Structural, static, and dynamic functional MRI predictors for conversion from mild cognitive impairment to Alzheimer's disease: Inter-cohort validation of Shanghai Memory Study and ADNI.

Mild cognitive impairment (MCI) is a critical prodromal stage of Alzheimer's disease (AD), and the mechanism underlying the conversion is not fully explored. Construction and inter-cohort validation of imaging biomarkers for predicting MCI conversion is of great challenge at present, due to lack of longitudinal cohorts and poor reproducibility of various study-specific imaging indices. We proposed a novel framework for inter-cohort MCI conversion prediction, involving comparison of structural, static, and dynamic functional brain features from structural magnetic resonance imaging (sMRI) and resting-state functional MRI (fMRI) between MCI converters (MCI_C) and non-converters (MCI_NC), and support vector machine for construction of prediction models. A total of 218 MCI patients with 3-year follow-up outcome were selected from two independent cohorts: Shanghai Memory Study cohort for internal cross-validation, and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort for external validation. In comparison with MCI_NC, MCI_C were mainly characterized by atrophy, regional hyperactivity and inter-network hypo-connectivity, and dynamic alterations characterized by regional and connectional instability, involving medial temporal lobe (MTL), posterior parietal cortex (PPC), and occipital cortex. All imaging-based prediction models achieved an area under the curve (AUC) > 0.7 in both cohorts, with the multi-modality MRI models as the best with excellent performances of AUC > 0.85. Notably, the combination of static and dynamic fMRI resulted in overall better performance as relative to static or dynamic fMRI solely, supporting the contribution of dynamic features. This inter-cohort validation study provides a new insight into the mechanisms of MCI conversion involving brain dynamics, and paves a way for clinical use of structural and functional MRI biomarkers in future.

Joint effect of testosterone and neurofilament light chain on cognitive decline in men: The Shanghai Aging Study.

INTRODUCTION: The association of testosterone and cognitive decline is inconclusive, and its joint effect with neurofilaments light chain (NfL) remains largely unknown. METHODS: A total of 581 non-demented older men in the Shanghai Aging Study were included. Blood total testosterone (TT), free testosterone (FT), and NfL were measured at baseline. The relationships between TT, FT, TT/FT-NfL, and cognitive decline were explored by Cox regression models. RESULTS: During a median follow-up of 6.7 years, there was an inverse association between TT/FT and cognitive decline (TT, trend p = .004, Q1 vs Q4, hazard ratio [HR] = 4.39, 95% confidence interval [CI] = 1.60 to 12.04; FT, trend p = .002, Q1 vs Q4, HR = 5.29, 95% CI = 1.50 to 16.89). Compared to participants with high TT/FT-low NfL, those with low TT/FT-high NfL had significantly higher risks of cognitive decline (TT, HR = 5.10, 95% CI = 1.11 to 23.40; FT, HR = 6.14, 95% CI = 1.34 to 28.06). DISCUSSION: Our findings suggest that the combination of testosterone and neurodegenerative markers may provide reliable predictive insights into future cognitive decline. HIGHLIGHTS: Testosterone is inversely associated with cognitive decline in older men. There is a joint effect of testosterone and NfL on cognitive decline. Sex hormone and neurodegeneration may synergistically contribute to cognitive deterioration.

Lifestyle and incident dementia: A COSMIC individual participant data meta­analysis.

INTRODUCTION: The LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics. METHODS: We combined data from 21 prospective cohorts across six continents (N = 31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis. RESULTS: A one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed. DISCUSSION: Modifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups. HIGHLIGHTS: A two-step individual participant data meta-analysis was conducted. This was done at a global scale using data from 21 ethno-regionally diverse cohorts. The association between a modifiable dementia risk score and dementia was examined. The association was modified by geographical region and age at baseline. Yet, modifiable dementia risk and protective factors appear relevant in all investigated groups and regions.

Education, neighborhood environment, and cognitive decline: Findings from two prospective cohort studies of older adults in China.

INTRODUCTION: The impacts of education on cognitive decline across different neighborhood environments (NEs) have rarely been studied. METHODS: We investigated and compared the associations between educational attainment and cognitive decline using data of 1286 participants from the Taizhou Imaging Study (TIS) and the Shanghai Aging Study (SAS). RESULTS: Compared with low-educated participants, in TIS with disadvantaged NE, high-educated participants manifested a significantly slower decline in global cognition (.062 Z score per year, P < .001), memory (.054 Z score per year, P < .05), and attention (.065 Z score per year, P < .01), whereas in SAS with advanced NE, highly educated individuals exhibited a slower decline only in attention (.028 Z score per year, P < .05). DISCUSSION: We observed the additive effect of educational attainment and NE on cognitive decline in older adults. Education is especially important for maintaining cognitive health in a disadvantaged environment.

Dose-response relationship between late-life physical activity and incident dementia: A pooled analysis of 10 cohort studies of memory in an international consortium.

INTRODUCTION: Though consistent evidence suggests that physical activity may delay dementia onset, the duration and amount of activity required remains unclear. METHODS: We harmonized longitudinal data of 11,988 participants from 10 cohorts in eight countries to examine the dose-response relationship between late-life physical activity and incident dementia among older adults. RESULTS: Using no physical activity as a reference, dementia risk decreased with duration of physical activity up to 3.1 to 6.0 hours/week (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.67 to 1.15 for 0.1 to 3.0 hours/week; HR 0.68, 95% CI 0.52 to 0.89 for 3.1 to 6.0 hours/week), but plateaued with higher duration. For the amount of physical activity, a similar pattern of dose-response curve was observed, with an inflection point of 9.1 to 18.0 metabolic equivalent value (MET)-hours/week (HR 0.92, 95% CI 0.70 to 1.22 for 0.1 to 9.0 MET-hours/week; HR 0.70, 95% CI 0.53 to 0.93 for 9.1 to 18.0 MET-hours/week). DISCUSSION: This cross-national analysis suggests that performing 3.1 to 6.0 hours of physical activity and expending 9.1 to 18.0/MET-hours of energy per week may reduce dementia risk.

Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium.

INTRODUCTION: Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups. METHODS: A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models. RESULTS: Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs. DISCUSSION: Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men.

Plasma Aß42/Aß40 and p-tau181 Predict Long-Term Clinical Progression in a Cohort with Amnestic Mild Cognitive Impairment.

BACKGROUND: Previous studies reported the value of blood-based biomarkers in predicting Alzheimer disease (AD) progression among individuals with different disease stages. However, evidence regarding the value of these markers in those with amnestic mild cognitive impairment (aMCI) is insufficient. METHODS: A cohort with 251 aMCI individuals were followed for up to 8 years. Baseline blood biomarkers were measured on a single-molecule array platform. Multipoint clinical diagnosis and domain-specific cognitive functions were assessed to investigate the longitudinal relationship between blood biomarkers and clinical AD progression. RESULTS: Individuals with low Aß42/Aß40 and high p-tau181 at baseline demonstrated the highest AD risk (hazard ratio = 4.83, 95% CI 2.37-9.86), and the most dramatic decline across cognitive domains. Aß42/Aß40 and p-tau181, combined with basic characteristics performed the best in predicting AD conversion (AUC = 0.825, 95% CI 0.771-0.878). CONCLUSIONS: Combining Aß42/Aß40 and p-tau181 may be a feasible indicator for AD progression in clinical practice, and a potential composite marker in clinical trials.

Development of a Plasma Biomarker Diagnostic Model Incorporating Ultrasensitive Digital Immunoassay as a Screening Strategy for Alzheimer Disease in a Chinese Population.

BACKGROUND: The ultrasensitive detection of blood-based biomarkers such as amyloid ß (Aß), tau, and neurofilament light (NFL) has drawn much attention in Alzheimer disease (AD) diagnosis. However, few studies have been conducted in the Chinese population. This study aimed to evaluate the ability of plasma biomarker diagnostic models for AD in the Chinese population based on a novel digital immunoassay technology. METHODS: 159 patients with AD, 148 patients with amnestic mild cognitive impairment (aMCI), and 121 cognitively normal control participants were recruited from 2 cohorts. The concentrations of plasma Aß42, Aß40, Aß42/Aß40, total tau (t-tau), phosphorylated tau 181 (p-tau 181), and NFL were quantified using an ultrasensitive single molecule array (Simoa) platform. Comprehensive and simplified diagnostic models were established based on the plasma biomarker profile and clinical characteristics. RESULTS: Among all blood biomarkers, p-tau181 had the greatest potential for identifying patients with cognitive impairment. The simplified diagnostic model, which combined plasma p-tau181, Aß42, and clinical features, achieved 93.3% area under the curve (AUC), 78.6% sensitivity, and 94.2% specificity for distinguishing AD from control participants, indicating a diagnostic ability approaching that of the comprehensive diagnostic model including 5 plasma biomarkers and clinical characteristics (95.1% AUC, 85.5% sensitivity, 94.2% specificity). Moreover, the simplified model reached 95.9% AUC and 94.0% AUC for early- and late-onset AD/control participants, respectively. CONCLUSIONS: We established AD diagnostic models using plasma biomarkers for Chinese participants. These findings suggest the simplified diagnostic model provides an accessible and practical way for large-scale screening in the clinic and community, especially in developing countries.

Disturbed microbial ecology in Alzheimer's disease: evidence from the gut microbiota and fecal metabolome.

BACKGROUND: Gut microbiota (GMB) alteration has been reported to influence the Alzheimer's disease (AD) pathogenesis through immune, endocrine, and metabolic pathways. This study aims to investigate metabolic output of the dysbiosis of GMB in AD pathogenesis. In this study, the fecal microbiota and metabolome from 21 AD participants and 44 cognitively normal control participants were measured. Untargeted GMB taxa was analyzed through 16S ribosomal RNA gene profiling based on next-generation sequencing and fecal metabolites were quantified by using ultrahigh performance liquid chromatography-mass spectrometry (UPLC-MS). RESULTS: Our analysis revealed that AD was characterized by 15 altered gut bacterial genera, of which 46.7% (7/15 general) was significantly associated with a series of metabolite markers. The predicted metabolic profile of altered gut microbial composition included steroid hormone biosynthesis, N-Acyl amino acid metabolism and piperidine metabolism. Moreover, a combination of 2 gut bacterial genera (Faecalibacterium and Pseudomonas) and 4 metabolites (N-Docosahexaenoyl GABA, 19-Oxoandrost-4-ene-3,17-dione, Trigofoenoside F and 22-Angeloylbarringtogenol C) was able to discriminate AD from NC with AUC of 0.955 in these 65 subjects. CONCLUSIONS: These findings demonstrate that gut microbial alterations and related metabolic output changes may be associated with pathogenesis of AD, and suggest that fecal markers might be used as a non-invasive examination to assist screening and diagnosis of AD.

Association of combined engagement in cognitive and physical activity with domain-specific cognitive function: The Shanghai Aging Study.

OBJECTIVES: This cross-sectional study aimed to examine the association of the combined engagement in cognitive activity (CA) and physical activity (PA) with domain-specific cognition in community-dwelling older adults. METHODS: We analysed data from 3192 dementia-free participants aged ≥50 years in the Shanghai Aging Study. CA was assessed using Shanghai Cognitive Activities Scale. PA was determined based on questionnaires and further transformed into metabolic equivalent values. We used multivariate linear and logistic regression models to estimate the ß and odds ratio of CA, PA, or combined CA and PA and each neuropsychological test. RESULTS: A high level of CA was associated with a better performance in most of the tests, except for the conflicting instructions task (CIT) and stick test (ST). In contrast, PA displayed no significant associations with any test. Engagement in high CA and high PA was associated with the best performance in Mini-Mental State Examination, recall in ST, categorisation in Modified Common Objects Sorting Test (MCOST), immediate recall, delayed recall, and recognition in Auditory Verbal Learning Test. Participants with "high CA and low PA" had the lowest risk of impairment in Go/No-Go correct tapping in CIT, rotate in ST, item naming, and category naming in MCOST, Trail Making Test (TMT)-A, and TMT-B. CONCLUSIONS: Our study suggests that engagement in both high CA and high PA may be the most efficacious way to maintain various domains of cognition. A higher level of CA may help to preserve cognition among older individuals who have difficulties in performing PA.

Cholesterol profiles and incident cognitive decline among older adults: the Shanghai Aging Study.

BACKGROUND: the association between cholesterol profiles and risk of cognitive decline among older adults was inconclusive. OBJECTIVE: to examine the association between cholesterol profiles and risk of cognitive decline in older adults with or without vascular risk factors (VRFs) in the prospective phase of the Shanghai Aging Study. DESIGN: a prospective community-based cohort study. SETTING: Shanghai, China. PARTICIPANTS: we prospectively followed 1,556 dementia-free participants aged ≥60 years with a baseline cholesterol profile for 5.2 years on average. Participants with at least one of obesity, diabetes, hypertension, stroke, and coronary artery disease were categorised to the VRFs group, and those free of any VRFs were categorised to the non-VRFs group. METHODS: total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol in serum were measured at baseline. At follow-up, consensus diagnosis of incident dementia and Alzheimer's disease (AD) were established based on medical, neurological, and neuropsychological examinations. Cox regression was used to assess the association between cholesterol and incident dementia/AD; multivariate linear regression was used to examine the relationship between cholesterol and an annual rate of Mini Mental State Examination (MMSE) score decline in participants with or without VRFs. RESULTS: among VRFs-free participants, TC (HR 0.62, 95%CI 0.40-0.95) and LDL-C (HR 0.47, 95%CI 0.28-0.80) were inversely associated with incident dementia, LDL-C was inversely associated with incident AD (HR 0.50, 95%CI 0.28-0.90). A significant correlation was found between incremental TC (ß = 0.08), LDL-C (ß = 0.09), and a slower annual decline of MMSE score. CONCLUSIONS: effect of cholesterol on cognitive decline may be modified by VRFs.

TOMM40 and APOE variants synergistically increase the risk of Alzheimer's disease in a Chinese population.

BACKGROUND: The apolipoprotein E (APOE) ε4 allele is a strong risk factor for Alzheimer's disease (AD) in Caucasian and African American populations. It suggests that other genetic factors may modulate AD pathogenesis in Chinese populations, among which the frequency of this allele is reduced but the AD prevalence is maintained. The translocase of outer mitochondrial membrane 40 (TOMM40), which is located adjacent to APOE, may play an APOE-dependent role in modulating AD pathogenesis. AIMS: This work aimed to investigate whether TOMM40 polymorphisms modulate AD risk independently of, or in conjunction with APOE polymorphisms in Chinese populations. METHODS: We conducted a case-control study including 834 patients with AD recruited from the Memory Clinic and 643 cognitively normal participants recruited from the community. The Taqman SNP method was used for APOE genotyping, while TOMM40 polymorphism genotyping was conducted via a polymerase chain reaction-ligase detection reaction. RESULTS: The TOMM40 rs10119 and rs71352238 alleles were associated with AD independently of the patient APOE status. The rs10119 AA genotype and rs71352238 CC genotype were risk genotypes of AD. Individuals carrying a TOMM40 rs10119 GG/APOE ε4+ (OR, 3.73; 95% CI 1.49-9.37; P = 0.005), TOMM40 rs10119 AG/APOE ε4+ (OR, 4.16; 95% CI 3.30-5.24; P < 0.001), or TOMM40 rs10119 AA/APOE ε4+ (OR, 14.78; 95% CI 8.56-25.54; P < 0.001) genotype exhibited a significantly higher AD risk. Those carrying a TOMM40 rs71352238 TT/APOE ε4+ (OR, 3.82; 95% CI 2.32-6.29; P < 0.001), TOMM40 rs71352238 CT/APOE ε4+ (OR, 4.40; 95% CI 3.46-5.56; P < 0.001), or TOMM40 rs71352238 CC/APOE ε4+ (OR, 14.02; 95% CI 7.81-25.17; P < 0.001) genotype also exhibited a significantly increased AD risk. DISCUSSION AND CONCLUSIONS: This study provides invaluable insights into the mechanisms underlying the prevalence of AD in Chinese populations, and supports that simultaneous TOMM40 and APOE genotyping in the clinical setting may identify individuals at high risk of developing AD.

Inability to Smell Peppermint Is Related to Cognitive Decline: A Prospective Community-Based Study.

BACKGROUND: A few studies have demonstrated the association of poorer olfactory identification (OI) with poorer cognition in population-based cohorts. None of them considered the outcome associated with the inability to smell a certain odor. OBJECTIVE: To verify the hypothesis that at least one specific odor is associated with incident cognitive decline among older adults. METHODS: In the Shanghai Aging Study, a sub-cohort of 948 dementia-free participants who had baseline OI measurements were prospectively followed for 5 years. RESULTS: An inability to smell peppermint (ß = -0.44, p < 0.001), rose (ß = -0.14, p = 0.040), or coffee (ß = -0.37, p = 0.002) was inversely related to the annual rate of change in the Mini Mental State Examination score, and an inability to smell peppermint was associated with a higher risk for incident dementia (hazard ratio 2.67, 95% CI 1.44-4.96) after adjustment for confounders. CONCLUSION: Our study suggests that some odors, especially peppermint, might be considered as a potential predictor for dementia in older populations.

Prevalence and incidence of dementia in an older Chinese population over two decades: The role of education.

INTRODUCTION: Secular trends of dementia prevalence and incidence have rarely been studied in the Chinese population. METHODS: We examined the changes in dementia prevalence and incidence by comparing data from Shanghai Epidemiological Survey of Dementia and Alzheimer's disease (SESD) and Shanghai Aging Study (SAS) conducted two decades apart. FINDINGS: The dementia prevalence and incidence in total participants in SAS were higher than that in SESD (prevalence: 6.44% vs 2.30%, P < .001; annual incidence: 2.58% vs 1.33%, P < .001). In participants with ≤6 years of education, the dementia prevalence in SAS was higher than that in SESD (6.39% vs 3.07%, P < .001); the annual dementia incidence in SAS was double that in SESD (3.63% vs 1.80%, P = .019). DISCUSSION: We observed an increasing trend of dementia prevalence and incidence in the Chinese elderly, especially those with low education. The dramatic rise in numbers of people with dementia may happen most likely in low-educated populations.

Serum TRPA1 mediates the association between olfactory function and cognitive function.

Background: Olfactory dysfunction was associated with poorer cognition. However, the association between transient receptor potential cation channel subfamily A member 1 (TRPA1) and cognitive function have not been studied. This study aimed to evaluate the mediation effect of TRPA1 on the association between olfactory and cognitive function among Chinese older adults. Methods: We recruited 121 participants with cognitive impairment (CI) and 135 participants with normal cognition (NC) from a memory clinic and the "Shanghai Aging Study." Olfactory identification of each participant was measured by the Sniffin' Sticks Screening Test 12 (SSST-12). Serum TRPA1 were quantified using the Enzyme-Linked Immunosorbent Assay. The mediation effects of TRPA1 on the association between olfactory function and cognitive function were explored using mediation analysis. Results: The CI group had a significantly higher proportion of the high level of serum TRPA1 (58.7%) than the NC group (42.2%) (p = 0.0086). After adjusted for gender, age, and years of education, mediation analysis verified that TRPA1 partially mediated the association between SSST-12 and Mini Mental State Examination (MMSE). It also verified that TRPA1 partially mediated the association between the identification of peppermint and MMSE. Conclusion: Our study emphasizes the mediation role of TRPA1 in the relationship between olfactory and cognitive function among older adults. Further research is necessary to explore the mechanism of TRPA1 on the relationship between olfactory and cognitive decline.

Stumbling Blocks in the Investigation of the Relationship Between Age-Related Hearing Loss and Cognitive Impairment.

The relationship between age-related hearing loss (ARHL) and cognitive impairment (CI) remains intricate. However, there is no robust evidence from experimental or clinical studies to elucidate their relationship. The key unaddressed questions are (a) whether there is a causal effect of ARHL on CI and (b) whether efficacious treatment of ARHL (such as hearing-aid use) ameliorates CI and dementia-related behavioral symptoms. Because of several methodological and systematic flaws/challenges, rigorous verification has not been conducted. Addressing these stumbling blocks is essential to unraveling the relationship between ARHL and CI, which motivated us to undertake this review. Here, we discuss the methodological problems from the perspectives of potential confounding bias, assessments of CI and ARHL, hearing-aid use, functional-imaging studies, and animal models based on the latest information and our experiences. We also identify potential solutions for each problem from the viewpoints of clinical epidemiology. We believe that "objectivity," specifically the use of more objective behavioral assessments and new computerized technologies, may be the key to improving experimental designs for studying the relationship between ARHL and CI.

The impact of kidney function on plasma neurofilament light and phospho-tau 181 in a community-based cohort: the Shanghai Aging Study.

BACKGROUND: The blood-based biomarkers are approaching the clinical practice of Alzheimer's disease (AD). Chronic kidney disease (CKD) has a potential confounding effect on peripheral protein levels. It is essential to characterize the impact of renal function on AD markers. METHODS: Plasma phospho-tau181 (P-tau181), and neurofilament light (NfL) were assayed via the Simoa HD-X platform in 1189 dementia-free participants from the Shanghai Aging Study (SAS). The estimated glomerular filter rate (eGFR) was calculated. The association between renal function and blood NfL, P-tau181 was analyzed. An analysis of interactions between various demographic and comorbid factors and eGFR was conducted. RESULTS: The eGFR levels were negatively associated with plasma concentrations of NfL and P-tau181 (B = - 0.19, 95% CI - 0.224 to - 0.156, P < 0.001; B = - 0.009, 95% CI - 0.013 to -0.005, P < 0.001, respectively). After adjusting for demographic characteristics and comorbid diseases, eGFR remained significantly correlated with plasma NfL (B = - 0.010, 95% CI - 0.133 to - 0.068, P < 0.001), but not with P-tau181 (B = - 0.003, 95% CI - 0.007 to 0.001, P = 0.194). A significant interaction between age and eGFR was found for plasma NfL (Pinteraction < 0.001). In participants ≥ 70 years and with eGFR < 60 ml/min/1.73 m2, the correlation between eGFR and plasma NfL was significantly remarkable (B = - 0.790, 95% CI - 1.026 to - 0,554, P < 0.001). CONCLUSIONS: Considering renal function and age is crucial when interpreting AD biomarkers in the general aging population.

Cognitive impairment as a comorbidity of epilepsy in older adults: Analysis of global and domain-specific cognition.

OBJECTIVE: This study aimed to explore the association between epilepsy and cognitive impairment and to determine the factors associated with cognitive impairment in older people with epilepsy. METHODS: People with epilepsy and controls aged ≥50 years were recruited and their global and domain-specific cognitive functions were evaluated by a comprehensive neuropsychological battery. Clinical characteristics were obtained from medical records. Analysis of covariance was used to examine the difference of cognition between two groups, after adjusting for age, gender, education years, hypertension, diabetes, and heart disease. A multiple linear regression model was used to explore the potential impact factors of cognitive functions among people with epilepsy. RESULTS: This study recruited 90 people with epilepsy and 110 controls. The proportion of cognitive impairment among older adults with epilepsy was 62.2%, which was significantly higher than controls (25.5%, p < .001). People with epilepsy performed worse on global cognition (p < .001), especially in domains of memory (p < .001), executive function (p < .001), language (p < .001), and attention (p = .031). Among older adults with epilepsy, age was negatively correlated with the scores of memory (ß = -.303, p = .029), executive function (ß = -.354, p = .008), and attention (ß = -.558, p < .001). Females performed better on executive function (ß = -.350, p = .002) than males. Education years had a positive correlation with global cognition (ß = .314, p = .004). Number of antiseizure medications was also negatively correlated with scores of spatial construction function (ß = -.272, p = .019). SIGNIFICANCE: Our results indicated that cognitive impairment was a major comorbidity of epilepsy. Number of antiseizure medications is suggested as a potential risk factor of impaired cognition in older people with epilepsy.

Apolipoprotein E ε4 Modifies the Effect of Possible Anticholinergic Drugs on Incident Dementia: The Shanghai Aging Study.

OBJECTIVES: To validate the hypothesis that apolipoprotein E (APOE) ε4 modifies the effect of possible anticholinergic drugs (PACDs) on incident dementia among older adults. DESIGN: A population-based prospective study. SETTING AND PARTICIPANTS: Dementia-free older adults in an urban community in Shanghai, China. METHODS: At baseline, PACDs were defined according to the Anticholinergic Cognitive Burden Scale. Standard daily dose (SDD) of PACDs was calculated. A battery of neuropsychological tests was used to assess cognition and the consensus diagnosis was conducted for incident dementia and Alzheimer's disease (AD). Multivariate Cox regression models were used to examine the association between PACD use and the risk of dementia and AD in APOE ε4 carriers and noncarriers. RESULTS: We followed 1406 dementia-free participants for a median of 5.3 years and defined 117 incident dementia cases, among which 89 were AD. Only in APOE ε4 carriers was PACD use associated with incident dementia [hazard ratio (HR) 5.71; 95% CI 2.04-15.94] and AD (HR 5.73; 95% CI 1.77-18.54); SDD was positively associated with incident dementia (HR 2.42; 95% CI 1.32-4.44) and AD (HR 2.16; 95% CI 1.06-4.41). CONCLUSIONS AND IMPLICATIONS: Using PACDs requires judicious consideration for the potential risk of dementia and AD in older adults carrying APOE ε4.

Olfactory function, neurofilament light chain, and cognitive trajectory: A 12-year follow-up of the Shanghai Aging Study.

This study aimed to determine whether blood neurofilament light chain (NfL) modifies the association of olfactory dysfunction (OD) with long-term cognitive decline. A total of 1125 non-demented older adults in the Shanghai Aging Study were evaluated for baseline olfaction (12-item Sniffin' Sticks Smell Test) and cognitive trajectory by a 12-year follow-up. Baseline blood NfL was quantified using Single Molecular Array assay, and dichotomized into low and high levels based on the median value of concentration. The Mini-Mental State Examination (MMSE) and Telephone Interview for Cognitive Status-40 were used to assess participants' cognitive function. Cognitive decline was ascertained when dementia was diagnosed or documented in the medical record during follow-up, or the MMSE declining rate (slope) was 1.0 SD larger than the group mean. OD participants presented a steeper trajectory of MMSE score (p interaction = 0.004) and a high risk of cognitive decline (adjusted HR [95% CI], 1.82 [1.11, 2.98]) only in those with high NfL. Participants with combined OD and high NfL showed the highest risk of cognitive decline (adjusted HR, 2.43 [1.20, 4.92]). OD, especially in combination with high blood NfL concentration, may be able to identify individuals who later incur cognitive deterioration.