Alzheimer's disease (AD) is defined biologically by amyloid and tau pathology. The emergence of biomarker-based diagnostic criteria, blood-based assays, and anti-amyloid therapeutic trials has substantially raised the evidentiary standard for all candidate AD interventions, including Chinese herbal medicine (CHM) formulas. However, CHM formula evidence for AD lacks critical appraisal and methodological standards. Thus, this review aims to: (1) critically evaluate the clinical, mechanistic, and translational evidence for oral or topical CHM formulas used in AD, specifically those selected according to Traditional Chinese Medicine (TCM) diagnostic; and (2) assess the methodological requirements necessary for credible development of such formulas in AD research. Preclinical studies suggest plausible effects of CHM formulas on amyloid-related pathways, tau phosphorylation, neuroinflammation, oxidative stress, and energy metabolism, but these findings remain hypothesis-generating rather than clinically validated. Most included studies relied on clinical diagnoses, likely encompassing mixed pathologies (e.g., vascular dementia, dementia with Lewy bodies, or depression-related cognitive impairment), rendering their results preliminary rather than confirmatory for biologically defined AD. Current evidence does not support CHM formulas as established therapies for AD. Future studies will require biomarker-confirmed diagnosis, rigorous formula quality control, prespecified TCM pattern stratification, clinically meaningful cognitive and functional endpoints, mechanistic target-engagement measures, and prospective safety and herb-drug interaction monitoring.
Background Validated cognitive decline and Alzheimer's disease risk scores (CAIDE, ANU-ADRI, LIBRA, LIBRA2) were developed in general-population cohorts; how they behave in the high-socioeconomic, health-selected populations typical of preventive-medicine programs and over-represented in ageing cohorts is undescribed. Objective Lacking a cognitive outcome, we did not test predictive validity but described score distributions, inter-score concordance, the components driving variance, and complementary biological data. Methods Four scores were computed for 895 participants aged ≥45 years in the Zoī cohort, a self-referred, self-funded preventive-medicine sample. Concordance was assessed by Spearman correlations and, after dichotomization, by pairwise agreement (percentage agreement, Cohen's κ). Principal component analysis identified components accounting for most between-person variance. Complementary data (DEXA body composition, HbA1c, erythrocyte omega-3) were cross-tabulated with score-derived risk categories. Results Concordance was moderate (ρ = 0.39–0.60), and dichotomized categories were fairly-to-moderately concordant across families (Cohen's κ 0.33–0.52). Protective variables showed ceiling effects (education ≥10 years, 86%; social/cognitive activity, 100%), leaving cardiovascular factors (BMI, hypertension, coronary heart disease) to account for most variance. Despite 91% having normal BMI (≤30 kg/m 2 ), DEXA-measured fat mass showed a dose-response gradient across all scores (CAIDE 4.36–6.26); HbA1c revealed a glycemic gradient invisible to self-reported diabetes. Conclusions In this high-socioeconomic cohort, the scores were moderately concordant and varied almost solely by cardiovascular components, protective factors being saturated. Whether this reflects uniformly low risk or reduced ability to separate individuals cannot be determined without a cognitive outcome. Complementary biological measurements added stratification, supporting augmented risk-assessment tools to be validated against cognitive endpoints.
Background Subjective cognitive decline (SCD) is a potential early indicator of Alzheimer's disease (AD). While SCD has been linked to white matter hyperintensity (WMH) burden, it is unclear whether regional WMH lesion volume is differentially associated with domains of cognitive complaints. Objective Examine whether regional WMH burden is associated with domain-specific SCD (memory, executive function) in cognitively unimpaired older adults with a family history of AD. Methods Participants were 150 cognitively unimpaired older adults (65–89 years) with subjective memory complaints and a first-degree family history of AD. Cognitive complaints were assessed with the Cognitive Change Index (CCI-20). WMHs were quantified from T1-weighted and FLAIR MRI using an automated pipeline and categorized into sample-based tertiles for total, subcortical, and lobar regions. Hierarchical regressions examined associations between WMH burden and CCI-20 memory, executive, and total scores, while adjusting for demographics, total intracranial volume, MRI site, APOE ε4 status, and mood symptoms. Results Greater WMH burden in the left temporal lobe was associated with increased memory complaints and total SCD, whereas no WMH region was associated with executive function complaints. APOE ε4 status and depressive symptoms were associated with greater memory and total cognitive complaints across models. Apathy was uniquely related to memory complaints. Conclusions Among older adults with elevated risk of AD, memory-SCD was associated with greater region-specific left temporal cerebrovascular lesion volume. Findings highlight the clinical relevance of left temporal WMH burden and the importance of considering regional vascular pathology, genetic risk, and mood when characterizing early subjective cognitive changes.
Background Malnutrition is a modifiable risk factor for cognitive deterioration. The Geriatric Nutritional Risk Index (GNRI) objectively assesses nutritional status, but its longitudinal association with incident cognitive impairment and distinct cognitive trajectories remains insufficiently characterized. Objective To assess the association between baseline GNRI and incident cognitive impairment. Methods We analyzed data from 2596 community-dwelling adults aged ≥60 years from the Health and Retirement Study (2016–2022). Baseline nutritional status was assessed by GNRI. Incident cognitive impairment was defined using the modified Telephone Interview for Cognitive Status. Group-based trajectory modeling identified longitudinal cognitive patterns. Cox proportional hazards regression and multinomial logistic regression models examined associations, adjusting for sociodemographic, lifestyle, and clinical covariates. Results Compared with the high GNRI group (≥98), low GNRI (<98) was associated with a higher hazard of incident cognitive impairment (HR = 1.25; 95% CI: 1.05–1.49). This association was linear (p for nonlinearity = 0.62). Longitudinal modeling identified four trajectory groups: “High-stable” (21.7%), “High-decline” (29.6%), “Moderate-decline” (41.4%), and “Low-rapid decline” (7.3%). In multinomial analyses, low GNRI (<98) was specifically associated with higher odds of the “Low-rapid decline” trajectory (OR = 1.61; 95% CI: 1.06–2.46) versus the “High-stable” reference, whereas intermediate-pattern associations were not significant. The association was consistent across subgroups, including those defined by body mass index and alcohol consumption (p for interaction > 0.05). Conclusions Low baseline GNRI was associated with a higher hazard of incident cognitive impairment and greater odds of membership in an adverse cognitive trajectory. The predictive and screening utility of GNRI requires further evaluation.
Background Individuals with higher educational attainment have a lower risk for dementia, including Alzheimer's disease, but it is less clear how the educational attainment of an individual's parents may influence dementia risk, particularly in diverse populations. Objective This study examined whether intergenerational educational attainment for two adjacent generations was associated with incident dementia risk. Methods Individuals from the Atherosclerosis Risk in Communities study were asked about their own educational level (at study baseline, 1987–1989; ages 44–66 years) and, several years later, that of each parent. Dementia status was ascertained from baseline through 2020 using expert committee diagnoses from in-person and telephonic neuropsychological assessments, informant interviews, hospitalization codes, and death certificates. Individuals without dementia at baseline, and with non-missing covariates/ educational history, were included. Educational level was classified (for individuals and the highest-educated parent) as less than high school, completed high school or GED, or more than high school. Cox proportional-hazard models were used to evaluate the association between intergenerational educational attainment and incident dementia risk. Results Among 10,626 individuals (21.8% Black; 55.9% female), models showed that high parental education level and individual education level were each significantly and independently associated with a lower hazard of dementia, although associations were strongest and most consistent for individual education. Individuals whose educational attainment surpassed that of their parents, compared to those with comparable levels, exhibited a significantly lower dementia risk. Conclusions An individual's own educational attainment may exert a more significant influence in lowering dementia risk, even when parental education is considered.
