The Journal of Prevention of Alzheimer's Disease最新文献

β-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer’s disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer’s Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current β-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases.

Background

Both blood (plasma and serum) and CSF tau phosphorylated at Threonine 217 (pTau217) have been shown to be able to discriminate early to mild Alzheimer’s disease (AD) from non-AD neurodegenerative disorders and healthy controls with high sensitivity and specificity.

Objectives

We report the full validation of the ALZpath ultra-sensitive pTau217 research-use only (RUO) assays for human EDTA plasma, serum, and CSF using the Quanterix Simoa HD-X platform, in support of clinical trials and early diagnosis of Alzheimer’s disease.

Methods

The ALZpath pTau217 Simoa Advantage v2 kit from ALZpath/Quanterix was used for method development and validation of pTau217 in human plasma, serum, and CSF. All three method validations have followed the 2018 FDA BMV and 2022 ICH M10 guidelines.

Results

Validation of pTau217 quantitation in human plasma, serum, and CSF demonstrated that the validated pTau217 assay has an analytical LLOQ of 0.00977 pg/mL. It is one of the most sensitive assays with a minimal required sample volume of 33.3 µl for plasma and serum, and 5 µl for CSF, and is relatively cost-effective, compared to the currently published data. The minimum required dilution (MRD) for plasma, serum, and CSF were determined. The analyte passed short-term stability tests. It was also tolerant of moderate hemolytic, and lipemic interferences in plasma and serum. pTau217 was detected in 100% of tested healthy control plasma, 90.0% of healthy control serum, 92.3% of healthy control CSF samples, and 100% of AD plasma and CSF samples. The validated assay was successfully applied in the analysis of AD samples, with data showing dramatic differences in the pTau217 levels between healthy control subjects and AD patients in both plasma and CSF.

Conclusion

Validation of the ALZpath pTau217 Simoa assay in human plasma, serum, and CSF demonstrates ultra sensitivity, high accuracy, and assay robustness. Together with other established and sensitive assays for pTau181, GFAP, and NfL, these assays have immediate utility for application in clinical trials and can play a role in the early diagnosis of neurodegenerative diseases.

Background

Care trajectories were disrupted during the COVID-19 pandemic. However, how COVID-19 influenced the number of new dementia diagnoses, and the quality of dementia work-ups, and treatment is understudied.

Objective

To investigate the change in new dementia registrations, diagnostics, and treatment in the pre-, COVID-19 and post-COVID-19 pandemic periods.

Design

A nationwide cohort study.

Setting

This population-based study used data from the Swedish Registry for Cognitive/Dementia disorders - SveDem, and other nationwide registries in Sweden.

Participants

Persons with dementia diagnosed between 2019 and 2021 were divided into three groups based on the date of diagnosis

the pre-COVID-19 period (01 January 2019 – 29 February 2020), the COVID-19 period (01 March 2020 – 31 December 2020), and the post-COVID-19 period (01 January 2021 – 31 August 2021).

Measurements

Outcomes included dementia diagnostics and treatments.

Results

The monthly average number of new dementia cases registered in SveDem was 595, 415 and 470, respectively in the pre-COVID-19, COVID-19 and post-COVID-19 period. Compared to the pre-COVID-19 period, the monthly number of registrations decreased, but provision of the basic diagnostic work-up, its individual tests, and the use of cholinesterase inhibitors, memantine and antipsychotics were not significantly different in the COVID-19 period. Compared to the pre-COVID-19 period, new dementia diagnoses continued to be low in the post-COVID-19 period, but diagnosed individuals were more likely to receive the complete basic diagnostic work-up (OR 1.14, 95% CI 1.00–1.29), blood analysis (OR 1.88, 95% CI 1.44–2.49), computed tomography and magnetic resonance imaging (OR 1.22, 95% CI 1.01–1.48), occupational therapy assessment (OR 1.13, 95% CI 1.04–1.22), and memantine (OR 1.19, 95% CI 1.07–1.31).

Conclusion

The quantity of new dementia registrations in SveDem decreased in the COVID-19 period and has not returned to pre-COVID-19 levels, but the quality of the work-ups which were conducted and registered in SveDem was similar or higher than in the pre-COVID-19 period. It is imperative to implement policies to increase SveDem registration with the aim of matching or exceeding pre-COVID-19 levels.

Background

Despite higher dementia prevalence in racial and ethnic minoritized communities, they are underrepresented in Alzheimer’s disease clinical trials. Community-based recruitment strategies are believed to yield positive outcomes in various fields, such as cancer and cardiovascular clinical trials, but their outcomes in Alzheimer’s disease and Related Dementias (AD/ADRD) require further study. In this systematic rapid review, we synthesized the available evidence on community-engaged recruitment strategies in enhancing participation in AD/ADRD clinical trials and observational study participation.

Methods

We searched and identified studies describing a community-based recruitment approach for racial and ethnic minoritized communities across seven databases (Pubmed, OVID MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL, PsychINFO, Web of Science, and EMBASE).

Results

Out of 1915 screened studies, 49 met the inclusion criteria. Most studies employed multiple community-based recruitment approaches, including educational presentations, collaborations with community-based faith organizations, community advisory boards, and engagement with local clinics or health professionals. 52% of studies targeted more than one racial and ethnic minoritized population, primarily African Americans and then Hispanic/Latino. Gaps in knowledge about AD/ADRD, its increased risk among minoritized populations, distrust, and stigma were noted as barriers to research participation. Approximately 50% of the studies specified whether they evaluated their recruitment approaches, and in studies where approaches were evaluated, there was substantial heterogeneity in methods utilized.

Conclusion

The quality of available evidence on the use of community-based recruitment approaches to include racial and ethnic minoritized populations in AD/ADRD research, particularly in clinical trials, is limited. Systematic assessment of recruitment strategies is urgently needed to increase the evidence base around community-engaged recruitment approaches.

Background

Plasma biomarkers of Alzheimer’s disease (AD), especially p-tau217, are promising tools to identify subjects with amyloid deposition in the brain, determined either by cerebrospinal fluid (CSF) or positron emission tomography. However, it is essential to measure them in an accurate and fully automated way in order to apply them in clinical practice.

Objectives

To evaluate the diagnostic performance of the fully-automated Lumipulse plasma p-tau217 assay in preclinical AD.

Design

Cross-sectional analyses from a prospective cohort.

Setting

A population-based study.

Participants

Volunteers over 55 years without cognitive impairment or contraindications for complementary tests.

Measurements

Plasma p-tau217 was measured with the fully-automated Lumipulse assay, as well as CSF Aβ40, Aβ42, p-taul81, and t-tau levels. We correlated plasma p-tau217 with CSF Aβ40, Aβ42 and p-tau181, and assessed the differences in plasma p-tau217 according to CSF amyloid status (A−/+), AD status (AD+ being those subjects A+T+ and AD- the rest) and ATN group. We performed ROC curves and measured the areas under the curve (AUC) using CSF amyloid as result, and both p-tau217 and ApoE4 status as predictor.

Results

We screened 209 cognitively unimpaired volunteers with a mean age 64 years (60–69) and 30.2% of ApoE4 carriers. Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho=−0.51; p-value<0.001) and p-tau181 (r=0.59; p-value<0.001). Its levels were significantly higher in A+ subjects (0.26 pg/ml) compared with A- (0.12 pg/ml; p-value<0.001); and along ATN groups. It predicts CSF amyloid pathology with an AUC of 0.85.

Conclusions

Plasma p-tau217 measured using the Lumipulse platform shows promise as an accurate biomarker of preclinical AD pathology.

Background

CT1812 is a first-in-class, sigma-2 receptor ligand, that prevents and displaces binding of amyloid beta (Aβ) oligomers. Normalization of quantitative electroencephalography (qEEG) markers suggests that CT1812 protects synapses from Aβ oligomer toxicity.

Objectives

Evaluate CT1812 impact on synaptic function using qEEG measurements.

Design

Phase 2, randomized, double-blind, placebo-controlled, 4-week crossover study.

Setting

VU University Medical Center and Brain Research Center Amsterdam, The Netherlands.

Participants

Adults with mild or moderate Alzheimer’s disease (AD).

Intervention

A daily 300 mg dose of CT1812 or placebo for 4 weeks.

Measurements

A resting-state, eyes closed qEEG assessment occurred on Day 1 and on Day 29 of Treatment Periods 1 and 2, and at follow-up. The primary endpoint was global relative theta power (4–8 Hz), along with secondary EEG measures including global alpha corrected Amplitude Envelope Correlation (AEC-c). Cognitive and functional assessments, fluid biomarkers, and safety and tolerability were assessed.

Results

16 patients were randomized, and 15 completed. A non-significant (p=0.123) but consistent reduction occurred in global relative theta power and in relative theta power in frontal, temporal, parietal, occipital and central (p<0.006) brain regions with CT1812. A nominally significant (p=0.034) improvement was observed in global alpha AEC-c. Adverse events occurred in 11 patients with CT1812 and 6 with placebo -most commonly nausea, diarrhea, and procedural headache. No severe or serious AEs, deaths or discontinuations were reported.

Conclusion

CT1812 improved established EEG markers of spontaneous brain activity (spectral power, functional connectivity) in patients with mild-to-moderate AD, suggesting improved neuronal/synaptic function within a 4-week timespan.

Background

Biomarker results are increasingly disclosed in research and clinical settings, but less is known about how individuals interpret their results or concerns raised during the disclosure visit that may need to be addressed by clinicians to ensure appropriate disclosure.

Methods

Fifty-two cognitively unimpaired older adults aged 65 to 89 years old from the Wisconsin Registry for Alzheimer’s Prevention, who had undergone an amyloid PET scan in the previous 18 months, were enrolled in the disclosure substudy. After ensuring psychological readiness, trained study clinicians disclosed amyloid PET results using a structured protocol. We assessed participants’ level of understanding, concerns, and the perceived personal significance of their biomarker results during the disclosure visit through a series of question prompts in real-time.

Results

Thirty-four received a non-elevated amyloid result and 18 received an elevated result. The average age was 72.2 years (range 65–81); most were women (64%) and non-Hispanic White (92%). Participants understood their results (98%), and both non-elevated and elevated groups provided similar responses around topics of sharing with others, privacy, accuracy of testing, and risk. Participants with elevated results were significantly more likely than those with non-elevated results to want to change their lifestyle (78% vs 12%, p=<0.01) and have questions about their results (61% vs 30%, p=0.05). Participants interpreted the personal significance of results in terms of several themes relating to individual risk status, emotional impact, whether the result was expected, and prevention/planning.

Conclusion

Results show that participants understand their biomarker results, and have a number of concerns during the disclosure process that clinical and research protocols could address. en These findings could be important considerations as effective processes are developed for widespread biomarker disclosure in clinical and research settings.

Background

Alzheimer’s disease (AD) has a high comorbidity with type 2 diabetes (T2D). However, there is still some controversy over whether T2D has a causal impact on AD at present.

Objectives

We aimed to reveal whether T2D has a causal effect on AD using large-scale genetic data.

Methods

Firstly, we performed a primary two-sample Mendelian randomization (MR) analysis to assess the potential causal effects of T2D on AD. For this analysis, we used the largest available genome-wide association studies (GWAS) T2D (T2D1, including 80,154 cases and 853,816 controls) and AD (AD1, including 111,326 cases and 677,663 controls) datasets. Additionally, we performed a validation MR analysis using two largely overlapping-sample datasets from FinnGen, including T2D (T2D2, including 57,698 cases and 308,252 controls) and AD (AD2, including 13,393 cases and 363,884 controls). In all MR analyses, the inverse variance-weighted method was used as the primary analysis method, supplemented by the weighted-median and MR-Egger techniques.

Results

In the primary analysis, we found that T2D was not associated with the risk of AD (OR: 0.98, CI: 0.95–1.01, P=0.241). Similarly, no significant association was detected in the validation MR analysis (OR: 0.97, CI: 0.64–1.47, P=0.884).

Conclusion

Our findings provide robust evidence that T2D does not have a causal impact on AD. Future studies need to further explore the effect of T2D on the non-AD components of the dementia phenotype.

Background

Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer’s disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway.

Objectives

We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies.

Design

EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia).

Setting

These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50–85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia.

Intervention

Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks.

Measurements

The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity.

Results

Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with am

Background

Sleep disturbances as well as cortisol hypersecretion are increasingly acknowledged as risk factors for Alzheimer’s disease (AD). However, the mechanisms underlying the association, and the interplay with cortisol abnormalities, remain unclear.

Objectives

This study aims to identify how self-reported sleep disturbances are associated with structural brain measures and diurnal cortisol dysregulation among memory clinic patients.

Design

A cross-sectional study performed at Karolinska University Hospital Memory Clinic, Sweden.

Participants

The study was based on 146 memory clinic patients diagnosed with either subjective cognitive impairment or mild cognitive impairment.

Measurements

Self-reported sleep was measured using the Karolinska Sleep Questionnaire. MRI or CT was used to quantify structural brain measures using four visual rating scales (Scheltens, Pasquier, Koedam, and Fazekas scales), and salivary cortisol was sampled to measure diurnal cortisol patterns through measures of cortisol immediately after awakening, cortisol awakening response, bedtime cortisol, total cortisol from awakening to bedtime, and the AM/PM cortisol ratio.

Results

Increased sleep apnea index (OR=1.20, 95% CI=1.04:1.39, p=0.015) was associated with greater odds of posterior brain atrophy, measured by the Koedam visual rating scale, and reduced awakening Cortisol (β=−0.03, 95% CI=− 0.07:0.00, p=0.045). Increased daytime sleepiness was associated with both reduced awakening cortisol (β=−0.03, 95% CI=−0.06:0.00, p=0.025) and a reduced AM/PM cortisol ratio (β=−0.04, CI=−0.08:−0.01, p= 0.021).

Conclusion

In a memory clinic cohort self-reported sleep disturbances are associated with both worse structural brain tissue integrity and altered diurnal cortisol profiles. These findings may add insights into possible mechanisms behind sleep disturbances in aging with subjective and cognitive impairment.