Alzheimer's Disease Medications Research Articles

Early start of anti-dementia medication is associated with lower health and social care costs in Alzheimer´s patients: a Finnish nationwide register study.

To evaluate the association between health and social care costs and early start of anti-dementia medication in a nationwide cohort of Finnish Alzheimer's disease (AD) patients. The cohort included 7454 Finnish AD patients who had their first AD diagnosis in 2012 and lived at home at the time of diagnosis. Data were collected retrospectively from the Finnish national health and social care registers. The primary outcome was 2-year cumulative direct costs after the incident AD diagnosis. The exploratory variable was early anti-dementia medication start (anti-dementia medication started within 3 months of the incident AD diagnosis). Sociodemographic variables, admission to 24-h care and care intensity level, as well as comorbidities were considered as adjusting variables. Of all patients, 88.9% started AD medication within 3months of diagnosis. The 2-year cumulative costs were €30,787 and €40,484 per patient for early and late starters, respectively. When adjusted for possible confounders, early start of anti-dementia medication was associated with 26.5% lower 2-year cumulative costs compared to late starters (relative cost 0.735; p < 0.001). Early diagnosis and start of anti-dementia medication is important for managing the costs of increasing number of AD patients.

A deep learning based convolutional neural network model with VGG16 feature extractor for the detection of Alzheimer Disease using MRI scans

Alzheimer's disease (AD) is one of the most prevalent types of dementia, which primarily affects people over age 60. In clinical practice, it is a challenging task to identify AD in its early stages, and there are currently very few reliable diagnostic systems available for the identification. Additionally, clinical studies for AD medications have a high risk of failure, and currently, there is no confirmed cure. There are various stages of AD: very mild demented, mild, and moderate. It is challenging to identify these stages, due to which the very mild demented case worsens and results in a complete health loss along with weak memory and makes it unable to perform daily tasks without the assistance of others. Early identification of mild cases can help patients to guide additional medical care to stop the disease's progression and avoid brain damage. Recently, there has been a substantial amount of interest in applying deep learning (DL) for early AD recognition. The limitations of these algorithms are that they cannot detect changes in the brain networks in patients with mild demented functional working brain networks. However, to stop AD growth, various scientists and researchers are striving to build methods for early identification by using MRI images. In this article, for early diagnoses of AD, two MRI datasets containing 6400 and 6330 images have been used, and the DL algorithm is utilized by applying a neural network classifier with a VGG16 feature extractor for the early diagnosis of AD, which results in the outcome in the form of accuracy, precision, recall, AUC and F1-score as (90.4%, 0.905, 0.904, 0.969, and 0.904), and (71.1%, 0.71, 0.711, 0.85, and 0.71) for dataset 1 and dataset 2, respectively. Furthermore, the results are compared with previous studies, which concluded the proposed model performs better. Lastly, this article is applicable to identify various machine learning (ML) and DL approaches that can be utilized to study AD stage identification.

Aduhelm, the Newly Approved Medication for Alzheimer Disease: What Epidemiologists Can Learn and What Epidemiology Can Offer.

Alzheimer disease (AD) is a progressive disorder common among older adults and culminating in profound cognitive impairments and high mortality risk. The US Food and Drug Administration (FDA) recently provided accelerated approval for Aduhelm, a medication for AD treatment. Aduhelm (Biogen Inc., Cambridge, Massachusetts) has been described as the first disease-modifying treatment for AD but has not been demonstrated to improve patients' cognitive or functional outcomes. In this commentary, we describe why Aduhelm approval was controversial and aspects of the current evidence of special pertinence to epidemiologists. The FDA decision was based primarily on 2 randomized controlled trials (RCTs), both terminated early, with conflicting findings about the cognitive benefits of Aduhelm. Both RCTs showed important adverse effects of the medication. The FDA cited the documented reduction in brain amyloid, an AD biomarker hypothesized as a surrogate outcome, to justify accelerated approval. Despite lack of racial/ethnic diversity in the RCT participants, concerns about health disparities have been invoked to argue for public funding of this expensive medication. The Centers for Medicare and Medicaid Services recently made a "Coverage with Evidence Development" determination for Aduhelm and similar medications. We end by describing how innovative study designs could accelerate postapproval research and evaluate the proposed surrogate outcomes.

Theranostic F-SLOH mitigates Alzheimer's disease pathology involving TFEB and ameliorates cognitive functions in Alzheimer's disease models

Accumulation of amyloid-β (Aβ) oligomers and phosphorylated Tau aggregates are crucial pathological events or factors that cause progressive neuronal loss, and cognitive impairments in Alzheimer's disease (AD). Current medications for AD have failed to halt, much less reverse this neurodegenerative disorder; therefore, there is an urgent need for the development of effective and safe drugs for AD therapy. In the present study, the in vivo therapeutic efficacy of an Aβ-oligomer-targeted fluorescent probe, F-SLOH, was extensively investigated in 5XFAD and 3XTg-AD mouse models. We have shown that F-SLOH exhibits an efficient inhibitory activity against Aβ aggregation in vivo, and acts as an effective theranostic agent for the treatment of multiple neuropathological changes in AD mouse models. F-SLOH has been found to significantly reduce not only the levels of Aβ oligomers, Tau aggregates and plaques but also the levels of amyloid precursor protein (APP) and its metabolites via autophagy lysosomal degradation pathway (ALP) in the brains of 5XFAD and 3XTg-AD mice. It also reduces astrocyte activation and microgliosis ultimately alleviating neuro-inflammation. Furthermore, F-SLOH mitigates hyperphosphorylated Tau aggregates, synaptic deficits and ameliorates synaptic memory function, and cognitive impairment in AD mouse models. The mechanistic studies have shown that F-SLOH promotes the clearance of C-terminal fragment 15 (CTF15) of APP and Paired helical filaments of Tau (PHF1) in stable cell models via the activation of transcription factor EB (TFEB). Moreover, F-SLOH promotes ALP and lysosomal biogenesis for the clearance of soluble, insoluble Aβ, and phospho Tau. Our results unambiguously reveal effective etiological capabilities of theranostic F-SLOH to target and intervene multiple neuropathological changes in AD mouse models. Therefore, F-SLOH demonstrates tremendous therapeutic potential for treating AD in its early stage.

Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease

The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment with aducanumab, an amyloid-β (Aβ)-targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia. To describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE. Secondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment with placebo among participants at 348 sites across 20 countries. Enrollment occurred from August 2015 to July 2018, and the trials were terminated early (March 21, 2019) based on a futility analysis. The combined studies consisted of a total of 3285 participants with Alzheimer disease who received 1 or more doses of placebo (n = 1087) or aducanumab (n = 2198; 2752 total person-years of exposure) during the placebo-controlled period. Primary data analyses were performed from November 2019 to July 2020, with additional analyses performed through July 2021. Participants were randomly assigned 1:1:1 to high-dose or low-dose intravenous aducanumab or placebo once every 4 weeks. Dose titration was used as a risk-minimization strategy. Brain magnetic resonance imaging was used to monitor patients for ARIA; associated symptoms were reported as adverse events. Of 3285 included participants, the mean (SD) age was 70.4 (7.45) years; 1706 participants (52%) were female, 2661 (81%) had mild cognitive impairment due to Alzheimer disease, and 1777 (54%) used symptomatic medications for Alzheimer disease. A total of 764 participants from EMERGE and 709 participants from ENGAGE were categorized as withdrawn before study completion, most often owing to early termination of the study by the sponsor. Unless otherwise specified, all results represent analyses from the 10-mg/kg group. During the placebo-controlled period, 425 of 1029 patients (41.3%) experienced ARIA, with serious cases occurring in 14 patients (1.4%). ARIA-edema (ARIA-E) was the most common adverse event (362 of 1029 [35.2%]), and 263 initial events (72.7%) occurred within the first 8 doses of aducanumab; 94 participants (26.0%) with an event exhibited symptoms. Common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H were headache (48 [46.6%]), confusion (15 [14.6%]), dizziness (11 [10.7%]), and nausea (8 [7.8%]). Incidence of ARIA-E was highest in aducanumab-treated participants who were apolipoprotein E ε4 allele carriers. Most events (479 of 488 [98.2%]) among those with ARIA-E resolved radiographically; 404 of 488 (82.8%) resolved within 16 weeks. In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (apolipoprotein E ε4 carriers: 16 of 742 [2.2%]; noncarriers, 13 of 334 [3.9%]). ARIA-microhemorrhage and ARIA-superficial siderosis occurred in 197 participants (19.1%) and 151 participants (14.7%), respectively. In this integrated safety data set from EMERGE and ENGAGE, the most common adverse event in the 10-mg/kg group was ARIA-E, which occurred in 362 of the 1029 patients (35.2%) in the 10-mg/kg group with at least 1 postbaseline MRI scan, with 94 patients (26.0%) experiencing associated symptoms. The most common associated symptom was headache. ClinicalTrials.gov Identifiers: NCT02484547, NCT02477800.

Effect of electroacupuncture on learning-memory ability and expression of IL-1β, IL-6 and TNF-α in hippocampus and spleen in mice with Alzheimer's disease

To explore the effect of electroacupuncture (EA) on the ability of spatial learning-memory and the expression of IL-1β, IL-6 and TNF-α in the hippocampus and spleen tissues and the number of hippocampal neurons and spleen lymphocytes in Alzheimer's disease (AD) mice, so as to study its mechanisms underlying improvement of AD. Twenty-four SAMP8 mice were randomly and equally divided into AD model, EA and medication groups, and 8 SAMR1 mice were used as the control group. EA (2 Hz, 0.1 mA) was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 20 min in the EA group, and intragastric administration of donepezil hydrochloride (0.92 mg/kg) was applied in the medication group, once daily for 15 d. The learning-memory ability was determined by Morris water maze task, and the histopathological changes of hippocampus were observed after H.E. staining, followed by determining neurons and the number of splenic lymphocytes. The expression levels of IL-1β, IL-6 and TNF-α in the hippocampus and spleen were detected by immunohistochemistry and Western blot, respectively. After mode-ling, the escape latency of place navigation test in the Morris water maze, the spleen index, immunoactivity and expression levels of IL-1β, IL-6 and TNF-α proteins in the hippocampus and spleen tissues were significantly increased (P<0.05, P<0.01). Compared with the model group, the escape latency, spleen index, immunoactivity and expression levels of IL-1β, IL-6 and TNF-α proteins in both hippocampus and spleen were significantly down-regulated in the medication (except the escape latency) and EA groups (P<0.01, P<0.05). The effect of EA was evidently superior to that of medication in shortening the escape latency, lowering the spleen index, and immunoactivity of hippocampal IL-6 and splenic TNF-α immunoactivity (P<0.01, P<0.05). Outcomes of H.E. staining showed disordered arrangement of neurons with nuclear pyknosis or apoptosis in partial neurons in the hippocampus, and thickened and swollen spleen capsule tissue with loose structure and an increased number of lymphocytes in the model group, which was relatively milder in the EA and medication groups. EA can improve the learning-memory ability of AD mice, which may be associated with its effect in relieving the inflammation reaction in the hippocampus and spleen tissues.

Can Emerging Therapies Resolve Unmet Needs With Current Treatment in Early-Stage Alzheimer Disease?

While no current medications for Alzheimer disease (AD) can modify the disease, the agents do slow symptom progression. The earlier the medications are started for patients diagnosed with AD, the greater the potential benefit. Clinical trials are in progress on drugs with a variety of mechanisms that may modulate the disease course: neuronal protection; protein synthesis or aggregation inhibition; immunologic priming with antibodies; vaccines; and secretase inhibition. Early diagnosis, whether in the primary care setting or the specialty setting, continues to be critical to give patients their best chance at managing their illness. Although current treatments cannot give patients back what they have already lost, in the near future, drugs may be able to slow or even halt their cognitive and functional decline if clinicians identify AD early enough in the disease process.

Personalizing the Care and Treatment of Alzheimer's Disease: An Overview.

Alzheimer’s disease (AD) is a progressive, complex, and multifactorial neurodegenerative disorder, still without effective and stable therapeutic strategies. Currently, available medications for AD are based on symptomatic therapy, which include acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist. Additionally, medications such as antipsychotic drugs, antidepressants, sedative, and hypnotic agents, and mood stabilizers are used for the management of behavioral and psychological symptoms of dementia (BPSD). Clinical research has been extensively investigated treatments focusing on the hallmark pathology of AD, including the amyloid deposition, tau hyperphosphorylation, neuroinflammation, and vascular changes; however, so far without success, as all new potential drugs failed to show significant clinical benefit. The underlying heterogeneous etiology and diverse symptoms of AD suggest that a precision medicine strategy is required, which would take into account the complex genetic, epigenetic, and environmental landscape of each AD patient. The article provides a comprehensive overview of the literature on AD, the current and potential therapy of both cognitive symptoms as well as BPSD, with a special focus on gut microbiota and epigenetic modifications as new emerging drug targets. Their specific patterns could represent the basis for novel individually tailored approaches aimed to optimize precision medicine strategies for AD prevention and treatment. However, the successful application of precision medicine to AD demands a further extensive research of underlying pathological processes, as well as clinical and biological complexity of this multifactorial neurodegenerative disorder.

Caregivers' willingness to pay for Alzheimer's disease medications in Taiwan.

Alzheimer's disease (AD) exerts significant financial expenses on caregivers, and knowledge of caregivers' support for out-of-pocket payment is of great importance for policymaking on the insurance coverage of future AD medication in Taiwan. We aimed to investigate caregivers' willingness to pay (WTP) for a hypothetical curative AD medication and the effect of different factors on the amount of WTP. Informal caregivers of patients with AD and informants of patients with amnestic mild cognitive impairment (MCI) were included. An iterative bidding game technique, followed by a dichotomous choice question and a final open-ended question were used to elicit caregivers' maximum WTP. The correlations between the WTP and characteristics of caregiver and patient were analyzed, including sex, educational level, severity of dementia, neuropsychiatric symptoms assessed by Neuropsychiatric Inventory, time needed to support patients assessed by Caregiver Activity Survey, and caregivers' monthly income. A total of 1134 informal caregivers of patients with AD or MCI were included. Caregivers of patients with AD were willing to pay for a curative AD medication, and their maximum WTP value was higher than informants of MCI patients. Among patients with AD and patients with MCI, caregivers' monthly income was positively correlated with WTP. Apathy subsyndrome was the only factor correlated with percentage of WTP in caregiver's income in the MCI group. Support for out-of-pocket WTP for a hypothetical curative AD medication was significantly related to caregiver's income.

Costly New Alzheimer Disease Medications on the Horizon-Financing Alternatives for Medicare.

Costly New Alzheimer Disease Medications on the Horizon-Financing Alternatives for Medicare.

Multi-Target Drug Candidates for Multifactorial Alzheimer's Disease: AChE and NMDAR as Molecular Targets.

Alzheimer's disease (AD) is one of the most common forms of dementia among elder people, which is a progressive neurodegenerative disease that results from a chronic loss of cognitive activities. It has been observed that AD is multifactorial, hence diverse pharmacological targets that could be followed for the treatment of AD. The Food and Drug Administration has approved two types of medications for AD treatment such as cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartic acid receptor (NMDAR) antagonists. Rivastigmine, donepezil, and galantamine are the ChEIs that have been approved to treat AD. On the other hand, memantine is the only non-competitive NMDAR antagonist approved in AD treatment. As compared with placebo, it has been revealed through clinical studies that many single-target therapies are unsuccessful to treat multifactorial Alzheimer's symptoms or disease progression. Therefore, due to the complex nature of AD pathophysiology, diverse pharmacological targets can be hunted. In this article, based on the entwined link of acetylcholinesterase (AChE) and NMDAR, we represent several multifunctional compounds in the rational design of new potential AD medications. This review focus on the significance of privileged scaffolds in the generation of the multi-target lead compound for treating AD, investigating the idea and challenges of multi-target drug design. Furthermore, the most auspicious elementary units for designing as well as synthesizing hybrid drugs are demonstrated as pharmacological probes in the rational design of new potential AD therapeutics.

Involvement of prohibitin 1 and prohibitin 2 upregulation in cBSA-induced podocyte cytotoxicity

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-β (Aβ) and hyper-phosphorylated tau accumulation are accountable for the progressive neuronal loss and cognitive impairments usually observed in AD. Currently, medications for AD offer moderate symptomatic relief but fail to cure the disease; hence development of effective and safe drugs is urgently needed for AD treatment. In this study, we investigated a Chinese medicine (CM) formulation named NeuroDefend (ND), for reducing amyloid β (Aβ) and tau pathology in transgenic AD mice models. Regular oral administration of ND improved cognitive function and memory in 3XTg-AD and 5XFAD mice. In addition, ND reduced beta-amyloid precursor protein (APP), APP C-terminal fragments (CTF-β/α), Aβ and 4G8 positive Aβ burden in 3XTg-AD and 5XFAD mice. Furthermore, ND efficiently reduced the levels of insoluble phospho-tau protein aggregates and AT8 positive phospho tau neuron load in 3XTg-AD mice. Hence, ND could be a promising candidate for the treatment of AD in humans. © 2019

Prevalence of Alzheimer's disease according to anticholinesterase drug usage from 2012 to 2017 in the state of Paraná, Brazil

Introduction: Alzheimer's disease (AD) is a public health problem in Brazil due to the growing number of older adults in this population. Knowing the prevalence of AD in the Paraná state is essential to improve patients’ quality of life. The objective of the study was to estimate AD prevalence in the state of Paraná, based on the prescription of anticholinesterases, from 2012 to 2017. Methods: Patients diagnosed with AD, aged 60 years or over, who used Brazil’s Unified Public Health System (SUS) and received AD medication from the Department of Pharmaceutical Assistance of the state of Paraná, from 2012 to 2017, were the target population of the present study. The medication data were collected from the Computerized system management and Monitoring of Exceptional Drugs (SISMEDEX), and the population’s data were collected from the Brazilian Institute of Geography and Statistics (IBGE). Results: The sample consisted of 52,687 patients, and the median prevalence of AD in the established period for the state was 642.6/100,000 inhabitants (0.64%). In all ages and macro-regions, women showed the highest prevalence rates. The median prevalence for women in the established period was 755.4/100,000 inhabitants (0.75%). Among men, the median prevalence was 510.2/100,000 inhabitants (0.51%). In the temporal analysis of prevalence, between 2012 and 2017, a reduction of 23% was found in the state rate. The prevalence rate of Paraná for AD is nine times lower than the Brazilian average. Conclusions: Paraná’s prevalence rate for AD is lower than the rates of Brazil and the world, suggesting that AD is underdiagnosed in most municipalities of this state.

Asthma and Chronic Obstructive Pulmonary Disease as a Comorbidity and Association with the Choice of Antidementia Medication Among Persons with Alzheimer's Disease.

Asthma and chronic obstructive pulmonary disease (COPD) are common comorbidities in persons with Alzheimer's disease (AD). However, pharmacotherapy of these diseases may have opposite mechanisms of action; anticholinergics in asthma/COPD and acetylcholinesterase inhibitors (AChEI) in AD. To investigate whether existing asthma/COPD affects the choice of AD medication, and the survival of the patients with AD. In this retrospective cohort study, data from the MEDALZ-study, which includes all community-dwelling persons with AD during 2005-2011 in Finland (n = 70718) was utilized. Persons with asthma/COPD (N = 7211) were defined as having a special reimbursement for asthma/COPD, or long-term use (≥250 days) of inhaled anticholinergics, inhaled corticosteroids, or leukotriene antagonists during the year before AD diagnosis. We compared persons with and without asthma/COPD regarding the choice of the initial antidementia medication (AChEI versus memantine) with logistic regression and mortality with Cox regression model during the follow-up (up to end of 2015). Memantine was favored over AChEIs as first-line treatment to AD in persons with asthma/COPD compared to those without asthma/COPD (odds ratio 1.23, 95% confidence interval (CI) 1.15-1.31). Memantine was also more commonly used among those who used multiple asthma/COPD medications (7.9% of memantine initiators used ≥3 asthma/COPD medications compared with 5.5% of those who initiated with AChEI). Mortality was higher in persons with asthma/COPD compared to those without asthma/COPD (adjusted hazard ratio 1.10, 95% CI 1.07-1.13). More frequent use of memantine instead of AChEI may result from an attempt to prevent possible worsening of asthma/COPD by AChEIs. Vulnerable persons with both AD and asthma/COPD need individually assessed pharmacotherapy for their medical conditions.

Alzheimer's disease medication and outcomes of hospitalisation among patients with dementia.

The use of Alzheimer disease medication for the treatment of dementia symptoms has shown significant benefits with regards to functional and cognitive outcomes as well as nursing home placement (NHP) and mortality. Hospitalisations in these patient groups are characterised by extended length of stays (LOS), frequent readmissions, frequent NHP and high-mortality rates. The impact of Alzheimer disease medication on the aforementioned outcomes remains still unknown. This study assessed the association of Alzheimer disease medication with outcomes of hospitalisation among patients with Alzheimer disease and other forms of dementia. A dynamic retrospective cohort study from 2004 to 2015 was conducted which claims data from a German health insurance company. People with dementia (PWD) were identified using ICD-10 codes and diagnostic measures. The main predictor of interest was the use of Alzheimer disease medication. Hospitalisation outcomes included LOS, readmissions, NHP and mortality during and after hospitalisation across four hospitalisations. Confounding was addressed using a propensity score throughout all analyses. A total of 1380 users of Alzheimer disease medication and 6730 non-users were identified. The use of Alzheimer disease medication was associated with significantly shorter LOS during the first hospitalisations with estimates for the second, third and fourth showed a tendency towards shorter hospital stays. In addition, current users of Alzheimer disease medication had a lower risk of hospital readmission after the first two hospitalisations. These associations were not significant for the third and fourth hospitalisations. Post-hospitalisation NHP and mortality rates also tended to be lower among current users than among non-users but differences did not reach statistical significance. Our results indicate that Alzheimer disease medication might contribute to a reduction of the LOS and the number of readmissions in PWD.

NeuroDefend, a novel Chinese medicine, attenuates amyloid-β and tau pathology in experimental Alzheimer's disease models

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-β (Aβ) and hyper-phosphorylated tau accumulation are accountable for the progressive neuronal loss and cognitive impairments usually observed in AD. Currently, medications for AD offer moderate symptomatic relief but fail to cure the disease; hence development of effective and safe drugs is urgently needed for AD treatment. In this study, we investigated a Chinese medicine (CM) formulation named NeuroDefend (ND), for reducing amyloid β (Aβ) and tau pathology in transgenic AD mice models. Regular oral administration of ND improved cognitive function and memory in 3XTg-AD and 5XFAD mice. In addition, ND reduced beta-amyloid precursor protein (APP), APP C-terminal fragments (CTF-β/α), Aβ and 4G8 positive Aβ burden in 3XTg-AD and 5XFAD mice. Furthermore, ND efficiently reduced the levels of insoluble phospho-tau protein aggregates and AT8 positive phospho tau neuron load in 3XTg-AD mice. Hence, ND could be a promising candidate for the treatment of AD in humans.

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials

ObjectiveTo assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD). DesignTwo 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258). SettingStudy 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries. ParticipantsPatients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. InterventionStudy 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5–2 mg/day or placebo (1:1) for 12 weeks. MeasurementsCohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29–203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression – Severity of illness (CGI-S) as related to agitation. Safety was also assessed. ResultsIn Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, −3.77; confidence limits, –7.38, –0.17; t(316) = –2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; −3.40, 3.86; t(314) = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5–2 mg/day did not achieve statistical superiority over placebo (–2.34; –5.49, 0.82; t(230) = −1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (−5.06; −8.99, −1.13; t(144) = −2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (−0.16; −0.39, 0.06; t(337) = −1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5–2 mg/day in Study 2 (−0.31; −0.55, −0.06; t(222) = −2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5–2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity. ConclusionsBrexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.

Non-steroidal anti-inflammatory drugs use in older adults decreases risk of Alzheimer's disease mortality.

Alzheimer disease (AD) mortality risk in a large cohort of subjects treated or not with non-steroidal anti-inflammatory drugs (NSAIDs) is unknown. Our objective was to determine whether NSAIDs use is associated with decreased risk of AD mortality. In this prospective, population-based study (Neurological Disorders in Central Spain [NEDICES]) of 5,072 people without AD (aged 65 years and older), sociodemographic, comorbidity factors, and current medications were recorded at baseline. Community-dwelling older adults were followed for a median of 12.7 years, after which the death certificates of deceased participants were examined. 2,672 (52.7%) of 5,072 participants died, including 504 (18.9%) NSAIDs users and 2,168 (81.1%) non-users. Of the 2,672 deceased participants, 113 (4.2%) had AD as a cause of death (8 [1.6%] among NSAIDs users and 105 [4.8%] among non-users, chi-square = 10.70, p = 0.001). In an unadjusted Cox model, risk of AD mortality was decreased in NSAIDs users (hazard ratio [HR] for AD mortality = 0.35, 95% confidence interval [CI] 0.17–0.72, p = 0.004) when compared to non-users. After adjusting for numerous demographic factors and co-morbidities, the HR for AD mortality in NSAIDs users was 0.29, 95% CI 0.12–0.73, p = 0.009. Stratified analyses showed a significantly decreased risk of AD mortality with aspirin, whereas non-aspirin NSAIDs only showed a statistical trend toward significance in the adjusted Cox regression models. NSAIDs use was associated with 71% decreased risk of AD mortality in older adults. Our results support the hypothesis that NSAIDs use is a protective factor of developing AD.

The LipiDiDiet trial: what does it add to the current evidence for Fortasyn Connect in early Alzheimer's disease?

Nutritional factors can influence the risk of developing Alzheimer’s disease (AD) and its rate of progression, and there is, therefore, increasing interest in nutrition as a modifiable risk factor for the disease. Synaptic loss is an important feature of early AD, and the formation of new synapses is dependent on key nutritional elements that are known to be deficient in patients with AD. The daily medical food, Souvenaid, contains Fortasyn Connect, a multinutrient combination developed to specifically address these deficiencies, comprising docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate, choline, phospholipids, selenium, folic acid, and vitamins B12, B6, C, and E. Although yielding heterogeneous findings, clinical studies of Fortasyn Connect provide preliminary evidence of clinically relevant benefits on cognitive outcomes in prodromal and early AD. The LipiDiDiet trial investigated the effects of Fortasyn Connect on cognition and related measures in prodromal AD, and is the first randomized, controlled, double-blind, multicenter trial study of a non-pharmacological intervention in this setting. The primary efficacy endpoint was change over 24 months in a composite score of cognitive performance using a neuropsychological test battery. Fortasyn Connect had no significant effect on this endpoint, but demonstrated a significant benefit on secondary endpoints, including domains of cognition affected by AD (attention, memory, executive function) and hippocampal atrophy, suggesting a potential benefit on disease progression. Other studies have demonstrated benefits for Fortasyn Connect on nutritional markers and levels of plasma homocysteine. Taken together, current evidence indicates that Fortasyn Connect may show benefit on domains of cognition affected by AD and nutritional measures that influence risk factors for its progression; that it has greater potential for benefit earlier rather than later in the disease; and that it is safe and well tolerated, alone or in combination with AD medications. Further research into its potential role in AD management is therefore warranted.

Policy-induced selection bias in pharmacoepidemiology: The example of coverage for Alzheimer's medications in British Columbia.

PurposesTo assess the impact of a government‐sponsored reimbursement policy for cholinesterase inhibitors (ChEIs) on trends in physician visits with a diagnosis of Alzheimer's disease (AD).MethodsLongitudinal population‐based study using interrupted time series methods. British Columbia outpatient claims data for individuals aged 65 and older were used to compute monthly AD visit rates and examine the impact of the ChEI reimbursement policy on the coding of AD. We examined trends in the number of patients with AD visits, the number of AD visits per patient, and visits with “competing” diagnoses (mental, neurological, and cerebrovascular disorders and accidental falls). Finally, we described demographic and clinical features of diagnosed patients.ResultsWe analyzed 1.9 million AD visits. Faster growth in recorded AD visits was observed after the policy was implemented, from monthly growth of 7.5 visits per 100 000 person‐months before the policy (95% confidence interval [CI], 6.1‐8.9) to monthly growth of 16.5 per 100 000 person‐months after the policy (95% CI, 14.8‐18.3). After the implementation of the policy, we observed increased growth in the number of patients with recorded AD visits and the number of AD visits per patient, as well as a shift in diagnoses away from mental diseases and accidental falls to AD (diagnosis substitution).ConclusionsBritish Columbia's reimbursement policy for ChEIs was associated with a significant acceleration in Alzheimer's visits. Evaluations of health services utilization and clinical outcomes following drug policy changes need to consider policy‐induced influences on the reliability of the data used in the analysis.