Introduction: We investigated whether lifelong exposure to stimulating activities (active life, AL) mitigates diabetes-associated dementia risk and brain aging. Methods: In the Swedish National Study on Aging and Care-Kungsholmen, 2286 dementia-free older adults (407 with MRI volumetric measures) were followed over 12 years to detect incident dementia. AL index (low, moderate, high) combined education, work complexity, leisure activities, and social network. Results: Participants with diabetes and low AL had higher dementia risk (hazard ratio [HR] = 2.36, 95% confidence interval [CI] 1.45-3.87) than patients who were diabetes-free with moderate-to-high AL (reference). Dementia risk in participants with diabetes and moderate-to-high AL did not differ from the reference. People with diabetes and low AL had the smallest brain volume, but those with diabetes and moderate-to-high AL exhibited total brain and gray-matter volumes that were similar to those of diabetes-free participants. AL did not modify the diabetes microvascular lesions association. Discussion: AL could mitigate the deleterious impact of diabetes on dementia, potentially by limiting the loss of brain tissue volume.
Introduction: The PSENs/APP mutation distribution in Chinese patients with familial Alzheimer's disease (FAD) remains unclear. We aimed to analyze the genetic features of Chinese FAD pedigrees with and without PSENs/APP mutations. Methods: In total, 1330 patients with Alzheimer's disease (AD) or mild cognitive impairment in 404 pedigrees were enrolled from the Chinese Familial Alzheimer's Disease Network. PSENs/APP mutations and APOE frequencies were determined. Results: In total, 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP mutations. Eleven missense mutations were first identified. In patients without PSENs/APP mutations. 44.31% carried one APOE epsilon 4 allele, and 14.85% two APOE epsilon 4 alleles. Discussion: The new PSENs/APP mutations indicate heterogeneity in AD pathogenesis between Chinese and other ethnic groups. The low mutation rate suggests the involvement of other genes/factors in Chinese FAD. APOE epsilon 4 might be a major gene for some FAD without PSENs/APP mutations.
Introduction: The effect of comorbid cardiometabolic diseases (CMDs), including diabetes, heart diseases, and stroke, on dementia remains unclear. Methods: A cohort of 2648 dementia-free adults aged >= 60 years was followed up for 12 years. An active lifestyle was defined in accordance with the engagement in leisure activities and/or a social network. Cox models were used in data analysis. Results: The multiadjusted hazard ratio (HR, 95% confidence interval) of dementia was 1.41 (1.07-1.86) for one, 2.38 (1.58-3.59) for two, and 4.76 (2.04-11.13) for three CMDs. In joint exposure analysis, the HR of dementia was 3.36 (2.14-5.30) for participants with CMDs plus an inactive lifestyle and 1.32 (0.95-1.84) for those with CMDs plus an active lifestyle (reference: no CMDs plus active lifestyle). An active lifestyle delayed dementia onset by 3.50 years in people with CMDs. Discussion: CMDs, especially when comorbid, are associated with increased dementia risk; however, leisure activities and social integration mitigate this risk.
Introduction: Metabolomics provide a promising tool to understand the pathogenesis and to identify novel biomarkers of dementia. This study aimed to determine circulating metabolites associated with incident dementia in a Chinese cohort, and whether a selected metabolite panel could predict dementia. Methods: Thirty-eight metabolites in baseline serum were profiled by nuclear magnetic resonance in 1440 dementia-free participants followed 5 years in the Shanghai Aging Study. Results: Higher serum levels of glutamine and O-acetyl-glycoproteins were associated with increased risk of dementia, whereas glutamate, tyrosine, acetate, glycine, and phenylalanine were negatively related to incident dementia. A panel of five metabolites selected by least absolute shrinkage and selection operator within cross-validation regression analysis could predict incident dementia with an area under the receiver-operating characteristic curve of 0.72. Discussion: We identified seven candidate serum metabolic biomarkers for dementia. These findings and the underlying biological mechanisms need to be further replicated and elucidated in future studies.
Introduction: The association of lifespan cognitive reserve (CR) with mild cognitive impairment (MCI) remains controversial. We aimed to examine the association of lifespan CR indicator with the risk of MCI and its progression to dementia, taking brain pathologies into account. Methods: In a community-based cohort study (mean age, 79 years) with annual followup (median, 5.16 years; maximum, 20 years), a cognitively intact group (n = 1182) and an MCI group (n = 420) were identified at baseline. During the follow-up, 611 participants died and underwent autopsies. CR indicator encompassing education, early life to late-life cognitive and social activities were obtained and tertiled. Results: The multi-adjusted hazard ratio (HR) of MCI was 0.72 (95% confidence interval [CI] 0.58 to 0.90) in the cognitively intact group, and the HR of dementia was 0.66 (95% CI 0.45 to 0.97) in the MCI group for participants with the highest CR indicator (reference: the lowest CR indicator). Among MCI participants with brain pathologies, dementia incidence was about 50% lower in people with the highest CR indicator than the lowest CR indicator. Discussion: High lifespan CR indicator reduces risk of MCI, and delays its progression to dementia.
Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
Introduction: The impact of prediabetes and diabetes on stroke and the development of dementia after a stroke remain unclear. Methods: A total of 2655 dementia-free participants (including a stroke-free cohort and a prevalent stroke cohort) were followed-up for 12 years. Dementia and post-stroke dementia were determined by clinical examinations and national registry data. Diabetes was ascertained via medical examination, medication use, medical records, or glycated hemoglobin (HbA1c) >= 6.5%. Prediabetes was defined as H bA1c >= 5.7% in diabetes-free participants. Results: In the stroke-free cohort, 236 participants developed ischemic stroke, and 47 developed post-stroke dementia. Diabetes was associated with ischemic stroke (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.16 to 2.67) and post-stroke dementia (HR 2.56, 95% CI 1.04 to 6.25). In the prevalent stroke cohort, diabetes was also related to dementia risk. Prediabetes was not significantly related to stroke or post-stroke dementia. Discussion: Diabetes, but not prediabetes, is associated with an increased risk of ischemic stroke and post-stroke dementia.
Introduction: Altered lipid metabolism is implicated in Alzheimer's disease (AD), but the mechanisms remain obscure. Aging-related declines in circulating plasmalogens containing omega-3 fatty acids may increase AD risk by reducing plasmalogen availability. Methods: We measured four ethanolamine plasmalogens (PlsEtns) and four closely related phosphatidylethanolamines (PtdEtns) from the Alzheimer's Disease Neu-roimaging Initiative (ADNI; n = 1547 serum) and University of Pennsylvania (U Penn; n = 112 plasma) cohorts, and derived indices reflecting PlsEtn and PtdEtn metabolism: PL-PX (PlsEtns), PL/PE (PlsEtn/PtdEtn ratios), and PBV (plasmalogen biosynthesis value; a composite index). We tested associations with baseline diagnosis, cognition, and cere-brospinal fluid (CSF) AD biomarkers. Results: Results revealed statistically significant negative relationships in ADNI between AD versus CN with PL-PX (P = 0.007) and PBV (P = 0.005), late mild cognitive impairment (LMCI) versus cognitively normal (CN) with PL-PX (P = 2.89 x 10(-5)) and PBV (P = 1.99 x 10(-4), and AD versus LMCI with POPE (P = 1.85 x 10(-4)). In the UPenn cohort, AD versus CN diagnosis associated negatively with PL/PE (P = 0.0191) and PBV (P = 0.0296). In ADNI, cognition was negatively associated with plasmalogen indices, including Alzheimer's Disease Assessment Scale 13-item cognitive subscale (ADAS-Cog13; PL-PX: P = 3.24 x 10(-6); PBV: P = 6.92 x 10(-5)) and Mini-Mental State Examination (MMSE; PL-PX: P = 1.28 x 10(-9); PBV: P = 6.50 x 10(-9)). In the UPenn cohort, there was a trend toward a similar relationship of MMSE with PL/PE (P = 0.0949). In ADN I, CSF total-tau was negatively associated with PL-PX (P = 5.55 x 10(-6)) and PBV (P = 7.77 x 10(-6)). Additionally, CSF t-tau/A beta(1-42) 42 ratio was negatively associated with these same indices (PL-PX, P= 2.73 x 10(-6); PBV, P = 4.39 x 10(-6)). In the UPenn cohort, PL/PE was negatively associated with CSF total-tau (P = 0.031) and t-tau/A beta(1-42) (P = 0.021). CSF A beta(1-42) was not significantly associated with any of these indices in either cohort. Discussion: These data extend previous studies by showing an association of decreased plasmalogen indices with AD, mild cognitive impairment (MCI), cognition, and CSF tau. Future studies are needed to better define mechanistic relationships, and to test the effects of interventions designed to replete serum plasmalogens.
Introduction: This study tested the self-reported sleep characteristics associated with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cognitively intact older adults. Methods: The linear and non-linear regression analyses were conducted in 736 cognitively normal participants (mean [standard deviation; SD] age, 62.3 [10.5] years, range 40 to 88 years, 59% female) who had measurements of cerebrospinal fluid (CSF) amyloid beta (A beta) and tTau proteins and sleep characteristics, after adjusting for age, gender, education, apolipoprotein E gene (APOE) epsilon 4 status, and general cognition. Results: Greater daytime sleepiness was associated with higher CSF indicators of amyloid deposition in female patients. No significant associations were revealed for CSF tTau proteins after Bonferroni correction. A U-shaped relationship was revealed for nocturnal sleep habits, such that those with insufficient or excessive nocturnal sleep duration had greater CSF biomarkers of amyloid deposition (the reflection range: bedtime: around 10:00 p.m. and sleep duration: 6.0 to 6.5 hours). Discussion: These findings consolidated the close relationship between sleep and AD.
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.
Introduction: The genetic risk effects of apolipoprotein E (APOE) on familial Alzheimer's disease (FAD) with or without gene mutations, sporadic AD (SAD), and normal controls (NC) remain unclear in the Chinese population. Methods: In total, 15 119 subjects, including 311 FAD patients without PSEN1, PSEN2, APP, TREM2, and SORL1 pathogenic mutations (FAD [unknown]); 126 FAD patients with PSENs/APP mutations (FAD [PSENs/APP]); 7234 SAD patients; and 7448 NC were enrolled. The risk effects of APOE epsilon 4 were analyzed across groups. Results: The prevalence of the APOE epsilon 4 genotype in FAD (unknown), FAD (PSENs/APP), SAD, and NC groups was 56.27%, 26.19%, 36.23%, and 19.54%, respectively. Further, the APOE epsilon 4 positive genotype had predictive power for FAD (unknown) risk (odds ratio: 4.51, 95% confidence interval: 3.57-5.45, P < .001). Discussion: APOE epsilon 4 positive genotype may cause familial aggregation, and the investigation of multiple interventions targeting APOE pathological function to reduce the risk for this disease warrants attention.
We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, outpatient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.
Introduction: We investigated the proteomic profiles of amyloid plaques (APs) from Alzheimer's disease (AD) and age-matched non-AD brains and APP/PS1 transgenic model mice. Methods: APs and adjacent control regions were collected from fresh-frozen brain sections using laser capture dissection. Proteins were quantitated using tag-labeling coupled high-throughput mass spectra. Results: Over 4000 proteins were accurately quantified, and more than 40 were identified as highly enriched in both AD and non-AD APs, including apoE, midkine, VGFR1, and complement C4. Intriguingly, proteins including synaptic structural proteins and complement C1r, C5, and C9 were found to be upregulated in AD APs but not non-AD APs. Moreover, the proteomic pattern of AD APs was distinct from APP/PS1 APs and exhibited correlation with aging hippocampus. Discussion: Our results provide new insight into AP composition. We demonstrate unexpected differences between AD, non-AD, and APP/PS1 mouse APs, which may relate to different pathological processes. (C) 2018 Published by Elsevier Inc. on behalf of the Alzheimer's Association.
Objective: The present work aims to evaluate the significance of sleep disturbance and electroencephalogram (EEG) alteration in the early stage of Alzheimer's disease (AD). Background and Rationale: Sleep disturbance is common in patients with AD. It is not known if it can occur at the early stage of AD and if EEG recording may help identify the early sign of the disease. Historical Evolution: Sleep disturbance in AD has generally been considered as late consequence of the neurodegenerative process. A growing body of evidence has suggested that the sleep disturbance may occur at the early stage of AD. Updated Hypothesis: Based on the previous epidemiologic studies and our recent findings, we propose that sleep disturbance may play an important role in the development of AD. Sleep EEG changes may serve as a valuable early sign for AD in the prepathological stage. Early Experimental Data: Our data suggested that A beta PPswe/PS1(Delta E9) transgenic AD mice at preplaque stage (3 and 4 months of age) exhibited different profile of sleep architecture and sleep EEG, which preceded the cognitive deficit and AD neuropathology. Future Experiments and Validation Studies: Future experiments should focus on sleep EEG changes in patients with mild cognitive impairment and early stage of AD. Follow-up studies in high-risk population of the elderly are equally important. In addition, the exact molecular mechanism underlying the sleep disturbance should be thoroughly investigated. Major Challenges for the Hypothesis: Studies on human participants with early stage of AD, especially the follow-up studies on the presymptomatic elderly in a large population, are difficult and time-consuming. Linkage to Other Major Theories: Our hypothesis may link previous theories to establish a bidirectional relationship between sleep disorders and AD, which may finally form a new schematic mechanism to understand the disease pathogenesis and disease progression. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.