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THE VALUE OF PRE-SCREENING IN THE ALZHEIMER’S PREVENTION INITIATIVE (API) AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE TRIAL

S. Rios-Romenets, M. Giraldo-Chica, H. López, F. Piedrahita, C. Ramos, N. Acosta-Baena, C. Muñoz, P. Ospina, C. Tobón, W. Cho, M. Ward, J.B. Langbaum, P.N. Tariot, E.M. Reiman, F. Lopera

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The Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) trial evaluates the anti-amyloid-β antibody crenezumab in cognitively unimpaired persons who, based on genetic background and age, are at high imminent risk of clinical progression, and provides a powerful test of the amyloid hypothesis. The Neurosciences Group of Antioquia implemented a pre-screening process with the goals of decreasing screen failures and identifying participants most likely to adhere to trial requirements of the API ADAD trial in cognitively unimpaired members of Presenilin1 E280A mutation kindreds. The pre-screening failure rate was 48.2%: the primary reason was expected inability to comply with the protocol, chiefly due to work requirements. More carriers compared to non-carriers, and more males compared to females, failed pre-screening. Carriers with illiteracy or learning/comprehension difficulties failed pre-screening more than non-carriers. With the Colombian API Registry and our prescreening efforts, we randomized 169 30-60 year-old cognitively unimpaired carriers and 83 non-carriers who agreed to participate in the trial for at least 60 months. Our findings suggest multiple benefits of implementing a pre-screening process for enrolling prevention trials in ADAD.

CITATION:
S. Rios-Romenets ; M. Giraldo-Chica ; H. López ; F. Piedrahita ; C. Ramos ; N. Acosta-Baena ; C. Muñoz ; P. Ospina ; C. Tobón ; W. Cho ; M. Ward ; J.B. Langbaum ; P.N. Tariot ; E.M. Reiman ; F. Lopera (2017): The Value of Pre-screening in the Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.44

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DEMENTIA: CREATING A KNOWLEDGE-BASED HEALTHCARE PROFESSION

C. Scerri

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CITATION:
C. Scerri (2017): Dementia: Creating a Knowledge-Based Healthcare Profession. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.43

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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.  

CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
L.M. Bonner ; A. Hanson ; G. Robinson ; E. Lowy ; S. Craft (2017): Care Management to Promote Treatment Adherence in Patients with Cognitive Impairment and Vascular Risk Factors: A Demonstration Project. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.28

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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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CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
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

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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.

CITATION:
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

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PRIMARY PREVENTION OF DEMENTIA: THE FUTURE OF POPULATION-BASED MULTIDOMAIN LIFESTYLE INTERVENTIONS

Y. Lee

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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.

CITATION:
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

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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.

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JPAD Volume 4, N°04 - 2017

 

Editorials

CONTINUING PROGRESS IN ALZHEIMER’S DISEASE TRIALS: CAUSE FOR OPTIMISM

P.S. Aisen

J Prev Alz Dis 2017;4(4):211-212

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CITATION:
P.S. Aisen (2017): Continuing Progress in Alzheimer’s Disease Trials: Cause for Optimism. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.34

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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

J Prev Alz Dis 2017;4(4):213-214

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CITATION:
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

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PROSPECTS FOR EFFECTIVE TREATMENT OF THE DEMENTIA-ALZHEIMER SYNDROME: A RENEWED ODYSSEY IN SEARCH OF THE MAGIC ELIXIR

Z.S. Khachaturian

J Prev Alz Dis 2017;4(4):215-217

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CITATION:
Z.S. Khachaturian (2017): Prospects for Effective Treatment of the Dementia-Alzheimer Syndrome: A Renewed Odyssey in Search of the Magic Elixir. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.42

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Original Research

EPIGALLOCATECHIN 3-GALLATE AS AN INHIBITOR OF TAU PHOSPHORYLATION AND AGGREGATION: A MOLECULAR AND STRUCTURAL INSIGHT

M. Guéroux, C. Fleau, M. Slozeck, M. Laguerre, I. Pianet

J Prev Alz Dis 2017;4(4):218-225

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Polyphenols such as Epigallocatechin-3 gallate (EGCG) are currently bearer of hope to prevent or at least to slow down the deleterious effect of Tauopathies such as Alzheimer disease. One of the main effects of these neurodegenerative pathologies is the hyperphosphorylation and consequent aggregation of the Tau protein that leads to the irremediable neuronal cells death. In the present paper, we show how EGCG can play a crucial role to prevent Tau aggregation: (i) in binding Tau in its phosphorylation region with an affinity of the same order of magnitude than kinases (0.5 mM), hindering their access to the protein and (ii) in modifying the 3D-structure of Tau whose preferential conformation changes in the presence of EGCG. For this purpose, two peptides were synthesized, one of 20 residues long issued from the first Proline-rich region of Tau (171Ile-190Lys), the second of 50 residues long (171Ile-220Thr) corresponding to more than 50% of the Tau Proline rich domaine. The total attribution of all the 1H, 13C and 15N resonances of the two peptides has been achieved thanks to a “divide and conquer” strategy leading to their 3D structure preference and their affinity towards EGCG.

CITATION:
M. Guéroux ; C. Fleau ; M. Slozeck ; M. Laguerre ; I. Pianet (2017): Epigallocatechin 3-gallate as an Inhibitor of Tau Phosphorylation and Aggregation: A Molecular and Structural Insight . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.35

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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

J Prev Alz Dis 2017;4(4):226-235

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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.

CITATION:
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

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Review Articles

PRECLINICAL AND CLINICAL DEVELOPMENT OF ABBV-8E12, A HUMANIZED ANTI-TAU ANTIBODY, FOR TREATMENT OF ALZHEIMER’S DISEASE AND OTHER TAUOPATHIES

T. West, Y. Hu, P.B. Verghese, R.J. Bateman, J.B. Braunstein, I. Fogelman, K. Budur, H. Florian, N. Mendonca, D.M. Holtzman

J Prev Alz Dis 2017;4(4):236-241

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Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer’s disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies. To test this hypothesis, a humanized anti-tau antibody (ABBV-8E12) was developed and a phase 1 clinical trial of this antibody has been completed. The double-blind, placebo-controlled phase 1 study tested single doses of ABBV-8E12 ranging from 2.5 to 50 mg/kg in 30 patients with progressive supranuclear palsy (PSP). ABBV-8E12 was found to have an acceptable safety profile with no clinically concerning trends in the number or severity of adverse events between the placebo and dosed groups. Pharmacokinetic modelling showed that the antibody has a plasma half-life and cerebrospinal fluid:plasma ratio consistent with other humanized antibodies, and there were no signs of immunogenicity against ABBV-8E12. Based on the acceptable safety and tolerability profile of single doses of ABBV-8E12, AbbVie is currently enrolling patients into two phase 2 clinical trials to assess efficacy and safety of multiple doses of ABBV-8E12 in patients with early Alzheimer’s disease or PSP.

CITATION:
T. West ; Y. Hu ; P.B. Verghese ; R.J. Bateman ; J.B. Braunstein ; I. Fogelman ; K. Budur ; H. Florian ; N. Mendonca ; D.M. Holtzman (2017): Preclinical and Clinical Development of ABBV-8E12, a Humanized Anti-Tau Antibody, for Treatment of Alzheimer’s Disease and Other Tauopathies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.36

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THE ALZHEIMER’S PREVENTION INITIATIVE GENERATION PROGRAM: EVALUATING CNP520 EFFICACY IN THE PREVENTION OF ALZHEIMER’S DISEASE

C. Lopez Lopez, A. Caputo, F. Liu, M.E. Riviere, M.-L. Rouzade-Dominguez, R.G. Thomas, J.B. Langbaum, R. Lenz, E.M. Reiman, A. Graf, P.N. Tariot

J Prev Alz Dis 2017;4(4):242-246

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Alzheimer’s disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer’s disease under the Alzheimer’s Prevention Initiative Generation Program. The Alzheimer’s Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer’s disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer’s disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer’s disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

CITATION:
C. Lopez Lopez ; A. Caputo ; F. Liu ; M.E. Riviere ; M.-L. Rouzade-Dominguez ; R.G. Thomas ; J.B. Langbaum ; R. Lenz ; E.M. Reiman ; A. Graf ; P.N. Tariot (2017): The Alzheimer’s Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.37

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DEVELOPMENT REVIEW OF THE BACE1 INHIBITOR LANABECESTAT (AZD3293/LY3314814)

J.R. Sims, K.J. Selzler, A.M. Downing, B.A. Willis, C.D. Aluise, J. Zimmer, S. Bragg, S. Andersen, M. Ayan-Oshodi, E. Liffick, J. Eads, A.M. Wessels, S. Monk, J. Schumi, J. Mullen

J Prev Alz Dis 2017;4(4):247-254

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Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer’s disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aβ) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aβ production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aβ species and soluble amyloid precursor proteins (sAPPβ) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aβ1-40 and Aβ1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.

CITATION:
J.R. Sims ; K.J. Selzler ; A.M. Downing ; B.A. Willis ; C.D. Aluise ; J. Zimmer ; S. Bragg ; S. Andersen ; M. Ayan-Oshodi ; E. Liffick ; J. Eads ; A.M. Wessels ; S. Monk ; J. Schumi ; J. Mullen (2017): Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.38

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CLINICAL DEVELOPMENT OF ADUCANUMAB, AN ANTI-A? HUMAN MONOCLONAL ANTIBODY BEING INVESTIGATED FOR THE TREATMENT OF EARLY ALZHEIMER’S DISEASE

S. Budd Haeberlein, J. O’Gorman, P. Chiao, T. Bussière, P. von Rosenstiel, Y. Tian, Y. Zhu, C. von Hehn, S. Gheuens, L. Skordos, T. Chen, A. Sandrock

J Prev Alz Dis 2017;4(4):255-263

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The amyloid hypothesis has been the dominant framework for Alzheimer’s disease (AD) research, including the development of anti-AD therapies. However, none of the phase III clinical trials conducted to date that targeted amyloid β (Aβ) production, aggregation, or clearance demonstrated a statistically significant treatment effect in patients with AD. This includes the approach of using monoclonal antibodies that recognize various Aβ epitopes and display different binding selectivity. While some monoclonal antibodies have failed in phase III trials, several are still in development. Aducanumab (BIIB037) is a human antibody that selectively targets aggregated forms of Aβ, including soluble oligomers and insoluble fibrils. In PRIME (NCT01677572), an ongoing phase Ib trial (N=196 patients dosed), aducanumab was shown to reduce Aβ plaques and slow decline in clinical measures in patients with prodromal or mild AD, with acceptable safety and tolerability. The main safety finding was amyloid-related imaging abnormalities (ARIA), a side effect associated with removal of Aβ, which was dose-dependent and occurred more often in ApoE ε4 carriers than non-carriers. ENGAGE (NCT02477800) and EMERGE (NCT02484547), the ongoing phase III trials of aducanumab in early AD, have been designed based on the outcomes of PRIME and on lessons from past clinical trials in patients with AD. Those study design features include patient selection with confirmed Aβ pathology, ensuring sufficient target engagement, and conducting clinical trials in patients at earlier symptomatic stages of AD.

CITATION:
S. Budd Haeberlein ; J. O’Gorman ; P. Chiao ; T. Bussière ; P. von Rosenstiel ; Y. Tian ; Y. Zhu ; C. von Hehn ; S. Gheuens ; L. Skordos ; T. Chen ; A. Sandrock (2017): Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer’s Disease . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.39

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DEVELOPING DISEASE-MODIFYING TREATMENTS IN ALZHEIMER’S DISEASE – A PERSPECTIVE FROM ROCHE AND GENENTECH

R. Doody

J Prev Alz Dis 2017;4(4):264-272

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Alzheimer’s disease (AD) is a chronic neurodegenerative disease for which no preventative or disease-modifying treatments currently exist. Pathological hallmarks include amyloid plaques and neurofibrillary tangles composed of hyper-phosphorylated tau protein. Evidence suggests that both pathologies are self-propagating once established. However, the lag time between neuropathological changes in the brain and the onset of even subtle clinical symptomatology means that patients are often diagnosed late when pathology, and neurodegeneration secondary to these changes, may have been established for several years. Complex pathological pathways associated with susceptibility to AD and changes that occur downstream of the neuropathologic process further contribute to the challenging endeavour of developing novel disease-modifying therapy. Recognising this complexity, effective management of AD must include reliable screening and early diagnosis in combination with effective therapeutic management of the pathological processes. Roche and Genentech are committed to addressing these unmet needs through developing a comprehensive portfolio of diagnostics and novel therapies. Beginning with the most scientifically supported targets, this approach includes two targeted amyloid-β monoclonal antibody therapies, crenezumab and gantenerumab, and an anti-tau monoclonal antibody, RO7105705, as well as a robust biomarker platform to aid in the early identification of people at risk or in the early stages of AD. Identification and implementation of diagnostic tools will support the enrolment of patients into clinical trials; furthermore, these tools should also support evaluation of the clinical efficacy and safety profile of the novel therapeutic agents tested in these trials. This review discusses the therapeutic agents currently under clinical development.

CITATION:
R. Doody ; (2017): Developing Disease-Modifying Treatments in Alzheimer’s Disease – A Perspective from Roche and Genentech. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.40

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NEFLAMAPIMOD: CLINICAL PHASE 2B-READY ORAL SMALL MOLECULE INHIBITOR OF P38? TO REVERSE SYNAPTIC DYSFUNCTION IN EARLY ALZHEIMER’S DISEASE

J. Alam, K. Blackburn, D. Patrick

J Prev Alz Dis 2017;4(4):273-278

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Neflamapimod (previously code named VX-745) is a clinical phase 2b-ready highly specific inhibitor of the intra-cellular enzyme p38 mitogen activated protein kinase alpha (“p38α”) that is being developed as a disease-modifying drug for Alzheimer’s disease (AD) that acts via targeting synaptic dysfunction. Neflamapimod was discovered through a proprietary structure-based drug discovery platform at Vertex Pharmaceuticals, and developed previously by Vertex through to phase 2a in rheumatoid arthritis. EIP Pharma licensed the compound in 2014 for development and commercialization as a treatment of central nervous system (CNS) disorders. Neflamapimod is the most advanced in the clinic drug that targets specific molecular mechanisms within neurons that leads to synaptic dysfunction, the pathogenic process that is now considered to be a major driver of the development of memory deficits and disease progression in the early stages of AD. Based on the scientific rationale of targeting synaptic dysfunction and the preclinical data, neflamapimod has the potential to both reverse memory deficits and slow disease progression. Phase 2a clinical data in patients with early-stage AD (MMSE 20-28, biomarker positive) provides evidence that the preclinical science may be translatable to human Alzheimer’s, as 6- to 12-weeks of neflamapimod treatment led to significant improvement in episodic memory, the best clinical measure of synaptic dysfunction in AD. A phase 2b six-month placebo-controlled 150-patient clinical study is anticipated to start by end of 2017. This study is designed to definitively demonstrate that neflamapimod reverses memory deficits, and also to provide preliminary evidence that the drug slows disease progression.

CITATION:
J. Alam ; K. Blackburn ; D. Patrick (2017): Neflamapimod: Clinical Phase 2b-Ready Oral Small Molecule Inhibitor of p38α to Reverse Synaptic Dysfunction in Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.41

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Clinical Trials and Aging: 10th Conference Clinical Trials on Alzheimer’s Disease, November 1-4, 2017, Boston, USA

CTAD: SYMPOSIA, ORAL COMMUNICATIONS, POSTERS

Abstracts

J Prev Alz Dis 2017;4(4):282-428

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