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

Background: Excessive sugar intake has been implicated in increased dementia risk; however, existing studies are constrained by small sample sizes and a primary focus on total sugar, with limited investigation into specific sugar subtypes. This study explores the relationship between sugar intake, its subtypes, and the incidence of dementia.

Methods: We analyzed 172,516 participants from the UK Biobank who completed at least one 24-hour dietary recall (Oxford WebQ). Cox proportional hazards models estimated the hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for total sugar and its subtypes (free sugar, fructose, glucose, sucrose, maltose, lactose, and other sugars) about the risk of dementia. Sex-stratified analyses were also performed.

Results: Higher intakes of total sugar (HR = 1.292, 95 % CI = 1.148--1.453) and free sugar intake (HR = 1.254, 95 % CI = 1.117--1.408) were significantly associated with increased dementia risk. Positive associations were also observed for non-milk extrinsic sugars (HR = 1.321, 95 % CI = 1.175--1.486) and sucrose (HR = 1.291, 95 % CI = 1.147--1.452). These associations were evident in women, with higher intakes of total sugars, free sugars, glucose, sucrose, and non-milk extrinsic sugars independently linked to increased dementia risk, whereas no significant associations were found in men.

Conclusion: Higher consumption of total sugars, free sugars, sucrose, and non-milk extrinsic sugars confers increased dementia risk, particularly among women.

The advent of amyloid-targeting therapies and biomarker-based risk stratification has transformed the understanding of Alzheimer's disease and related disorders. These conditions are now recognized as chronic, detectable and modifiable, often presenting decades before clinical symptoms appear. While this paradigm shift enables earlier intervention, it also raises ethical and psychological challenges that necessitate a redefined role for psychiatry. Instead of merely supporting late-stage care, psychiatry is well-placed to facilitate risk communication, promote resilience, and encourage adaptive behavior in individuals navigating preclinical or prodromal neurodegeneration. This article outlines an ethical, stepwise communication framework, clarifies the distinction between diagnosis and probabilistic risk, and explores psychiatric contributions-from motivational models to lifestyle-based prevention-that bridge the gap between biological insight and subjective experience. By reinterpreting risk as a chance for intervention rather than resignation, psychiatry broadens the therapeutic scope and helps safeguard independence, dignity and quality of life-making it a pivotal participant in dementia prevention and individualized, person-centered care.

Background: The multifactorial nature of Alzheimer's disease (AD) has become increasingly evident. In addition to well-established features like neurodegeneration, amyloid-beta and tau deposition, or glial changes, other processes-such as metabolic, circulatory, and inflammatory factors-may also play a key role in driving or accelerating AD-related pathology and cognitive decline. These factors represent important targets for slowing disease progression.

Objectives: Although many studies have examined individual risk factors and meta-analyses have been performed, a large-scale, comprehensive comparison using formal medical data from a single, unified cohort is needed.

Design: A retrospective case-control study leveraging comprehensive health database.

Setting: Data were obtained from the UK-Biobank, a large (∼500 K people) population-based biomedical database in the United Kingdom.

Participants: The study included participants aged 40-69 at enrollment between 2006 and 2010, comprising 3,843 individuals who were clinically diagnosed with AD by August 2022 and 387,275 individuals without dementia or cognitive-impairment diagnoses.

Measurements: ICD-10-coded diagnoses, recorded at least 10 years prior to AD diagnosis, were analyzed. Logistic regression was used to estimate the impact and significance of various medical conditions and their interactions with genetic risk factors, while accounting for demographic determinants.

Results: The analysis identified 45 medical factors (96 ICD-10 entities) across multiple systems-particularly metabolic, circulatory, gastrointestinal, and sensorimotor-that significantly differentiated individuals with clinical AD from cognitively unimpaired individuals. Interaction analyses revealed that circulatory and metabolic factors had a weaker influence on AD risk in Apolipoprotein E ε4 carriers, suggesting a gene-environment interaction in disease susceptibility.

Conclusions: These findings enhance the understanding of system-level risk factors for clinical AD, highlight the relevance of less frequently reported factors in the AD prevention literature-such as gastrointestinal and sensorimotor disorders-and underscore the complex interplay between genetic susceptibility and vascular risk factors.

Background: Recent multidomain prevention trials for dementia have shifted toward more targeted approaches, focusing on specific combinations of risk factors and interventions at certain times. However, the optimal combinations of modifiable risk factors that can be targeted to maximize intervention effect remain unclear. Identifying risk factor combinations with the highest prevalence and largest effect sizes can enhance efficiency of trial design.

Objectives: To identify risk factor combinations that are both highly prevalent and have the most detrimental effect on cognition, and to assess their interaction effect and synergism.

Design: Longitudinal analysis of Canadian Longitudinal Study on Aging (CLSA).

Setting: Community.

Participants: 30,097 adults aged 45 to 85 at baseline MEASUREMENTS: The five most prevalent dyad, triad, and tetrad combinations of 12 modifiable risk factors were identified. Cognition was assessed with a composite Z-score from a neuropsychological test battery. Linear mixed effect models were used to examine the association between the identified combinations and 3-year cognitive changes. Interaction was assessed on additive scale, and synergism was explored.

Results: The combinations that were both highly prevalent and had the most detrimental effect on global cognition were: hearing loss and physical inactivity for the dyad (mean difference in change score = -0.07 SD; 95 % CI: -0.09 to -0.06; p < 0.001; effect size = -0.28), hearing loss, physical inactivity, and hypertension for the triad (mean difference in change score = -0.07; 95 % CI: -0.09 to -0.06; p < 0.001; effect size = -0.28), and hearing loss, physical inactivity, hypertension, and sleep disturbance for the tetrad (mean difference in change score = -0.05; 95 % CI: -0.07 to -0.03; p < 0.001; effect size = -0.20). Similar patterns were observed for memory and executive function. A significant synergistic interaction was observed between hearing loss and physical inactivity for global cognition (p = 0.005).

Conclusions: The combined effect of multiple risk factors varied by its combinations. The combination of hearing loss and physical inactivity offers a greater potential benefit than other dyad combinations. Hypertension and sleep disturbance can be further included for triad and tetrad combinations. Auditory health and exercise should be prioritized for multidomain interventions.

Addressing modifiable dementia risk factors requires reliable risk assessment methods. We aimed to synthesise knowledge on risk scores for all cause dementia, Alzheimer's disease (AD) and vascular dementia, classify them according to target population, evaluate their content, cost, appropriateness of validation studies, and suitability for implementing risk reduction guidelines. A systematic search was conducted of PubMed, Cochrane Collaboration, ProQuest, Scopus, Embase, and PsycINFO databases using a pre-registered protocol. Data on risk factors, target population, predictive validity, cost, and alignment with WHO guidelines were extracted. Random-effects meta-analysis was performed. Of 45 risk scores identified, 29 were for all-cause dementia, including 11 based on late-life cohorts, 6 on midlife, and 7 covering mid to late-life. The pooled C-statistic across development and validation studies of dementia risk scores was 0.69 (95 % CI: 0.67, 0.71). Development study AUCs were higher than validation study AUCs and dropped from 0.74 to 0.66 for risk scores developed for clinical samples and from 0.79 to 0.71 for AD specific scores (which include functional indicators non-independent of disease). There were no validated risk scores for vascular dementia. Dem-NCD, CogDrisk, ANU-ADRI and LIBRA risk scores incorporated most WHO-recommended risk factors and demonstrated accuracy comparable to the overall pooled C-statistic. We conclude that across the field, there are methodological limitations relating to validation, and inappropriate comparison of tools designed for different purposes or target populations. However, there are now several validated, risk scores for all-cause dementia and AD that assess modifiable factors and offer cost-effective dementia risk assessment and risk reduction advice.

Importance: Childhood maltreatment has been associated with greater risk for Alzheimer's disease and related dementias. Better understanding of this association will have implications for prevention and intervention efforts.

Objective: To determine whether individuals with documented histories of childhood maltreatment and matched controls differ in cognitive functioning in late midlife and whether maltreatment leads to higher rates of cognitive impairment.

Design: Prospective cohort design SETTING: Metropolitan Midwestern county area PARTICIPANTS: Children with documented maltreatment histories and demographically matched controls were followed up into late midlife (N = 447, Mage = 59.4). Control group children were matched to maltreated children on age, sex, race and ethnicity, and approximate family social class during the time the cases were processed.

Exposure: Children with documented cases of physical and sexual abuse and neglect during 1967 to 1971 in the county juvenile (family) or adult criminal courts. Cases were restricted to children ages 0-11 at the time of the maltreatment to ensure that the temporal direction of consequences was clear.

Main outcome and measures: Using a comprehensive neuropsychological assessment battery, multiple tests of cognitive functioning and the Functional Activities Questionnaire were administered. Participants were categorized as having cognitive impairment with no dementia (CIND) or dementia.

Results: Individuals with histories of childhood maltreatment performed worse on all 12 neuropsychological tests, compared to matched controls (Cohen's d 0.28 to 0.42) and had significantly higher risk for CIND [AOR = 1.86), amnestic CIND [AOR = 1.68) and non-amnestic [AOR = 1.48). About 13 % of maltreated individuals met criteria for amnestic CIND. Few met criteria for dementia. Males, females, Blacks, Whites, older and younger individuals, and those physically or sexually abused or neglected showed the effects of maltreatment.

Conclusions and relevance: Cognitive repercussions of childhood maltreatment continue into late midlife. Findings reinforce the importance of early detection and preventive interventions that may decrease risks associated with childhood maltreatment in later adulthood. Because we use documented court cases from childhood, this design reduces potential biases associated with reliance on retrospective self-reports of childhood adversities. To our knowledge, this is the first study to examine long-term consequences of childhood neglect for cognitive impairment.

Introduction: There is very limited knowledge on the relationship between pregnancy hypertension and the occurrence of pre-clinical Alzheimer's disease (AD).

Methods: Community-dwelling midlife women without dementia were enrolled from well-woman clinics of the National University Hospital, Singapore. Sociodemographic parameters and history of pregnancy hypertension were obtained. Cognition was assessed using the Montreal Cognitive Assessment-Basic tool. Fasted blood samples were stored for batched analysis of renal function, APOE genotyping and p-tau217 levels using Simoa® ALZpath p-tau217 Advantage PLUS (Quanterix, MA, USA). General linear modelling was used to examine the association between pregnancy hypertension and p-tau217.

Results: Among 743 women (mean age 62.9 ± 6.0; range: 50.7 to 76.6 years) enrolled, 68 (9.2%) reported pregnancy hypertension. General linear modelling showed that an older age [mean difference: 0.002 (95% CI: 0.001, 0.003)], mild cognitive impairment [0.016 (0.001, 0.032)], lower BMI [0.068 (0.027, 0.109)], eGFR<60 mL/min/1.73 m² [0.132 (0.072, 0.193)] and the APOE4 carrier genotype [0.038 (0.018, 0.058)] were independently associated with higher serum p-tau217 levels. History of pregnancy hypertension remained significantly associated with subsequent higher serum p-tau217 [0.040 (0.013, 0.067)], after adjustment for age, mild cognitive impairment, hypertension, BMI, renal function, and APOE4 genotype status.

Discussion: Pregnancy hypertension was associated with AD pathology with mean differences similar to high risk APOE4 carrier genotypes. Information on pregnancy hypertension could help physicians to identify women who might benefit from early p-tau217 screening for Alzheimer's disease, allowing for early clinical intervention.

Latino migrants are at increased risk for cognitive decline, yet the influence of immigration-related factors, such as time lived in the United States (U.S.), remains poorly understood. In the Boston Latino Aging Study (BLAST), 130 older Latino migrants completed a comprehensive neuropsychological assessment. We examined whether the proportion of years lived in the U.S. was associated with cognitive performance, adjusting for age, education, and acculturation. Greater time in the U.S was significantly associated with lower phonemic fluency, while no associations were found for other domains. Notably, 16 % of phonemic fluency errors involved English intrusions during a Spanish-language task, suggesting cross-linguistic interference. These findings underscore the importance of considering language dynamics and sociocultural context in studies of Latino cognitive aging.

Background: AR1001 is a phosphodiesterase-5 inhibitor that produces improved cognitive performance and reduces amyloid-β and phosphorylated tau burdens in preclinical models of Alzheimer's disease (AD).

Objectives: To evaluate the safety and efficacy of AR1001 in participants with mild-to-moderate Alzheimer's disease (AD).

Design: Randomized, double-blind, placebo-controlled phase 2 trial conducted at 21 sites in the United States.

Participants: Adults aged 55-80 years with mild-to-moderate dementia as determined by National Institutes of Aging-Alzheimer's Association (NIA-AA) stage 4 or 5 and Mini-mental State Exam (MMSE) score 16-26.

Intervention: Once daily oral administration of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks followed by 26 weeks optional extension.

Measurements: Co-primary efficacy endpoints were changes from baseline at Week 26 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog 13) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included measures of cognition, daily living, and depression. Levels of plasma biomarkers pTau-181, pTau-217, Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also examined.

Results: A total of 210 participants were enrolled and 82% completed 26 weeks of treatment. AR1001 10 mg and 30 mg were well-tolerated with a similar safety profile compared to placebo. After 26 weeks, there were no differences in ADAS-Cog13, ADCS-CGIC, or in secondary efficacy endpoints between groups. Levels of plasma biomarkers pTau-181, pTau-217, and GFAP were improved in the 30 mg AR1001 group compared to placebo.

Conclusion: AR1001 was safe and well tolerated. Although primary efficacy endpoints were not met after 26 weeks of treatment, participants receiving 30 mg AR1001 showed favorable changes in AD-related plasma biomarkers compared to placebo.

Trial registration: clinicaltrials.gov; NCT03625622.

Background: The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for late-onset Alzheimer's disease (AD), yet there is little consensus about how and when the allele exerts its influence on the brain.

Methods: In this scoping review, we synthesized research examining APOE ε4-related differences on MRI-derived measures of brain structure, function, and connectivity in cognitively unimpaired, middle-aged adults (aged 40-65 years). Four online databases (Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, Scopus) were searched on July 11, 2024, and forward/backward reference searching was conducted on identified studies. We extracted data on sample characteristics, methods, and key APOE ε4-related results.

Results: Our pre-registered search strategy identified 30 relevant studies. Overall, we found little evidence of robust, consistent differences between APOE ε4 carriers and non-carriers at midlife, especially in relation to brain structure. However, among the studies identified, small samples were common, and limited consideration was afforded to factors such as sex and ethnocultural diversity.

Conclusion: Overall, the existing literature indicates that APOE ε4 exerts little, if any, influence on brain structure at midlife, while differences in brain function and connectivity remain poorly characterized.