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

Background and Objectives

On July 6, 2023 the U.S. Food and Drug Administration approved the anti-amyloid monoclonal antibody lecanemab (Leqembi®) for treatment of patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD). Our early experience and lessons learned with lecanemab in a regional community medical center are described.

Design, Setting, and Participants

This retrospective observational study highlights the first 71 patients treated with lecanemab at our multidisciplinary Norton Neuroscience Institute Memory Center. All patients had positive cerebrospinal fluid biomarkers for AD and underwent at least 1 lecanemab infusion. Two patients had additional amyloid PET scans which were positive.

Results

The mean age was 72 years (49–90 years), and 44 (62%) patients were female. Most were Caucasian (68 [96%]), and 54 [76%] were referred to our Memory Center by their primary care provider. Comorbidities were common, including hypertension (34 [48%]), hypercholesterolemia (51 [72%]), diabetes mellitus (17 [24%]), and cardiovascular disease excluding hypertension (22 [31%]). The mean body mass index was 27.0 (range: 17.8–45.0). A total of 36 (51%) patients were heterozygous for the ApoE4 genotype, and 9 (13%) were homozygous. A total of 61 [86%] patients had been treated with donepezil; 40 (56%) patients had received memantine. Of the 50 patients who completed 1 or more safety monitoring brain MRIs following infusion, 12 (24%) had amyloid-related imaging abnormalities (ARIA) detected: solitary ARIA-H (hemorrhage) in 5, solitary ARIA-E (edema) in 3, and both ARIA-H and ARIA-E in 4. Of the 12 patients with ARIA, 9 were asymptomatic, 4 were homozygous for the ApoE4 genotype, and 6 were heterozygous for the ApoE4 genotype. Of the 9 who were homozygous for the ApoE4 genotype in this study, 4 (44%) had evidence of ARIA. Of the 36 who were heterozygous for the ApoE4 genotype, 6 (17%) were diagnosed with ARIA. Twenty-six (37%) patients experienced infusion reactions after their first lecanemab infusion: headaches (12 patients) and shaking/chills/rigors (11 patients) were most common. Twenty-three (88%) of these 26 patients reported the side effects either at the infusion center or within the first 24 hours post-infusion. One patient died shortly after the first lecanemab infusion of a myocardial infarction. It is uncertain whether or not this death was related to lecanemab treatment.

Conclusion

Through our early experience with lecanemab, we have recognized several areas of improvement which have clarified and enhanced the lecanemab infusion experience.

Background

Many cognitively unimpaired older adults are interested in learning their Alzheimer’s disease (AD) biomarker status, but little is known about motivations to undergo biomarker testing and result disclosure in the setting of preclinical AD trials.

Objectives

Examine whether motivations to undergo AD biomarker testing and disclosure differ for individuals who have elevated amyloid compared to those with not elevated amyloid, and whether disclosure of amyloid results impacts participants’ motivations.

Design, Setting, Participants

We conducted post-hoc analyses using data from the EARLY study, a preclinical AD trial of the beta-secretase inhibitor atabecestat. As part of the screening process of the trial, participants underwent biomarker testing and disclosure. We analyzed data from n=2241 participants.

Measurements

We analyzed data from the Views and Perceptions of Amyloid Imaging (VPAI), a 9-item questionnaire assessing how strongly participants agreed with motivating factors for undergoing amyloid testing. The VPAI was administered at the first screening visit and again after amyloid disclosure.

Results

Prior to amyloid disclosure, a greater proportion of participants in the elevated amyloid group responded at the two highest levels of endorsement for the items, “to confirm the feeling that I might already be developing symptoms of AD dementia” (p<0.001) and “to prepare my family for my possible illness in the future” (p=0.008), compared to participants in the not elevated amyloid group. Following disclosure, the not elevated amyloid group had higher odds of positive change in categorical VPAI item level scores for the items “to put mind at ease” (OR: 0.54; p<0.001), “to confirm the feeling that I might already be developing symptoms of AD dementia” (OR: 0.79; p=0.049), and “to prepare my family for my possible illness in the future” (OR: 0.67; p=<0.001), while the elevated amyloid group had higher odds of positive change for the item “curiosity” (OR:1.32; p=0.014).

Conclusions

Investigators might consider adjusting recruitment strategies for future trials to align with the motivations to undergo biomarker testing and disclosure most strongly endorsed by participants with elevated amyloid.

Background

Shift work, the proven circadian rhythm-disrupting behavior, has been linked to the increased risk of Alzheimer’s disease (AD). However, the putative causal effect and potential mechanisms of shift work for AD were still unclear.

Methods

Mendelian randomization (MR) analysis was performed to discover the putative causal effect of shift work for AD. Expression quantitative trait loci (eQTLs) and transcriptome data were integrated to identify genes causally associated with AD from circadian-related genes. An in vitro experiment was also conducted to validate the expression of target genes. Based on the identified genes, a novel integrative program and 4,077 samples from 16 microarray datasets were leveraged to assess the extent of circadian rhythm disruption (CRD), defined as the clock deviation level (CDL).

Findings/Results

Shift work causally increased the risk of AD [odds ratio (OR) = 2.49, 95% CI = 1.79 - 3.19, p = 0.01]. Seven circadian-related genes were causally associated with AD, including CCS, CDS2, MYRIP, NRP1, PLEKHA5, POLR1D, and PPP4C. These genes were significantly correlated with the circadian rhythm pathway. CDL was higher in CRD mice group, shift work group, sleep restriction group, and AD patients compared to control mice group (p = 0.043), non-shift group (p = 0.004), sleep extension group (p = 0.025), and health controls (multiple cohorts, p < 0.05). Additionally, CDL was also significantly correlated with AD’s clinical biomarkers.

Interpretations/Conclusion

By combining GWAS and transcriptome data, this study demonstrated the causal role of CRD behavior in AD, identified the potential target genes in shift work-induced AD, and generated CDL to characterize CRD status, which provided evidence and prospects for disease prevention and future therapeutic interventions.

Background

Arterial hypertension contributes to both the development and progression of dementia due to both Alzheimer’s disease (A.D.) and vascular pathology. However, the effects of different classes of anti-hypertensives (A.H.T.s), on the rate of dementia progression and brain neuropathology are unknown.

Objective

To investigate the effect of each class of A.H.T., both as single and combined, on the rate of dementia progression. In addition, we analyzed the effect of A.H.T.s on brain neuropathology in AD participants, indicated by Braak staging, hippocampal atrophy, and baseline CSF levels of A-β42, total (T) tau, and P-181 tau.

Methods

We have used the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS).

Results

A.H.T.s were associated with reduced yearly increase in the CDR-SOB scores of 1.025 during a 10-year follow-up (P<0.001). The overall survival rate was higher in A.H.T. users than non-users [HR: 0.912: 0.860, 0.967) P=0.002]. These trends continued when stratifying participants by age, gender, and APOE4 allele. Participants who did not use A.H.T.s had a mean yearly increase of 1.71±1.7 in the CDR-SOB scores. This value was reduced to 1.48±1.6, P=0.006 and 1.45±1.6, P=0.024 for participants with documented use of βB and A.R.B.s, respectively. Combining diuretics with α1-AB or ACEI led to synergistic effects in reducing the rise in CDR-SOB scores. The proportion of participants who were diagnosed having AD postmortem with severe Braak staging was significantly lower in A.H.T.-users than non-users. The severity of Braak staging, and hippocampal atrophy differed in participants >70 vs. <70 years old, in both males and females. A significant relationship was observed between hippocampal atrophy and Braak staging; and between hippocampal atrophy and baseline CSF levels of P-181 tau.

Conclusion

Our results could have implications for halting the progression of dementia regardless of the etiology being related to AD or vascular pathology. The choice of combination of A.H.T. therapy should also consider the combination which would lead to an optimum benefit in slowing the progression of dementia. Additionally, our results underline a more complex A.D. disease model than previously thought, which opens new treatment options.

Background

The potential of biomarkers in the detection of Alzheimer’s disease (AD) is prominent. Acoustics may be useful in this context but the evaluation and weighting for specific acoustic parameters on continuous speech is missing. This meta-analysis aimed to explore the significance of acoustic parameters from acoustic speech analysis on continuous speech, as a diagnostic tool for clinical AD.

Methods

Applying PRISMA protocol, a comprehensive search was done in MEDLINE, Scopus, Web of Science, and CENTRAL, from 1960 to January 2024. Cross-sectional studies comparing the acoustic speech analysis between AD patients and healthy controls (HC), were taken into account. The bias risk of the included studies were examined via JBI checklist. Using Review Manager v.5.4.1, the mean differences of acoustic speech parameters among AD and HC were weighted, and the pooled analysis and the heterogeneity statistics were conducted.

Results

In total, 1112 records (without duplicates) were obtained, and 11 papers with 7 acoustic parameters were included for this study, and 8 from 11 studies were identified with a low level of bias. Five from 7 acoustic parameters revealed significant differences among the two groups (p-values ≤ 0.01), in which for all rate-related and interruption-related acoustic parameters were the most prominent and less in temporal-related acoustic parameters.

Conclusions

Although a small number of acoustic parameters on continuous speech could be evaluated in the detection of clinical AD, the greatest potential of acoustic biomarkers for AD appeared to exist in two of three categories. Further contributions of high-quality studies are needed to support evidence for acoustics as biomarkers for AD.

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.