Alzheimer's Disease Research Articles

Applications and Developments of Gene Therapy Drug Delivery Systems for Neurological Disorders

AbstractNeurological diseases (NDs) such as Alzheimer's disease, Parkinson's disease, ischemic strokes, spinal cord injuries, and other similar conditions that continue to pose a substantial health and economic burden on a global scale. It is crucial to tackle the difficulties provided by current medications due to the adverse effects and its immunological reactions to develop improved treatments for neurodegenerative illnesses. Gene therapy is currently being extensively used in preclinical and clinical studies for various diseases because of its ability to enhance the delivery and effectiveness of treatments. Various gene delivery techniques, including messenger RNA, small interfering RNA, antisense oligonucleotides, microRNA, CRISPR/Cas9 system, and plasmid DNA, have been created to address these difficulties. The goal of this study is to provide a clear overview of the pathophysiological underpinnings of NDs illnesses while also illuminating recent developments in gene delivery vector technologies. It goes over the main classifications of these vectors, their individual benefits and drawbacks, and their specific applications in the delivery of gene therapy.

Insight from molecular modeling and ADMET analysis: Design, synthesis and in vitro acetylcholinesterase and butyrylcholinesterase assessment of thiazolidinone containing benzoxazole hybrids derivatives

Alzheimer's disease (AD) is a brain disorder medically defined as loss of memory and analytical reasoning abilities of an infected person. The adult or aged peoples are more likely to be adversely affected by this disease. Following this prospect, this study is conducted to synthesize a novel class of (Z)-2-(((Z)-2-(benzo[d]oxazol-2-ylthio)-1-phenylethylidene)hydrazono)-3-phenylthiazolidin-4-one based derivatives and evaluate its performance towards the treatment of AD. This study showed the better results when compared to the inhibition potential of the standard drug Donepezil against AChE (IC50= 4.10 ± 1.05 µM) and against BuChE (IC50=6.59 ± 1.63 µM), the inhibition potential shown by benzimidazole based thiadiazole scaffolds against the targeted enzymes is of wide range. The inhibition potential of all the scaffolds against AChE ranged from 2.89 ± 0.65 µM to 19.04 ± 0.49 µM and against BuChE ranged from 3.70 ± 0.98 µM to 23.19 ± 0.71 µM. Moreover, to investigate the binding interaction of effective scaffolds against the active sites of AChE and BuChE, molecular docking studies were carried out and the analysis data evaluated the substantial binding interaction of scaffolds against the targeted enzymes. The structural characteristic of each scaffold is determined by using different spectroscopic techniques. In this work only three analogues found to be the most active having the observed IC50 values 7d, 3.05 ± 0.19 µM, 2.90 ± 0.87 µM(for BuChE), 7g, 3.88 ± 0.32 µM(for AChE), 4.98 ± 0.54 µM(for BuChE), 7k 2.89 ± 0.65 µM(for AChE), 3.70 ± 0.98 µM(for BuChE). Furthermore, the selected analogues considered for In-Vivo and cytotoxic study as well as structure modification carried out in search of more active analogues.

Lecanemab's Path Forward: Navigating the Future of Alzheimer's Treatment in Europe Amidst the EMA's Rejection.

Lecanemab (Leqembi©, Biogen), a humanized anti-amyloid-beta monoclonal antibody, has been approved for early-stage Alzheimer's disease (AD) in several countries, including the US and Japan. However, the European Medicines Agency (EMA) recently issued a negative opinion on its marketing authorization, reflecting concerns over the clinical value and manageability of anti-amyloid treatments. This decision highlights the ongoing disconnect between research advancements and clinical practice, where the focus on biological markers over tangible clinical improvements remains contentious. Despite promising biological effects, lecanemab's clinical outcomes have been modest, raising questions about its therapeutic role. The EMA's refusal underscores the need to address doubts surrounding the real-world effectiveness and safety of such treatments, especially concerning amyloid-related imaging abnormalities (ARIAs), a common side effect observed in clinical trials. The recent approval of lecanemab by the UK's Medicines and Healthcare products Regulatory Agency, despite the National Institute for Health and Care Excellence's rejection on cost-effectiveness grounds, further fuels the debate on the feasibility of anti-amyloid therapies. This commentary emphasizes the importance of real-world data on lecanemab's impact on cognitive decline, daily functioning, and side-effect management. As the global clinical use of lecanemab increases, continuous and standardized reporting on its outcomes is crucial for guiding future regulatory decisions and for potentially bridging the gap between research and practice in AD treatment.

Costs of Care in Relation to Alzheimer's Disease Severity in Sweden: A National Registry-Based Cohort Study.

The advancement of diagnostic and therapeutic interventions in early Alzheimer's disease (AD) has demanded the economic evaluation of such interventions. Resource utilization and cost estimates in early AD and, more specifically, the amyloid-positive population are still lacking. We aimed to provide cost estimates in AD in relation to disease severity and compare these with the control population. We also aimed to provide cost estimates for a subset of the AD population with both clinical diagnosis and amyloid-positive confirmation. This was a retrospective longitudinal analysis of resource utilization using data from national registries. A cohort from the national Swedish registry for cognitive/dementia disorders (SveDem) includes all clinically diagnosed AD between 2013 and 2020. The study population included 31,951 people with AD and 63,902 age- and sex-matched controls (1:2). The population was followed until death, the end of December 2020, or 2years from the last clinic visit. Direct medical and social costs were estimated from other national registries. Direct medical costs include costs for medications and inpatient and outpatient clinical visits. Direct social costs include costs for institutionalization, home care, short-term care, support for daytime activities, and housing support. Mean annual costs and 95% confidence intervals were obtained by bootstrapping, presented in 2021 Swedish Krona (SEK) (1 SEK=0.117 USD, 1 SEK=0.0985 EUR in 2021), and disaggregated by AD severity, cost component, sex, age group, and care setting. Mean annual costs for individuals with clinically diagnosed AD were SEK 99,906, SEK 290,972, SEK 479,524, and SEK 795,617 in mild cognitive impairment (MCI), mild, moderate, and severe AD. The mean annual costs for the population with both clinical diagnosis and amyloid-positive AD confirmation (N=5610) were SEK 57,625, SEK 179,153, SEK 333,095, and SEK 668,073 in MCI, mild, moderate, and severe AD, respectively. The mean annual costs were higher in institutionalized than non-institutionalized patients, females than males, and older than younger age groups. Inpatient and drug costs were similar in all AD severity stages, but outpatient costs decreased with AD severity. Costs for institutionalization, home care, support for daytime activities, and short-term care increased with AD severity, whereas the cost of housing support decreased with AD severity. This is the first study estimating annual costs in people with AD from MCI to severe AD, including those for the amyloid-positive population. The study provides cost estimates by AD severity, cost components, care settings, sex, and age groups, allowing health economic modelers to apply the costs based on different model structures and populations.

Influence of APOE4 genotype on PCSK9-lipids association in cerebrospinal fluid and serum of patients in the Alzheimer's disease continuum.

Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the APOE4 genotype are not clarified. We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the APOE4 genotype. We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients. CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD APOE4 carriers showed higher PCSK9 and 24-HC (+61.3%, p = 0.027 and +32.7%, p = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = -0.444, p = 0.049) and, exclusively among AD APOE4 carriers, a negative association between CSF PCSK9 and 24-HC (r = -0.786, p = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520, p = 0.004), driven by APOE4 carriers (r = 0.544, p = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465, p = 0.039) in AD. None of these results were found in MCI-AD patients. PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum.

Anthropometric and Demographic Features Affect the Interpretation of Cerebrospinal Fluid Biomarkers in Patients with Different Dementia Syndromes and Cognitively Healthy Adults.

Clinical distinction between dementia with Lewy bodies (DLB) and late-onset Alzheimer's disease (AD) is difficult, while several features might affect the analyses of biomarkers. This study aimed to verify associations of anthropometric and demographic features with cerebrospinal fluid biomarkers, their ratios, and restructured traditional regression formulas in patients with DLB and AD, as well as in cognitively healthy controls. Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive status, and with controls according to sex and age to investigate associations of sex, age, dementia duration, total sleep time, body mass index, alcohol use, smoking, sanitation, and APOE-ε4 alleles on the measurement of cerebrospinal fluid α-synuclein, biomarker ratios, and restructured traditional regression formulas involving amyloid-β (Aβ42,Aβ40,Aβ38), tau, and phospho-tau Thr181. Overall, 81 participants were included with DLB (n = 27;11 APOE-ε4 +) or AD (n = 27;12 APOE-ε4 +), and controls (n = 27;4 APOE-ε4 +); two thirds were women. Cerebrospinal fluid evidence of amyloidosis and tauopathy was more prevalent among women with AD, while Aβ42/Aβ38 could also discriminate men with DLB from men with AD. Restructured traditional regression formulas had higher diagnostic accuracy for women with AD. Aging, higher body mass index, and APOE-ε4 alleles were associated with amyloidosis in DLB, while only in AD were higher body mass index associated with lower tau pathology load, and more alcohol use associated with higher phospho-tau Thr181/Aβ42. These findings confirm the effects of anthropometric and demographic features on cerebrospinal fluid biomarkers, and also differences in aberrant amyloidosis and tauopathy between DLB and AD.

Impaired insulin signaling and diet-induced type 3 diabetes pathophysiology increase amyloid β expression in the Drosophila model of Alzheimer's disease

Compelling evidence has strongly linked unregulated sugar levels to developing Alzheimer's disease, suggesting Alzheimer's to be ‘diabetes of the brain or ‘type 3 diabetes. Insulin resistance contributes to the pathogenesis of Alzheimer's disease due to uncontrolled and unchecked blood glucose, though the interrelatedness between Alzheimer's disease and type 2 diabetes is debatable. Here we describe the consequences of inducing type 3 diabetes by feeding Drosophila on a high sucrose diet, which effectively mimics the pathophysiology of diabetes. High sucrose diet increases glycogen and lipid accumulation. Inducing type 3 diabetes worsened neurodegeneration and accelerated disease progression in Drosophila expressing the Alzheimer's Familial Arctic mutation. High sucrose milieu also negatively affected locomotor ability and reduced the lifespan in the Alzheimer's disease model of Drosophila. The results showed that creating diabetic conditions by using insulin receptor (InR) knockdown in the eyes of Drosophila led to a degenerative phenotype, indicating a genetic interaction between the insulin signaling pathway and Alzheimer's disease. The expression of PERK reflects disruption in the endoplasmic reticulum homeostasis due to amyloid-β (Aβ) under a high sucrose diet. These observations demonstrated association between type 3 diabetes and Alzheimer's disease, and that a high sucrose environment has a degenerating effect on Alzheimer's disease condition.

Hospitalization Due to Infections Before and After Alzheimer's Disease Diagnosis

ObjectivesThere is a lack of studies on the rate and temporal changes of infections in relation to Alzheimer's disease (AD) diagnosis. We studied the infection rate in persons with and without AD yearly 5 years before and after AD diagnosis. DesignRegister-based cohort study. Setting and ParticipantsWe used the Medication Use and Alzheimer's Disease cohort with 70,718 Finnish community dwellers diagnosed with AD between 2005 and 2011 and an equal number of age, sex- and region-of-residence–matched comparison persons. MethodsData on comorbidities, medication use, and hospital days due to infection were retrieved from multiple nationwide registers. The rate of hospitalization and accrued hospital days due to infections were calculated yearly during the follow-up. The accumulation of hospital days was investigated with the negative binomial model. ResultsDuring the follow-up, one-half of persons with AD had inpatient stays due to infections compared with 34% of persons without AD. The infection rate increased substantially 1 to 2 years before AD diagnosis. At AD diagnosis, the rate of inpatient stays and outpatient visits due to infection was higher (15 per 100 person-years) in persons with AD than in comparison persons (9 per 100 person-years), and the accumulation of hospital days in persons with AD was higher a year after the diagnosis (incidence rate ratio, 1.21; 95% CI, 1.11-1.32) due to higher infection rate. The most common infection diagnoses in both groups were pneumonia and genitourinary infections. Conclusions and ImplicationsCompared with matched comparison persons, the higher hospitalization rate due to infections could be caused by systemic inflammation related to AD, infections generally treated in outpatient care, delirium symptoms associated with infections, and caregiver burden. The prevention of infections should be part of the care of cognitive disorders throughout the disease.

Associated risk and resilience factors of Alzheimer's disease in women with early bilateral oophorectomy: Data from the UK Biobank.

Bilateral oophorectomy (BO) confers immediate estradiol loss. We examined prevalence and predictors of Alzheimer's disease (AD) in women with early BO comparing their odds ratios of AD to those of women with spontaneous menopause (SM). A cohort from UK Biobank (n = 34,603) included women aged 60 + at baseline with and without AD who had early BO or SM. AD was determined based on AD related ICD-10 or ICD-9 code. We used logistic regression to model the association of menopause type with AD. Model predictors included age, education, age at menopause, hormone therapy (HT), APOE4, body mass index (BMI), cancer history, and smoking history. Those with early BO had four times the odds of developing AD (OR = 4.12, 95% CI [2.02, 8.44]) compared to those with SM. APOE4 (OR = 4.29, 95% CI [2.43, 7.56]), and older age (OR = 1.16, 95% CI [1.05, 1.28]) were associated with increased odds of AD in the BO group. Greater years of education were associated with reduced odds of AD for both BO (OR = 0.91, 95% CI [0.85, 0.98]), and SM (OR = 0.95, 95% CI [0.90, 0.99]), while ever use of HT was associated with decreased odds of AD only for the BO group (OR = 0.43, 95% CI [0.23, 0.82]). Women with early BO, particularly with an APOE4 allele, are at high risk of AD. Women with early BO who use HT and those with increased education have lower odds of developing AD.

The Role of Neuropeptide Y in the Pathogenesis of Alzheimer’s Disease: Diagnostic Significance and Neuroprotective Functions

Background. Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases. It has been suggested that the factors that cause pathologic changes and lead to the development of AD may also include changes in certain neuropeptides. The implication of the neuropeptide (NPY) in the pathogenesis of AD and its potential therapeutic role is possible due to the following properties: involvement in adult neurogenesis, regulatory effects on the immune system, the inhibition of potential-dependent Ca2+ channels, and the reduction in glutamate excitotoxicity. The aim of our review was to summarize recent data on the role of NPY in AD development and to explore its potential as a biomarker and a possible therapeutic target. Materials and methods. We performed a systematic review of studies, for which we search using the keywords “Alzheimer’s disease and neuropeptide Y”, “Alzheimer’s disease and NPY”, “AD and NPY”, “Neuropeptide Y and Neurodegenerative disease”. Nineteen articles were included in the review. Results. The NPY levels in cerebrospinal fluid and plasma have been found to be reduced or unchanged in AD patients; however, these findings need to be confirmed in more recent studies. Data obtained in transgenic animal models support the role of NPY in AD pathogenesis. The neuroprotective effects of NPY have been demonstrated in vitro and in vivo in AD models. Conclusion. The findings may open new possibilities for using NPY as a diagnostic marker to detect AD at earlier stages of the disease or as a potential therapeutic target due to its neuroprotective properties.

The association of the triglyceride-glucose index with Alzheimer's disease and its potential mechanisms.

The correlation between Alzheimer's disease (AD) and the glucose-triglyceride (TyG) index remains undetermined. This study aimed to investigate the relationship between the TyG index and AD, as well as the relationship between the TyG index and cerebrospinal fluid (CSF) AD biomarkers and cognition. Six hundred twenty-eight non-dementia participants were included. The TyG index, pathological markers, and cognitive measures were studied using multiple linear regression. Also calculated using a multivariate Cox regression model were the hazard ratio (HR) and its 95% confidence interval (CI). Ten thousand bootstrap iterative causal mediation analyses were performed to investigate the potential mediating effect of AD pathology on cognition. The TyG index was linked to CSF AD biomarkers (βAβ42 = 0.880; βTau = -0.674; βpTau = -0.884; βAβ42/pTau = 1.764; βAβ42/Tau = 1.554; βpTau/Tau = -0.210) and cognitive measurements (βMEM = 0.570; βEF = 0.535; βADAS11 = -0.789). Mediation analysis revealed that the TyG index may influence cognition via CSF AD biomarkers, including Aβ42, tau, and pTau. Furthermore, each 1-unit increase in TyG index was associated with a 29.5% reduction in the risk of incident AD. A delayed rate of cognitive decline and a reduced risk of AD were found to be correlated with higher levels of the TyG index, but this does not mean increasing TyG index levels is beneficial for health. Through AD pathology, the TyG index may influence AD and cognitive changes.

Regional differences in glucose metabolic decline and tau deposition in the Alzheimer's continuum brain.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood. We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis. We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted. There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions. Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions.

Added value of inflammatory plasma biomarkers to pathologic biomarkers in predicting preclinical Alzheimer's disease.

Plasma biomarkers have recently emerged for the diagnosis, assessment, and disease monitoring of Alzheimer's disease (AD), but have yet to be fully validated in preclinical AD. In addition to AD pathologic plasma biomarkers (amyloid-β (Aβ) and phosphorylated tau (p-tau) species), a proteomic panel can discriminate between symptomatic AD and cognitively unimpaired older adults in a dementia clinic population. Examine the added value of a plasma proteomic panel, validated in symptomatic AD, over standard AD pathologic plasma biomarkers and demographic and genetic (apolipoprotein (APOE) ɛ4 status) risk factors in detecting preclinical AD. 125 cognitively unimpaired older adults (mean age = 66 years) who completed Aβ PET and plasma draw were analyzed using multiple regression with Aβ PET status (positive versus negative) as the outcome to determine the best fit for predicting preclinical AD. Model 1 included age, education, and gender. Model 2 and 3 added predictors APOE ɛ4 status (carrier versus non-carrier) and AD pathologic blood biomarkers (Aβ42/40 ratio, p-tau181), respectively. Random forest modeling established the 5 proteomic markers from the proteomic panel that best predicted Aβ PET status, and these markers were added in Model 4. The best model for predicting Aβ PET status included age, years of education, APOE ɛ4 status, Aβ42/40 ratio, and p-tau181. Adding the top 5 proteomic markers did not significantly improve the model. Proteomic markers in plasma did not add predictive value to standard AD pathologic plasma biomarkers in predicting preclinical AD in this sample.

Mortality for Alzheimer's disease during the COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) negatively impacts the progression of Alzheimer's disease. The aim of this study was to determine whether mortality from Alzheimer's disease has changed during the COVID-19 pandemic. We searched the WONDER database, to obtain cumulative and sex-specific age-adjusted death rates of Alzheimer's disease between the years 2018 and 2022. Cumulative age-adjusted mortality rate displayed a peak in 2020, followed by gradual decline thereafter. The data for both sexes mirror that of total population, peaking in 2020, followed by a decline thereafter. The relative increase in age-adjusted mortality for Alzheimer's disease in 2020 compared to 2019 was + 8.7% in the total population, + 6.1% in men and + 10.1% in women. Frail people, such as those with Alzheimer's disease, may be more vulnerable to the risk of dying during an outbreak of infectious disease, paving the way for increased preventive and protective measures in the unfortunate event of the next pandemic.

Mitochondrial Quality Control in Alzheimer’s Disease: Insights from Caenorhabditis elegans Models

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that is classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and the intracellular accumulation of neurofibrillary tangles (NFTs) that are rich in aberrantly modified tau protein. In addition to aggregative and proteostatic abnormalities, neurons affected by AD also frequently possess dysfunctional mitochondria and disrupted mitochondrial maintenance, such as the inability to eliminate damaged mitochondria via mitophagy. Decades have been spent interrogating the etiopathogenesis of AD, and contributions from model organism research have aided in developing a more fundamental understanding of molecular dysfunction caused by Aβ and toxic tau aggregates. The soil nematode C. elegans is a genetic model organism that has been widely used for interrogating neurodegenerative mechanisms including AD. In this review, we discuss the advantages and limitations of the many C. elegans AD models, with a special focus and discussion on how mitochondrial quality control pathways (namely mitophagy) may contribute to AD development. We also summarize evidence on how targeting mitophagy has been therapeutically beneficial in AD. Lastly, we delineate possible mechanisms that can work alone or in concert to ultimately lead to mitophagy impairment in neurons and may contribute to AD etiopathology.

Association between selective serotonin reuptake inhibitors and mortality following COVID-19 among patients with Alzheimer's disease.

Recent research suggests that selective serotonin reuptake inhibitors (SSRIs) may reduce mortality in COVID-19 patients; however, research into their benefits for elderly Alzheimer's disease (AD) patients remains limited. To investigate the relationship between SSRIs therapy and the mortality risk after COVID-19 infection in elderly patients with and without AD. This retrospective cohort study leveraged a large database containing over 100 million electronic health records in the US from the TriNetX platform to compare the hazard rates of mortality after COVID-19 infection in elderly AD patients prescribed SSRIs versus propensity-score matched individuals prescribed other antidepressants. This study was also conducted in separate cohorts of patients without AD to compare the findings. When compared with non-SSRI antidepressants, SSRIs were associated with lower risk for mortality after COVID-19 infection in elderly patients without AD over early, middle, and later stages of the pandemic with HRs of 0.84 (95% CI: 0.75-0.93), 0.86 (95% CI: 0.79-0.93), and 0.77 (95% CI: 0.71-0.33), respectively. When comparing SSRIs with non-SSRI antidepressants for mortality risk following COVID-19 among patients with AD, HRs of 0.95 (95% CI: 0.71-1.27), 0.80 (95% CI: 0.61-1.06), and 0.99 (95% CI: 0.75-1.32), were found respectively. Our findings suggest that the use of SSRIs is significantly associated with reduced mortality risk following COVID-19 in elderly patients without AD compared to other antidepressants. While a lower mortality risk was also observed among AD patients, the association was not statistically significant.

Discovery of novel metabolic biomarkers in blood serum for diagnosis of Alzheimer's disease.

Blood metabolites have emerged as promising candidates in the search for biomarkers for Alzheimer's disease (AD), as evidence shows that various metabolic derangements contribute to neurodegeneration in AD. We aim to identify metabolic biomarkers for AD diagnosis. We conducted an in-depth analysis of the serum metabolome of AD patients and age, sex-matched cognitively unimpaired older adults using ultra-high-performance liquid chromatography-high resolution mass spectrometry. The biomarkers associated with AD were identified using machine learning algorithms. Using the discovery dataset and support vector machine (SVM) algorithm, we identified a panel of 14 metabolites predicting AD with a 1.00 area under the curve (AUC) of receiver operating characteristic (ROC). The SVM model was tested against the verification dataset using an independent cohort and retained high predictive accuracy with a 0.97 AUC. Using the random forest (RF) algorithm, we identified a panel of 13 metabolites that predicted AD with a 0.96 AUC when tested against the verification dataset. These findings pave the way for an efficient, blood-based diagnostic test for AD, holding promise for clinical screenings and diagnostic procedures.

Meta-analysis reveals an inverse relationship between Alzheimer’s disease and cancer

In previous studies, Alzheimer's disease (AD) has consistently been linked to aging, and recent reports have suggested an inverse relationship between AD and cancer, although the underlying mechanism remains unclear. We performed an epidemiological meta-analysis to assess cancer likelihood in AD patients and vice versa and explored APOE gene expression’s role in tumor immunity across 33 The Cancer Genome Atlas (TCGA) cancer types. Our analysis revealed that people with AD are epidemiologically less likely to develop cancer than individuals without AD (RR: 0.53), and cancer patients are less likely to develop AD than non-cancer patients (RR: 0.61). Notably, APOE expression was positively associated with anti-tumor immune signatures and prevalent in early-stage tumors. This research reveals that AD patients are less likely to develop cancer and vice versa, pinpoints the crucial APOE gene as a risk factor for AD with anti-tumor activity, and provides new insight on the epidemiologically observed inverse relationship of the two diseases.

Association analyses of nutritional markers with Parkinson’s disease and Alzheimer’s disease

IntroductionParkinson’s disease (PD) and Alzheimer’s disease (AD) are common neurodegenerative diseases with multifaceted etiology. Nutritional and metabolic abnormalities are frequently implicated in PD and AD. In this observational study, we analyzed a series of nutritional markers, and aimed to understand their association with AD and PD risk. MethodsA total of 424 PD patients, 314 AD patients, and 388 healthy controls were included. Nutritional markers including Hemoglobin A1c, vitamin B12, folate, apolipoprotein B (ApoB), apolipoprotein A1 (ApoA1), low-density lipoprotein (LDL), high-density lipoprotein, triglyceride, total cholesterol (TC), uric acid and homocysteine (HCY) were measured. Significance for odds ratios examining was P < 0.0045 after bonferroni correction. ResultsMultifactor risk analysis showed that ApoB, LDL, and TC reduce PD risk, while HCY increase PD risk. ApoA1 and HCY are protective and risk factors for AD, respectively. ConclusionThe cross-sectional study demonstrates that HCY and lipid metabolism markers are associated with PD and AD risks. Our findings support the involvement of one-carbon metabolism and lipid metabolism disturbance in PD and AD.

Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity.

The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618-482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = -0.309, 95% CI: -0.38 to -0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10, 95% CI: -0.188 to -0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.