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

Background

A decline in episodic memory is one of the earliest cognitive characteristics of Alzheimer disease and memory tests are heavily featured in cognitive composite endpoints that are used to demonstrate treatment efficacy. Assessments of episodic memory can take many forms including free recall, associate learning, and paragraph or story recall. Plasma biomarkers of Alzheimer disease are now widely available and will likely form the backbone of cohort enrichment strategies for future clinical trials. Thus, it is critical to evaluate which episodic memory measures are most sensitive to plasma markers of Alzheimer disease pathology.

Objectives

To compare the associations of common episodic memory tests with plasma biomarkers of Alzheimer disease.

Design

Longitudinal cohort study.

Setting

Academic medical center in the midwestern United States.

Participants

A total of 161 cognitively normal older adults with at least one plasma biomarker assessment and two or more annual clinical and cognitive assessments which included up to three different tests of episodic memory.

Measurements

Episodic memory performance using free recall, paired associates recall or paragraph recall. Plasma Aβ42, Aβ40, ptau217, and neurofilament light chain were measured.

Results

Free recall on the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) was substantially more sensitive to longitudinal cognitive change associated with abnormal baseline plasma Aβ42/Aβ40 and ptau217 compared to other measures of episodic memory. A cognitive composite that included only free recall showed larger decline associated with baseline Aβ42/Aβ40 when compared to those that included paragraph recall. Differences in decline across composites were minimal when considering baseline ptau217 or NfL.

Conclusion

Episodic memory is a critical domain to assess in preclinical Alzheimer disease. Methods of assessing memory are not equal and longitudinal change in free recall substantially outperformed both paired associates and paragraph recall. Clinical trial results will depend critically on the episodic memory test(s) that are chosen for a composite endpoint and free recall from the FCSRT + IR is an optimal memory measure to include rather than paired associates or paragraph recall.

Changes in biomarker levels of Alzheimer’s disease (AD) reflect underlying pathophysiological changes in the brain and can provide evidence of direct and downstream treatment effects linked to disease modification. Recent results from clinical trials of anti–amyloid β (Aβ) treatments have raised the question of how to best characterize the relationship between AD biomarkers and clinical endpoints. Consensus methodology for assessing such relationships is lacking, leading to inconsistent evaluation and reporting. In this review, we provide a statistical framework for reporting treatment effects on early and late accelerating AD biomarkers and assessing their relationship with clinical endpoints at the subject and group levels. Amyloid positron emission tomography (PET), plasma p-tau, and tau PET follow specific trajectories during AD and are used as exemplar cases to contrast biomarkers with early and late progression. Subject-level correlation was assessed using change from baseline in biomarkers versus change from baseline in clinical endpoints, and interpretation of the correlation is dependent on the biomarker and disease stage. Group-level correlation was assessed using the placebo-adjusted treatment effects on biomarkers versus those on clinical endpoints in each trial. This correlation leverages the fundamental advantages of randomized placebo-controlled trials and assesses the predictivity of a treatment effect on a biomarker or clinical benefit. Harmonization in the assessment of treatment effects on biomarkers and their relationship to clinical endpoints will provide a wealth of comparable data across clinical trials and may yield new insights for the treatment of AD.

Background

No multidomain intervention trials have been designed for the prevention of cognitive decline in older adults with type 2 diabetes.

Objectives

To investigate the efficacy of a multidomain intervention in preventing cognitive decline in older adults with type 2 diabetes and cognitive impairment.

Design

Eighteen-month, multi-centered, randomized controlled trial.

Setting

Twelve hospitals in Japan.

Participants

Outpatients with type 2 diabetes aged 70–85 years with cognitive impairment.

Intervention

The multidomain intervention program includes management of metabolic and vascular risk factors, exercise, nutritional counseling, and promotion of social participation. Participants in the control group received usual care and treatment for type 2 diabetes.

Measurements

The primary outcome was the change in a composite score combining several neuropsychological tests from baseline to the 18-month follow-up. To assess the differences in cognitive changes between the intervention and control groups, a mixed-effects model for repeated measures was used.

Results

Between March 13, 2019, and May 8, 2020, 361 participants were screened, and 154 were randomly assigned to either the intervention group (n = 81) or the control group (n = 73). Finally, 110 participants completed the trial. The between-group difference in the composite score changes was 0.068 (95% confidence interval, −0.091 to 0.226). Analyses for secondary outcomes indicated a positive impact of the intervention on memory and indicated that the intervention led to changes in dietary habits with increased intakes of niacin and meat, along with weight reduction compared to the control group.

Conclusion

The multidomain intervention did not demonstrate efficacy in preventing cognitive decline. However, this trial provided proof-of-concept evidence that multidomain interventions may offer cognitive benefits and contribute to changes in dietary behavior and weight reduction in older adults with type 2 diabetes and cognitive impairment. These findings should be confirmed in future studies.

Background

The functions of regulated cell death (RCD) are closely related to Alzheimer’s disease (AD). However, very few studies have systematically investigated the diagnosis and immunologic role of RCD-related genes in AD patients.

Methods

8 multicenter AD cohorts were included in this study, and then were merged into a meta cohort. Then, an unsupervised clustering analysis was carried out to detect unique subtypes of AD based on RCD-related genes. Subsequently, differently expressed genes (DEGs) and weighted correlation network analysis (WGCNA) between subtypes were identified. Finally, to establish an optimal risk model, an RCD. score was constructed by using computational algorithm (10 machine-learning algorithms, 113 combinations).

Results

We identified two distinct subtypes based on RCD-related genes, each exhibiting distinct hallmark pathway activity and immunologic landscape. Specifically, cluster.A patients had a higher immune infiltration, a higher immune modulators and poor AD progression. Utilizing the shared DEGs and WGCNA of these subtypes, we constructed an RCD. score that demonstrated excellent predictive ability in AD across multiple datasets. Furthermore, RCD.score was identified to exhibit the strongest association with poor AD progression. Mechanistically, we observed activation of signaling pathways and effective immune infiltration and immune modulators in the high RCD.score group, thus leading to a poor AD progression. Additionally, Mendelian randomization screening revealed four genes (CXCL1, ENTPD2, METTL7A, and SERPINB6) as feature genes for AD.

Conclusion

The RCD model is a valuable tool in categorizing AD patients. This model can be of great assistance to clinicians in determining the most suitable personalized treatment plan for each individual AD patient.

Evidence-based dementia risk assessment is required to inform individual and policy-level dementia risk reduction interventions. We developed the CogDrisk Short Form (CogDrisk-SF) to assess dementia risk factors, for situations where time and resources are limited. To evaluate concurrent validity with the original CogDrisk, we conducted an online survey using a repeated-measures, counterbalanced design. Community dwelling participants (n = 647, 50.1% were female, mean age 62.2 years, age range 40–89) completed the survey. The mean(sd) score for CogDrisk-SF and the CogDrisk was 9.7 (5.3) and 9.9 (5.5), respectively. The intraclass correlation between the risk score obtained from CogDrisk and CogDrisk-SF was 0.92. Fish intake, insomnia and depression had percentage agreements of 79%, 87% and 89% respectively. Other items had >95% agreement except for loneliness (94%), hypertension (94%), cholesterol (93%), atrial fibrillation (91%) and cognitive activity (90%). Very high agreement between the CogDrisk-SF and original CogDrisk shows that CogDrisk-SF is valid for use in research and clinical practice.

Background

Recently, two monoclonal antibodies that lower amyloid plaques have shown promising results for the treatment of Mild Cognitive Impairment (MCI) and mild dementia due to Alzheimer’s disease (AD). These treatments require the identification of cognitively impaired older adults with biomarker evidence of AD pathology using CSF biomarkers or amyloid-PET. Previous studies showed plasma biomarkers (plasma Aβ42/Aβ40 and p-tau181) and hippocampal volume from structural MRI correlated with brain amyloid pathology. We hypothesized plasma biomarkers with hippocampal volume would identify patients who are suitable candidates for disease-modifying therapy.

Objectives

To evaluate the performance of plasma AD biomarkers and hippocampal atrophy to detect MCI or AD with amyloid pathology confirmed by amyloid-PET or CSF biomarkers in ADNI.

Design

A cross-sectional and longitudinal study.

Setting and Participants

Data were from the Alzheimer’s Disease Neuroimaging Initiative. Participants were aged 55–90 years old with plasma biomarker and structural MRI brain data.

Measurements

The optimum cut-off point for plasma Aβ42/Aβ40, p-tau181, and NFL and the performance of combined biomarkers and hippocampal atrophy for detecting cognitive impairment with brain amyloid pathology were evaluated. The association between baseline plasma biomarkers and clinical progression, defined by CDR-Sum of Boxes (CDR-SB) and diagnostic conversion over two years, was evaluated using a Weibull time-to-event analysis.

Results

A total of 428 participants were included; 167 had normal cognition, 245 had MCI, and 16 had mild AD. Among MCI and AD, 140 participants had elevated amyloid levels by PET or CSF. Plasma Aβ42/Aβ40 provided the best accuracy (sensitivity 79%, specificity 66%, AUC 0.73, 95% CI 0.68–0.77) to detect drug candidate participants at baseline. Combined plasma Aβ42/40, p-tau181, and hippocampal atrophy increased the specificity for diagnosis (96%), but had lower sensitivity (34%), and AUC (0.65). Hippocampal atrophy combined with the abnormal plasma p-tau181 or hippocampal atrophy alone showed high sensitivity to detect clinical progression (by CDR-SB worsening) of the drug-candidate participants within the next 2 years (sensitivity 93% and 89%, respectively).

Conclusion

Plasma biomarkers and structural MRI can help identify patients who are currently eligible for anti-amyloid treatment and are likely to progress clinically, in cases where amyloid-PET or CSF biomarkers are not available.

Background

The Everyday Cognition (ECog) 12-item scale, a functional decline measurement, can distinguish dementia from cognitively unimpaired (CU). Limited data compare ECog-12 performance by raters (self vs. informant) and scoring systems (average numeric vs. categorical grouping) to differentiate cognitive statuses.

Objectives

To evaluate the performance of ECog-12 in differentiation cognitive statuses.

Design

A cross-sectional diagnostic test study.

Setting and Participants

Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study are analyzed. Participants were aged 55–90 years old divided into subgroups based on diagnostic criteria.

Measurements

We evaluated ECog-12 performance across different diagnostic groups, such as CU vs cognitive impairment (CI; mild cognitive impairment (MCI), and dementia), and the association between ECog-12 and CI. This procedure was repeated for self- and partner (informant)-reports. Additionally, types of ECog scores were also assessed, where an average ECog score was calculated (continuous numeric) as well as a categorical grouping (“any occasional declined” or “any consistently declined”) based on item-level responses to ECog questions.

Results

ECog-12 cut-off scores of 1.36 (self-reported) and 1.45 (partner-reported) distinguish CU from CI with AUC 0.7 and 0.78, respectively. Adding a memory-concern question improved self-reported-ECog AUC to 0.79. Self- and partner-reported “consistently-declined” ECog-12 categorical grouping provided AUC 0.69 and 0.78. The study partner reported ECog-12 showed a greater association with CI than self-reported, with odds ratios of 35.45 and 8.79, respectively.

Conclusion

Study partner-reported ECog scores performed better than self-reported ECog-12 in differentiating cognitive statuses, and a higher study partner reported ECog score was a higher prognostic risk for CI. A memory concern question could enhance self-reported ECog-12 performance. This further emphasizes the need to obtain data from study partners for research and clinical practice.

Background

Linking data from clinical trials and real-world claims may improve the robustness of trial data and provide information on the health, economic, and societal impacts of a disease.

Objective

To report on the feasibility of linking trial data to Medicare claims data in early symptomatic Alzheimer’s disease (AD) in the US.

Design and Setting

Alzheimer’s Disease Linkage to Real-World Evidence (AD-LINE) was a noninterventional cohort study that included participants recruited from the GRADUATE program whose trial data were linked to their Medicare claims.

Participants

AD-LINE participants were 66 years and older with early symptomatic AD (ie, mild cognitive impairment [MCI] due to AD or mild AD dementia) and were enrolled in the GRADUATE program and a Medicare fee-for-service or Medicare Advantage plan.

Measurements

The Centers for Medicare & Medicaid Services linked participants’ clinical trial identifiers to their Medicare beneficiary identifiers using a deterministic, exact matching process. Demographics and clinical characteristics of the AD-LINE cohort at baseline were collected. Outcomes measured in this study included healthcare resource utilization derived from Medicare claims data.

Results

In total, 147 participants across 21 US sites were invited to participate and 111 provided informed consent. Of those, 61 patients had linkable data (ie, Medicare beneficiary identifier), Medicare Parts A/B enrollment, and no health maintenance organization (HMO) enrollment in the year before trial entry. Of the 61 participants whose data were analyzed in this study, 30 had MCI due to AD and 31 had mild AD dementia. Participants in the MCI due to AD group had more healthcare resource utilization on average in the baseline period than those in the mild AD dementia group (29.9 [SD, 20.9] vs 24.5 claims [SD, 12.3]). In an ad hoc analysis, a relatively high concordance (85.3%) was seen between the rates of clinically confirmed AD diagnosis and evidence of AD diagnosis in claims data.

Conclusion

This linkage process may serve as a proof of concept for researchers interested in linking clinical trial and real-world claims data. The lessons learned from AD-LINE and innovation of data linkage approaches may encourage key stakeholders to link data in the future.

Background

Fruits are an important source of flavonoids, and greater intake of dietary flavonoids in older adults has been shown to be associated with decreased risk of dementia. It is unclear whether this relationship is similar or different between younger adults and older adults.

Objectives

We examined for associations between midlife and late-life intake of flavonoid-rich fruits and incident dementia. We hypothesized that greater total cumulative intake of flavonoid-rich fruits in midlife and late-life adults would be associated with reduced risk of all-cause dementia.

Design

Longitudinal, cohort study design.

Setting

Framingham Heart Study, which is a longitudinal, multi-generational community-based cohort based in Framingham, Massachusetts, USA.

Participants

Participants from the Framingham Heart Study Offspring cohort were included (n = 2,790) who attended the fifth core exam between 1991 to 1995, and were dementiafree and at least 45 years of age at that time, as well as had valid food frequency questionnaires from the fifth to ninth core exams.

Measurements

Consumption of fruits with high flavonoid content or are important contributors to overall flavonoid intake was collected via food frequency questionnaire. Flavonoid-rich fruits from the food frequency questionnaire included raisins or grapes, prunes, bananas, fresh apples or pears, apple juice or cider, oranges, orange juice, grapefruit, grapefruit juice, strawberries, blueberries, and peaches, apricots, or plums. Dementia ascertainment was based on a multidisciplinary consensus committee, and included all-cause dementia and Alzheimer’s disease dementia diagnoses based on research criteria. Cox models were used to examine associations between cumulative fruit intake and incident dementia, stratified by midlife (45–59 years; n = 1,642) and late-life (60–82 years; n = 1,148).

Results

Greater cumulative total fruit intake in midlife, but not late-life, was significantly associated with a 44% decreased risk of all-cause dementia (HR = 0.56; 95% CI = 0.32–0.98; p = 0.044). Decreased risk of all-cause dementia was also associated with higher intake of apples or pears in midlife and late-life, as well as higher intake of raisins or grapes in midlife only, and higher intake of oranges, grapefruit, blueberries, and peaches, apricots, or plums in late-life only.

Conclusions

Among participants from the Framingham Heart Study, greater overall consumption of flavonoid-rich fruits in midlife was associated with reduced risk of dementia, though intake of specific fruits in midlife and late-life may have a protective role against dev