Alzheimer's Disease Cooperative Study-Activities Research Articles

Comparative Efficacy and Safety of Monoclonal Antibodies for Cognitive Decline in Patients with Alzheimer's Disease: A Systematic Review and Network Meta-Analysis.

Recent clinical trials of anti-Aβ monoclonal antibodies (mAbs) in the treatment of early Alzheimer's disease (AD) have produced encouraging cognitive and clinical results. The purpose of this network meta-analysis (NMA) was to compare and rank mAb drugs according to their efficacy and safety. PubMed, Embase, Web of Science, and the Cochrane Library were searched for randomized controlled trials testing various mAbs for the treatment of cognitive decline in patients with AD, up to March 31, 2023. R software (version 4.2.3) along with JAGS and STATA software (version 15.0) were used for statistical analysis. Odds ratio (OR) for binary variables, mean difference (MD) for continuous variables, and their 95% confidence intervals (CI) were utilized to estimate treatment effects and rank probabilities for each mAb in terms of safety and efficacy outcomes. We calculated the surface under the cumulative ranking area (SUCRA) to evaluate each mAb, with higher SUCRA values indicating better efficacy or lower likelihood of adverse events. Thirty-three randomized controlled trials with a total of 21,087 patients were included in the current NMA, involving eight different mAbs. SUCRA values showed that aducanumab (87.01% and 99.37%, respectively) was the most likely to achieve the best therapeutic effect based on the changes of Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale Sum of Boxes (CDR-SB) scores. Donanemab (88.50% and 99.00%, respectively) performed better than other therapies for Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Positron Emission Tomography-Standardized Uptake Value ratio (PET-SUVr). Lecanemab (87.24%) may be the most promising way to slow down the decrease of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score. In the analysis of the incidence of adverse events (subjects with any treatment-emergent adverse event), gantenerumab (89.12%) had the least potential for adverse events, while lecanemab (0.79%) may cause more adverse events. Solanezumab (95.75% and 80.38%, respectively) had the lowest incidence of amyloid-related imaging abnormalities characterized by edema and effusion (ARIA-E) and by cerebral microhemorrhages (ARIA-H) of the included immunotherapies. While SUCRA values provided a comprehensive measure of treatment efficacy, the inherent statistical uncertainty required careful analysis in clinical application. Despite immunotherapies significantly increasing the risks of adverse events and ARIA, the data suggest that mAbs can effectively improve the cognitive function of patients with mild and moderate AD. According to the NMA, aducanumab was the most likely to achieve significant improvements in different cognitive and clinical assessments (statistically improved MMSE and CDR-SB), followed by donanemab (statistically improved ADAS-Cog, and PET-SUVr) and lecanemab (statistically improved ADCS-ADL).

Cross-sectional and longitudinal assessments of function in prodromal-to-mild Alzheimer's disease: A comparison of the ADCS-ADL and A-IADL-Q scales.

Prior observational work in a heterogeneous cohort of participants with mild cognitive impairment suggests the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) may have greater sensitivity for functional decline than the more established Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. However, the relative utility of the A-IADL-Q versus the ADCS-ADL for clinical trials in early Alzheimer's disease (AD) remains uncertain. We compared baseline and longitudinal performance of the A-IADL-Q and ADCS-ADL in participants with biomarker-confirmed prodromal (pAD; n=158) or mild (mAD; n=283) AD enrolled in the 18-month Tauriel study of semorinemab (NCT03289143). The A-IADL-Q exhibited numerically stronger discrimination between pAD and mAD participants at baseline per Cohen's d analyses and similar sensitivity to longitudinal decline across cohorts over 18 months relative to the ADCS-ADL. The comparable performance of the ADCS-ADL and A-IADL-Q supports the utility of the A-IADL-Q in early AD clinical trials. The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) may be more sensitive than the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) for distinguishing prodromal and mild Alzheimer's disease (AD).A-IADL-Q and ADCS-ADL are similarly sensitive to decline in early AD over 18 months.Comparable performance of these indices supports A-IADL-Q use in future AD trials.Additional AD clinical trial data could extend findings across more diverse cohorts.

Technical Review of Clinical Outcomes Assessments Across the Continuum of Alzheimer's Disease.

Insight into the relationship between concepts that matter to the people affected by Alzheimer's disease (AD) and the clinical outcome assessments (COAs) commonly used in AD clinical studies is limited. Phases 1 and 2 of the What Matters Most (WMM) study series identified and quantitatively confirmed 42 treatment-related outcomes that are important to people affected by AD. We compared WMM concepts rated as "very important" or higher to items included in COAs used commonly in AD studies. Twenty COAs designed to assess signs, symptoms, and impacts across the spectrum of AD were selected for review. Among these 20 COAs, only 5 reflected 12 or more WMM concepts [Integrated Alzheimer's Disease Rating Scale (iADRS), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory-Mild Cognitive Impairment (ADCS-ADL-MCI), Alzheimer's Disease Composite Scores (ADCOMS), and Clinical Dementia Rating; Clinical Dementia Rating-Sum of Boxes (CDR/CDR-SB)]. Multiple symptoms and impacts of AD identified as important and meaningful in the WMM studies map only indirectly at best to 7 of the 20 most widely used COAs. While many frequently used COAs in AD capture some concepts identified as important to AD populations and their care partners, overlap between any single measure and the concepts that matter to people affected by AD is limited. The highest singly matched COA reflects fewer than half (45%) of WMM concepts. Use of multiple COAs expands coverage of meaningful concepts. Future research should explore the content validity of AD COAs planned for AD trials based on further confirmation of the ecological validity of the WMM items. This research should inform development and use of core outcome sets that capture WMM items and selection or development of new companion tools to fully demonstrate clinically meaningful outcomes spanning WMM.

Effects of Sport Stacking on Neuropsychological, Neurobiological, and Brain Function Performances in Patients With Mild Alzheimer's Disease and Mild Cognitive Impairment: A Randomized Controlled Trial

ObjectiveTo investigate the effects of sport stacking on the overall cognition and brain function in patients with mild Alzheimer's disease (AD) and mild cognitive impairment (MCI).MethodsA single-blind randomized controlled design was performed using sport stacking for 30 min, 5 days/week for 12 weeks. Forty-eight subjects with mild AD or MCI were randomly divided into the sport stacking group (T-mAD = 12, T-MCI = 12) and the active control group (C-mAD = 11, C-MCI = 13). Auditory Verbal Learning Test (AVLT), Alzheimer's Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL), Geriatric Depression Scale (GDS-30), and Pittsburgh Sleep Quality Index (PSQI) were performed, the level of amyloid β-protein-40 (Aβ-40), Aβ-42, brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1(IGF-1), tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and soluble trigger receptor expressed on myeloid cells 2 (sTREM2) in plasma were tested, and brain functional connectivity in resting state and activation under finger movement task were analyzed by functional near-infrared spectroscopy (fNIRS).ResultsThirty-nine patients completed the trial. After 4 weeks, we found a significant increase in AVLT score in T-MCI (6.36 ± 5.08 vs. −1.11 ± 4.23, p = 0.004), and T-mAD group (4.60 ± 4.77 vs. −0.11 ± 2.89, p = 0.039). After 12 weeks, there was a significantly improved in AVLT (9.64 ± 4.90 vs. −0.33 ± 6.10, p = 0.002) and ADCS-ADL (3.36 ± 3.59 vs. −1.89 ± 2.71, p = 0.003) in T-MCI. There was a significant improvement in AVLT (5.30 ± 5.42 vs. 0.44 ± 2.40) in T-mAD (p < 0.05). Plasma levels of BDNF were upregulated in both T-MCI and T-mAD, and IGF-1 increased in T-MCI (P < 0.05) compared to the control groups. The functional connectivity in MCI patients between DLPFC.R and SCA.R, SMA.L, and SCA.R was decreased. In contrast, in mAD patients, the brain regional function connection was increased between DLPFC.R and Broca's.L. The activation of channel 36 located in the left primary somatosensory cortex was significantly increased after 12-week training, which was correlated with the improved AVLT and the increase of BDNF.ConclusionOur findings suggested that sport stacking is effective for patients with MCI and mild AD, possibly through increasing the expression of neuroprotective growth factors and enhancing neural plasticity to improve neurocognitive performance.Clinical Trial Registrationhttps://www.ClinicalTrials.gov, ChiCTR.org.cn, identifier: ChiCTR-2100045980.

Effects of Orally Administered Nicotinamide Riboside on Bioenergetic Metabolism, Oxidative Stress and Cognition in Mild Cognitive Impairment and Mild Alzheimer's Disease

<h3>Introduction</h3> Alzheimer's Disease (AD) is a neurodegenerative disease affecting millions of people worldwide, representing significant health and economic burdens. There has been a recent drive to develop more effective AD treatments. A potential strategy involves enhancing brain bioenergetics, or the metabolism of fuel molecules to create and use energy through glycolysis and oxidative phosphorylation (OxPhos). The regulation of mitochondrial turnover and function in the brain declines as we age, and it has become increasingly accepted that these metabolic alterations precede hallmark AD pathology, including amyloid-beta (Aβ) plaques and neurofibrillary tangles. An overlapping set of mechanisms involving redox dysregulation, oxidative stress, and mitochondrial dysfunction may be related to mild cognitive impairment (MCI) and AD. Nicotinamide adenine dinucleotide (NAD) has been identified as a promising molecular target for bioenergetic treatments as it is requisite for many redox reactions. The redox ratio (RR, i.e., NAD+/NADH) is a mark of the system's ability to carry out ATP synthesis. NAD+ levels decrease as we age, which compromises energy production in the mitochondria, impairs clearance of damaged mitochondria, and impacts our brain's capacity to react to oxidative stress. Since mitochondrial dysfunction and oxidative stress are believed to play a role in the pathophysiology of age-related diseases, boosting NAD levels could be an effective AD treatment. Nicotinamide Riboside (NR) is a naturally occurring, over the counter, commercially available, and safe vitamin B3-based NAD+ precursor supplement. Several lines of evidence suggest that NR is a mitochondrially-favored NAD+ precursor. Data supports the safety and efficacy of using NR to increase NAD+ levels in humans, but these studies have not measured the RR at critical tissue sites, such as the brain, to determine the therapeutic potential of oral NR supplementation. This study proposes a novel intervention strategy for patients with MCI or mild AD that targets redox dysregulation and oxidative stress in the brain using NR. Our primary objective is to validate the effect of NR supplementation on NAD+ levels and RR in the brain of patients with MCI or mild AD. Our secondary aim is to quantify the impact of NR supplementation on ensuing markers of mitochondrial function and oxidative stress in MCI and mild AD patients. Our third, exploratory aim, is to correlate neuroimaging measurements with clinical assessments. <h3>Methods</h3> A 12-week open-label, clinical trial of NR supported by the National Institute on Aging (R01AG066670, Du/Forester), we plan to enroll a total of 50 participants - 25 with MCI and 25 with mild AD, all with at least one copy of the APOE ε4 allele. Participants will be asked to take 1,000 mg NR daily over 12-weeks, and to come in for three scanning visits. We will use novel neuroimaging methods —spectroscopy on a 4T scanner to enable in vivo measurement of NAD+, NADH and RR, along with markers of mitochondrial function tied to NAD, including creatine kinase (CK), ATPase, and glutathione (GSH)—a molecule essential for cellular repair. Our primary outcome measures are NAD+ levels and RR. Our secondary outcome measures are CK/ATPase activity and GSH levels. Our exploratory outcome measures include the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for cognition and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) for daily functioning. <h3>Results</h3> Previous clinical trials of NR pharmacokinetics in humans support the safety and efficacy of using NR to increase NAD+ levels in the plasma. Emerging data also highlights important health benefits this supplement may have. We recently received preliminary spectroscopic data following a course of NR supplementation in healthy volunteers (N=4) which observed elevations in NAD+ and RR after two weeks. Only a small difference of downstream effects, CK/ATPase activity and GSH levels, were observed, which could be due to the short period of NR treatment. We hypothesize that oral NR will increase NAD+ and RR in the medial prefrontal cortex and will increase GSH levels and CK/ATPase activity in the brain. For our exploratory aim, we hypothesize that oral NR will improve cognitive status and functional abilities, as measured by the RBANS and ADCS-ADL. <h3>Conclusions</h3> We are investigating NR to target redox dysregulation and oxidative stress in the brain in those with MCI or mild AD. We aim to document and quantify the neurobiological and clinical effects of NR supplementation in MCI and mild AD using in vivo brain imaging. This novel intervention strategy of brain bioenergetics has thus far received minute empirical attention and may represent an alternative strategy for treating MCI and mild AD. Early detection and repair of neural dysfunction at this critical stage could significantly alter disease course and improve functional outcomes. <h3>This research was funded by</h3> National Institutes of Health

A Multinational, Multicenter, Randomized, Double-Blind, Active Comparator, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Donepezil Transdermal Patch in Patients With Alzheimer's Disease.

Background and PurposeOral administration of cholinesterase inhibitors is often associated with adverse gastrointestinal effects, and so developing an alternative administration route, such as transdermal, is urgently needed. The primary objective of this study was to determine the efficacy and safety of the IPI-301 donepezil transdermal patch compared with donepezil tablets (control) in mild-to-moderate probable Alzheimer’s disease (AD).MethodsThis prospective, randomized, double-blind, double-dummy, two-arm parallel, multicenter trial included 399 patients, among whom 303 completed the trial. For randomization, the patients were stratified based on previous treatment and donepezil dose; patients in each stratum were randomized to the test and control groups at a 1:1 ratio.ResultsThe difference between the control group and the IPI-301 group, quantified as the Hodges–Lehmann estimate of location shift, was 0.00 (95% confidence interval: -1.00 to 1.33), with an upper limit of less than 2.02. The change in Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score differed significantly between the IPI-301 and control groups (p=0.02). However, the changes in the full-itemized ADCS-ADL scores at week 24 did not differ significantly between the two groups. There were no differences between the two groups regarding the scores for the Clinician Interview-Based Impression of Change (p=0.9097), Mini-Mental State Examination (p=0.7018), Neuropsychiatric Inventory (p=0.7656), or Clinical Dementia Rating (p=0.9990). Adverse events, vital signs, and laboratory test results were comparable between the two groups.ConclusionsIPI-301 was safe and efficacious in improving cognitive function in patients with mild-to-moderate AD.

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Patients With Alzheimer Disease: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial.

BackgroundAlzheimer disease has no known cure. As existing pharmacologic interventions only modestly slow cognitive decline, there is a need for new treatments. Recent trials of repetitive transcranial magnetic stimulation (rTMS) have reported encouraging results for improving or stabilizing cognition in patients diagnosed with Alzheimer dementia. However, owing to small samples and lack of a well-controlled double-blind design, the results to date are inconclusive. This paper presents the protocol for a large placebo-controlled double-blind study designed with sufficient statistical rigor to measure the efficacy of rTMS treatment in patients with Alzheimer dementia.ObjectiveThe objectives are to (1) recruit and enroll up to 200 eligible participants, (2) estimate the difference in treatment effects between active treatment and sham treatment, (3) estimate the difference in treatment effects between two doses of rTMS applications, (4) estimate the duration of treatment effects among responders to active rTMS treatment, and (5) estimate the effect of dementia severity on treatment outcomes among patients receiving active rTMS treatment.MethodsWe have designed our study to be a double-blind, randomized, placebo-controlled clinical trial investigating the short- and long-term (up to 6 months) benefits of active rTMS treatment at two doses (10 sessions over 2 weeks and 20 sessions over 4 weeks) compared with sham rTMS treatment. The study will include patients aged ≥55 years who are diagnosed with Alzheimer disease at an early to moderate stage and have no history of seizures and no major depression. The primary outcome measure is the change in the Alzheimer Disease Assessment Scale-Cognitive Subscale score from pretreatment to posttreatment. Secondary outcomes are changes in performance on tests of frontal lobe functioning (Stroop test and verbal fluency), changes in neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), and changes in activities of daily living (Alzheimer Disease Co-operative Study-Activities of Daily Living Inventory). Tolerability of the intervention will be assessed using a modification of the Treatment Satisfaction Questionnaire for Medication. We assess participants at baseline and 3, 5, 8, 16, and 24 weeks after the intervention.ResultsAs of November 1, 2020, we have screened 523 individuals, out of which 133 were eligible and have been enrolled. Out of the 133 individuals, 104 have completed the study. Moreover, as of November 1, 2020, there has been no serious adverse event. We anticipate that rTMS will considerably improve cognitive function, with effects lasting up to 3 months. Moreover, we expect rTMS to be a well-tolerated treatment with no serious side effect.ConclusionsThis protocol design will allow to address both the rTMS active treatment dose and its short- and long-term effects compared with sham treatment in large samples.Trial RegistrationClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815International Registered Report Identifier (IRRID)DERR1-10.2196/25144

Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer's disease: A randomized, placebo-controlled, phase 3 clinical trial (MINDSET).

IntroductionA previous phase 2b study supported the use of the 5‐HT6 receptor antagonist intepirdine as adjunctive therapy to donepezil for Alzheimer's disease (AD) dementia. A phase 3 study, MINDSET, was performed to test this hypothesis.MethodsMINDSET was a global, double‐blind, randomized, placebo‐controlled trial in 1315 mild‐to‐moderate AD dementia patients on stable donepezil. Patients received 35 mg/day intepirdine or placebo for 24 weeks. The co‐primary endpoints were change from baseline to week 24 on the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) and Alzheimer's Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL).ResultsThere were no statistically significant differences between intepirdine and placebo groups (adjusted mean [95% confidence interval]) on the co‐primary endpoints ADAS‐Cog (−0.36 [−0.95, 0.22], P = 0.2249) and ADCS‐ADL (−0.09 [−0.90, 0.72], P = 0.8260). Intepirdine demonstrated a favorable safety profile similar to placebo.DiscussionIntepirdine as adjunctive therapy to donepezil did not produce statistical improvement over placebo on cognition or activities of daily living in mild‐to‐moderate AD dementia patients.

Assessment of Plasma Amyloid-β42/40 and Cognitive Decline Among Community-Dwelling Older Adults

Plasma measurement of amyloid-β (Aβ) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce. To investigate the associations between plasma Aβ42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns. This multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020. Plasma Aβ42 and Aβ40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aβ assessment was defined as the baseline for this study. Cognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed. A total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aβ42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aβ42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aβ42/40 ratio greater than 0.107. In this study, low plasma Aβ42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aβ42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.

Meal-related difficulties and weight loss in older people: Longitudinal data from MAPT study.

Difficulties with meal-related activities (preparing meals and food shopping) may influence food intake, and contribute to nutritional risk among elderly people. All known studies on this topic had a cross-sectional design, thereby no causal relationships could be derived. We aim to investigate if difficulties with meal-related activities can contribute to subsequent weight loss in community-dwelling older people. We used data of older subjects from the MAPT Study (n=1531, median age=74 years, 64% women), who provided prospective data on weight every 6 months and cognitive, physical condition, and functional capacities every year during a 3-year period. Difficulties preparing meals and shopping were evaluated each year with the Alzheimer's Disease Cooperative Study-Activities of Daily Living Prevention Instrument (ADCS ADL-PI) Scale. The risk of losing weight (≥5% or≥3kg in the following year) was estimated using a time-dependent Cox regression model. During the 3-year follow-up, a total of 851 subjects experienced at least a 5% or 3kg weight loss. Two hundred thirty-seven subjects declared having difficulties with meal preparation at least once, and 133 declared having difficulties shopping. Subjects reporting any meal-related difficulties were older (p<0.001), had more depressive symptoms (p<0.001), and a lower physical function (p<0.001) compared to those without difficulties. They also had a lower cognitive score (preparing meals: p<0.001; shopping: p=0.005) and a lower body mass index (preparing meals: p=0.005; shopping: p=0.023) at the end of the study. Meal-related activities were not associated with weight loss in unadjusted analysis and after adjustment for sex, age, depression, physical and cognitive status. Difficulties preparing meals and shopping had no effect on weight loss in community-dwelling older people, despite their association with advanced age, functional decline, and depressive symptoms.

A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study.

IntroductionThe search for drugs to treat Alzheimer's disease (AD) has failed to yield effective therapies. Here we report the first genome‐wide search for biomarkers associated with therapeutic response in AD. Blarcamesine (ANAVEX2‐73), a selective sigma‐1 receptor (SIGMAR1) agonist, was studied in a 57‐week Phase 2a trial (NCT02244541). The study was extended for a further 208 weeks (NCT02756858) after meeting its primary safety endpoint.MethodsSafety, clinical features, pharmacokinetic, and efficacy, measured by changes in the Mini‐Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study‐Activities of Daily Living scale (ADCS‐ADL), were recorded. Whole exome and transcriptome sequences were obtained for 21 patients. The relationship between all available patient data and efficacy outcome measures was analyzed with unsupervised formal concept analysis (FCA), integrated in the Knowledge Extraction and Management (KEM) environment.ResultsBiomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE:P < .041), genomic variants SIGMAR1 p.Gln2Pro (ΔMMSE:P < .039; ΔADCS‐ADL:P < .063) and COMT p.Leu146fs (ΔMMSE:P < .039; ΔADCS‐ADL:P < .063), and baseline MMSE score (slope MMSE:P < .015). Their combined impact on drug response was confirmed at week 148 with linear mixed effect models.DiscussionConfirmatory Phase 2b/3 clinical studies of these patient selection markers are ongoing. This FCA/KEM analysis is a template for the identification of patient selection markers in early therapeutic development for neurologic disorders.

Safety and tolerability of GRF6019 in mild-to-moderate Alzheimer's disease dementia.

IntroductionThis phase 2 trial evaluated the safety, tolerability, and feasibility of repeated infusions of the plasma fraction GRF6019 in mild‐to‐moderate Alzheimer's disease.MethodsIn this randomized, double‐blind, dose‐comparison trial, 47 patients were randomized 1:1 to receive daily infusions of 100 mL (n = 24) or 250 mL (n = 23) of GRF6019 for 5 consecutive days over two dosing periods separated by a treatment‐free interval of 3 months.ResultsThe mean (standard deviation [SD]) age of the enrolled patients was 74.3 (6.9), and 62% were women. Most adverse events (55%) were mild, with no clinically significant differences in safety or tolerability between the two dose levels. The mean (SD) baseline Mini‐Mental State Examination score was 20.6 (3.7) in the 100 mL group and 19.6 (3.7) in the 250 mL group; at 24 weeks, the within‐patient mean change from baseline was –1.0 points (95% confidence interval [CI], –3.1 to 1.1) in the 100 mL group and +1.5 points (95% CI, –0.4 to 3.3) in the 250 mL group. The within‐patient mean change from baseline on the Alzheimer's Disease Assessment Scale‐Cognitive subscale was –0.4 points (95% CI, –2.9 to 2.2) in the 100 mL group, while in the 250 mL group it was –0.9 points (95% CI, –3.0 to 1.2). The within‐patient mean change from baseline on the Alzheimer's Disease Cooperative Study‐Activities of Daily Living was –0.7 points in the 100 mL group (95% CI, –4.3 to 3.0) and –1.3 points (95% CI, –3.4 to 0.7) in the 250 mL group. The mean change from baseline on the Category Fluency Test, Clinical Dementia Rating Scale–Sum of Boxes, Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change, and Neuropsychiatric Inventory Questionnaire was similar for both treatment groups and did not show any worsening.DiscussionGRF6019 was safe and well tolerated, and patients experienced no cognitive decline and minimal functional decline. These results support further development of GRF6019.

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease

Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures. ClinicalTrials.gov identifier: NCT02167256.

Factors associated with long-term impact on informal caregivers during Alzheimer's disease dementia progression: 36-month results from GERAS.

To identify, in caregivers of patients with Alzheimer's disease (AD) dementia, factors associated with subjective (personal, physical, emotional, and social) and objective (informal caregiver time and costs) caregiver burden. Prospective longitudinal European observational study: post-hoc analysis. Clinic. Community-dwelling patients in France and Germany aged ≥ 55 years (n = 969) with probable AD and their informal caregivers. Mini-Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), 12-item Neuropsychiatric Inventory (NPI-12), Zarit Burden Interview (ZBI), informal caregiver basic and instrumental ADL hours (Resource Utilization in Dementia instrument), and informal caregiver costs. Mixed-effect models of repeated measures (MMRM) were run, including baseline and time-dependent covariates (change from baseline [CFB] to 18 months in MMSE, ADCS-ADL, and NPI-12 scores) associated with CFB in ZBI score/informal caregiver time over 36 months (analyzed using linear regression models) and informal caregiver costs over 36 months (analyzed using generalized linear models). Greater decline in patient function (ADCS-ADL) over 18 months was associated with increased subjective caregiver burden (ZBI), hours, and costs over 36 months. Increased behavioral problems (NPI-12) over 18 months also negatively impacted ZBI. Cognitive decline (MMSE) over 18 months did not affect change in caregiver burden. Long-term informal caregiver burden was driven by worsening functional abilities and behavioral symptoms but not cognitive decline, over 18 months in community-dwelling patients with AD dementia. Identifying the drivers of caregiver burden could highlight areas in which interventions may benefit both caregivers and patients.

Efficacy of Cilostazol Administration in Alzheimer's Disease Patients with White Matter Lesions: A Positron-Emission Tomography Study.

This study tested the efficacy of the phosphodiesterase type III inhibitor cilostazol in Alzheimer's disease patients with white matter lesions treated with donepezil in comparison with donepezil monotherapy using fluorodeoxyglucose (18F) positron-emission tomography (FDG PET). A 24-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted. Thirty-six Alzheimer's disease patients with white matter lesions who received donepezil (n = 18 each in the cilostazol and placebo groups) were enrolled. Participants underwent pre and post FDG PET imaging scans and three rounds of clinical and neuropsychological tests. The cilostazol group did not show a significant decrease of regional glucose metabolism; however, regional glucose metabolism was significantly decreased in the parietal and frontal lobes of the placebo group. The repeated measures ANOVA measuring differences in uptake change revealed that regional glucose metabolism in the left inferior frontal gyrus was significantly more preserved in the cilostazol group than that in the placebo group (p < 0.005). Mean changes from baseline on the Mini-Mental State Exam, Alzheimer's Disease Assessment Scale-cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, and the Clinical Dementia Rating Sum of Boxes did not differ between the two groups. In the cilostazol group, the increase of glucose metabolism correlated with the improvment of the Alzheimer's Disease Assessment Scale-cognitive score. We conclude that cilostazol treatment added to donepezil may delay the decline in regional cerebral metabolism in Alzheimer's disease with white matter lesions compared with donepezil monotherapy. In additon, our results verified the efficacy of cilostazol in improving or protecting cognitive function in Alzheimer's disease through increased glucose metabolism. However, the long-term effect of cilostazol on cognitive function and Alzheimer's disease modification must be tested in further studies with larger sample size and longer study period. Trial registration: http://clinicaltrials.gov : NCT01409564.

The Alzheimer's disease THErapy with NEuroaid (ATHENE) study protocol: Assessing the safety and efficacy of Neuroaid II (MLC901) in patients with mild-to-moderate Alzheimer's disease stable on cholinesterase inhibitors or memantine—A randomized, double-blind, placebo-controlled trial

BackgroundDementia is a large and growing health care burden globally, and its major cause is Alzheimer's disease (AD). MLC901 (Neuroaid II) is a simplified form of MLC601 (Neuroaid), a Traditional Chinese Medicine with neuroprotective and neuroproliferative properties in cellular and animal models of brain injury. MLC601 has been shown to modulate amyloid precursor protein (APP) processing in human neuroblastoma cell cultures and increase the levels of soluble APPα. In addition, MLC901 has been shown to reduce tau phosphorylation in vitro. Hence, MLC901 may have possible multimodal actions and a disease-modifying effect in AD. In previous clinical studies, MLC601 has shown promising effects in AD. ObjectiveTo investigate the safety and efficacy of MLC901 add-on therapy to standard treatment in mild-to-moderate probable AD patients stable on standard treatment and to evaluate if MLC901 has a disease-modifying effect in AD. MethodsThis is a 6-month randomized, double-blind, placebo-controlled trial in mild-to-moderate probable AD where MLC901 will be given as an add-on therapy to standard AD treatment, followed by an extension study for another 6 months, where all subjects will be treated with open-label MLC901 in addition to standard treatment. The primary outcome is safety as measured by adverse events, vital signs, electrocardiogram, laboratory tests, and physical and neurological examinations. Secondary outcomes evaluating cognition, behavior, and activities of daily living at various time points include the Alzheimer's Disease Assessment Scale–cognitive subscale, Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change, Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Mini–Mental State Examination. ConclusionMLC901 has the potential to improve cognition in AD patients. It may also have a role in delaying disease progression. This study will be the first to provide safety and efficacy data for MLC901 in mild-to-moderate probable AD patients already receiving standard therapy.

Mapping the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory to the Health Utility Index Mark III.

To map the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL) to the Health Utility Index Mark III (HUI3) in people living with dementia (PWD) and to compare the performance of five methods for mapping. A cross-sectional study of 346 dyads of community-dwelling PWD and family caregiver was carried out in Singapore. ADCS-ADL and HUI3 were rated by the family caregivers. Disease severity ratings and Mini Mental State Examination (MMSE) results were retrieved from medical records. A recently proposed mapping method called the Mean Rank Method (MRM) was described and applied, and the results were compared with regression-based mapping, including ordinary least squares, censored least absolute deviation (CLAD), Tobit and response mapping. The MRM produced a mapped utility distribution that closely resembled the observed utility distribution. The standard deviations (SDs) of the observed and MRM-mapped utility were both 0.340, whereas the SDs of the other mapped utilities ranged from 0.243 (response mapping) to 0.283 (CLAD). Regressing the MRM- and CLAD-mapped and observed utility values upon disease severity and MMSE gave similar regression lines (each P > 0.05). Regressing the other mapped utility values upon the covariates under- (over-) estimated the utility of good (poor) clinical states. However, regression-based mapping methods gave a better fit at the individual level, as measured by root mean square error, mean absolute error and R2. K fold cross-validation gave similar results. The MRM is accurate at the group level. The regression-based mapping methods are more accurate for making individual-level prediction. In addition, CLAD also performed reasonably well at the group level.

Randomized, controlled, proof-of-concept trial of MK-7622 in Alzheimer's disease

IntroductionWe evaluated the selective M1 muscarinic positive allosteric modulator, MK-7622, as adjunctive cognitive enhancing therapy in individuals with Alzheimer's disease. MethodsA randomized, double-blind, proof-of-concept trial was performed. Participants with mild-to-moderate Alzheimer's disease, being treated with an acetylcholinesterase inhibitor, were randomized 1:1 to 45 mg of MK-7622 or placebo for 24 weeks. Endpoints included the mean change from baseline in Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) at 12 weeks and Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory at 24 weeks. ResultsTwo hundred forty participants were randomized. The trial was stopped for futility after meeting prospectively defined stopping criteria. MK-7622 did not improve cognition at 12 weeks (group difference in ADAS-Cog11: 0.18 [95% confidence interval: −1.0 to 1.3]) or function at 24 weeks (group difference in Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory: 0.06 [95% confidence interval: −2.4 to 2.5]). More participants taking MK-7622 discontinued study medication because of adverse events than those taking placebo (16% vs 6%) and who experienced cholinergically related adverse events (21% vs 8%). DiscussionMK-7622 (45 mg) does not improve cognition or function when used as adjunctive therapy in mild-to-moderate Alzheimer's disease.

A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer's disease: A pilot study

IntroductionHuman studies on low-dose resveratrol are scarce. This study aims to evaluate the safety, tolerability, and efficacy of an oral preparation of resveratrol, glucose, and malate (RGM) in slowing the progression of Alzheimer's disease (AD). MethodsThirty-nine subjects with mild to moderate AD who were free of life-threatening disease and who did not have contraindications to the use of the study product were screened. Progression of AD was measured by change in the cognitive portion of the Alzheimer's Disease Assessment Scale–cognitive subscale. Secondary outcomes included Clinician's Global Impression of Change, Mini–Mental State Examination, Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale, and Neuropsychiatric Inventory. 15 mL of the following preparation per dose, i.e., 5 g dextrose, 5 g malate, and 5 mg resveratrol, or matching placebo was ingested with an 8 oz glass of commercial unsweetened grape juice twice a day for 1 year. Group differences in the rate of change in the outcome measures were examined using generalized estimating equations. ResultsThe treatment and control groups were similar on all of the screening variables. At 12 months, change scores on Alzheimer's Disease Assessment Scale–cognitive subscale, Mini–Mental State Examination, Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale, or Neuropsychiatric Inventory all showed less deterioration in the treatment than the control group; however, none of the change scores reached statistical significance. The most common AE were falls, all in the control group. None of the falls were deemed to be study related. ConclusionLow-dose oral resveratrol is safe and well tolerated. Interpretation of the effects on clinical outcomes trajectories remains uncertain. A larger study is required to determine whether low-dose resveratrol may be beneficial. Trial RegistrationClinicalTrials.gov (NCT00678431), Registered 05/15/2008.

The conceptual relevance of assessment measures in patients with mild/mild-moderate Alzheimer's disease

IntroductionThis study aims to evaluate the conceptual relevance of four measures of disease activity in patients with mild/mild-moderate Alzheimer's disease (AD): (1) the Alzheimer's Disease Assessment Scale–Cognitive Subscale; (2) the Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory; (3) the Neuropsychiatry Inventory; and (4) the Dependence Scale. MethodsA conceptual model depicting patient experience of mild AD was developed via literature review; concepts were compared with the items of the four measures. Relevance of the concepts included in the four measures was evaluated by patients with mild AD in a survey and follow-up interviews. ResultsThe four measures assessed few of the symptoms/impacts of mild AD identified within the literature. Measured items addressing emotional impacts were deemed most relevant by participants but were included in the measures only superficially. DiscussionThe four assessment measures do not appear to capture the concepts most relevant to/important to patients with mild/mild-moderate AD.