Exploring the role of vitamin E in Alzheimer’s disease : an epidemiological and clinical perspective

Vitamin E, the main non-enzymatic lipophylic antioxidant in the human body, has a major role in protecting the brain from damage mediated by free radicals. The term vitamin E encompasses eight natural congeners (forms): four tocopherols and four tocotrienols, named α, β, γ, and δ. Most investigation of vitamin E in relation to dementia and Alzheimer´s disease (AD) has focused primarily only on α-tocopherol, with conflicting findings. However, increasing knowledge regarding the biological properties of vitamin E provides a strong biological rationale that other forms of vitamin E, beyond just α-tocopherol, may play a role in AD pathogenesis. The aim of the present project is to investigate the relation of all eight natural vitamin E forms with mild cognitive impairment (MCI) and AD in older adults, by combining both an epidemiological and a clinicbased approach. Study I. Plasma levels of all eight natural vitamin E forms, and markers of vitamin E oxidative/nitrosative damage (α-tocopherylquinone, 5-nitro-γ-tocopherol), were investigated in subjects with AD, MCI, and normal cognition (CN) in a clinical-based, multi-centre European study (AddNeuroMed Project). Compared to CN subjects, AD and MCI cases had lower plasma levels of total tocopherols, total tocotrienols and total vitamin E. Both MCI and AD cases had 85% lower odds to be in the highest tertile of plasma total tocopherols and total vitamin E, and they were, respectively, 92% and 94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, both disorders were associated with increased plasma indices of vitamin E oxidative/nitrosative damage (ratios α-tocopherylquinone/α-tocopherol and 5-nitro-γ-tocopherol/γ-tocopherol). Study II. Within the AddNeuroMed Project, analysis which integrated plasma levels of vitamin E forms with structural magnetic resonance (MRI) parameters, derived from automated regional analysis, was used to differentiate AD and MCI cases from CN individuals, and to predict MCI conversion to AD. The analysis of MRI and vitamin E data alone provided an accuracy of 83.2% and 92.8% respectively, for AD versus CN, and of 58.1% and 87.8% for MCI versus CN. The integrated analysis of plasma vitamin E and MRI data enhanced the accuracy, which were 98.2% for AD versus CN and 90.7% for MCI versus CN. This combination of data also correctly identified 85% of the MCI who converted to clinical AD at one year follow-up and 67% of the non-converters. Study III. The association of plasma levels of eight natural vitamin E forms with the incidence of AD was examined in a Swedish population-based prospective study (Kungsholmen Project) of oldest-old individuals (age 80+), using six-year follow-up data. Subjects with higher concentrations of total tocopherols, total tocotrienols or total vitamin E had approximately a 50% reduced risk of developing AD in comparison to subjects with lower plasma levels (highest versus lowest tertile). Study IV. The association of serum levels of all eight natural vitamin E forms and markers of vitamin E oxidative/nitrosative damage, with the incidence of cognitive impairment (MCI or AD) was investigated in a Finnish population-based prospective study (CAIDE) of older adults (age 65+), using eight-year follow-up data. The odds of cognitive impairment was reduced for subjects in the medium tertile of γ- tocopherol serum levels, relative to those subjects in the lowest tertile [odds ratio and 95% confidence interval: 0.27(0.10-0.78)]. Subjects with a higher serum value for the index of γ-tocopherol nitrosative damage (5-nitro-γ-tocopherol/γ-tocopherol ratio; high and middle versus lowest tertile) were about three times more likely to develop cognitive impairment. Conclusions. α-tocopherol is the only vitamin E form currently used to define vitamin E dietary requirements, and it is the only congener tested in randomized controlled trials in subjects with AD and MCI. The results of this project provide evidence that suggests that the other natural forms of vitamin E can also be important in cognitive impairment and AD in older adults. Thus, all natural vitamin E forms should be considered when studying the association of this micronutrient with cognitive impairment and AD. These findings also suggest that some aspects of vitamin E supplementation in preventing and treating AD should be re-examined. This should include the timing of intervention, the composition of supplementation, and the assessment of plasma levels of all vitamin E forms. The latter can help identify subjects who could benefit from vitamin E supplementation, and monitor in-vivo biological response to treatment

Vitamin E family: Role in the pathogenesis and treatment of Alzheimer's disease

AbstractIntroductionVitamin E family, composed by tocopherols and tocotrienols, is a group of compounds with neuroprotective properties. The exact role in the pathogenesis and the benefit of vitamin E as treatment for Alzheimer's disease (AD) are still under debate.MethodsA literature search in PubMed, Medline, and Cochrane databases has been carried out. All types of studies, from bench and animal models to clinical, were included.ResultsHigh plasma vitamin E levels are associated with better cognitive performance, even if clear evidence of their ability to prevent or delay cognitive decline in AD is still lacking. Each vitamin E form is functionally unique and shows specific biological functions. Tocotrienols seem to have superior antioxidant and anti-inflammatory properties compared with tocopherols.DiscussionThe benefit of vitamin E as a treatment for AD is still under debate, mainly because of the inconsistent findings from observational studies and the methodological limitations of clinical trials

Development of a Cognitive Training Support Programme for prevention of dementia and cognitive decline in at-risk older adults

BackgroundEvidence for the beneficial effects of cognitive training on cognitive function and daily living activities is inconclusive. Variable study quality and design does not allow for robust comparisons/meta-analyses of different cognitive training programmes. Fairly low adherence to extended cognitive training interventions in clinical trials has been reported.AimsThe aim of further developing a Cognitive Training Support Programme (CTSP) is to supplement the Computerised Cognitive Training (CCT) intervention component of the multimodal Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), which is adapted to different cultural, regional and economic settings within the Word-Wide FINGERS (WW-FINGERS) Network. The main objectives are to improve adherence to cognitive training through a behaviour change framework and provide information about cognitive stimulation, social engagement and lifestyle risk factors for dementia.MethodsSix CTSP sessions were re-designed covering topics including (1) CCT instructions and tasks, (2) Cognitive domains: episodic memory, executive function and processing speed, (3) Successful ageing and compensatory strategies, (4) Cognitive stimulation and engagement, (5) Wellbeing factors affecting cognition (e.g., sleep and mood), (6) Sensory factors. Session content will be related to everyday life, with participant reflection and behaviour change techniques incorporated, e.g., strategies, goal-setting, active planning to enhance motivation, and adherence to the CCT and in relevant lifestyle changes.ConclusionsThrough interactive presentations promoting brain health, the programme provides for personal reflection that may enhance capability, opportunity and motivation for behaviour change. This will support adherence to the CCT within multidomain intervention trials. Efficacy of the programme will be evaluated through participant feedback and adherence metrics

Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia

We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOE epsilon 4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.Peer reviewe

Serum Thioredoxin-80 is associated with age, ApoE4, and neuropathological biomarkers in Alzheimer’s disease: a potential early sign of AD

[EN] Background: Thioredoxin-80 (Trx80) is a cleavage product from the redox-active protein Thioredoxin-1 and has been previously described as a pro-inflammatory cytokine secreted by immune cells. Previous studies in our group reported that Trx80 levels are depleted in Alzheimer's disease (AD) brains. However, no studies so far have investigated peripheral Trx80 levels in the context of AD pathology and whether could be associated with the main known AD risk factors and biomarkers. Methods: Trx80 was measured in serum samples from participants from two different cohorts: the observational memory clinic biobank (GEDOC) (N = 99) with AD CSF biomarker data was available and the population-based lifestyle multidomain intervention trial Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (N = 47), with neuroimaging data and blood markers of inflammation available. The GEDOC cohort consists of participants diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, whereas the FINGER participants are older adults at-risk of dementia, but without substantial cognitive impairment. One-way ANOVA and multiple comparison tests were used to assess the levels of Trx80 between groups. Linear regression models were used to explore associations of Trx80 with cognition, AD CSF biomarkers (A beta 42, t-tau, p-tau and p-tau/t-tau ratio), inflammatory cytokines, and neuroimaging markers. Results: In the GEDOC cohort, Trx80 was associated to p-tau/t-tau ratio in the MCI group. In the FINGER cohort, serum Trx80 levels correlated with lower hippocampal volume and higher pro-inflammatory cytokine levels. In both GEDOC and FINGER cohorts, ApoE4 carriers had significantly higher serum Trx80 levels compared to non-ApoE4 carriers. However, Trx80 levels in the brain were further decreased in AD patients with ApoE4 genotype. Conclusion: We report that serum Trx80 levels are associated to AD disease stage as well as to several risk factors for AD such as age and ApoE4 genotype, which suggests that Trx80 could have potential as serum AD biomarker. Increased serum Trx80 and decreased brain Trx80 levels was particularly seen in ApoE4 carriers. Whether this could contribute to the mechanism by which ApoE4 show increased vulnerability to develop AD would need to be further investigated.Open access funding provided by Karolinska Institute. This research was supported by the Margaretha af Ugglas Foundation, the Karolinska institutet KID funding, Gun och Bertil Stohnes Stiftelse, Stiftelsen Syskonen Svenssons, the Karolinska Institutet fund for geriatric research Stiftelsen Gamla Tjanarinnor, and the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet

Occupational complexity and cognition in the FINGER multidomain intervention trial

Introduction Lifetime exposure to occupational complexity is linked to late-life cognition, and may affect benefits of preventive interventions. Methods In the 2-year multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), we investigated, through post hoc analyses (N = 1026), the association of occupational complexity with cognition. Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. Results Higher levels of occupational complexity were associated with better baseline cognition. Measures of occupational complexity had no association with intervention effects on cognition, except for occupational complexity with data, which was associated with the degree of intervention-related gains for executive function. Discussion In older adults at increased risk for dementia, higher occupational complexity is associated with better cognition. The cognitive benefit of the FINGER intervention did not vary significantly among participants with different levels of occupational complexity. These exploratory findings require further testing in larger studies.Peer reviewe

Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial.

BACKGROUND: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. OBJECTIVE: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. METHODS: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. RESULTS: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. CONCLUSION: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 305374. The study has also been funded by the “Multimodal preventive trials for Alzheimer’s Disease: towards multinational strategies-programme: MIND-AD”, Academy of Finland (291803) and VTR, Kuopio University Hospital (5772815), Swedish Research Council (529-2014-7503), The Stockholms Sjukhem foundation, the Netherlands Organization for Health Research and Development, (733051041), and the French National Research Agency (ANR-14-JPPS-0001-02)

Dementia beyond 2025: knowledge and uncertainties

International audienceGiven that there may well be no significant advances in drug development before 2025, prevention of dementia/AD through the management of vascular and lifestyle-related risk factors may be a more realistic goal than treatment. Level of education and cognitive reserve assessment in neuropsychological testing deserve attention, as well as cultural, social and economic aspects of caregiving. Assistive technologies for dementia care remain complex. Serious games are emerging as virtual educational and pleasurable tools, designed for individual and cooperative skill-building. Public policies are likely to pursue improving awareness and understanding of dementia; providing good quality early diagnosis and intervention for all; improving quality of care from diagnosis to the end of life, using clinical and economic endpoints; delivering dementia strategies quicker, with an impact on more people. Dementia should remain presented as a stand-alone concept, distinct from frailty or loss of autonomy. The basic science of sensory impairment and social engagement in people with dementia needs to be developed. E-learning and serious games programmes may enhance public and professional education. Faced with funding shortage, new professional dynamics and economic models may emerge through coordinated, flexible research networks. Psychosocial research could be viewed as an investment in quality of care, rather than an academic achievement in a few centres of excellence. This would help provide a competitive advantage to the best operators. Stemming from care needs, a logical, systems approach to dementia care environment through organizational, architectural and psychosocial interventions may be developed, to help reduce symptoms in people with dementia and enhance quality of life. Dementia-friendly environments, culture and domesticity are key factors for such interventions

Recruitment and Baseline Characteristics of Participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)-A Randomized Controlled Lifestyle Trial

Peer reviewe