Ahead of print articles
COMBINING GEOSPATIAL ANALYSIS WITH DEMENTIA RISK UTILISING GENERAL PRACTICE DATA: A SYSTEMATIC REVIEW
N. Bagheri, K. Wangdi, N. Cherbuin, K.J. Anstey
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Geographical information systems (GIS) and geospatial analysis techniques will help to identify significant dementia risk clusters (hotspots) across communities and will enable policy makers to target prevention interventions to the right place. This review synthesises the published literature on geospatial analysis techniques for quantifying and mapping dementia risk, and reviews available dementia risk assessment tools. A systematic literature review was undertaken in four medical and life sciences databases (PubMed, Cochrane Central, Embase, and Web of Sciences) from their inception to March 2017 for all articles relating to dementia. The search terms included: ‘dementia’, ‘Alzheimer’s disease’, ‘general practice database’, ‘family physician’, ‘AD risk assessment tools’, ‘Geographical Information Systems’ and ‘geospatial analysis’, ‘geographical variation’ and ‘spatial variation’. To date, most geospatial studies on dementia have been carried out retrospectively using population based data. An alternative approach is utilisation of a rich source of general practice (family physician) databases to predict dementia risk based on available dementia risk assessment tools. In conclusion, the estimated risks of dementia can thus be geo-attributed and mapped at a small scale using geographical information systems and geospatial analysis techniques to identify dementia risk clusters across the communities and refine our understanding of the interaction between socio-demographic and environmental factors, and dementia risk clusters.
N. Bagheri ; K. Wangdi ; N. Cherbuin ; K.J. Anstey (2017): Combining Geospatial Analysis with Dementia Risk Utilising General Practice Data: A Systematic Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.33
RECRUITMENT OF AT-RISK PARTICIPANTS FOR CLINICAL TRIALS: A MAJOR PARADIGM SHIFT FOR ALZHEIMER’S DISEASE PREVENTION
J. Alber, A.K.W. Lee, W. Menard, D. Monast, S.P. Salloway
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J. Alber ; A.K.W. Lee ; W. Menard ; D. Monast ; S.P. Salloway (2017): Recruitment of At-Risk Participants for Clinical Trials: A Major Paradigm Shift for Alzheimer’s Disease Prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.32
COSTS AND RESOURCE USE ASSOCIATED WITH ALZHEIMER’S DISEASE IN ITALY: RESULTS FROM AN OBSERVATIONAL STUDY
G. Bruno, M. Mancini, G. Bruti, G. Dell’Agnello, C. Reed
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Background: The GERAS II study aimed to assess societal costs and resource use associated with Alzheimer’s disease (AD) for patients and their primary caregivers in Italy and Spain, stratified for different severity stages of AD at baseline. This report presents baseline results for Italy.
Design: GERAS II was a prospective, multicentre, observational study of routine care in AD.
Setting: Community-dwelling patients attending specialist secondary care centres (memory clinics/Alzheimer’s Evaluation Units) and their primary informal caregivers were recruited into the study.
Participants: Patients were aged ≥55 years, presented within the normal course of care, had a diagnosis of probable AD and a Mini-Mental State Examination (MMSE) score of ≤26. Patients and caregivers were stratified according to patient AD dementia severity at baseline: mild, MMSE score 21–26; moderate, MMSE score 15–20; or moderately severe/severe, MMSE score <15.
Measurements: Data collected for patients and caregivers included demographics/clinical characteristics; current medication; patient cognitive, functional and behavioural assessments; patient and caregiver health-related quality of life (HRQoL); and patient and caregiver resource use. The costs associated with the resources used were calculated. Costs were broken down into patient healthcare costs, patient social care costs and caregiver informal care costs.
Results: Of 198 patients enrolled from Italy, 29 (15%) had mild AD dementia, 80 (40%) had moderate AD dementia, and 89 (45%) had moderately severe/severe AD dementia. Patient and caregiver characteristics showed some differences between AD dementia severity groups; for example, a numerically higher proportion of patients with mild and moderately severe/severe AD dementia were taking memantine compared with those with moderate AD dementia. Patient functioning and behavioural and psychological symptoms worsened with increasing AD dementia severity (p<0.05 between groups for all measures). No significant difference between the disease severity groups was observed in patient HRQoL, and there was no clear pattern in resource use. However, all measures of caregiver time spent helping the patient differed significantly between groups (p<0.05) and were highest in patients with moderately severe/severe AD dementia. Mean (standard deviation) total monthly societal costs per patient (2013 values) were €1850 (1901), €1552 (1322) and €2728 (2184) for patients with mild, moderate and moderately severe/severe AD dementia, respectively (p<0.001 between groups). Caregiver informal care costs were the greatest contributor to total societal costs and amounted to €1370, €1223 and €2223 per patient per month for mild, moderate and moderately severe/severe AD dementia groups, respectively (p<0.001 between groups).
Conclusion: Total Italian societal costs generally increased with increasing AD dementia severity. However, costs were slightly lower for moderate than for mild AD dementia, possibly reflecting the observed unusual trend of greater caregiver time and higher memantine use in patients with mild versus moderate AD dementia.
G. Bruno ; M. Mancini ; G. Bruti ; G. Dell’Agnello ; C. Reed (2017): Costs and Resource Use Associated with Alzheimer’s Disease in Italy: Results from an Observational Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.31
VITAMIN E SUPPLEMENTATION REDUCES CELLULAR LOSS IN THE BRAIN OF A PREMATURE AGING MOUSE MODEL
G. La Fata, N. van Vliet, S. Barnhoorn, R.M.C. Brandt, S. Etheve, E. Chenal, C. Grunenwald, N. Seifert, P. Weber, J.H.J. Hoeijmakers, M.H. Mohajeri, W. P. Vermeij
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Background: Aging is a highly complex biological process driven by multiple factors. Its progression can partially be influenced by nutritional interventions. Vitamin E is a lipid-soluble anti-oxidant that is investigated as nutritional supplement for its ability to prevent or delay the onset of specific aging pathologies, including neurodegenerative disorders.
Purpose: We aimed here to investigate the effect of vitamin E during aging progression in a well characterized mouse model for premature aging.
Method: Xpg-/- animals received diets with low (~2.5 mg/kg feed), medium (75 mg/kg feed) or high (375 mg/kg feed) vitamin E concentration and their phenotype was monitored during aging progression. Vitamin E content was analyzed in the feed, for stability reasons, and in mouse plasma, brain, and liver, for effectiveness of the treatment. Subsequent age-related changes were monitored for improvement by increased vitamin E or worsening by depletion in both liver and nervous system, organs sensitive to oxidative stress.
Results: Mice supplemented with high levels of vitamin E showed a delayed onset of age-related body weight decline and appearance of tremors when compared to mice with a low dietary vitamin E intake. DNA damage resulting in liver abnormalities such as changes in polyploidy, was considerably prevented by elevated amounts of vitamin E. Additionally, immunohistochemical analyses revealed that high intake of vitamin E, when compared with low and medium levels of vitamin E in the diet, reduces the number of p53-positive cells throughout the brain, indicative of a lower number of cells dying due to DNA damage accumulated over time.
Conclusions: Our data underline a neuroprotective role of vitamin E in the premature aging animal model used in this study, likely via a reduction of oxidative stress, and implies the importance of improved nutrition to sustain health.
G. La Fata ; N. van Vliet ; S. Barnhoorn ; R.M.C. Brandt ; S. Etheve ; E. Chenal ; C. Grunenwald ; N. Seifert ; P. Weber ; J.H.J. Hoeijmakers ; M.H. Mohajeri ; W. P. Vermeij (2017): Vitamin E Supplementation Reduces Cellular Loss in the Brain of a Premature Aging Mouse Model . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.30
COGNITIVE FRAILTY AND INCIDENCE OF DEMENTIA IN OLDER PERSONS
H. Shimada, H. Makizako, K. Tsutsumimoto, T. Doi, S. Lee, T. Suzuki
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BACKGROUND: Cognitive frailty may be a preventive or therapeutic target for preventing dementia and functional decline with age.
OBJECTIVES: To examine the relationship between physical and cognitive frailty and the incidence of dementia in community-living older persons.
DESIGN: A prospective cohort study. Setting: General community in Japan. Participants: A total of 4072 persons aged ≥ 65 years.
SETTING: A community in Japan.
PARTICIPANTS: A total of 4072 community-dwelling older persons aged ≥ 65 years participated in the study.
MEASUREMENTS: We characterized physical frailty as ≥ 3 of the following criteria: slow walking speed, muscle weakness, exhaustion, low physical activity, and weight loss. We used the National Center for Geriatrics and Gerontology-Functional Assessment Tool, which includes tests of word list memory, attention, and executive function, and processing speed to screen for cognitive frailty. The presence of ≥ 2 cognitive impairments, indicated by an age-adjusted score of at least 1.5 standard deviations below the reference threshold, was defined as cognitive frailty. The incidence of dementia was determined using data collected by the Japanese Health Insurance System over 24 months.
RESULTS: The overall prevalence rates of physical frailty, cognitive impairment, and cognitive frailty (i.e., coexistence of frailty and cognitive impairment) were 5.1%, 5.5%, and 1.1%, respectively. During the follow-up period, 81 participants (2.0%) developed dementia. We found significant relationships between the incidence of dementia and cognitive impairment (hazard ratio (HR): 3.85, 95% confidence interval (95% CI): 2.09–7.10) and cognitive frailty (HR: 6.19, 95% CI: 2.7–13.99). However, the association between dementia and physical frailty did not reach significance (HR: 1.95, 95% CI: 0.97–3.91).
CONCLUSIONS: Individuals with cognitive frailty had the highest risk of dementia. Future research should implement dementia prevention strategies among older persons with cognitive frailty.
H. Shimada ; H. Makizako ; K. Tsutsumimoto ; T. Doi ; S. Lee ; T. Suzuki (2017): Cognitive Frailty and Incidence of Dementia in Older Persons. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.29
CARE MANAGEMENT TO PROMOTE TREATMENT ADHERENCE IN PATIENTS WITH COGNITIVE IMPAIRMENT AND VASCULAR RISK FACTORS: A DEMONSTRATION PROJECT
L.M. Bonner, A. Hanson, G. Robinson, E. Lowy, S. Craft
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Dementia prevention is highly important. Improved control of vascular risk factors has the potential to decrease dementia risk, but may be difficult. Therefore, we developed and piloted a care management protocol for Veterans at risk for dementia. We enrolled 32 Veterans with diabetes and hypertension, at least one of which was poorly controlled, and cognitive impairment. Participants were randomly assigned to a 6-month care management intervention or to usual care. At enrollment, 6-months and 12-months, we assessed cognitive performance, mood, and diabetes and hypertension control. At follow-up, diastolic blood pressure was lower in intervention participants at 6 months (p=.041) and 12 months (p=.022); hemoglobin A1c, global mental status and mood did not differ between groups. Recall of a distractor list (p=.006) and logical memory long-delay recall (p=.036) were better at 6 months in the intervention group (p=.006). Care management may contribute to improved control of dementia risk factors.
L.M. Bonner ; A. Hanson ; G. Robinson ; E. Lowy ; S. Craft (2017): Oversimplification of Dementia Risk Reduction Messaging Is a Threat to Knowledge Translation in Dementia Prevention Research. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.28
OVERSIMPLIFICATION OF DEMENTIA RISK REDUCTION MESSAGING IS A THREAT TO KNOWLEDGE TRANSLATION IN DEMENTIA PREVENTION RESEARCH
K.J. Anstey, R. Peters
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K.J. Anstey ; R. Peters (2017): Oversimplification of Dementia Risk Reduction Messaging Is a Threat to Knowledge Translation in Dementia Prevention Research. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.27
EFFECTS OF OMEGA-3 FATTY ACIDS ON RESTING CEREBRAL PERFUSION IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT: A RANDOMIZED CONTROLLED TRIAL
C. Schwarz, M. Wirth, L. Gerischer, U. Grittner, A.V. Witte, T. Köbe, A. Flöel
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Alteration of cerebral perfusion can be considered as a possible therapeutic target in mild cognitive impairment. This randomized, placebo-controlled, double-blind proof-of-concept study assessed effects of omega-3 fatty acids on cerebral perfusion in patients with mild cognitive impairment. In thirteen patients (omega:n=5; placebo:n=8) cerebral perfusion was measured before and after 26-weeks intervention within posterior cortical regions using magnetic resonance imaging. There was a medium effect of intervention on cerebral blood flow (η2=0.122) and blood volume (η2=0.098). The omega group showed an increase in blood flow (mean difference: 0.02 [corresponds to 26.1%], 95% confidence interval:0.00-0.05) and blood volume (mean difference: 0.08 [corresponds to 18.5%], 95% confidence interval:0.01-0.15), which was not observed in the placebo group. These preliminary findings suggest that omega-3 fatty acids supplementation may improve perfusion in cerebral regions typically affected in mild cognitive impairment.Regulation of perfusion may help to maintain brain structure and function and potentially delay conversion to dementia.
C. Schwarz ; M. Wirth ; L. Gerischer ; U. Grittner ; A.V. Witte ; T. Köbe ; A. Flöel (2017): Effects of Omega-3 Fatty Acids on Resting Cerebral Perfusion in Patients with Mild Cognitive Impairment: A Randomized Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.23
TRAJECTORY OF THE MAPT-PACC-PRECLINICAL ALZHEIMER COGNITIVE COMPOSITE IN THE PLACEBO GROUP OF A RANDOMIZED CONTROL TRIAL: RESULTS FROM THE MAPT STUDY: LESSONS FOR FURTHER TRIALS
J.K. Chhetri, P. de Souto Barreto, C. Cantet, M. Cesari, N. Coley, S. Andrieu, B. Vellas
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Defining the primary cognitive endpoint is a major decision for Alzheimer’s disease preventive trials. As an example for further trials we present in detail the three-year cognitive decline in the placebo group of MAPT trial, a randomized controlled trial (RCT) using a cognitive composite score (MAPT-PACC). Participants were dementia-free adults 70 years or older, with subjective memory complaints. Our findings as expected showed subjects with older age (>75), higher beta amyloid brain deposition, APOE-ε4 allele carriers, with low RBC DHA+EPA levels and higher CDR level are at higher risk of cognitive decline. The data presented in this paper can be useful for future preventive trials to choose the primary cognitive end point, assess the clinical relevance of cognitive changes and perform sample size calculation for several targeted population eg. ApoE4, amyloid +, oldest old, lower n3-PUFA. We believe that the trial group with CDR 0.5, without being selected by a memory test endpoint is a good target population for AD preventive trials.
J.K. Chhetri ; P. de Souto Barreto ; C. Cantet ; M. Cesari ; N. Coley ; S. Andrieu ; B. Vellas (2017): Trajectory of the MAPT-PACC-Preclinical Alzheimer Cognitive Composite in the Placebo Group of a Randomized Control Trial: Results from the MAPT Study: Lessons for Further Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.21
ASSOCIATIONS OF LONG-TERM TEA CONSUMPTION WITH DEPRESSIVE AND ANXIETY SYMPTOMS IN COMMUNITY-LIVING ELDERLY: FINDINGS FROM THE DIET AND HEALTHY AGING STUDY
S.-P. Chan, P.Z.Yong, Y. Sun, R. Mahendran, J.C.M. Wong, C. Qiu, T.-P. Ng, E.-H. Kua, L. Feng
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Objective: To examine the association between long-term tea consumption and depressive and anxiety symptoms in community-living elderly.
Design: Community based cross-sectional study.
Setting: The Diet and Healthy Aging Study (DaHA), a prospective cohort study in Singapore.
Participants: 614 elderly aged 60 years and above, who were free of dementia and cognitive impairment.
Measurements: Information on tea consumption was obtained through interviewer-administered questionnaire. Long-term tea drinking was defined as regular consumption for at least 15 years. Depressive and anxiety symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15) and the 20-item Geriatric Anxiety Inventory (GAI), respectively. A generalized structural equation model (gSEM) was applied to ascertain the association between long-term tea consumption and depressive and anxiety symptoms.
Results: About 59% of the subjects had consumed tea for over 15 years. Long term tea consumption was significantly associated with a reduced odds of having depressive and anxiety symptoms, after adjusting for demographics (i.e., age, gender, education and ethnicity), comorbid conditions (i.e., heart disease, diabetes, stroke, hypertension and hyperlipidaemia) and long-term coffee consumption.
Conclusion: There was evidence suggesting that long-term tea consumption was associated with reduced depressive and anxiety symptoms among community-living elderly. This suggests that it is worthwhile to further investigate the role of tea’s bioactive compounds in promoting mental health in aging.
S.-P. Chan ; P.Z.Yong ; Y. Sun ; R. Mahendran ; J.C.M. Wong ; C. Qiu ; T.-P. Ng ; E.-H. Kua ; L. Feng (2017): Associations of Long-Term Tea Consumption with Depressive and Anxiety Symptoms in Community-Living Elderly: Findings from the Diet and Healthy Aging Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.20
THE RELATIONSHIP OF OMEGA 3 POLYUNSATURATED FATTY ACIDS IN RED BLOOD CELL MEMBRANES WITH COGNITIVE FUNCTION AND BRAIN STRUCTURE: A REVIEW FOCUSSED ON ALZHEIMER’S DISEASE
C. Hooper, P. De Souto Barreto, M. Pahor, M. Weiner, B. Vellas
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Significant research attention has focussed on the identification of nutraceutical agents for the prevention of cognitive decline as a natural means of cognitive preservation in the elderly. There is some evidence for a reduction of brain omega 3 polyunsaturated fatty acids (n-3 PUFAs) in normal aging and in Alzheimer’s disease. n-3 PUFAs exhibit anti-inflammatory and anti-amyloidogenic properties as well as being able to reduce tau phosphorylation. Many observational studies have demonstrated a link between n-3 PUFAs and cognitive aging, and some, but not all, randomized controlled trials have demonstrated a benefit of n-3 PUFA supplementation on cognition, particularly in those subjects with mild cognitive impairment. The identification of a biomarker that reflects n-3 PUFA intake over time and consequent tissue levels is required. In this narrative review we discuss the evidence associating red blood cell membrane n-3 PUFAs with cognitive function and structural brain changes associated with Alzheimer’s disease.
C. Hooper ; P. De Souto Barreto ; M. Pahor ; M. Weiner ; B. Vellas (2017): The Relationship of Omega 3 Polyunsaturated Fatty Acids in Red Blood Cell Membranes with Cognitive Function and Brain Structure: A Review Focussed on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.19
PRIMARY PREVENTION OF DEMENTIA: THE FUTURE OF POPULATION-BASED MULTIDOMAIN LIFESTYLE INTERVENTIONS
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Dementia affects 46.8 million of the world’s population, and is projected to increase to 131.5 million by 2050 (1). Increasingly, with no available disease-modifying drug or cure for the disease, preventive strategies are being pursued to curb the worldwide epidemic. Accumulating evidence supports the importance of dementia prevention, with seven risk factors (diabetes mellitus, midlife obesity, midlife hypertension, physical inactivity, depression, smoking, and low education) estimated to contribute to 9.6 million cases, equivalent to a third of Alzheimer’s disease worldwide (2). The potential public health impact of prevention is huge as a 20% reduction per decade from 2010 in the prevalence of these risk factors would translate to a 16.3% (1.5 million) reduction in dementia prevalence by 2050.
Y. Lee (2017): Primary Prevention of Dementia: The Future of Population-based Multidomain Lifestyle Interventions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.17
CTAD 2016 abstract: EXPEDITION3: A PHASE 3 TRIAL OF SOLANEZUMAB IN MILD DEMENTIA DUE TO ALZHEIMER’S DISEASE
L.S. Honig, A. Hake, K. Sundell, C. Carlson, V. Poole Hoffmann, M. Case, H. Liu-Seifert, R. Dean, R. DeMattos, M. Mintun, R. Khanna, K.J. Selzler, E. Siemers
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Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid beta (Aβ) plaques, neurofibrilliary tangles, and neuronal loss with clinical symptoms including cognitive and functional impairment. Solanezumab, a humanized monoclonal antibody, was studied to determine if it would slow the progression of AD by increasing clearance of soluble Aβ from the brain. Methods: EXPEDITION3 was a double-blind, placebo-controlled, Phase 3 global study conducted in 11 countries at 210 sites in patients age 55 to 90 years with mild dementia due to AD (mild AD) (Mini–Mental State Examination [MMSE] score of 20 through 26), with confirmed amyloid pathology based on biomarkers (amyloid positive by F18 florbetapir PET or CSF Aβ1-42), with an optional open-label extension. Patients were randomized to 400-mg solanezumab (N=1057) or placebo (N=1072) administered intravenously every 4 weeks. The primary efficacy outcome was change on the 14-item Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog14) from baseline to Week 80. Key functional measures assessed included the Instrumental activities of the Alzheimer’s Disease Cooperatives Study Activities of Daily Living Inventory (ADCS-iADL) and the Functional Activities Questionnaire (FAQ). Additional efficacy measures assessed included the MMSE and the Clinical Dementia Rating scale–Sum of Boxes (CDR-SB). Key safety assessments included adverse event (AE) reporting and magnetic resonance imaging (MRI). Biomarkers included plasma changes in Aβ1-40 and Aβ1-42, CSF changes in total and phosphorylated tau (p-tau), and neuroimaging measures including positron emission tomography (PET) scans using florbetapir F18 and F18 flortaucipir, and volumetric MRI. Results: There was no statistically significant difference between treatment groups for the primary endpoint, ADAS-Cog14 (p=.095); numerically there was 11% less decline in cognition in the solanezumab-treated group compared with placebo. For the key secondary endpoints, treatment effects favoring solanezumab were seen on cognitive and functional measures, including 13% less decline on the MMSE (p=.014), 15% less decline on the CDR-SB (p=.004), and 14% less decline on the ADCS-iADL (p=.019). FAQ did not show statistically significant differences (7% less decline, p=.140). Solanezumab-treated patients showed a statistically significant greater increase in plasma Aβ1-40 and Aβ1-42 compared with placebo-treated patients (p<.001 for each biomarker), confirming peripheral target engagement. Changes between treatment groups for florbetapir PET, CSF total tau and p-tau, and flortaucipir PET did not show significant treatment differences. Whole brain atrophy and ventricular enlargement were not statistically different between treatment groups, as demonstrated by volumetric MRI. Safety findings were comparable across study treatment groups with respect to deaths, serious AEs (SAEs), discontinuations due to an AE and treatment-emergent AEs (TEAEs). There were few statistically significant treatment group differences at the individual Preferred Term level for TEAEs and none for any SAEs. Conclusions: EXPEDITION3, a Phase 3 trial of solanezumab initiated in a mild AD patient population, did not meet the primary objective of decreasing cognitive decline. Several secondary clinical endpoints, including both cognitive and functional measures, directionally favored solanezumab, but the effect sizes were small. Factors possibly relevant to interpretation of the study results include drug target, disease stage studied, and drug dosage delivered. Solanezumab had a favorable safety profile at the dose studied.
JPAD Volume 4, N°03 - 2017
SWINGS AND ROUNDABOUTS IN CNS DRUG BIOMARKERS
M.B. Isaac, S. Vamvakas
J Prev Alz Dis 2017;4(3):134-135Show summaryHide summary
Despite substantial advances in the understanding of central nervous system (CNS) disorders, healthcare systems worldwide face an unprecedented challenge in dealing with the unmet needs in this area (1). Meanwhile, the CNS drug pipeline looks worryingly dry. There are several reasons for this, including the obvious complexity of the CNS, a lack of interdisciplinary collaborations, increased drug development costs and the higher risk of clinical failure of CNS drugs, compared with those in other areas of drug development. The year 2016 was also disappointing in terms of failed trials of Alzheimer’ Dementia (AD) drugs.
M.B. Isaac ; S. Vamvakas (2017): Swings and Roundabouts in CNS Drug Biomarkers. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.18
CLINICAL EFFECTS OF ORAL TRAMIPROSATE IN APOE4/4 HOMOZYGOUS PATIENTS WITH MILD ALZHEIMER’S DISEASE SUGGEST DISEASE MODIFICATION
J Prev Alz Dis 2017;4(3):136-137Show summaryHide summary
M.N. Sabbagh (2017): Clinical Effects of Oral Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease Modification. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.24
DEMENTIA PREVENTION BY DISEASE-MODIFICATION THROUGH NUTRITION
A.D. Smith, H. Refsum
J Prev Alz Dis 2017;4(3):138-139Show summaryHide summary
It is agreed that disease-modification is the most desirable approach to tackling dementia (1), but we are often told that it is not yet feasible and that “no disease modifying therapy has proven effective in clinical trials” (2). The purpose of our Editorial is to show that disease-modification is not only feasible but that there is good evidence that it has already been achieved in subjects with Mild Cognitive Impairment (MCI).
A.D. Smith ; H. Refsum (2017): Dementia Prevention by Disease-Modification through Nutrition. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.16
POTENTIAL UTILITY OF PRACTICE EFFECTS IN PREVENTIVE TRIALS
J Prev Alz Dis 2017;4(3):140-142Show summaryHide summary
S. Villeneuve (2017): Potential Utility of Practice Effects in Preventive Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.25
DIABETES MITIGATES THE ROLE OF MEMORY COMPLAINT IN PREDICTING DEMENTIA RISK: RESULTS FROM THE PREVENTION OF ALZHEIMER’S DISEASE WITH VITAMIN E AND SELENIUM STUDY
X. Zhang, F.A. Schmitt, A.M. Caban-Holt, X. Ding, R.J. Kryscio, E. Abner
J Prev Alz Dis 2017;4(3):143-148Show summaryHide summary
Background: Subjective memory complaints (SMCs) are associated with increased risk of dementia in older adults, but the role of comorbidities in modifying this risk is unknown.
Objectives: To assess whether comorbidities modify estimated dementia risk based on SMCs.
Design: The Prevention of Alzheimer’s Disease with Vitamin E and Selenium Study (PREADVISE) was designed as an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized, multi-center prostate cancer prevention trial with sites in the Unites States, Puerto Rico, and Canada. In 2009, PREADVISE and SELECT were changed into cohort studies.
Setting: Secondary analysis of PREADVISE data.
Participants: PREADVISE recruited 7,540 non-demented male volunteers from participating SELECT sites from 2002 to 2009. SMCs, demographics, and comorbidities including hypertension, diabetes, coronary artery bypass graft (CABG), stroke, sleep apnea, and head injury were ascertained by participant interview.
Measurements: Cox models were used to investigate whether baseline comorbidities modified hazard ratios (HR) for SMC-associated dementia risk using two methods: (1) we included one interaction term between SMC and a comorbidity in the model at a time, and (2) we included all two-way interactions between SMC and covariates of interest and reduced the model by “backward” selection. SMC was operationalized as any complaint vs. no complaint.
Results: Baseline SMCs were common (23.6%). In the first analyses, with the exception of stroke, presence of self-reported comorbidities was associated with lower estimated HR for dementia based on SMC status (complaint vs. no complaint), but this difference was only significant for diabetes. In the second analysis, the two-way interactions between SMC and race as well as SMC and diabetes were significant. Here, black men without diabetes who reported SMC had the highest estimated dementia risk (HR=5.05, 95% CI 2.55-10.00), while non-black men with diabetes who reported SMC had the lowest estimated risk (HR=0.71, 95% CI 0.35-1.41).
Conclusions: SMCs were more common among men with comorbidities, but these complaints appeared to be less predictive of dementia risk than those originating from men without comorbidities, suggesting that medical conditions such as diabetes may explain SMCs that are unrelated to an underlying neurodegenerative process.
X. Zhang ; F.A. Schmitt ; A.M. Caban-Holt ; X. Ding ; R.J. Kryscio ; E. Abner (2017): Diabetes Mitigates the Role of Memory Complaint in Predicting Dementia Risk: Results from the Prevention of Alzheimer’s Disease with Vitamin E and Selenium Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.7
CLINICAL EFFECTS OF TRAMIPROSATE IN APOE4/4 HOMOZYGOUS PATIENTS WITH MILD ALZHEIMER’S DISEASE SUGGEST DISEASE MODIFICATION POTENTIAL
S. Abushakra, A. Porsteinsson, P. Scheltens, C. Sadowsky, B. Vellas, J. Cummings, S. Gauthier, J.A. Hey, A. Power, P. Wang, L. Shen, M. Tolar
J Prev Alz Dis 2017;4(3):149-156Show summaryHide summary
Background: Alzheimer’s Disease (AD) patients homozygous for the APOE4 allele (APOE4/4) have a distinct clinical and biological phenotype with high levels of beta amyloid (Aβ) pathology and toxic Aβ oligomers. Tramiprosate, an oral agent that inhibits Aβ monomer aggregation into toxic oligomers, was evaluated in two Phase 3 Mild to Moderate AD studies which did not show efficacy in the overall population. Re-analyses of these trials showed the most consistent clinical benefits in APOE4/4 patients. We analyzed efficacy in the APOE4/4 patients with Mild disease.
Objectives: To determine the optimal stage of AD for future trials in APOE4/4 homozygotes.
Design: Two randomized, double-blind, placebo-controlled parallel-arm multi-center studies of 78-weeks duration.
Setting: Academic Alzheimer’s disease centers, community-based memory clinics, and neuropsychiatric research sites.
Participants: Participants included 2,025 AD patients with MMSE 16-26. Approximately 13-15% had APOE4/4 genotype (N= 147 and 110 per study), mean age 71.1 years, 56% females. Almost all were on stable symptomatic drugs.
Intervention: Randomized subjects received oral placebo, 100mg BID, or 150mg BID of tramiprosate.
Measurements: Co-primary outcomes were change from baseline in the ADAS-cog11 and CDR-SB. Disability assessment for dementia (DAD) was a secondary outcome.
Results: In APOE4/4 homozygotes receiving 150mg BID tramiprosate, efficacy in the traditional Mild AD patients (MMSE 20-26) was higher than the overall group (MMSE 16-26) and efficacy in the Mild patients (MMSE 22-26) was highest. Tramiprosate benefits compared to placebo on ADAS-cog, CDR-SB, and DAD were 125%, 81% and 71%, respectively (p<0.02). The Mild subgroup (MMSE 22-26) showed cognitive stabilization with no decline over 78 weeks, both ADAS-cog and DAD effects increased over time. Tramiprosate safety in APOE4/4 patients was favorable. Most common adverse events were nausea, vomiting, depression and decreased weight.
Conclusions: The Mild subgroup of APOE4/4 AD patients (MMSE 22-26) showed larger benefits on the high dose of tramiprosate than the overall Mild and Moderate group. Consistent with its preclinical effects on Aβ oligomers, tramiprosate seemed to stabilize cognitive performance, supporting its disease modification potential. Confirmatory studies using ALZ-801, an improved pro-drug formulation of tramiprosate, will target APOE4/4 patients with Mild AD.
S. Abushakra ; A. Porsteinsson ; P. Scheltens ; C. Sadowsky ; B. Vellas ; J. Cummings ; S. Gauthier ; J.A. Hey ; A. Power ; P. Wang ; L. Shen ; M. Tolar (2017): Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease Modification Potential . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.26
FROM BRAIN DISEASE TO BRAIN HEALTH: PRIMARY PREVENTION OF ALZHEIMER’S DISEASE AND RELATED DISORDERS IN A HEALTH SYSTEM USING AN ELECTRONIC MEDICAL RECORD-BASED APPROACH
A.M. Fosnacht, S. Patel, C. Yucus, A. Pham, E. Rasmussen, R. Frigerio, S. Walters, D. Maraganore
J Prev Alz Dis 2017;4(3):157-164Show summaryHide summary
Background: Alzheimer’s disease and aging brain disorders are progressive, often fatal neurodegenerative diseases. Successful aging, modern lifestyles and behaviors have combined to result in an expected epidemic. Risks for these diseases include genetic, medical, and lifestyle factors; over 20 modifiable risks have been reported.
Objectives: We aim to primarily prevent Alzheimer’s disease and related disorders through electronic medical record (EMR)-based screening, risk assessments, interventions, and surveillance.
Design: We identified modifiable risks; developed human, systems and infrastructural resources; developed interventions; and targeted at-risk groups for the intervention.
Setting: A Community Based Health System.
Participants: In year one (June 2015 to May 2016), 133 at-risk patients received brain health services with the goal of delaying or preventing Alzheimer’s disease and related disorders.
Measurements: We created mechanisms to identify patients at high risk of neurodegenerative disease; EMR-based structured clinical documentation support tools to evaluate risk factors and history; evidence-based interventions to modify risk; and the capacity for annual surveillance, pragmatic trials, and practice-based and genomic research using the EMR.
Results: This paper describes our Center for Brain Health, our EMR tools, and our first year of healthy but at-risk patients.
Conclusion: We are translating research into primary prevention of Alzheimer’s disease and related disorders in our health system and aim to shift the paradigm in Neurology from brain disease to brain health.
A.M. Fosnacht ; S. Patel ; C. Yucus ; A. Pham ; E. Rasmussen ; R. Frigerio ; S. Walters ; D. Maraganore (2017): From Brain Disease to Brain Health: Primary Prevention of Alzheimer’s Disease and Related Disorders in a Health System Using an Electronic Medical Record-Based Approach. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.3
SEX AND AGE DIFFERENCES IN THE ASSOCIATION OF BLOOD PRESSURE AND HYPERTENSION WITH COGNITIVE FUNCTION IN THE ELDERLY: THE RANCHO BERNARDO STUDY
D. Kritz-Silverstein, G.A. Laughlin, L.K. McEvoy, E. Barrett-Connor
J Prev Alz Dis 2017;4(3):165-173Show summaryHide summary
Objectives: This study examines sex and age differences in associations of systolic and diastolic blood pressure (SBP, DBP), pulse pressure and hypertension with cognitive function in a community-dwelling population.
Design: Cross-sectional study.
Setting: Research clinic visit in 1988-91.
Participants: Participants were 693 men and 1022 women aged 50-97
Measurements: Blood pressure was measured and 12 cognitive function tests were administered.
Results: Average age was 73.8±9.9 in men and 73.2±9.3 in women; 62.6% of men and 63.4% of women were hypertensive (SBP≥140 mmHg, DBP≥90 mmHg, or antihypertensive medication use). Each 5-unit increment in SBP, DBP, or pulse pressure and categorical hypertension was associated with significantly increased odds of poor verbal fluency performance in men and poor Trails B performance in women, with strongest associations for hypertension (OR=1.97, CI:1.01,3.85 in men; OR=1.51, CI:1.01,2.26 in women). After age stratification, associations remained statistically significant in younger (<80 years ) but not older (≥80 years) participants.
Conclusion: Blood pressure as a continuous or categorical variable was associated with poor performance on cognitive function tests, but domains varied by sex and associations were found only in those younger than 80 years. The absent associations in those aged 80 years and older could support the hypothesis that increased blood flow is required to maintain cerebral perfusion with advancing age, or could reflect a survivor effect.
D. Kritz-Silverstein ; G.A. Laughlin ; L.K. McEvoy ; E. Barrett-Connor (2017): Sex and Age Differences in the Association of Blood Pressure and Hypertension with Cognitive Function in the Elderly: The Rancho Bernardo Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.6
B-VITAMIN THERAPY FOR KIDNEY TRANSPLANT RECIPIENTS LOWERS HOMOCYSTEINE AND IMPROVES SELECTIVE COGNITIVE OUTCOMES IN THE RANDOMIZED FAVORIT ANCILLARY COGNITIVE TRIAL
T.M. Scott, G. Rogers, D.E. Weiner, K. Livingston, J. Selhub, P.F. Jacques, I.H. Rosenberg, A.M. Troen, for the FACT Study Investigators
J Prev Alz Dis 2017;4(3):174-182Show summaryHide summary
Background: Objectives: Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, stroke and dementia. Results of clinical trials using B-vitamins to reduce the cognitive risks attributed to tHcy have been inconsistent. The high prevalence of both hyperhomocysteinemia and cognitive impairment among kidney transplant recipients makes them an important population in which to evaluate the effect of lowering homocysteine on cognitive function. We therefore evaluated whether B-vitamin therapy to lower tHcy would prevent cognitive-decline in a cohort of stable kidney transplant recipients.
Design: The study was a longitudinal ancillary of the FAVORIT trial, a randomized, placebo-controlled multi-site trial of high-dose B vitamins to reduce cardiovascular and cerebrovascular events in clinically stable kidney transplant recipients with elevated tHcy.
Participants: 584 participants from 18 sites across North America.
Intervention: The intervention consisted of a daily multivitamin containing high-doses of folate (5.0 mg), vitamin B12 (1.0 mg) and vitamin B6 (50 mg). The placebo consisted of a daily multi-vitamin containing no folate and recommended daily allowances of vitamins B12 and B6 (0 mg folate; 2.0 µg vitamin B12; 1.4 mg vitamin B6).
Measurements: Annual neuropsychological assessment for up to 5 years (mean 3.3 years) using a standardized test battery. Efficacy was analyzed on an intention-to-treat basis using end-of-trial data. Subgroup analyses included stratification for baseline plasma B-vitamin and tHcy concentrations.
Results: At baseline, cognitive impairment was common with 61% of participants falling more than one standard deviation below published norms for at least one cognitive test. Fewer than 1% of participants had insufficient plasma folate < 5 ng/ml or vitamin B12 < 148 pmol/L. However, 44.6% had plasma B6 concentrations < 30 nmol/L. At follow-up, processing speed and memory scores were modestly but significantly better in the B-vitamin supplement group than in controls (p≤0.05). There was no interaction between baseline tHcy, B-vitamin status and treatment on the cognitive outcomes.
Conclusions: High-dose B-vitamin supplementation provided modest cognitive benefit for kidney transplant recipients with elevated baseline tHcy. Since nearly all participants were folate and vitamin B12 sufficient at baseline, the potential cognitive benefits of folate and B12 supplementation in individuals with poor B-vitamin status remains to be determined.
T.M. Scott ; G. Rogers ; D.E. Weiner ; K. Livingston ; J. Selhub ; P.F. Jacques ; I.H. Rosenberg ; A.M. Troen ; for the FACT Study Investigators (2017): B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.15
THE ROSAS COHORT: A PROSPECTIVE, LONGITUDINAL STUDY OF BIOMARKERS FOR ALZHEIMER’S DISEASE. STRATEGY, METHODS AND INITIAL RESULTS
A. de Mauléon, M. Soto, V. Kiyasova, J. Delrieu, I. Guignot, S. Galtier, M. Lilamand, C. Cantet, F. Lala, N. Sastre, S. Andrieu, M. Pueyo, P.J. Ousset, B. Vellas
J Prev Alz Dis 2017;4(3):183-193Show summaryHide summary
Objective: The aims of the Research Of biomarkers in Alzheimer’s diseaSe (ROSAS) study were to determine the biofluid and imaging biomarkers permitting an early diagnosis of Alzheimer’s disease and better characterisation of cognitive and behavioural course of the pathology. This paper outlines the overall strategy, methodology of the study, baseline characteristics of the population and first longitudinal results from the ROSAS cohort.
Methods: Longitudinal prospective monocentric observational study performed at the Alzheimer’s disease Research centre in Toulouse. A total of 387 patients were studied and analyzed in 3 groups: 184 patients with dementia of Alzheimer’s type, 96 patients with memory disorders without dementia (Mild Cognitive Impairment) and 107 patients without abnormal memory tests (control group), and were followed up during 4 years. Patient’s sociodemographic characteristics, risk factors, medical conditions, previous and current medications, neuropsychological assessment and overall cognitive status were recorded. Blood and urine samples were collected at every year, Magnetic Resonance Imaging were performed at inclusion, after one year of follow-up and at the end of the study.
Results: At baseline, three different groups of the cohort differed interestingly in age, level of education, and in percentage of ApoEε4 carriers whereas the history of cardiovascular and endocrine pathologies were similar among the groups. During the follow-up period (3-4 years) 42 mild cognitive impairment patients (43.8%) progressed to dementia, 7 controls progressed into mild cognitive impairment and 1 patient in the control group converted from mild cognitive impairment group to dementia of Alzheimer’s type group. During the first year of follow up, the incidence of progression from mild cognitive impairment to dementia of Alzheimer’s type was 12.7 per 100, during the second year 33.9 per 100 and 46.7 per 100 for the third year.
Conclusion: This paper presents the baseline characteristics of the unique French prospective monocenter study in which the natural course of dementia of Alzheimer’s type was evaluated. Future analysis of blood and urine samples collection from the ROSAS study will permit to identify possible biofluid biomarkers predicting the early stages of the dementia of Alzheimer’s type and risk of progression from Mild Cognitive Impairment to Alzheimer’s disease.
A. de Mauléon ; M. Soto ; V. Kiyasova ; J. Delrieu ; I. Guignot ; S. Galtier ; M. Lilamand ; C. Cantet ; F. Lala ; N. Sastre ; S. Andrieu ; M. Pueyo ; P.J. Ousset ; B. Vellas (2017): The ROSAS Cohort: A Prospective, Longitudinal Study of Biomarkers for Alzheimer’s Disease. Strategy, Methods and Initial Results. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.8
OBJECTIVE COGNITIVE IMPAIRMENT AND PROGRESSION TO DEMENTIA IN WOMEN: THE PROSPECTIVE EPIDEMIOLOGICAL RISK FACTOR STUDY
J. Skov Neergaard, K. Dragsbæk, C. Christiansen, M. Asser Karsdal, S. Brix, K. Henriksen
J Prev Alz Dis 2017;4(3):194-200Show summaryHide summary
Background: Identification of subjects with a progressive disease phenotype is an urgent need in the pharmaceutical industry where most of the recent clinical trials in Alzheimer’s disease have failed.
Objectives: The objective of this study was to identify subgroups of individuals with objective cognitive impairment (OCI), who were most likely to progress to dementia and to identify the risk factors associated with progression.
Design: Prospective cohort study.
Participants: 5,380 elderly women from Denmark.
Measurements: The Short Blessed Test and a category fluency test with animal naming, was used to assess cognitive function, and to classify them into different groups of OCI.
Results: OCI was identified in 852 subjects at baseline. The risk of dementia was elevated for OCI subjects as compared to subjects with normal cognition (HR 1.46[1.19-1.79]). The courses of OCI were studied in a sub-cohort who completed the cognitive assessment at both the baseline and the follow-up visit (n = 1,933). Of these subjects 203 had OCI at baseline. The multi-domain subtypes of OCI were associated with progressive OCI. Subjects most likely to progress were older, physically inactive, had a higher level of total cholesterol (>6.5 mmol/L) and had a history of depression as compared to subjects with a non-progressive course of OCI.
Conclusions: In this cohort we identified a risk profile associated with progression from OCI in older women. The degree of impairment at baseline was an important predictor of conversion to dementia, additionally several modifiable risk factors were associated with progression.
J. Skov Neergaard ; K. Dragsbæk ; C. Christiansen ; M. Asser Karsdal ; S. Brix ; K. Henriksen (2017): Objective Cognitive Impairment and Progression to Dementia in Women: The Prospective Epidemiological Risk Factor Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.4
EVALUATION OF THE NEUROPROTECTIVE POTENTIAL OF N-ACETYLCYSTEINE FOR PREVENTION AND TREATMENT OF COGNITIVE AGING AND DEMENTIA
Y. Hara, N. McKeehan, P.A. Dacks, H.M. Fillit
J Prev Alz Dis 2017;4(3):201-206Show summaryHide summary
Alzheimer’s disease is a progressive neurodegenerative disease for which there is no cure and only a few treatments providing little relief. Increased oxidative stress that is associated with aging is strongly implicated in the pathogenesis and progression of Alzheimer’s disease. Studies have shown that levels of the endogenous antioxidant glutathione decline at an early stage of Alzheimer’s disease with decreased levels correlating with worse cognitive functions. N-acetylcysteine, a drug also widely available as a dietary supplement, is a precursor of L-cysteine, which in turn is a component of glutathione. Because cysteine availability is a limiting factor for glutathione synthesis, treatment with N-acetylcysteine may increase glutathione levels and thereby counter oxidative stress, promote redox -regulated cell signaling, and improve immune responses. In this review, we evaluate the existing literature and the potential of N-acetylcysteine in promoting cognitive health and alleviating cognitive decline associated with dementia. Discussion will also include possible mechanisms of action of N-acetylcysteine, its effects on aging biology, and safety of long-term use. Based on the available literature, a nutraceutical formulation containing N-acetylcysteine among other compounds has shown some pro-cognitive benefits in Alzheimer’s patients and older adults, but the evidence for N-acetylcysteine alone is less robust. Although N-acetylcysteine crosses the blood-brain-barrier, low bioavailability is an obstacle. One promising avenue of research may be to explore derivatives of N-acetylcysteine such as N-acetylcysteine amide, which has been reported in preclinical studies to have higher permeability through cellular and mitochondrial membranes with increased central nervous system bioavailability compared to N-acetylcysteine.
Y. Hara ; N. McKeehan ; P.A. Dacks ; H.M. Fillit (2017): Evaluation of the Neuroprotective Potential of N-Acetylcysteine for Prevention and Treatment of Cognitive Aging and Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.22