Summary Interventions that have even quite modest effects at the individual level could drastically reduce the future burden of dementia associated with Alzheimer's disease at the population level. ...In the past three decades, both pharmacological and lifestyle interventions have been studied for the prevention of cognitive decline or dementia in randomised controlled trials of individuals mostly aged older than 50–55 years with or without risk factors for Alzheimer's disease. Several trials testing the effects of physical activity, cognitive training, or antihypertensive interventions showed some evidence of efficacy on a primary cognitive endpoint. However, most of these trials had short follow-up periods, and further evidence is needed to confirm effectiveness and establish the optimum design or dose of interventions and ideal target populations. Important innovations in ongoing trials include the development of multidomain interventions, and the use of biomarker or genetic inclusion criteria. Challenges include the use of adaptive trial designs, the development of standardised, sensitive outcome measures, and the need for interventions that can be implemented in resource-poor settings.
Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ...β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease.
We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function.
The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group.
Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).
Summary In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD ...biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.
Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later ...Alzheimer-related cognitive decline.
To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid.
Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).
Individuals were classified at baseline as having normal (n = 243) or elevated (n = 202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid β.
Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 worst to 30 best points), Clinical Dementia Rating Sum of Boxes (CDR-Sum of Boxes; 0 best to 18 worst points), and Logical Memory Delayed Recall (0 worst to 25 best story units).
Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR-Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points 95% CI, 0.94-2.10; P < .001), MMSE (mean difference, 0.56 points 95% CI, 0.32-0.80; P < .001), and CDR-Sum of Boxes (mean difference, 0.23 points 95% CI, 0.08-0.38; P = .002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units 95% CI, -0.02 to 1.48; P = .056).
Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.
Alzheimer's disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor ...protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer's disease.
We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function).
A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group.
Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).
Dementia prevention research has progressed rapidly in recent years, with publication of several large lifestyle intervention trials, and renewed interest in pharmacological interventions, notably ...for individuals with Alzheimer’s disease biomarkers, warranting an updated review of results and methodology. We identified 112 completed trials testing the efficacy of single-domain pharmacological (n = 33, 29%), nutritional (n = 27, 24%), physical activity (n = 18, 16%) and cognitive stimulation (n = 13, 12%), or multidomain (n = 22, 20%) interventions on incident dementia, or a relevant intermediate marker (e.g. cognitive function, biomarkers or dementia risk scores) in people without dementia. The earliest trials tested pharmacological interventions or nutritional supplements, but lifestyle interventions predominated in the last decade. In total, 21 (19%) trials demonstrated a clear beneficial effect on the pre-specified primary outcome (or all co-primary outcomes), but only two (10%) were large-scale (testing blood pressure lowering (Syst-Eur) or multidomain (FINGER) interventions on incident dementia and cognitive change in cognitive function, respectively). Of the 116 ongoing trials, 40% (n = 46) are testing multidomain interventions. Recent methodological shifts concern target populations, primary outcome measures, and intervention design, but study design remains constant (parallel group randomised controlled trial). Future trials may consider using adaptive trials or interventions, and more targeted approaches, since certain interventions may be more effective in certain subgroups of the population, and at specific times in the life-course. Efforts should also be made to increase the representativeness and diversity of prevention trial populations.
•Over 110 prevention trials have now been published, but many were small-scale.•Pharmacological and lifestyle interventions have been tested; most showed no effect.•2 large trials (testing multidomain or blood pressure interventions) were positive.•Ongoing trials are notably testing multidomain interventions and anti-amyloid drugs.•Methodological shifts concern target populations, endpoints and intervention design.
Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of ...amyloid and in preclinical studies promoted its clearance from the brain.
In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease.
Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval CI, -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49).
Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.).
Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor ...protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease.
We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used.
The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated.
As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT00594568.)
Alzheimer's disease (AD) is the only leading cause of death for which no disease-modifying therapy is currently available. Recent disappointing trial results at the dementia stage of AD have raised ...multiple questions about our current approaches to the development of disease-modifying agents. Converging evidence suggests that the pathophysiological process of AD begins many years before the onset of dementia. So why do we keep testing drugs aimed at the initial stages of the disease process in patients at the end-stage of the illness?
Treatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 ...levels and activities of daily living (ADL) scores.
For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples.
Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels.
Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders.
ClinicalTrials.gov NCT01504854.
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