent effective cardiopulmonary function examinations. Mini-Mental Status Examination (MMSE) and Short Form-36 scales (SF-36) were used to assess cognitive function and HRQOL, respectively.

Decline in left ventricular ejection fractions (LVEF) [adjusted odds ratio (AOR), 1.98; 95% confidential interval (CI), 1.03-3.81)] and vital capacity (VC) (AOR, 2.08; 95%CI, 1.07-4.04) was associated with cognitive impairment. After adjusting confounding factors, relationships between cognitive function and physical functioning (PF) (AOR, 0.98; 95%CI, 0.97-0.99) still existed.

Healthcare professionals should pay more attention to cardiopulmonary health and HRQOL in the nursing home residents. Actions of public health strategies focus on the improvement of cardiopulmonary function, and PF among older nursing home residents with cognitive impairment is required.

Aggregated protein is the common cause of a wide variety of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease, etc. It is proven that protein aggregation like amyloid β (Aβ) is one of the critical factors causing AD and, its diagnosis in the early stages of the disease is important for the treatment or prevention of AD. To have a better understanding of protein aggregation and its pathologies, there is a huge need to design and develop new and more trustworthy probe molecules for in vitro amyloid quantification and in vivo amyloid imaging. In this study, 17 new biomarker compounds, have been synthesized from benzofuranone derivatives, to detect and identify amyloid in vitro (dye-binding assay) as well as in the cell by staining method. According to the results, some of these synthetic derivatives can be considered suitable identifiers and quantifiers to detect amyloid fibrils in vitro. Compared to thioflavin T, 4 probes out of 17 probes have shown good results in selectivity and detectability of Aβ depositions, and their binding properties were also confirmed with in silico analysis. The drug-likeness prediction results for selected compounds by the Swiss ADME server show a satisfactory percentage of blood-brain barrier (BBB) permeability and gastrointestinal (GI) absorption. Among all of them, compound 10 was able to show better binding properties than others, and in vivo study showed that this compound was capable of detecting intracellular amyloid.Communicated by Ramaswamy H. Sarma.

Heart failure (HF) may increase the risk of dementia via shared risk factors.

The authors investigated the incidence, types, clinical correlates, and prognostic impact of dementia in a population-based cohort of patients with index HF.

The previously territory-wide database was interrogated to identify eligible patients with HF (N = 202,121) from 1995 to 2018. Clinical correlates of incident dementia and their associations with all-cause mortality were assessed using multivariable Cox/competing risk regression models where appropriate.

Among a total cohort aged ≥18 years with HF (mean age 75.3 ± 13.0 years, 51.3% women, median follow-up 4.1 [IQR: 1.2-10.2] years), new-onset dementia occurred in 22,145 (11.0%), with age-standardized incidence rate of 1,297 (95% CI: 1,276-1,318) per 10,000 in women and 744 (723-765) per 10,000 in men. Types of dementia were Alzheimer's disease (26.8%), vascular dementia (18.1%), and unspecified dementia (55.1%). Independent predictors of dementia included: older age (≥75 years, subdistribution hazard ratio [SHR]: 2.22), female sex (SHR: 1.31), Parkinson's disease (SHR: 1.28), peripheral vascular disease (SHR: 1.46), stroke (SHR: 1.24), anemia (SHR: 1.11), and hypertension (SHR: 1.21). The population attributable risk was highest for age ≥75 years (17.4%) and female sex (10.2%). New-onset dementia was independently associated with increased risk of all-cause mortality (adjusted SHR: 4.51; P < 0.001).

New-onset dementia affected more than 1 in 10 patients with index HF over the follow-up, and portended a worse prognosis in these patients. Older women were at highest risk and should be targeted for screening and preventive strategies.

The heart is a functional syncytium controlled by a delicate and sophisticated balance ensured by the tight coordination of its several cell subpopulations. Accordingly, cardiomyocytes together with the surrounding microenvironment participate in the heart tissue homeostasis. In the right atrium, the sinoatrial nodal cells regulate the cardiac impulse propagation through cardiomyocytes, thus ensuring the maintenance of the electric network in the heart tissue. Notably, the central nervous system (CNS) modulates the cardiac rhythm through the two limbs of the autonomic nervous system (ANS): the parasympathetic and sympathetic compartments. The autonomic nervous system exerts non-voluntary effects on different peripheral organs. The main neuromodulator of the Sympathetic Nervous System (SNS) is norepinephrine, while the principal neurotransmitter of the Parasympathetic Nervous System (PNS) is acetylcholine. Through these two main neurohormones, the ANS can gradually regulate cardiac, vascular, visceral, and glandular functions by turning on one of its two branches (adrenergic and/or cholinergic), which exert opposite effects on targeted organs. Besides these neuromodulators, the cardiac nervous system is ruled by specific neuropeptides (neurotrophic factors) that help to preserve innervation homeostasis through the myocardial layers (from epicardium to endocardium). Interestingly, the dysregulation of this neuro-signaling pathway may expose the cardiac tissue to severe disorders of different etiology and nature. Specifically, a maladaptive remodeling of the cardiac nervous system may culminate in a progressive loss of neurotrophins, thus leading to severe myocardial denervation, as observed in different cardiometabolic and neurodegenerative diseases (myocardial infarction, heart failure, Alzheimer's disease). This review analyzes the current knowledge on the pathophysiological processes involved in cardiac nervous system impairment from the perspectives of both cardiac disorders and a widely diffused and devastating neurodegenerative disorder, Alzheimer's disease, proposing a relationship between neurodegeneration, loss of neurotrophic factors, and cardiac nervous system impairment. This overview is conducive to a more comprehensive understanding of the process of cardiac neuro-signaling dysfunction, while bringing to light potential therapeutic scenarios to correct or delay the adverse cardiovascular remodeling, thus improving the cardiac prognosis and quality of life in patients with heart or neurodegenerative disorders.

Cerebral amyloid angiopathy (CAA) is a kind of disease in which amyloid β (Aβ) and other amyloid protein deposits in the cerebral cortex and the small blood vessels of the brain, causing cerebrovascular and brain parenchymal damage. CAA patients are often accompanied by cardiac injury, involving Aβ, tau and transthyroxine amyloid (ATTR). Aβ is the main injury factor of CAA, which can accelerate the formation of coronary artery atherosclerosis, aortic valve osteogenesis calcification and cardiomyocytes basophilic degeneration. In the early stage of CAA (pre-stroke), the accompanying locus coeruleus (LC) amyloidosis, vasculitis and circulating Aβ will induce first hit to the heart. When the CAA progresses to an advanced stage and causes a cerebral hemorrhage, the hemorrhage leads to autonomic nervous function disturbance, catecholamine surges, and systemic inflammation reaction, which can deal the second hit to the heart. Based on the brain-heart axis, CAA and its associated cardiac injury can create a vicious cycle that accelerates the progression of each other.

The aim of this case-control study was to investigate whether cognitively impaired individuals have a higher burden of calcified carotid artery atheroma (CCAA) than controls without cognitive impairment.

The study included 154 cases with Alzheimer's disease (n = 52), mild cognitive impairment (n = 51), or subjective cognitive decline (n = 51) diagnosed at a university memory clinic. Seventy-six cognitively healthy controls were sampled through the Swedish population register. All participants underwent clinical oral and panoramic radiographic examinations. Two oral and maxillofacial radiologists performed blinded analyses of the panoramic radiographs for signs of CCAA, which was registered as absent or present and, if present, unilateral or bilateral. Consensus assessment was used for all statistical analyses.

CCAA was common (40%) in this middle-aged and older Swedish population. We found no differences in the prevalence of CCAA between cases and controls (40% vs. 42%).

Cognitively impaired patients do not have a higher burden of CCAA than matched controls without cognitive impairment.

Some observational studies suggested that heart failure (HF) is associated with increased risk of late-onset Alzheimer's disease (AD). On the other hand, a recently published Two-Sample Mendelian Randomization (2SMR) study was reported as inconclusive but the estimated odds ratios (ORs) were less than one indicating a potential causal association between genetically predicted HF and lowered risk of AD. Both HF and AD are quite common among elderly persons and frequently occur together resulting in a series of severe medical challenges and increased financial burden on healthcare. It is of great medical and financial interest to further investigate the statistical significance of the potential causal associations between genetically predicted HF and lowered risk of AD using large independent cohorts. To fill this important knowledge gap, the present study used the 2SMR method based on summary data from a recently published large genome-wide association study (GWAS) for AD on subjects with European ancestry. The 2SMR analysis provided statistically significant evidence of an association with ORs less than one between genetically predicted HF and late-onset AD (Inverse Variance Weighted, OR = 0.752, p = 0.004; MR Egger, OR = 0.546, p = 0.100; Weighted Median, OR = 0.757, p = 0.014). Further investigations of the significant associations between HF and late-onset AD, including specific genes related to the potential protective effect of HF-related medications on cognitive decline, are warranted.

Alzheimer's disease is among the challenging diseases to social and healthcare systems because no treatment has been achieved yet. Although the ambiguous pathological mechanism underlying this disorder, ion channel dysfunction is one of the recently accepted possible mechanism. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play important roles in cellular excitability and synaptic transmission. Ivabradine (Iva), an HCN blocker, is acting on HCN channels, and is clinically used for angina and arrhythmia. The current study aimed to investigate the therapeutic effects of Iva against scopolamine (Sco) induced dementia. To test our hypothesis, Sco and Iva injected rats were tested for behavioural changes, followed by ELISA and histopathological analysis of the hippocampus. Induced dementia was confirmed by behavioural tests, inflammatory cytokines and oxidative stress tests and histopathological signs of neurodegeneration, multifocal deposition of congo red stained amyloid beta plaques and the decreased optical density of HCN1 immunoreactivity. Iva ameliorated the scopolamine-induced dysfunction, the hippocampus restored its normal healthy neurons, the amyloid plaques disappeared and the optical density of HCN1 immunoreactivity increased in hippocampal cells. The results suggested that blockage of HCN1 channels might underly the Iva therapeutic effect. Therefore, Iva might have beneficial effects on neurological disorders linked to HCN channelopathies.

Intermittent hypoxia, or intermittent low oxygen interspersed with normal oxygen levels, has differential effects that depend on the "dose" of hypoxic episodes (duration, severity, number per day, and number of days). Whereas "low dose" daily acute intermittent hypoxia (dAIH) elicits neuroprotection and neuroplasticity, "high dose" chronic intermittent hypoxia (CIH) similar to that experienced during sleep apnea elicits neuropathology. Sleep apnea is comorbid in >50% of patients with Alzheimer's disease-a progressive, neurodegenerative disease associated with brain amyloid and chronic Tau dysregulation (pathology). Although patients with sleep apnea present with higher Tau levels, it is unknown if sleep apnea through attendant CIH contributes to onset of Tau pathology. We hypothesized CIH characteristic of moderate sleep apnea would increase dysregulation of phosphorylated Tau (phospho-Tau) species in Sprague-Dawley rat hippocampus and prefrontal cortex. Conversely, we hypothesized that dAIH, a promising neurotherapeutic, has minimal impact on Tau phosphorylation. We report a dose-dependent intermittent hypoxia effect, with region-specific increases in 1) phospho-Tau species associated with human Tauopathies in the soluble form and 2) accumulated phospho-Tau in the insoluble fraction. The latter observation was particularly evident with higher CIH intensities. This important and novel finding is consistent with the idea that sleep apnea and attendant CIH have the potential to accelerate the progression of Alzheimer's disease and/or other Tauopathies.NEW & NOTEWORTHY Sleep apnea is highly prevalent in people with Alzheimer's disease, suggesting the potential to accelerate disease onset and/or progression. These studies demonstrate that intermittent hypoxia (IH) induces dose-dependent, region-specific Tau phosphorylation, and are the first to indicate that higher IH "doses" elicit both endogenous, (rat) Tau hyperphosphorylation and accumulation in the hippocampus. These findings are essential for development and implementation of new treatment strategies that minimize sleep apnea and its adverse impact on neurodegenerative diseases.