Alzheimer''s and Dementia: Translational Research and Clinical Interventions最新文献

Introduction: The societal costs of dementia and cognitive decline are substantial and likely to increase during the next decades due to the increasing number of people in older age groups. The aim of this multicenter cluster-randomized controlled trial was to assess the cost-effectiveness of a multi-domain intervention to prevent cognitive decline in older people who are at risk for dementia.

Methods: We used data from a multi-centric, two-armed, cluster-randomized controlled trial (AgeWell.de trial, ID: DRKS00013555). Eligible participants with increased dementia risk at baseline (Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE Dementia Risk Score ≥ 9), 60-77 years of age, were recruited by their general practitioners, and assigned randomly to a multi-domain lifestyle intervention or general health advice. We performed a cost-effectiveness analysis from the societal perspective. The time horizon was 2 years. Health care utilization was measured using the "Questionnaire for Health-Related Resource Use in Older Populations." As effect measure, we used quality-adjusted life-years (QALYs) based on the 5-level EQ-5D version (EQ-5D-5L). We calculated the incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves (CEAC) using the net-benefit approach. Exploratory analyses considering women and the EQ visual analogue scale (EQ VAS) were conducted.

Results: Data were available for 819 participants (mean age 69.0 [standard deviation (SD)5-level EQ-5D version 4.9]); 378 were treated in the intervention group and 441 in the control group. The participants in the intervention group caused higher costs (+€445.88 [SD: €1,244.52]) and gained additional effects (+0.026 QALY [SD: 0.020]) compared to the participants in the control group (the difference was statistically significant). The ICER was €17,149.23/QALY. The CEAC showed that the probability of the intervention being cost-effective was moderate, reaching 59% at a willingness-to-pay (WTP) of €50,000/QALY. The exploratory analyses showed promising results, especially in the female subsample.

Discussion: Considering aspects like the WTP and the limited time horizon, the multi-domain intervention was cost-effective compared to general health advice.

Highlights: The first German randomized controlled trial (RCT) evaluating a multicomponent approach against cognitive decline.We found a favorable incremental cost-effectiveness ratio.The probability of cost-effectiveness reached 78.6%.Women could be an important target group.A longer time horizon is needed.

Introduction: Corneal confocal microscopy (CCM) detects neurodegeneration in mild cognitive impairment (MCI) and dementia and identifies subjects with MCI who develop dementia. This study assessed whether abnormalities in corneal endothelial cell (CEC) morphology are related to corneal nerve morphology, brain volumetry, cerebral ischemia, and cognitive impairment in MCI and dementia.

Methods: Participants with no cognitive impairment (NCI), MCI, and dementia underwent CCM to quantify corneal endothelial cell density (CECD) and area (CECA), corneal nerve fiber morphology, magnetic resonance imaging (MRI) brain volumetry, and severity of brain ischemia.

Results: Of the 114 participants, 14 had NCI, 77 had MCI, and 23 had dementia. CECD (1971.3 ± 594.6 vs 2316.1 ± 499.5 cells/mm², p < 0.05) was significantly lower in the dementia compared to the NCI group. CECD and CECA were comparable between the MCI and NCI groups (p = 0.13-0.65). Corneal nerve fiber density (CNFD) (31.7 ± 5.6 vs 24.5 ± 9.2 and 17.3 ± 5.3 fibers/mm², p < 0.01), corneal nerve branch density (CNBD) (111.8 ± 58.1 vs 50.4 ± 36.4 and 52.7 ± 21.3 branches/mm², p < 0.0001), and corneal nerve fiber length (CNFL) (24.6 ± 6.6 vs 16.5 ± 6.8 and 16.2 ± 5.0 mm/mm², p < 0.0001) were lower in the MCI and dementia groups compared to the NCI group. Lower CECD partially mediated the impact of age and diabetes on CNFL reduction (p < 0.05), whereas CECA lost its significance after adjustment (p = 0.20). CEC morphology does not affect the association between corneal nerve fiber loss and MCI/dementia. CECD and CECA had no significant association with cerebral ischemic lesions (p = 0.21-0.47), dementia (p = 0.11-0.35), or cognitive decline (p = 0.37-0.38). However, lower CECD and higher CECA were associated with decreased cortical gray matter volume (p < 0.05-0.01).

Discussion: CEC loss occurs in patients with dementia, and both endothelial cell loss and hypertrophy are associated with cortical gray matter atrophy. CNF loss occurs in individuals with MCI and dementia. Corneal nerve and endothelial cell abnormalities could act as biomarkers for neurovascular pathology in dementia.

Highlights: Corneal endothelial cell density is significantly reduced in patients with dementia.Corneal nerve fiber density, branch density, and length are lower in subjects with mild cognitive impairment (MCI) and dementia.Corneal endothelial cell loss and hypertrophy are associated with cortical gray matter atrophy.Corneal nerve and endothelial cell abnormalities could act as biomarkers for neurovascular pathology in dementia.Reduced corneal endothelial cell density partially mediates the effects of age and diabetes on corneal nerve fiber loss.

Introduction: Anthropometric, demographic, genetic, and clinical features may affect cognitive, behavioral, and functional decline, while clinical trials seldom consider minimal clinically important differences (MCIDs) in their analyses.

Methods: MCIDs were reviewed taking into account features that may affect cognitive, behavioral, or functional decline in clinical trials of new disease-modifying therapies.

Results: The higher the number of comparisons of different confounders in statistical analyses, the lower P values will be significant. Proper selection of confounders is crucial to accurately assess MCIDs without compromising statistical significance.

Discussion: Statistical adjustment of the significance of MCIDs according to multiple comparisons is essential for the generalizability of research results. Wider inclusion of confounding variables in the statistics may help bring trial results closer to real-world conditions and improve the prediction of the efficacy of new disease-modifying therapies, though such factors must be carefully selected not to compromise the statistical significance of the analyses.

Highlights: Anthropometric, demographic, and clinical features may affect cognitive, behavioral, and functional decline.Clinical trials seldom take minimal clinically important differences (MCIDs) or their confounders into account.Generalizability of research results requires the assessment of multiple confounding factors.The higher the number of comparisons involved, the lower P values will be considered significant.Use of MCIDs adjusted for confounding factors should be implemented when outcomes are not susceptible to translation into absolute benefits.

Introduction: The impact of cholesterol on late-life cognition remains controversial. We investigated the association of high-density lipoprotein cholesterol (HDL-C) and non-HDL-C with memory in a nationally representative cohort.

Methods: Health and Retirement Study (HRS) participants (N = 13,258) aged 50+ (mean age: 67.2 years) followed from 2006 to 2020 provided cholesterol measures every 4 years and cognitive assessments biennially. Linear mixed models predicted memory scores using both baseline and time-updated cholesterol values.

Results: Higher baseline HDL-C (mean: 53.9 mg/dL) predicted better memory scores (β: 0.05, 95% confidence interval [CI]: 0.03 to 0.08), but not memory change. Baseline non-HDL-C (mean: 143 mg/dL) predicted poorer memory scores (β: -0.01, 95% CI: -0.02 to 0.00), but not memory change. Time-updated HDL-C predicted better memory (β: 0.02, 95% CI: 0.00 to 0.04), but non-HDL-C showed no such associations.

Discussion: While higher peripheral HDL-C is linked to better memory, the small effect sizes and absence of associations of HDL-C and non-HD-CL with memory change suggests that peripheral cholesterol has a small effect on the variation of memory scores.

Highlights: Higher HDL-C levels predict better memory scores but not memory change across 14 years of follow-up.Baseline higher LDL-C levels predict poorer memory scores across time, but not memory change.The small effects and absence of consistent association between cholesterol levels and memory change suggest that cholesterol plays a minor role in cognitive decline.

Introduction: Without disease-modifying interventions, Medicare and Medicaid spending on Alzheimer's disease (AD) management is expected to reach 637 billion USD annually by 2050. The recent advent of promising AD therapies after decades of a near-total failure rate in clinical trials suggests that more disease-modifying therapies are on the horizon. In this review, we assess the late-stage pipeline of disease-modifying candidates for AD and offer a novel classification of intervention candidates by treatment paradigms-groups of candidates that share an underlying biological mechanism of action and general disease target.

Methods: We extracted data from the National Library of Medicine clinical trials database regarding Phase 2 and 3 trials of disease-modifying AD therapies. We categorized trials into eight unique treatment paradigms, which we defined by combinations of therapy (biologic, small molecule, cell and gene therapy, other) and target (amyloid, tau, other). We analyzed primary endpoints, eligibility criteria including clinical ratings of cognition, trial phase and length, and funding sources.

Results: We identified 123 unique disease-modifying intervention candidates in 175 late-stage clinical trials. Biologic and small molecule drugs comprised 30% and 54% of trials, respectively. Eligibility criteria favored patients between the ages of 60 and 80 years with mild cognitive impairment. Including multi-phase trials, 81% of studies were engaged in Phase 2 and 27% in Phase 3. Notably, within the Biologic-Amyloid paradigm, 64% of trials were engaged in Phase 3.

Discussion: Current studies of disease-modifying therapies for AD comprise a diverse set of approaches to treating the disease. However, effort is largely concentrated in a few treatment paradigms and a narrow patient population, causing varying rates of progress among treatment paradigms in the late-stage clinical trial pipeline. Strategies may be warranted to accelerate successes in the most promising therapeutical paradigms and nurture growth within nascent areas lacking resources but not potential.

Highlights: An analysis of Alzheimer's disease trial treatment paradigms was conducted.From April 2021 to March 2023, 175 trials of 123 unique candidates were reviewed.Biologic and small molecule drugs comprised 30% and 54% of trials, respectively.Eligibility criteria favored ages 60 through 80 with mild cognitive impairment.

Introduction: The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD.

Methods: A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure-based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O-GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy.

Results: Ceperognastat is a potent, central nervous system (CNS)-penetrant, low-dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat.

Discussion: Ceperognastat is an orally available, highly potent, CNS-penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O-GlcNAc-tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program.

Highlights: Ceperognastat is a highly potent, CNS-penetrant OGA inhibitor.Ceperognastat is both orally available and CNS-penetrant even when given at low doses.Ceperognastat can achieve > 95% OGA enzyme occupancy in the animal and human brain.Ceperognastat had an acceptable safety profile in Phase 1 clinical studies.