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

Background: α-Synuclein (α-Syn) pathology is present in 30-50 % of Alzheimer's disease (AD) patients, and its interactions with tau proteins may further exacerbate pathological changes in AD. However, the specific role of different aggregation forms of α-Syn in the progression of AD remains unclear.

Objectives: To explore the relationship between various aggregation types of CSF α-Syn and Alzheimer's disease progression.

Design: We conducted a retrospective analysis of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine the association between different α-Syn aggregation forms-Syn0 (no detectable α-Syn aggregates) and Syn1 (α-Syn aggregates detected, resembling those found in Parkinson's disease)-with the pathological and clinical features of AD. Additionally, we evaluated their potential as predictors of conversion from mild cognitive impairment (MCI) to AD.

Setting: The ADNI database.

Participants: A total of 250 participants, including 70 cognitively normal controls, 119 patients diagnosed with MCI, and 61 patients diagnosed with AD.

Measurements: Pearson correlation was employed to assess the relationship between α-Syn levels and cerebrospinal fluid (CSF) biomarkers, including total tau (T-tau), phosphorylated tau (p-tau), and amyloid-β₄₂ (Aβ₄₂). Multivariate Cox proportional hazards models were applied, adjusting for APOE4 status, age, and sex, to determine the association between α-Syn forms and AD-related pathological and clinical outcomes. Kaplan-Meier curves were used to evaluate the prognostic value of different α-Syn aggregation states in predicting the conversion from MCI to AD.

Results: Compared with controls, overall MCI and AD patients had elevated α-Syn levels. Notably, in the α-Syn0 group, α-Syn levels were increased in the MCI patients and further increased in AD patients, whereas in the α-Syn1 group, α-Syn levels did not significantly differ across diagnostic groups. Both in the α-Syn0 and α-Syn1 groups, α-Syn levels were found to correlate more strongly with CSF tau levels than with Aβ₄₂, indicating a possible role for α-Syn in tau-related pathology in AD. Importantly, α-Syn0-AD patients exhibited more rapid cognitive decline and greater hippocampal atrophy than α-Syn1-AD patients. However, MCI patients with CSF α-Syn1 aggregation status had an increased risk of conversion to AD.

Conclusions: CSF α-Syn is associated with tau pathology and neurodegeneration in Alzheimer's disease. The distinct aggregation profiles of α-Syn serve as valuable biomarkers, offering insights into differing prognoses in AD and aiding in the prediction of early disease progression.

Background: Dementia is a significant cause of disability and dependency. Persons with high dementia risk but intact cognition will benefit from preventive interventions.

Objectives: The aim was to validate dementia risk score Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) in a national population-based cohort with data on age, education, hypertension, obesity, hyperlipidemia and physical activity. Secondly, we examined if substituting obesity item with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) would improve predictive value of CAIDE risk score.

Design: Longitudinal, population-based cohort study.

Setting: General population, Finland PARTICIPANTS: Representative sample of Finnish adult population aged over 30 years from Health 2000 Survey (n = 5,806).

Measurements: CAIDE dementia risk score and substituting BMI with HOMA-IR.

Results: Dementia was diagnosed in 571 (9.8 %) participants during the 19 years follow-up. CAIDE risk score predicted dementia well: AUC (area under curve) ROC (receiver-operating characteristic) was 0.78 (95 % CI from 0.76 to 0.79). Secondly, replacing obesity with HOMA-IR in CAIDE risk score generated similar results: ROC AUC 0.78 (95 % CI from 0.76 to 0.80). Adding APOE ε4 status further improved predictive value of risk score: ROC AUC 0.81 (95 % CI from 0.80 to 0.83).

Conclusions: CAIDE dementia risk score predicts dementia well in a national population-based cohort. Adding APOE ε4 genotype improved predictive value of risk score. Insulin resistance measured by HOMA-IR is comparable to obesity as part of CAIDE risk score. These findings imply that CAIDE risk score is applicable for assessing risk of dementia and highlight importance of modifiable risk factors of dementia.

Background: The effect of statins use on the incidence of Alzheimer's disease (AD) is still under debate, and it could be modified by a series of factors.

Objectives: We aimed to examine the association of statins use with the risk of cognitive impairment and AD, and assess the moderating roles of genetic susceptibility and other individual-related factors.

Design: A longitudinal study was conducted from the UK Biobank where individuals completed baseline surveys (2006-2010) and were followed (mean follow-up period: 9 years).

Setting: A population-based study.

Participants: A total of 371,019 dementia-free participants (mean age 56.4 years; 53.6% female).

Measurements: The effects of statins use on cognitive performance and incident AD were examined by using linear regression model and Cox proportional hazards regression model, respectively. We further evaluated the moderating roles of genetic risks and individual-related factors on both multiplicative and additive scales.

Results: The findings showed statins use was associated with an increased risk of AD development [hazard ratio (HR) 1.19 (95% CI: 1.08, 1.30)] compared with no use of statins. We further found significant negative additive interactions of statins use with APOE ε4 allele. Besides, the effects of statins use would be modified by age, sex and cardiovascular diseases (CVDs).

Discussions: A protective effect of statins use was observed in those who carried two APOE ε4 alleles. Also, sex, age and CVDs could modify the effects of statins use, which would provide insights for the guideline of the statins therapy.

Background: Protein abundance levels, sensitive to both physiological changes and external interventions, are useful for assessing the Alzheimer's disease (AD) risk and treatment efficacy. However, identifying proteomic prognostic markers for AD is challenging by their high dimensionality and inherent correlations.

Methods: Our study analyzed 1128 plasma proteins, measured by the SOMAscan platform, from 858 participants 55 years and older (mean age 63 years, 52.9 % women) of the Framingham Heart Study (FHS) Offspring cohort. We conducted regression analysis and machine learning models, including LASSO-based Cox proportional hazard regression model (LASSO) and generalized boosted regression model (GBM), to identify protein prognostic markers. These markers were used to construct a weighted proteomic composite score, the AD prediction performance of which was assessed using time-dependent area under the curve (AUC). The association between the composite score and memory domain was examined in 339 (of the 858) participants with available memory scores, and in a separate group of 430 participants younger than 55 years (mean age 46, 56.7 % women).

Results: Over a mean follow-up of 20 years, 132 (15.4 %) participants developed AD. After adjusting for baseline age, sex, education, and APOE ε4 + status, regression models identified 309 proteins (P ≤ 0.2). After applying machine learning methods, nine of these proteins were selected to develop a composite score. This score improved AD prediction beyond the factors of age, sex, education, and APOE ε4 + status across 15-25 years of follow-up, achieving its peak AUC of 0.84 in the LASSO model at the 22-year follow-up. It also showed a consistent negative association with memory scores in the 339 participants (beta = -0.061, P = 0.046), 430 participants (beta = -0.060, P = 0.018), and the pooled 769 samples (beta = -0.058, P = 0.003).

Conclusion: These findings highlight the utility of machine learning method in identifying proteomic markers in improving AD prediction and emphasize the complex pathology of AD. The composite score may aid early AD detection and efficacy monitoring, warranting further validation in diverse populations.

Background: Cognitive training (CT) has been one of the important non-pharmaceutical interventions that could delay cognitive decline. Currently, no definite CT methods are available. Furthermore, little attention has been paid to the effect of CT on mood and instrumental activities of daily living (IADL).

Objectives: To assess the effectiveness of a multicomponent CT using a training program of executive functions, attention, memory and visuospatial functions (TEAM-V Program) on cognition, mood and instrumental ADL.

Design: A randomized, single-blinded, treatment-as-usual controlled trial.

Setting: Geriatric clinic in Bangkok, Thailand.

Participants: 80 nondemented community-dwelling older adults (mean age 65.7 ± 4.3 years).

Intervention: The CT (TEAM-V) Program or the treatment-as-usual controlled group. The TEAM-V intervention was conducted over 5 sessions, with a 2-week interval between each session. A total of 80 participants were randomized (n = 40 the TEAM-V Program; n = 40 the control group).

Measurements: The Thai version of Montreal Cognitive Assessment (MoCA), The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Thai version of Hospital Anxiety and Depression Scale (HADS) and The Chula ADL were used to assess at baseline, 6 months, 1 year and 2 years.

Results: Compared with the control arm (n = 36), the TEAM-V Program (n = 39) was associated with significantly improved general cognition (MoCA, P = 0.02) at 2 years. Compared with baseline, participants receiving the TEAM-V Program were associated with significantly improved immediate recall (word recall task, P < 0.001), retrieval and retention of memory processes (word recognition task, P = 0.01) and attention (number cancellation part A, P = 0.01) at 2 years. No training effects on anxiety (P = 0.94), depression (P = 0.093) and IADL (P = 0.48) were detected.

Conclusions: The TEAM-V Program was effective in improving global cognitive function. Even though, the program did not significantly improve anxiety, depression and IADL compared with the control group, memory and attention improved in the intervention group compared with baseline. Further studies incorporating a larger sample size, longitudinal follow-up and higher-intensity CT should be conducted.

Background: The associations of early-onset coronary heart disease (CHD) and genetic susceptibility with incident dementia and brain white matter hyperintensity (WMH) remain unclear. Elucidation of this problem could promote understanding of the neurocognitive impact of early-onset CHD and provide suggestions for the prevention of dementia.

Objectives: This study aimed to investigate whether observed and genetically predicted early-onset CHD were related to subsequent dementia and WMH volume.

Design: Prospective cohort study.

Setting: UK Biobank.

Participants: 500 671 individuals without dementia at baseline.

Measurements: Early-onset CHD (male ≤55 years; female ≤65 years) was ascertained using hospital inpatient records. Incident dementia including all-cause dementia, Alzheimer's disease, and vascular dementia was ascertained using hospital inpatient records, mortality register data, and self-reported data. WMH volume was measured through brain magnetic resonance imaging (MRI). Cox proportional hazards models and linear regression models were used to analyze the associations of early-onset CHD with incident dementia and WMH. Subsequently, a polygenetic risk score (PRS) analysis was conducted to investigate the associations of genetically predicted early-onset CHD with outcomes.

Results: Among 500 671 individuals (female: 272 669, 54.5%; mean age: 57.0 ± 8.1 years), 9 294 dementia occurred during a median follow-up of 13.8 years. Compared with the non-CHD group, both early-onset (n = 16 133) and late-onset CHD (n = 43 944) groups had higher risks of developing dementia (hazard ratio [HR]: 1.99, 95% confidence interval [CI]: 1.81 to 2.19 for early-onset group; HR: 1.20, 95% CI: 1.14 to 1.27 for late-onset group). Among CHD participants, early-onset CHD was associated with a significantly higher risk of incident dementia, compared with late-onset CHD (HR: 1.56, 95% CI: 1.39 to 1.75). In a subset of 40 290 individuals who completed brain MRI scans during a median follow-up of 9.3 years, participants with early-onset CHD exhibited the largest WMH volume among the three groups (early-onset CHD, late-onset CHD, and non-CHD, P_trend<0.001). The PRS analysis supported the associations of early-onset CHD with dementia (odds ratio [OR] for the highest quartile: 1.37, 95% CI: 1.28 to 1.46, P_trend<0.001) and WMH volume (β for the highest quartile: 0.042, 95% CI: 0.017 to 0.068, P_trend=0.002).

Conclusions: Early-onset CHD and genetic susceptibility are associated with a higher risk of incident dementia and a larger WMH volume. Additional attention should be paid to the neurocognitive status of individuals with early-onset CHD.

Background: The identification of the modifiable lifestyle factors including dietary habits in older adults of preclinical Alzheimer's disease (AD) and early effective interventions are of great importance.

Objectives: We studied whether the consumption of fresh vegetables and fruits was different between cognitively unimpaired (CU) and cognitively impaired (CI) population and mainly investigated the associations between vegetable and fruit consumption and PET and plasma AD biomarkers in older CU adults with higher β-amyloid (Aβ) burden.

Design, setting, and participants: Older adults with the age of 50-85 years were enrolled for a cross-sectional and longitudinal study. The groups depended on whether the participants were CU or CI. Partial participants whose habits remained unchanged were followed up.

Measurements: The consumption data of vegetables and fruits were collected using a validated self-reported questionnaire. We mainly investigated the associations between vegetable and fruit consumption and various biomarkers in CU participants with positive ¹⁸F-florbetapir PET scan (Aβ-PET), part of whom also underwent plasma AD biomarkers tests and ¹⁸F-MK6240 PET scan (tau-PET). Correlation and multiple linear regression analyses were used to investigate the associations between vegetable and fruit consumption and AD biomarkers.

Results: A total of 1433 participants were enrolled, of which CU accounted for 49.4 %. Most of the intake habits of vegetables and fruits was different between CU and CI participants. 177 CU participants with Aβ-PET positive were selected for the following study. Multiple linear regression analysis showed higher consumption of fresh vegetables (>200 g/d), dark vegetables (>100 g/d, ≥2d/week), fruits (>100 g/d), berries (>100 g/d) and grapes (>100 g/d) more or less had associations with the plasma biomarkers including Aβ40, t-Tau, p-Tau-181 and neurofilament light chain as well as amyloid and Tau PET biomarkers. Most of the habits were associated with the change of cognitive function after an approximately two-year follow-up. Especially, higher intakes of fruits and grapes correlated with both lower Aβ and Tau burden and inversely with cognitive decline after follow-up.

Conclusion: Our data indicates that higher consumption of vegetables, dark vegetables, fruits, berries and grapes is associated with amyloid and Tau PET and plasma biomarkers in preclinical AD participants and the changes of cognitive function after follow-up. Higher intakes of fruits (>100 g/d) and grapes (>100 g/d) may be more helpful for reducing the risk of AD development.

Background: Cognitive impairment is a growing concern in Southeast Asian populations, where the burden of cerebrovascular disease (CeVD) is high. Currently, there is no point-based scoring system for identifying cognitive impairment in these populations.

Objective: To develop and validate a simple point-based Cognitive Impairment Scoring System (CISS) for identifying individuals with cognitive impairment no dementia (CIND) and concomitant CeVD in Southeast Asian populations.

Design: A cross-sectional study using data from two population-based studies.

Setting: Community-based setting in Southeast Asia.

Participants: 1,511 Southeast Asian adults (664 with CIND, 44.0 %).

Measures: Two CISS measures were developed: a basic measure including 11 easily assessable risk factors, and an extended measure incorporating seven additional neuroimaging markers. Performance was evaluated using receiver operating characteristic analysis (AUC) and calibration plots.

Results: The AUC for CISS-basic and CISS-extended were 0.81 (95 %CI, 0.76-0.86) and 0.85 (95 %CI, 0.81-0.89), respectively. Calibration plots indicated satisfactory fit for both the basic measure (p=0.82) and the extended measure (p=0.17). The basic measure included age, gender, ethnicity, education, systolic blood pressure, BMI, smoking history, diabetes, hyperlipidemia, stroke history, and mild/moderate depression. The extended measure added neuroimaging markers of CeVD and brain atrophy.

Conclusion: The CISS provides a quick, objective, and clinically relevant tool for assessing cognitive impairment risk in Southeast Asian populations. The basic measure is suitable for initial community-based screenings, while the extended measure offers higher specificity for probable diagnosis. This point-based system enables rapid estimation of cognitive status without requiring complex calculations, potentially improving early detection and management of cognitive impairment in clinical practice.

Background: The causal relationship between lipid metabolites and Alzheimer's disease (AD) remains unclear and contradictory. This study aimed to systematically assess the causal relationship between lipid metabolites and AD.

Methods: A two-step bidirectional Mendelian Randomization (MR) study was employed. The principal analytical technique used to evaluate causation was inverse variance weighting (IVW). Furthermore, mediation analysis was conducted to evaluate the possible function of lipidomes as mediators in the lipid-AD pathway.

Results: Among the 213 lipid metabolites analyzed, significant causal associations with AD were identified Cholesterol esters in large LDL(L-LDL-CE) (OR = 1.236, 95 %CI = 1.052-1.453, P = 0.010), Total cholesterol in large LDL(L-LDL-TC) (OR = 1.506, 95 %CI = 1.235-1.835, P < 0.001), Total cholesterol in medium LDL(M-LDL-TC) (OR = 1.378, 95 %CI = 1.132-1.677, P = 0.001). Mediation analysis further revealed ceramide (d42:2) and phosphatidylinositol (PI) (18:1_18:1) as potential mediators in this relationship.

Conclusion: The identification of specific lipid metabolites with causal effects on AD provides new insights into AD pathogenesis and highlights potential targets for preventive strategies.

Introduction: Apolipoprotein E ε4 (APOE ε4) bring the higher risk of Alzheimer' Disease (AD). It is essential to evaluate whether the diagnostic performances and critical values of cerebrospinal fluid (CSF) biomarkers are influenced by APOE ε4, which has guiding significance for the clinical practical application.

Methods: The differences in CSF biomarkers and their performances between APOE ε4 carriers and non-carriers in distinguishing AD, mild cognitive impairment (MCI) and preclinical AD from normal controls (NCs) were analyzed. The receiver operating characteristic (ROC) curves were generated to compare the area under the curve (AUC) between APOE ε4 carriers and non-carriers, as well as the critical values corresponding Youden Index.

Results: In a cross sectional convenience sample of 1610 participants, lower Aβ42 and Aβ42/Aβ40 and higher p-Tau 181/Aβ42 in CSF were observed among APOE ε4 carriers than non-carriers in NC, MCI, and AD groups (P< 0.05). The performance of CSF p-tau/Aβ42 in distinguishing MCI from NC among APOE ε4 carriers was superior to non-carriers [AUC: 0.714 (95%CI: 0.673- 0.752) vs 0.600 (95%CI: 0.564- 0.634), P< 0.001], although it was similar in distinguishing AD from NC between APOE ε4 carriers and non-carriers [AUC: 0.874 (95%CI: 0.835-0.906) vs 0.876 (95%CI: 0.843- 0.904)]. In the longitudinal cohort of 254 participants, the association of CSF Aβ42, Aβ42/Aβ40 and p-Tau181/Aβ42 with cognitive decline were stronger in APOE ε4 carriers compared to non-carriers (P< 0.05). Meanwhile, the critical values were different depending on APOE genotype.

Discussion: The CSF level of p-Tau181/Aβ42 was significantly different between APOE ε4 carriers and non-carriers at different stages of AD. The results indicate that the performances of CSF biomarkers are influenced by APOE ε4, which should be considered in the practical application.