Journal of Alzheimer's Disease最新文献

Background: Survival after an Alzheimer's disease (AD) diagnosis is vital for patients, their families, caregivers, and healthcare providers. Hawaii, known for its diverse ethnic population, exhibits significant racial health disparities.

Objective: This study examined racial/ethnic and socioeconomic disparities in AD survival in Hawaii and developed machine learning models to predict overall survival using Hawaii Medicare data.

Methods: Nine years of Hawaii Medicare data were utilized to gather information on AD development after age 65, following patients to capture all-cause survival or until censoring. The study examined the effects of race/ethnicity and socioeconomic status (SES) on mortality risk. Cox regression analysis was conducted on overall survival, accounting for covariates. A Survival Random Forest was employed to model survival, incorporating K years of longitudinal health profiles.

Results: The study included 9393 AD subjects. Analysis revealed that Asian Americans (AA) had a later age at AD diagnosis (p < 0.001), with an average age of 85.9, compared to 82.7 and 83.3 years for whites and Native Hawaiians and Pacific Islanders (NHPI), respectively. Low SES showed a marginal increase in hazard (Hazard Ratio [HR] = 1.36, p < 0.001). After covariate adjustment, compared to AAs with better SES, increased hazards were found for their white counterpart (HR = 1.18, p < 0.001) and groups with low SES: AA (HR = 1.28, p < 0.001), white (HR = 1.51, p < 0.001), and NHPI (HR = 1.39, p < 0.001). The predictive model had a Concordance-Index of 0.82, showing reasonable predictability.

Conclusions: Racial/ethnic and SES disparities significantly influence AD onset and survival. Combined with longitudinal health status data, machine learning demonstrates reasonable predictability of survival.

Background: The introduction of therapeutics for Alzheimer's disease has led to increased interest in precisely quantifying amyloid-β (Aβ) burden for diagnosis, treatment monitoring, and further clinical research. Recent positron emission tomography (PET) hardware innovations including digital detectors have led to superior resolution and sensitivity, improving quantitative accuracy. However, the effect of PET scanner on Centiloid remains relatively unexplored and is assumed to be minimized by harmonizing PET resolutions.

Objective: To quantify the differences in Centiloid between scanners in a paired cohort.

Methods: 36 participants from the Australian Imaging, Biomarker and Lifestyle study (AIBL) cohort were scanned within a year on two scanners. Each participant underwent ¹⁸F-NAV4694 imaging on two of the three scanners investigated, the Siemens Vision, the Siemens mCT and the Philips Gemini. We compared Aβ Centiloid quantification between scanners and assessed the effectiveness of post-reconstruction PET resolution harmonization. We further compared the scanner differences in target sub-regions and with different reference regions to assess spatial variability.

Results: Centiloid from the Vision camera was found to be significantly higher compared to the Gemini and mCT; the difference was greater at high-Centiloid levels. Post-reconstruction resolution harmonization only accounted for and corrected ∼20% of the Centiloid (CL) difference between scanners. We further demonstrated that residual differences have effects that vary spatially between different subregions of the Centiloid mask.

Conclusions: We have demonstrated that the type of PET scanner that a participant is scanned on affects Centiloid quantification, even when scanner resolution is harmonized. We conclude by highlighting the need for further investigation into harmonization techniques that consider scanner differences.

Background: Endogenous Alu RNAs form double-stranded RNAs recognized by double-stranded RNA sensors and activate IRF and NF-kB transcriptional paths and innate immunity. Deamination of adenosines to inosines by the ADAR family of enzymes, a process termed A-to-I editing, disrupts double-stranded RNA structure and prevents innate immune activation. Innate immune activation is observed in Alzheimer's disease, the most common form of dementia. We have previously reported loss of A-to-I editing in hippocampus vasculature, but no change in cortex or cortex vasculature, associated with Alzheimer's disease.

Objective: Here, we investigated the status of Alu RNA A-to-I editing in cortex extracellular vesicles in Alzheimer's disease.

Methods: We used existing RNA-seq data sets and the SPRINT software package to determine levels of Alu RNA A-to-I editing in cortex extracellular vesicles in Alzheimer's disease and control groups and compared these editing profiles to those found in both total cortex and hippocampus vasculature.

Results: We find substantial loss of Alu A-to-I editing in cortex extracellular vesicles in Alzheimer's disease. By measuring editing patterns on a gene-by-gene basis, we determined that editing patterns in cortex extracellular vesicles resemble editing patterns in hippocampus vasculature rather than total cortex.

Conclusions: We conclude that hippocampus vasculature unedited Alu RNAs are packaged in extracellular vesicles, travel to the cortex, deliver their cargo and stimulate innate immunity and alter other basic biological processes contributing to Alzheimer's disease progression.

SPI1, a transcription factor implicated in myeloid cell development, has emerged as a genetic risk factor for Alzheimer's disease (AD). Recent in vivo studies reveal that Spi1 knockdown in mice exacerbates AD pathology by increasing amyloid-β aggregation and gliosis while Spi1 overexpression ameliorates these features. Transcriptomic analyses suggest that Spi1 regulates microglial immune response, complement activation, and phagocytosis. SPI1 regulation of these processes may explain how SPI1 affects AD risk. Further studies, including human validation, are needed to explore the dynamic influence of SPI1 across AD stages, its applicability to clinical settings, and its potential as a therapeutic target.

Background: Although the association between dementia such as Alzheimer's disease and traumatic brain injury (TBI) is well established, there are significant knowledge gaps with respect to the perspective of dementia and epilepsy without TBI. Objective: We aimed to investigate the relationship between dementia and epilepsy in a population-based study of patients without history of TBI. Methods: This study included a random sample of 30,715 patients with no history of TBI, including 6143 with epilepsy as the study cohort and 24,572 without epilepsy as the comparison cohort. Stratified Cox proportional hazard regression was used to calculate the adjusted hazard ratio (HR), with 95% confidence interval, for the risk of developing dementia in the two cohorts. Results: Patients with epilepsy but no history of TBI had increased risk of dementia (adjusted HR = 1.84). For patients aged 55-64 years, the adjusted HR for dementia was 4.5-fold higher among females in the study cohort than among males. Additionally, this study revealed that risk of dementia among above 75-year population lowest than other age subgroups (adjusted HR = 1.45). Conclusions: The study demonstrated an association between dementia and epilepsy in the patients who had no history of TBI. The effect was pronounced in patients aged 55-64 years, especially in the female population, suggesting that epilepsy needs to be more intensively prevented and controlled in this age group.

Background: Our previous studies have established that the broad-spectrum anti-epileptic drug lamotrigine (LTG) confers protection against cognitive impairments, synapse and nerve cell damage, as well as characteristic neuropathologies in APP/PS1 mice, a mouse model of Alzheimer's disease (AD). However, the precise molecular mechanisms responsible for this protective effect induced by LTG remain largely elusive.

Objective: In this study, we aimed to investigate the mechanisms underlying the beneficial effects of LTG against AD.

Methods: Five-month-old APP/PS1 mice were treated with 30 mg/kg of LTG daily for three consecutive months. Subsequently, high-throughput ribosome profiling sequencing was conducted to identify differentially translated genes (DTGs) rescued by LTG in the brains of these mice. To gain further insights into the potential functions and pathways of these LTG-rescued DTGs, gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. RNA expression, protein levels, and translational efficiency were assessed to explore how LTG regulated gene expression processes in AD-related DTGs. Additionally, Aβ₄₂ peptide-stimulated primary neurons were used to uncover the potential mechanisms and signaling pathway by which LTG mitigated oxidative stress under AD context.

Results: For the first time, we reveal that LTG inactivates mitochondrial complexes in the brains of APP/PS1 mice by suppressing the translational efficiency of mitochondrial complexes-related genes. More importantly, we demonstrate that LTG mitigates mitochondrial-mediated oxidative stress in neurons within the context of AD by activation of SIRT6/PGC-1α pathway.

Conclusions: These findings provide further insights into the mechanisms underlying the protective effects of LTG against AD.

Obstructive sleep apnea (OSA) affects a large portion of middle-aged and older adults. It has been linked to increased risk of cognitive decline and Alzheimer's disease. OSA can impair cognitive performance and patients with cognitive complaints can frequently present with this sleep disorder. Although instruments able for correctly screening patients with cognitive impairment and OSA exist, there is no evidence about utility and feasibility of their use in the memory clinics. The study by Lam et al. showed that, in case of impossibility of performing polysomnography-that is the gold standard for OSA diagnosis, pulse oximetry can represent a good instrument for screening patients with cognitive impairment for OSA, and they do not advice for using sleep interview or STOP-Bang questionnaire for screening this sleep disorder.

Background: Subjective cognitive decline (SCD) is the early predementia syndrome. that occurs even before the development of objective cognitive decline. SCD plus refers to an additional set of criteria that increases the likelihood of developing mild cognitive impairment and further progressing to Alzheimer's disease (AD). Studying the progression of SCD-plus participants will help in understanding the importance of diagnosing this condition at an early stage and delaying its onset.

Objective: The present tries to examine neurocognitive changes in individuals who met the criteria of SCD-plus patients. The study also investigated the imaging correlates of these individuals in both cohorts.

Methods: This study included 94 participants from Srinivaspura Aging, Neuro Senescence, and COGnition (SANSCOG) and Tata Longitudinal Study of Aging (TLSA) cohorts who satisfy the criteria of SCD plus. Mann-Whitney U test was used to compare the SCD plus participants and healthy controls. Regression analysis was performed to find the association between SCD plus and cognition.

Results: The SCD-plus group performed poorer than the healthy group in episodic memory delayed recall (p = 0.049), name face recognition (p = 0.023), and letter fluency (p = 0.004) tasks. The generalized linear model revealed that the SCD-plus group had lower left cerebellar cortex (p = 0.010) and right inferior occipital cortex (p = 0.016) volumes than the healthy control group.

Conclusions: The participants in the SCD-plus group performed poorly on memory and language-related tasks, and the volumes of the associated brain regions decreased. This study suggested that the SCD-plus group had characteristics similar to AD group and can help in identifying AD at the earliest.

Background: Some studies have suggested that glaucoma may be associated with neurodegeneration and a higher risk of dementia.

Objective: To evaluate whether exposure to different categories of topical glaucoma medications is associated with differential dementia risks in people with glaucoma.

Methods: We used data from Adult Changes in Thought, a population-based, prospective cohort study that follows cognitively normal older adults from Kaiser Permanente Washington (KPWA) until Alzheimer's disease (AD) and related dementia development. We included participants with a diagnosis of glaucoma, KPWA pharmacy records of filling topical glaucoma medication (alpha-adrenergic agonists [AAA], beta-adrenergic antagonists, miotics, carbonic anhydrase inhibitors [CAI], and prostaglandins) and at least 10 years of pharmacy records. Eight-year sliding windows were derived for each medication class by computing days on each medication starting 10 years earlier and excluding the most recent 2 years. Cox regression used all 5 classes of medication simultaneously to predict AD and all-cause dementia.

Results: We included 521 participants (mean age 78 [range 65-96], 62% female) with APOE genotype data. Beta-adrenergic antagonists were the most frequently prescribed (n = 431) followed by prostaglandins (351), AAA (239), CAI (162), and miotics (142). Adjusting for time-varying exposure to other glaucoma medications, APOE, demographics, and smoking, each year of use of alpha-adrenergic agonists in an 8-year window was associated with a higher risk of developing dementia (HR = 1.33, 95% CI = 1.03-1.72).

Conclusions: Among older adults with treated glaucoma, exposure to alpha-adrenergic agonists appears to be associated with risk for developing all-cause dementia.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors is a novel category of medications for diabetes, exhibiting neuroprotective potential. However, evidence regarding whether the use of SGLT2 inhibitors effectively reduces the risk of Alzheimer's disease (AD) remains unclear.

Objective: Our study employed Mendelian randomization (MR) analysis to investigate potential causal relationships between SGLT2 inhibition, metabolites, and AD.

Methods: In our research, we used a two-sample MR method to explore the link between SGLT2 inhibitor use and AD, addressing both its late-onset and early-onset forms. Furthermore, we executed a two-step MR analysis to explore how circulating metabolites, primarily endogenous in nature due to SGLT2 inhibition, mediate the relationship between SGLT2 inhibition and AD. The genetic instruments for SGLT2 inhibition were pinpointed through their association with SLC5A2 gene expression and the decreased glycated hemoglobin (HbA1c) levels.

Results: Genetic analysis indicated that SGLT2 inhibition, which effectively reduces HbA1c by enhancing renal glucose excretion and improving glycemic control, was associated with a lower likelihood of developing AD for every 1 SD decrease in HbA1c (OR = 0.48, [0.36, 0.63], p < 0.001). Our MR analysis revealed that SGLT2 inhibition significantly affected 27 of the 123 metabolites examined, adhering to a Bonferroni correction threshold (p < 4.06 × 10-4). Among these 27 significant metabolites, citrate was also associated with AD, showing a significant association (0.81 [0.79, 0.83], p < 0.001).

Conclusions: The study provides strong evidence linking SGLT2 inhibition with a lower AD risk, highlighting citrate's potential mediating role for subsequent clinical research.