Incident Alzheimer's Disease Research Articles

Inequalities in the Prevention and Treatment of Alzheimer Disease.

Incidence of Alzheimer disease (AD) is going to rise in the next years and to become a health and social emergency. The prevention and the therapeutic management of AD still present unmet needs worldwide. The recent approval of monoclonal antibodies against amyloid β (anti-Aβ mAbs) for AD has increased the level of uncertainty regarding on how such drugs should be administered, to whom, and for how long. Concerns about cost-effectiveness ratios of anti-Aβ mAbs and the need for actual strategies of risk prevention have further dug barriers of inequalities between the national health care systems. Planning research to address questions on the real feasibility of the correct therapeutic management, improving international cooperation on surveillance of risk factors, implementing pathways for timely diagnosis, and effective medical and social support for patients with AD worldwide would be extremely valuable to fight against this upcoming pandemic.

A Comprehensive Investigation into the Relationship between Dietary Therapy Strategies for Metabolic Illnesses and the Underlying Myriad Factors

Abstract: Maintaining a well-balanced diet and considering how to fulfill all the adequate nutrition required by the body will help us live a healthy lifestyle. The risk of illness, infection, exhaustion, and poor performance increases when a balanced diet is absent. The anti-treatment technique of food modification has gained a lot of attention in research over the past few decades. Popular diets include Mediterranean, vegan, and low-carbohydrate diets. The vegan diet is a plant-based eating plan that eliminates animal products and emphasizes fruits, vegetables, legumes, whole grains, nuts, and seeds. The Palaeolithic age diet emphasizes eating full, unprocessed foods available to early people while avoiding grains, legumes, dairy products, refined sugar, and processed foods. Proponents claim it can improve health, and aid in weight loss. Numerous dietary patterns, such as caloric restriction (CR), dietary approaches to stop hypertension (DASH), ketogenic diets (KD), the Mediterranean diet (Medi), and Mediterranean-DASH diet Intervention for Neurological Delay (MIND) diet, have been tried to reduce body weight, any other disease infections, and cognitive decline. Increased Mediterranean diet adherence was linked to reductions in cardiovascular and neurological conditions, including Alzheimer's disease (AD) and related cognitive loss. The MIND diet, a new good dietary pattern has been linked to a significantly lower incidence of AD and slower rates of cognitive deterioration. The current piece of work emphasizes the introduction, nutritional components, and health advantages of different types of diet.

A potential association between COVID-19 vaccination and development of alzheimer's disease.

The challenges of the COVID-19 pandemic extend to concerns about vaccine side effects, particularly potential links to neurodegenerative diseases such as Alzheimer's disease (AD). This study investigates the association between COVID-19 vaccination and the onset of AD and its prodromal state, mild cognitive impairment (MCI). A nationwide, retrospective cohort study leveraging data from the Korean National Health Insurance Service was conducted. The study, conducted in Seoul, South Korea, analyzed data from a random 50% sample of city residents aged 65 and above, totaling 558,017 individuals. Participants were divided into vaccinated and unvaccinated groups, with vaccinations including mRNA and cDNA vaccines. The study focused on AD and MCI incidences post-vaccination, identified via ICD-10 codes, using multivariable logistic and Cox regression analyses. Patients with vascular dementia or Parkinson's disease served as controls. Findings showed an increased incidence of MCI and AD in vaccinated individuals, particularly those receiving mRNA vaccines, within three months post-vaccination. The mRNA vaccine group exhibited a significantly higher incidence of AD (Odds Ratio [OR]: 1.225; 95% Confidence Interval [CI]: 1.025-1.464; p = 0.026) and MCI (OR: 2.377; CI: 1.845-3.064; p < 0.001) compared to the unvaccinated group. No significant relationship was found with vascular dementia or Parkinson's disease. Preliminary evidence suggests a potential link between COVID-19 vaccination, particularly mRNA vaccines, and increased incidences of AD and MCI. This underscores the need for further research to elucidate the relationship between vaccine-induced immune responses and neurodegenerative processes, advocating for continuous monitoring and investigation into the vaccines' long-term neurological impacts.

An Ensemble Classification Model to Predict Alzheimer’s Incidence as Multiple Classes

This study introduces an ensemble classification model designed to categorize Alzheimer’s disease (AD) into four distinct classes—mild dementia, no dementia, moderate dementia, and very mild dementia—using Magnetic Resonance Imaging (MRI). The proposed model entitled the Ensemble Classification Model to Predict Alzheimer's Incidence as Multiple Classes (PAIMC) that integrates a six-dimensional analysis of MR images, encompassing entropies, Fractal Dimensions, Gray Level Run Length Matrix (GLRLM), Gray Level Co-occurrence Matrix (GLCM), morphological features, and Local Binary Patterns. A four-fold multi-label cross-validation approach was employed on a benchmark dataset to evaluate the model's performance. Quantitative analysis reveals that PAIMC consistently achieves superior Decision Accuracy, F-Score, Specificity, Sensitivity Recall, and Precision metrics compared to existing state-of-the-art models. For instance, PAIMC's Decision Accuracy and Precision outperform the second-best model by a notable margin across all folds. The model also demonstrates a significant improvement in Sensitivity Recall and Specificity, reinforcing its efficacy in the multi-class classification of AD stages. A novel data diversity assessment measure was developed and utilized, further confirming the robustness of the PAIMC model. The results underscore the potential of PAIMC as a highly accurate tool for AD classification in clinical settings.

Alzheimer's diseases in America, Europe, and Asian regions: a global genetic variation.

Alzheimer's disease (AD) is one of the multifaceted neurodegenerative diseases influenced by many genetic and epigenetic factors. Genetic factors are merely not responsible for developing AD in the whole population. The studies of genetic variants can provide significant insights into the molecular basis of Alzheimer's disease. Our research aimed to show how genetic variants interact with environmental influences in different parts of the world. We searched PubMed and Google Scholar for articles exploring the relationship between genetic variations and global regions such as America, Europe, and Asia. We aimed to identify common genetic variations susceptible to AD and have no significant heterogeneity. To achieve this, we analyzed 35 single-nucleotide polymorphisms (SNPs) from 17 genes (ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, TOMM40, MS4A6A, ARID5B, SORL1, APOC1, MTHFD1L, BDNF, TFAM, and PICALM) from different regions based on previous genomic studies of AD. It has been reported that rs3865444, CD33, is the most common polymorphism in the American and European populations. From TOMM40 and APOE rs2075650, rs429358, and rs6656401, CR1 is the common investigational polymorphism in the Asian population. The results of all the research conducted on AD have consistently shown a correlation between genetic variations and the incidence of AD in the populations of each region. This review is expected to be of immense value in future genetic research and precision medicine on AD, as it provides a comprehensive understanding of the genetic factors contributing to the development of this debilitating disease.

Perturbations of Telmisartan Alone and in Combination with Ranolazineor Dapagliflozin on the Amplitude and Gating of Voltage-gated Na + Current in Neuroblastoma Neuronal Cells.

A recent study investigated the correlation between telmisartan (TEL) exposure and Alzheimer's disease (AD) risk among African Americans (AAs) and European Americans. Their findings indicated that moderate-to-high TEL exposure was linked to a decreased incidence of AD among AAs. These results suggest a potential association between TEL and a reduced risk of AD specifically within the AA population. Here, we investigated the effects of TEL, either alone or in combination with ranolazine (Ran) or dapagliflozin (Dapa), on voltage-gated Na + currents ( INa ) in Neuro-2a cells. TEL, primarily used for treating hypertension and cardiovascular disorders, showed a stimulatory effect on INa , while Ran and Dapa reversed this stimulation. In Neuro-2a cells, we demonstrated that with exposure to TEL, the transient ( INa(T) ) and late ( INa(L) ) components of INa were differentially stimulated with effective EC 50 's of 16.9 and 3.1 μM, respectively. The research implies that TEL's impact on INa might be associated with enhanced neuronal excitability. This study highlights the complex interplay between TEL, Ran, and Dapa on INa and their potential implications for AD, emphasizing the need for further investigation to understand the mechanisms involved.

Associations Between Neuroinflammation-Related Conditions and Alzheimer's Disease: A Study of US Insurance Claims Data.

Early detection of Alzheimer's disease (AD) is a key component for the success of the recently approved lecanemab and aducanumab. Patients with neuroinflammation-related conditions are associated with a higher risk for developing AD. Investigate the incidence of AD among patients with neuroinflammation-related conditions including epilepsy, hemorrhage stroke, multiple sclerosis (MS), and traumatic brain injury (TBI). We used Optum's de-identified Clinformatics Data Mart Database (CDM). We derived covariate-matched cohorts including patients with neuroinflammation-related conditions and controls without the corresponding condition. The matched cohorts were: 1) patients with epilepsy and controls (N = 67,825 matched pairs); 2) patients with hemorrhage stroke and controls (N = 81,510 matched pairs); 3) patients with MS and controls (N = 9,853 matched pairs); and 4) patients TBI and controls (N = 104,637 matched pairs). We used the Cox model to investigate the associations between neuroinflammation-related conditions and AD. We identified that epilepsy, hemorrhage stroke, and TBI were associated with increased risks of AD in both males and females (hazard ratios [HRs]≥1.74, p < 0.001), as well as in gender- and race-conscious subpopulations (HRs≥1.64, p < 0.001). We identified that MS was associated with increased risks of AD in both males and females (HRs≥1.47, p≤0.004), while gender- and race-conscious subgroup analysis shown mixed associations. Patients with epilepsy, hemorrhage stroke, MS, and/or TBI are associated with a higher risk of developing AD. More attention on cognitive status should be given to older patients with these conditions.

Alzheimer incidence and prevalence with and without asthma: A Medicare cohort study

International data suggest that asthma, like other inflammatory diseases, might increase Alzheimer disease (AD) risk. We sought to explore risk pathways and future mitigation strategies by comparing diagnostic claims-based AD incidence and prevalence among US patients with asthma with those without asthma. This cohort study included a national Medicare 20% random sample (2013-2015). Adult patients with asthma with more than 12 months continuous Medicare were compared with subjects without asthma overall and as matched. Asthma was defined by 1 inpatient or 2 outpatient codes for asthma. The main outcomes were 2-year incident or prevalent AD defined by International Classification of Diseases, Ninth Revision code 331.0 or Tenth Revision code G30.0, G30.1, G30.8, or G30.9. Among 5,460,732 total beneficiaries, 678,730 patients were identified with baseline asthma and more often identified as Black or Hispanic, were Medicaid eligible, or resided in a highly disadvantaged neighborhood than those without asthma. Two-year incidence of AD was 1.4% with asthma versus 1.1% without asthma; prevalence was 7.8% versus 5.4% (both P≤ .001). Per 100,000 patients over 2 years, 303 more incident AD diagnoses occurred in those with asthma, with 2,425 more prevalent cases (P< .001). Multivariable models showed that asthma had greater odds of 2-year AD incidence (adjusted odds ratio, 1.33 [95% CI, 1.29-1.36]; matched 1.2 [95% CI, 1.17-1.24]) and prevalence (adjusted odds ratio, 1.48 [95% CI, 1.47-1.50]; matched 1.25 [95% CI, 1.22-1.27]). Asthma was associated with 20% to 33% increased 2-year incidence and 25% to 48% increased prevalence of claims-based AD in this nationally representative US sample. Future research should investigate risk pathways of underlying comorbidities and social determinants as well as whether there are potential asthma treatments that may preserve brain health.

Statin Initiation and Risk of Incident Alzheimer Disease and Cognitive Decline in Genetically Susceptible Older Adults.

The association of statin initiation with incident Alzheimer disease (AD) dementia and cognitive decline by the APOE ε4 allele is unknown. Our objective was to examine whether the association of statin initiation with incident AD dementia and cognitive decline differs by the APOE ε4 allele. This population-based longitudinal cohort study was conducted in 4 urban communities in Chicago, IL, United States, consisting of 4,807 participants. Statin initiation is based on the inspection of medications during home assessments. Clinical diagnosis for incident AD used the NINCDS-ADRDA criteria, and longitudinal measurements of global cognition consisted of episodic memory, perceptual speed, and the Mini-Mental State Examination tests. The study participants had a mean age of 72 years, consisting of 63% female individuals and 61% non-Hispanic Black individuals. During the study period, 1,470 (31%) participants reported statin initiation. In a covariate-adjusted competing risk model, statin initiation was associated with a reduced risk of incident clinical AD [hazard ratio (HR) 0.81 (95% CI 0.70-0.94)] compared with nonusers. This association was statistically significantly lower (p interaction = 0.015) among participants with the APOE ε4 allele [HR 0.60 (95% CI 0.49-0.74)] compared with those without the APOE ε4 allele [HR 0.96 (95% CI 0.82-1.12)]. The annual decline in global cognition (β = 0.021, 95% CI 0.007-0.034) and episodic memory (β = 0.020, 95% CI 0.007-0.033) was also substantially slower among participants with the APOE ε4 allele after statin initiation compared with nonusers. However, the association of statin initiation with cognitive decline was not significant among those without the APOE ε4 allele. Our findings suggest that statins might be associated with a lower risk of incident AD among individuals with the APOE ε4 allele. The benefits of statin therapy need further consideration in randomized clinical trials, especially among those with the APOE ε4 allele. This study provides Class II evidence that among those aged 65 years or older, statin initiation was associated with a reduced risk of Alzheimer disease, especially in the presence of an APOE-e4 allele.

Nucleoside Reverse Transcriptase Inhibitor Exposure Is Associated with Lower Alzheimer's Disease Risk: A Retrospective Cohort Proof-of-Concept Study.

Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer's disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted.

Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons.

Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. To investigate the potential therapeutic benefit of sildenafil on AD. We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil's mechanism-of-action. We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32- 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49- 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.

Motoric Cognitive Risk Syndrome and the Risk of Incident Dementia: A Systematic Review and Meta-Analysis of Cohort Studies

Background: Epidemiologic studies have indicated an association of motoric cognitive risk syndrome (MCR), a pre-dementia stage characterized by the presence of cognitive complaints and a slow gait, with increased risk of incident dementia. Objectives: We aimed to clarify this association using meta-analysis. Methods: We systematically searched the PubMed, Embase, and Web of Science databases up to December 2022 for relevant studies that investigated the association between MCR and incident all-cause dementia and Alzheimer’s disease (AD). The random-effects model was used to determine a pooled-effect estimate of the association. Results: We identified seven articles that corresponded with nine cohort studies investigating the association between MCR and the risk of dementia. Pooled analysis showed that MCR was associated with a significantly increased risk of incident all-cause dementia (HR = 2.28; 95% CI: 1.90–2.73) and AD (HR = 2.05; 95% CI: 1.61–2.61). Sensitivity analysis showed that there was no evidence that individual studies influenced the pooled-effect estimate, verifying the robustness of the results. Conclusions: Our results confirm that MCR is an independent risk factor of incident all-cause dementia and AD. Future studies are needed to better understand the mechanisms underlying this association.

Chronic Non-cancer Pain and Associated Risks of Incident Mild Cognitive Impairment and Alzheimer's Disease and Related Dementias in Middle-Aged and Older Adults.

The goal of this study is to investigate the association between chronic non-cancer pain (CNCP) and mild cognitive impairment (MCI)/Alzheimer's disease and related dementias (ADRDs) development among adults aged ≥50 using administrative claims data from a national commercial health insurance company during 2007-2017. To reduce selection bias, propensity-score matching was applied to select comparable CNCP and non-CNCP patients. Time-dependent Cox proportional-hazards regressions were conducted to estimate the hazard ratios (HRs) of incident MCI/ADRDs. Of 170,900 patients with/without CNCP, 0.61% developed MCI and 2.33% had been diagnosed with ADRDs during the follow-up period. Controlling for potential confounders, CNCP patients had a 123% increase in MCI risk (HR = 2.23; 95% CI = 1.92-2.58) and a 44% increase in ADRDs risk (HR = 1.44; 95% CI = 1.34-1.54) relative to non-CNCP patients. CNCP is a risk factor for MCI/ADRDs. Promoting awareness and improving early CNCP diagnosis in middle-aged and older adults should be incorporated into cognitive impairment and dementia prevention.

Impact of Concurrent Visual and Hearing Impairment on Incident Alzheimer's Disease: The LIFE Study.

The prevalence of Alzheimer's disease (AD) is increasing in Japan due to population aging. The association between sensory impairment and incident AD remains unclear. This study aimed to investigate the impact of sensory impairment on incident AD. We analyzed residents of five municipalities participating in the Longevity Improvement & Fair Evidence (LIFE) Study. The participants comprised individuals who had newly applied for long-term care needs certification between 2017 and 2022 and had no cognitive impairment upon application or AD diagnosis within the preceding six months. Participants were classified according to sensory impairment status: visual impairment (VI), hearing impairment (HI), neither sensory impairment (NSI), and dual sensory impairment (DSI). The month succeeding the certification application was set as the index month, and the interval from that month until AD onset was assessed. Multivariable Cox proportional hazards analysis was performed to calculate the risk of AD onset according to sensory impairment status while adjusting for sex, age, dependence level, self-reliance level, and comorbidities. Among 14,186 participants, we identified 1,194 (8.4%) who developed AD over a median follow-up period of 22.6 months. VI and HI only were not associated with incident AD. However, DSI conferred a significantly higher risk (HR: 1.6, CI: 1.1-2.2, p = 0.008) of AD onset than NSI. Individuals with concurrent DSI have a higher risk of developing AD than those with single or NSI. Preventing and treating sensory impairment may not only improve functional outcomes, but could also help to reduce the future risk of AD.

Altered Motor Activity Patterns within 10-Minute Timescale Predict Incident Clinical Alzheimer's Disease.

Fractal motor activity regulation (FMAR), characterized by self-similar temporal patterns in motor activity across timescales, is robust in healthy young humans but degrades with aging and in Alzheimer's disease (AD). To determine the timescales where alterations of FMAR can best predict the clinical onset of AD. FMAR was assessed from actigraphy at baseline in 1,077 participants who had annual follow-up clinical assessments for up to 15 years. Survival analysis combined with deep learning (DeepSurv) was used to examine how baseline FMAR at different timescales from 3 minutes up to 6 hours contributed differently to the risk for incident clinical AD. Clinical AD occurred in 270 participants during the follow-up. DeepSurv identified three potential regions of timescales in which FMAR alterations were significantly linked to the risk for clinical AD: <10, 20-40, and 100-200 minutes. Confirmed by the Cox and random survival forest models, the effect of FMAR alterations in the timescale of <10 minutes was the strongest, after adjusting for covariates. Subtle changes in motor activity fluctuations predicted the clinical onset of AD, with the strongest association observed in activity fluctuations at timescales <10 minutes. These findings suggest that short actigraphy recordings may be used to assess the risk of AD.

Protective role of Bacillus Calmette–Guérin vaccine in Alzheimer's disease progression: A systematic review and meta-analysis

Introduction: Alzheimer's disease (AD) represents a significant societal challenge, highlighting the need to explore effective prevention and treatment approaches. Recent literature has suggested that Bacillus Calmette-Guérin (BCG) vaccine may be a viable therapeutic option for immune disorders associated with AD due to its immunomodulatory properties and protection against various diseases. MethodsThis systematic review aimed to evaluate the association of BCG vaccine in the prevention of AD using six medical-scientific databases. A meta-analytical approach was undertaken to estimate the risk of AD incidence in patients with and without BCG vaccine exposure, followed by subgroup analyses. A risk of bias (RoB) assessment was performed using the Newcastle-Ottawa Scale (NOS). ResultsSix cohort studies meeting our inclusion criteria were included (47,947 participants) in the study. From our meta-analysis, intravesical BCG vaccine administration lowered the risk of incidence of AD by 26% in non-muscle-invasive bladder cancer (p < 0.00001). Subgroup analyses showed that BCG vaccination showed a potentially notable preventive effect on AD in older adults (>75 years) and female participants. Conversely, significant heterogeneity in results was observed among male participants and those aged <75 years. The RoB was low in three studies and unclear in the remaining studies. ConclusionsAlthough our results support the potential benefits of BCG vaccine in preventing AD in specific demographics, we remain cautious about interpreting such results. Further research examining the implications of BCG vaccination for prevention and possible treatment of AD should be undertaken in the future.

Borolatonin limits cognitive deficit and neuron loss while increasing proBDNF in ovariectomised rats.

Borolatonin is a potential therapeutic agent for some neuronal diseases such as Alzheimer's disease (AD). Its administration exerts ameliorative effects such as those induced by the equimolar administration of melatonin in behavioral tests on male rats and in neuronal immunohistochemistry assays. In this study, motivated by sex differences in neurobiology and the incidence of AD, the ability of borolatonin to induce changes in female rats was assessed. Effects of borolatonin were measured by the evaluation of both behavioral and immunohistopathologic approaches; additionally, its ability to limit amyloid toxicity was determined in vitro. Surprisingly, behavioral changes were similar to those reported in male rats, but not those evaluated by immunoassays regarding neuronal survival; while pro-brain-derived neurotrophic factor (BDNF) immunoreactivity and the limitation of toxicity by amyloid in vitro were observed for the first time. Borolatonin administration induced changes in female rats. Differences induced by the administration of borolatonin or melatonin could be related to the differences in the production of steroid hormones in sex dependence. Further studies are required to clarify the possible mechanism and origin of differences in disturbed memory caused by the gonadectomy procedure between male and female rats.

Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and the Risk of Alzheimer Disease: A Cohort Study.

Repurposing phosphodiesterase type 5 inhibitors (PDE5Is) as drugs for Alzheimer disease (AD) risk reduction has shown promise based on animal studies. However, evidence in humans remains inconclusive. Therefore, we conducted a cohort study to evaluate the association between PDE5I initiation compared with nonuse and the risk of developing AD in men with erectile dysfunction (ED). Using electronic health records from IQVIA Medical Research Data UK (formerly known as the THIN database), we identified men aged ≥40 years with a new diagnosis of ED between 2000 and 2017. Individuals with a previous diagnosis of dementia, cognitive impairment, confusion, or prescription for dementia symptoms were excluded. The occurrence of incident AD was identified using diagnostic read codes. To minimize immortal-time bias, PDE5I initiation was treated as a time-varying exposure variable. Potential confounders were adjusted using inverse probability of treatment weighting based on propensity scores. Cox proportional hazard models were used to estimate the adjusted hazard ratio (HR) with 95% CIs. A secondary analysis explored the association between AD and the cumulative number of PDE5I prescriptions. Sensitivity analyses included lag (delay) periods of 1 and 3 years after cohort entry to address the prodromal stage of AD. The study included 269,725 men, with 1,119 newly diagnosed with AD during a median follow-up of 5.1 (interquartile range 2.9-8.9) years. The adjusted HR in PDE5I initiators compared with nonuse was 0.82 (95% CI 0.72-0.93). The associated risk of AD decreased in individuals issued >20 prescriptions: HR 0.56 (95% CI 0.43-0.73) for 21-50 prescriptions and HR 0.65 (95% CI 0.49-0.87) for >50 prescriptions. Sensitivity analysis with a 1-year lag period supported the primary findings (HR 0.82, 95% CI 0.72-0.94), but the results differed with the inclusion of a 3-year lag period (HR 0.93, 95% CI 0.80-1.08). PDE5I initiation in men with ED was associated with a lower risk of AD, particularly in those most frequently issued prescriptions. The differences between primary and sensitivity analyses highlight the need to explore the optimal lag period. To enhance the generalizability of our findings, a randomized controlled trial including both sexes and exploring various PDE5I doses would be beneficial to confirm the association between PDE5I and AD.

Leveraging generative AI to prioritize drug repurposing candidates for Alzheimer’s disease with real-world clinical validation

Drug repurposing represents an attractive alternative to the costly and time-consuming process of new drug development, particularly for serious, widespread conditions with limited effective treatments, such as Alzheimer’s disease (AD). Emerging generative artificial intelligence (GAI) technologies like ChatGPT offer the promise of expediting the review and summary of scientific knowledge. To examine the feasibility of using GAI for identifying drug repurposing candidates, we iteratively tasked ChatGPT with proposing the twenty most promising drugs for repurposing in AD, and tested the top ten for risk of incident AD in exposed and unexposed individuals over age 65 in two large clinical datasets: (1) Vanderbilt University Medical Center and (2) the All of Us Research Program. Among the candidates suggested by ChatGPT, metformin, simvastatin, and losartan were associated with lower AD risk in meta-analysis. These findings suggest GAI technologies can assimilate scientific insights from an extensive Internet-based search space, helping to prioritize drug repurposing candidates and facilitate the treatment of diseases.

The changes of neurogenesis in the hippocampal dentate gyrus of SAMP8 mice and the effects of acupuncture and moxibustion

BackgroundInfluenced by the global aging population, the incidence of Alzheimer's disease (AD) has increased sharply. In addition to increasing β-amyloid plaque deposition and tau tangle formation, neurogenesis dysfunction has recently been observed in AD. Therefore, promoting regeneration to improve neurogenesis and cognitive dysfunction can play an effective role in AD treatment. Acupuncture and moxibustion have been widely used in the clinical treatment of neurodegenerative diseases because of their outstanding advantages such as early, functional, and benign two-way adjustment. It is urgent to clarify the effectiveness, greenness, and safety of acupuncture and moxibustion in promoting neurogenesis in AD treatment. MethodsSenescence-accelerated mouse prone 8 (SAMP8) mice at various ages were used as experimental models to simulate the pathology and behaviors of AD mice. Behavioral experiments, immunohistochemistry, Western blot, and immunofluorescence experiments were used for comparison between different groups. ResultsAcupuncture and moxibustion could increase the number of PCNA+ DCX+ cells, Nissl bodies, and mature neurons in the hippocampal Dentate gyrus (DG) of SAMP8 mice, restore the hippocampal neurogenesis, delay the AD-related pathological presentation, and improve the learning and memory abilities of SAMP8 mice. ConclusionThe pathological process underlying AD and cognitive impairment were changed positively by improving the dysfunction of neurogenesis. This indicates the promising role of acupuncture and moxibustion in the prevention and treatment of AD.