Potential impact of unblinding on observed treatment effects in Alzheimer's disease trials

INTRODUCTION: Adverse effects of monoclonal antibodies against amyloid beta are common, and may affect validity of randomized controlled trials (RCTs) through unblinding of participants.METHODS: We used observations from published phase 3 RCTs in Alzheimer's disease to calculate the magnitude of unblinding effects on cognition that would be required to explain observed cognitive benefits in RCTs. RESULTS: In trials of lecanemab, aducanumab, and donanemab, incidence of amyloid-related imaging abnormalities with active treatment ranged from 22% to 44%, the vast majority of which presumably led to unblinding. Effects of unblinding on the Clinical Dementia Rating Sum of Boxes required to fully explain observed drug effects ranged from 1.1 point (95% confidence interval: 0.2–2.0) with aducanumab, to 3.3 points (2.1–4.4) with donanemab and 3.7 points (2.0–5.6) with lecanemab. Infusion-related reactions were common, with potential unblinding effects particularly for lecanemab. Similar patterns were observed for the Alzheimer's Disease Assessment Scale Cognitive subscale. DISCUSSION: Psychological treatment effects due to unblinding may explain a substantial share of observed treatment effects in RCTs.</p

Adiposity and the development of dyslipidemia in APOE epsilon 2 homozygous subjects:A longitudinal analysis in two population-based cohorts

Background and aims: Familial dysbetalipoproteinemia (FD), characterized by remnant lipoprotein accumulation and premature cardiovascular disease, occurs in homozygous carriers of the APOE epsilon 2 allele, but genetic predisposition alone does not suffice for the clinical phenotype. Cross-sectional studies suggest that a second metabolic hit-notably adiposity or insulin resistance-is required, but the association between these risk factors and development of FD has not been studied prospectively. Methods: For this study, we evaluated 18,987 subjects from two large prospective Dutch population-based cohorts (PREVEND and Rotterdam Study) of whom 118 were homozygous APOE epsilon 2 carriers. Of these, 69 subjects were available for prospective analyses. Dyslipidemia-likely to be FD-was defined as fasting triglyceride (TG) levels >3 mmol/L in untreated subjects or use of lipid lowering medication. The effect of weight, body mass index (BMI), waist circumference, type 2 diabetes mellitus and non-TG metabolic syndrome on development of dyslipidemia was investigated. Results: Eleven of the 69 epsilon 2 epsilon 2 subjects (16%) developed dyslipidemia-likely FD-during follow-up. Age-, sexand cohort-adjusted risk factors for the development of FD were BMI (OR 1.19; 95%CI 1.04-1.39), waist circumference (OR 1.26 95%CI 1.01-1.61) and presence of non-TG metabolic syndrome (OR 4.39; 95%CI 1.04-18.4) at baseline. Change in adiposity during follow-up was not associated with development of dyslipidemia. Conclusions: Adiposity increases the risk of developing an FD-like lipid phenotype in homozygous APOE epsilon 2 subjects. These results stress the importance of healthy body weight in subjects at risk of developing FD

Benzodiazepine use in relation to long-term dementia risk and imaging markers of neurodegeneration:a population-based study

Background: Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well-established acute adverse effects on cognition, but long-term effects on neurodegeneration and dementia risk remain uncertain. Methods: We included 5443 cognitively healthy (MMSE ≥ 26) participants from the population-based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005–2008) was derived from pharmacy dispensing records, from which we determined drug type and cumulative dose. Benzodiazepine use was defined as prescription of anxiolytics (ATC-code: N05BA) or sedative-hypnotics (ATC-code: N05CD) between inception of pharmacy records and study baseline. Cumulative dose was calculated as the sum of the defined daily doses for all prescriptions. We determined the association with dementia risk until 2020 using Cox regression. Among 4836 participants with repeated brain MRI, we further determined the association of benzodiazepine use with changes in neuroimaging markers using linear mixed models. Results: Of all 5443 participants, 2697 (49.5%) had used benzodiazepines at any time in the 15 years preceding baseline, of whom 1263 (46.8%) used anxiolytics, 530 (19.7%) sedative-hypnotics, and 904 (33.5%) used both; 345 (12.8%) participants were still using at baseline assessment. During a mean follow-up of 11.2 years, 726 participants (13.3%) developed dementia. Overall, use of benzodiazepines was not associated with dementia risk compared to never use (HR [95% CI]: 1.06 [0.90–1.25]), irrespective of cumulative dose. Risk estimates were somewhat higher for any use of anxiolytics than for sedative-hypnotics (HR 1.17 [0.96–1.41] vs 0.92 [0.70–1.21]), with strongest associations for high cumulative dose of anxiolytics (HR [95% CI] 1.33 [1.04–1.71]). In imaging analyses, current use of benzodiazepine was associated cross-sectionally with lower brain volumes of the hippocampus, amygdala, and thalamus and longitudinally with accelerated volume loss of the hippocampus and to a lesser extent amygdala. However, imaging findings did not differ by type of benzodiazepines or cumulative dose. Conclusions: In this population-based sample of cognitively healthy adults, overall use of benzodiazepines was not associated with increased dementia risk, but potential class-dependent adverse effects and associations with subclinical markers of neurodegeneration may warrant further investigation.</p

Antidepressant use in relation to dementia risk, cognitive decline, and brain atrophy

INTRODUCTION: We aimed to assess the effect of antidepressant use on dementia risk, cognitive decline, and brain atrophy. METHODS: In this prospective cohort study, we included 5511 dementia-free participants (Mini-Mental State Examination [MMSE] &gt; 25) of the Rotterdam study (57.5% women, mean age 70.6 years). Antidepressant use was extracted from pharmacy records from 1991 until baseline (2002–2008). Incident dementia was monitored from baseline until 2018, with repeated cognitive assessment and magnetic resonance imaging (MRI) every 4 years. RESULTS: Compared to never use, any antidepressant use was not associated with dementia risk (hazard ratio [HR] 1.14, 95% confidence interval [CI] 0.92–1.41), or with accelerated cognitive decline or atrophy of white and gray matter. Compared to never use, dementia risk was somewhat higher with tricyclic antidepressants (HR 1.36, 95% CI 1.01–1.83) than with selective serotonin reuptake inhibitors (HR 1.12, 95% CI 0.81–1.54), but without dose–response relationships, accelerated cognitive decline, or atrophy in either group. DISCUSSION: Antidepressant medication in adults without indication of cognitive impairment was not consistently associated with long-term adverse cognitive effects. Highlights: Antidepressant medications are frequently prescribed, especially among older adults. In this study, antidepressant use was not associated with long-term dementia risk. Antidepressant use was not associated with cognitive decline or brain atrophy. Our results support safe prescription in an older, cognitively healthy population.</p

Antidepressant use in relation to dementia risk, cognitive decline, and brain atrophy

INTRODUCTION: We aimed to assess the effect of antidepressant use on dementia risk, cognitive decline, and brain atrophy. METHODS: In this prospective cohort study, we included 5511 dementia-free participants (Mini-Mental State Examination [MMSE] &gt; 25) of the Rotterdam study (57.5% women, mean age 70.6 years). Antidepressant use was extracted from pharmacy records from 1991 until baseline (2002–2008). Incident dementia was monitored from baseline until 2018, with repeated cognitive assessment and magnetic resonance imaging (MRI) every 4 years. RESULTS: Compared to never use, any antidepressant use was not associated with dementia risk (hazard ratio [HR] 1.14, 95% confidence interval [CI] 0.92–1.41), or with accelerated cognitive decline or atrophy of white and gray matter. Compared to never use, dementia risk was somewhat higher with tricyclic antidepressants (HR 1.36, 95% CI 1.01–1.83) than with selective serotonin reuptake inhibitors (HR 1.12, 95% CI 0.81–1.54), but without dose–response relationships, accelerated cognitive decline, or atrophy in either group. DISCUSSION: Antidepressant medication in adults without indication of cognitive impairment was not consistently associated with long-term adverse cognitive effects. Highlights: Antidepressant medications are frequently prescribed, especially among older adults. In this study, antidepressant use was not associated with long-term dementia risk. Antidepressant use was not associated with cognitive decline or brain atrophy. Our results support safe prescription in an older, cognitively healthy population.</p

Cluster-Based White Matter Signatures and the Risk of Dementia, Stroke, and Mortality in Community-Dwelling Adults

Background and ObjectivesMarkers of white matter (WM) injury on brain MRI are important indicators of brain health. Different patterns of WM atrophy, WM hyperintensities (WMHs), and microstructural integrity could reflect distinct pathologies and disease risks, but large-scale imaging studies investigating WM signatures are lacking. This study aims to identify distinct WM signatures using brain MRI in community-dwelling adults, determine underlying risk factor profiles, and assess risks of dementia, stroke, and mortality associated with each signature.MethodsBetween 2005 and 2016, we measured WMH volume, WM volume, fractional anisotropy (FA), and mean diffusivity (MD) using automated pipelines on structural and diffusion MRI in community-dwelling adults aged older than 45 years of the Rotterdam study. Continuous surveillance was conducted for dementia, stroke, and mortality. We applied hierarchical clustering to identify separate WM injury clusters and Cox proportional hazard models to determine their risk of dementia, stroke, and mortality.ResultsWe included 5,279 participants (mean age 65.0 years, 56.0% women) and identified 4 distinct data-driven WM signatures: (1) above-average microstructural integrity and little WM atrophy and WMH; (2) above-average microstructural integrity and little WMH, but substantial WM atrophy; (3) poor microstructural integrity and substantial WMH, but little WM atrophy; and (4) poor microstructural integrity with substantial WMH and WM atrophy. Prevalence of cardiovascular risk factors, lacunes, and cerebral microbleeds was higher in clusters 3 and 4 than in clusters 1 and 2. During a median 10.7 years of follow-up, 291 participants developed dementia, 220 had a stroke, and 910 died. Compared with cluster 1, dementia risk was increased for all clusters, notably cluster 3 (hazard ratio [HR] 3.06, 95% CI 2.12-4.42), followed by cluster 4 (HR 2.31, 95% CI 1.58-3.37) and cluster 2 (HR 1.67, 95% CI 1.17-2.38). Compared with cluster 1, risk of stroke was higher only for clusters 3 (HR 1.55, 95% CI 1.02-2.37) and 4 (HR 1.94, 95% CI 1.30-2.89), whereas mortality risk was increased in all clusters (cluster 2: HR 1.27, 95% CI 1.06-1.53, cluster 3: HR 1.65, 95% CI 1.35-2.03, cluster 4: HR 1.76, 95% CI 1.44-2.15), compared with cluster 1. Models including clusters instead of an individual imaging marker showed a superior goodness of fit for dementia and mortality, but not for stroke.DiscussionClustering can derive WM signatures that are differentially associated with dementia, stroke, and mortality risk. Future research should incorporate spatial information of imaging markers.</p