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

Background

Cognitive reserve (CR) has been linked to dementia and might be a predictor of aged-related outcomes. However, the association between CR and risk of other chronic diseases and mortality remains unclear.

Objectives

We aimed to investigate the association of CR with survival free from major chronic diseases.

Design, Setting and Participants

This community-based longitudinal study used data from the UK Biobank. A total of 412,509 participants (mean age 55.71±8.10) free of major chronic disease (including dementia, diabetes, cardiovascular diseases, chronic obstructive pulmonary disease, and cancer) completed the baseline examination between 2006 to 2010 and were followed for changes in health status.

Measurements

Latent class analysis was used to generate an indicator of CR (categorized as low, moderate, or high) based on education, occupation, television viewing time, confiding, social connection, and leisure activities. Major chronic diseases and survival status were ascertained through self-reported history and/or linkages to medical and death records. Chronic disease-free survival was defined as survival without any of the aforementioned chronic diseases. Effect modifications and interactions between the CR indicator and sex, age, and lifestyle factors (including smoking status, alcohol consumption, physical activity, and body mass index) were explored.

Results

Over a median follow-up of 12.49 (interquartile range 11.42–13.41, range 0.01–15.87) years, 112,190 (27.2%) participants died or developed at least one chronic disease. High CR indicator was associated with lower risk of chronic disease/death (hazard ratio 0.82, 95% confidence interval: 0.80–0.83) compared to low CR indicator. Chronic disease-free survival was prolonged by 1.33 (1.21–1.44) years among participants with high CR compared to low CR indicator. Furthermore, the association between the CR indicator and chronic disease-free survival was strengthened among individuals aged <60 years and current smokers.

Conclusion

High CR indicator is associated with a lower risk of chronic disease/death and may prolong chronic disease-free survival. Our findings underscore the importance of CR-enhancing lifestyle and experiences in health longevity, especially for younger individuals and current smokers.

Alzheimer’s disease (AD) is an age-related degenerative disease, which is characteristic by the deposition of senile plaques (SP) outside the cells, the neurofibrillary tangles (NFTs) inside the neurons, and the loss of synapse and neurons. Neuroinflammation may play an important role in the pathogenesis of AD. Microglia are the immune cells in the central nervous system. However, microglia might become disease-related microglia (DAMs) when stimulated by the external environment. DAMs have been shown to be involved in a series of events of AD development including Aβ accumulation and tau phosphorylation. The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor that is mainly expressed by microglia in the central nervous system (CNS). TREM2 plays an important role in the physiological function of microglia, and the dyshomeostasis of TREM2 is related to the development of late-onset AD. This article summarized the latest advances in TREM2 biology and its impact on the roles of microglia in AD development, with a particular emphasis on the structure, ligands, signal transduction, and the agonistic antibodies of TREM2 for AD treatment. We further discussed the survival, migration, phagocytosis, inflammation, and cellular metabolism of microglia, as well as the role of sTREM2 in neuroprotection and as a biomarker for AD. It provides a reference for further research on the molecular mechanism of microglial TREM2 in the occurrence and development of AD and on the therapeutic strategies targeted on the microglial TREM2.

Background

Spelling assessments can provide a valuable marker of cognitive change in Alzheimer’s disease and related dementias (ADRD) and play an important role in ADRD research. However, most commercial assessments are not well-suited to the needs of researchers or participants; they are expensive and often require face-to-face administration by a trained examiner. To help overcome these barriers and foster progress in ADRD research, the National Institute on Aging (NIA)-funded Mobile Toolbox (MTB) offers a library of cognitive measures that can be self-administered remotely on a participant’s own smartphone, including a brand-new Spelling test.

Objective

The goal of this paper is to describe the design, piloting, calibration, and validation of the MTB Spelling test.

Design

We describe a pilot study, calibration study, and three validation studies, all of which use a cross-sectional design.

Setting

The pilot study, calibration study, and validation studies 2 and 3 were conducted remotely, while validation study 1 was conducted in the lab.

Participants

Participants for all of the studies were recruited from the general population by a thirdparty market research firm and the samples were stratified by age, gender, race, ethnicity, and education to represent the U.S. population. The pilot sample included 1,950 participants and the calibration study included 1335 participants over the age of 8. Validation study 1 included 92 participants ages 20 to 84, validation study 2 included 1021 participants ages 18 to 90, and validation study 3 included 168 participants ages 28 to 87.

Measurements

Participants in each of the studies completed the MTB Spelling test. Participants in validation studies 1 and 2 completed measures from the NIH Toolbox including Oral Reading Recognition as a measure of convergent validity, and Visual Reasoning and the Rey Auditory Verbal Learning as measures of divergent validity. As an additional measure of convergent validity, participants in study 1 also completed the Spelling subtest from the Wechsler Individual Achievement Test, 4th Edition.

Results

The MTB Spelling test demonstrated evidence of internal consistency (r=.79 to.83) convergent validity (r=.56 to.81, p<.01), discriminant validity (r =.23 to.36, p <.01), test-retest reliability (ICC=.63), and correlations with normal cognitive aging (r = −.06 to −.04, p >.01).

Conclusion

Findings suggest the MTB Spelling test is a reliable and valid measure of English spelling abilities in general population samples, and has potential in ADRD research.

Background

Past research suggests that subjective cognitive decline serves as an early and potentially important indicator that individuals may be at risk for future cognitive decline or neurodegenerative conditions. However, there is a dearth of studies on factors influencing the experience of subjective cognitive decline in Black Americans, especially in Black American men.

Objective

The current study explored correlates of subjective cognitive decline in Black American men.

Participants

A total of 117 Black American men, with a mean age of 38.5 (SD = 7.14) years, participated in the study.

Measurement

Participants completed a survey that assessed their demographic characteristics, self-rated health, neighborhood problems, length of residency in neighborhood, bodily symptoms, sleep comorbidities, sleep difficulties, and subjective cognitive decline. Linear regression analyses was performed and standardized beta coefficients were reported to describe the estimated independent effect of the predictor variables.

Results

We found that socioecomic status (β = −.222, p=.003), bodily symptoms (β =.246, p=.005), length of residency in neighborhood (β =.157, p=.029), and sleep difficulties (β =.305, p<.001) were significant correlates of subjective cognitive decline among Black American men.

Conclusion

These findings underscore the intricate roles of socioeconomic status, bodily symptoms, neighborhood factors, and sleep health in shaping subjective cognitive experiences in this population. Research on subjective cognitive decline can contribute to the early identification of individuals at risk for cognitive decline, allowing for timely interventions, lifestyle modifications, and potential preventive measures.

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.