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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

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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.

CITATION:
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

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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

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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.

CITATION:
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

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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

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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.

CITATION:
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

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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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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

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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.

CITATION:
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

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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

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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. Setting: Population-based. 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.

CITATION:
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

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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

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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.

CITATION:
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

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JPAD Volume 4, N°02 - 2017

 

Editorials

GETTING MORE CLINICALLY MEANINGFUL MEASURES OF FUNCTIONAL IMPAIRMENT FOR ALZHEIMER’S DISEASE

H. Fillit

J Prev Alz Dis 2017;2:67-68

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CITATION:
H. Fillit (2017): Getting More Clinically Meaningful Measures of Functional Impairment for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.11

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EXPANDING THE TOOLKIT FOR STUDIES OF AGING

A.S. Buchman, P.A. Boyle, D.A. Bennett

J Prev Alz Dis 2017;2:69-70

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CITATION:
A.S. Buchman ; P.A. Boyle ; D.A. Bennett (2017): Expanding the Toolkit for Studies of Aging. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.14

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Original Research

DEPENDENCE LEVELS AS INTERIM CLINICAL MILESTONES ALONG THE CONTINUUM OF ALZHEIMER’S DISEASE: 18-MONTH RESULTS FROM THE GERAS OBSERVATIONAL STUDY

K. Kahle-Wrobleski, J.S. Andrews, M. Belger, W. Ye, S. Gauthier, D.M. Rentz, D. Galasko

J Prev Alz Dis 2017;2:72-80

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Background: While functional loss forms part of the current diagnostic criteria used to identify dementia due to Alzheimer’s disease, the gradual and progressive nature of the disease makes it difficult to recognize clinically relevant signposts that could be helpful in making treatment and management decisions. Having previously observed a significant relationship between stages of functional dependence (the level of assistance patients require consequent to Alzheimer’s disease deficits, derived from the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Scale) and cognitive severity, we investigated whether measures of functional dependence could be utilized to identify clinical milestones of Alzheimer’s disease progression. OBJECTIVES: To describe the patterns of change in dependence over the course of 18 months in groups stratified according to cognitive Alzheimer’s disease dementia severity (determined using the Mini-Mental State Examination score) and to identify characteristics associated with patients showing worsening dependence (progressors) versus those showing no change or improvement (non-progressors). DESIGN: Analysis of longitudinal data from the GERAS study. SETTING: GERAS is an 18-month prospective, multicenter, naturalistic, observational cohort study reflecting the routine care of patients with Alzheimer’s disease in France, Germany, and the United Kingdom. PARTICIPANTS: 1495 community-living patients, aged ≥55 years, diagnosed with probable Alzheimer’s disease dementia, and their caregivers. MEASUREMENTS: Dependence levels, cognitive function, behavioral symptoms, caregiver burden, and cost were assessed at baseline and at 18 months. RESULTS: Of 971 patients having both baseline and 18-month data, 42% (408) were progressors and 563 (58%) were non-progressors. This general pattern held for all three levels of baseline Alzheimer’s disease dementia severity – mild (Mini-Mental State Examination score 21–26), moderate (15–20) or moderately severe/severe (<15) – with 40–45% of each group identified as progressors and 55–60% as non-progressors. No baseline differences were seen between progressors and non-progressors in cognitive scores or behavioral symptoms, although progressors had significantly shorter times since diagnosis and showed milder functional impairment. Baseline factors predictive of increasing dependence over 18 months included more severe cognitive impairment, living with others, and having multiple caregivers. A higher level of initial dependence was associated with less risk of dependence progression. Total societal costs of care also increased with greater dependence. CONCLUSIONS: In this large cohort, 42% of Alzheimer’s disease dementia patients at all levels of cognitive severity became more dependent within 18 months of observation while 58% did not progress. Dependence levels may be considered as meaningful interim clinical milestones that reflect Alzheimer’s disease-related functional deficits, although a time frame that extends beyond 18 months may be necessary to observe changes if used in clinical trials or other longitudinal studies. Recognition of predictors of greater dependence offers opportunities for intervention.

CITATION:
K. Kahle-Wrobleski ; J.S. Andrews ; M. Belger ; W. Ye ; S. Gauthier ; D.M. Rentz ; D. Galasko (2017): Dependence Levels as Interim Clinical Milestones Along the Continuum of Alzheimer’s Disease: 18-Month Results from the GERAS Observational Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.2

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ACTIVITIES OF DAILY LIVING MEASURED BY THE HARVARD AUTOMATED PHONE TASK TRACK WITH COGNITIVE DECLINE OVER TIME IN NON-DEMENTED ELDERLY

G.A. Marshall, S.L. Aghjayan, M. Dekhtyar, J.J. Locascio, K. Jethwani, R.E. Amariglio, K.A. Johnson, R.A. Sperling, D.M. Rentz

J Prev Alz Dis 2017;2:81-86

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Background: Impairment in activities of daily living is a major burden to both patients and caregivers. Mild impairment in instrumental activities of daily living is often seen at the stage of mild cognitive impairment. The field of Alzheimer’s disease is moving toward earlier diagnosis and intervention and more sensitive and ecologically valid assessments of instrumental or complex activities of daily living are needed. The Harvard Automated Phone Task, a novel performance-based activities of daily living instrument, has the potential to fill this gap. Objective: To further validate the Harvard Automated Phone Task by assessing its longitudinal relationship to global cognition and specific cognitive domains in clinically normal elderly and individuals with mild cognitive impairment. Design: In a longitudinal study, the Harvard Automated Phone Task was associated with cognitive measures using mixed effects models. The Harvard Automated Phone Task’s ability to discriminate across diagnostic groups at baseline was also assessed. Setting: Academic clinical research center. Participants: Two hundred and seven participants (45 young normal, 141 clinically normal elderly, and 21 mild cognitive impairment) were recruited from the community and the memory disorders clinics at Brigham and Women’s Hospital and Massachusetts General Hospital. Measurements: Participants performed the three tasks of the Harvard Automated Phone Task, which consist of navigating an interactive voice response system to refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and make a bank account transfer and payment (APT-Bank). The 3 tasks were scored based on time, errors, repetitions, and correct completion of the task. The primary outcome measure used for each of the tasks was total time adjusted for correct completion. Results: The Harvard Automated Phone Task discriminated well between young normal, clinically normal elderly, and mild cognitive impairment participants (APT-Script: p<0.001; APT-PCP: p<0.001; APT-Bank: p=0.04). Worse baseline Harvard Automated Phone Task performance or worsening Harvard Automated Phone Task performance over time tracked with overall worse performance or worsening performance over time in global cognition, processing speed, executive function, and episodic memory. Conclusions: Prior cross-sectional and current longitudinal analyses have demonstrated the utility of the Harvard Automated Phone Task, a new performance-based activities of daily living instrument, in the assessment of early changes in complex activities of daily living in non-demented elderly at risk for Alzheimer’s disease. Future studies will focus on cross-validation with other sensitive activities of daily living tests and Alzheimer’s disease biomarkers.

CITATION:
G.A. Marshall ; S.L. Aghjayan ; M. Dekhtyar ; J.J. Locascio ; K. Jethwani ; R.E. Amariglio ; K.A. Johnson ; R.A. Sperling ; D.M. Rentz (2017): Activities of Daily Living Measured by the Harvard Automated Phone Task Track with Cognitive Decline over Time in Non-Demented Elderly. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.10

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SHORT-TERM PRACTICE EFFECTS AND AMYLOID DEPOSITION: PROVIDING INFORMATION ABOVE AND BEYOND BASELINE COGNITION

K. Duff, D.B. Hammers, B.C.A. Dalley, K.R. Suhrie, T.J. Atkinson, K.M. Rasmussen, K.P. Horn, B.E. Beardmore, L.D. Burrell, N.L. Foster, J. M. Hoffman

J Prev Alz Dis 2017;2:87-92

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Background: Practice effects, which are improvements in cognitive test scores due to repeated exposure to testing materials, may provide information about Alzheimer’s disease pathology, which could be useful for clinical trials enrichment. Objectives: The current study sought to add to the limited literature on short-term practice effects on cognitive tests and their relationship to amyloid deposition on neuroimaging. Participants: Twenty-seven, non-demented older adults (9 cognitively intact, 18 with mild cognitive impairment) received amyloid imaging with 18F-Flutemetamol, and two cognitive testing sessions across one week to determine practice effects. Results: A composite measure of 18F-Flutemetamol uptake correlated significantly with all seven cognitive tests scores on the baseline battery (r’s = -0.61 – 0.59, all p’s<0.05), with higher uptake indicating poorer cognition. Practice effects significantly added to the relationship (above and beyond the baseline associations) with 18F-Flutemetamol uptake on 4 of the 7 cognitive test scores (partial r’s = -0.45 – 0.44, p’s<0.05), with higher uptake indicating poorer practice effects. The odds ratio of being “amyloid positive” was 13.5 times higher in individuals with low practice effects compared to high practice effects. Conclusions: Short-term practice effects over one week may be predictive of progressive dementia and serve as an affordable screening tool to enrich samples for preventative clinical trials in Alzheimer’s disease.

CITATION:
K. Duff ; D.B. Hammers ; B.C.A. Dalley ; K.R. Suhrie ; T.J. Atkinson ; K.M. Rasmussen ; K.P. Horn ; B.E. Beardmore ; L.D. Burrell ; N.L. Foster ; J. M. Hoffman (2017): Short-Term Practice Effects and Amyloid Deposition: Providing Information Above and Beyond Baseline Cognition. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.9

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ALBUMIN, HEMOGLOBIN, AND THE TRAJECTORY OF COGNITIVE FUNCTION IN COMMUNITY-DWELLING OLDER JAPANESE: A 13-YEAR LONGITUDINAL STUDY

H. Murayama, S. Shinkai, M. Nishi, Y. Taniguchi, H. Amano, S. Seino, Y. Yokoyama, H. Yoshida, Y. Fujiwara, H. Ito

J Prev Alz Dis 2017;2:93-99

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Background: Cognitive function can substantially decline over a long period, and understanding the trajectory of cognitive function is important. However, little is known about the linkage between nutritional biomarkers and long-term cognitive change. Objectives: We analyzed 13-year longitudinal data for older Japanese to examine the associations of serum albumin and hemoglobin levels with the trajectory of cognitive function. Design: Longitudinal study. Setting: Community-based. Participants: A total of 1,744 community-dwelling adults aged 65 years or older who participated in annual health examinations in Kusatsu town, Gunma Prefecture, Japan, from 2002–2014. Measurements: Cognitive function was assessed annually by the Mini-Mental State Examination (MMSE). Albumin and hemoglobin levels at baseline (the year when a respondent first participated in the health examination) were divided into quartiles. Hierarchical linear modeling was used to analyze intrapersonal and interpersonal differences in cognitive function. Results: Participants’ MMSE scores decreased at an accelerated rate over the 13-year period. Participants with the lowest baseline albumin level (below the first quartile line) showed a greater accelerated decline in MMSE scores over time, compared with those with the highest level (above the third quartile line). Moreover, MMSE scores in participants with a lower hemoglobin level and lower MMSE score at baseline tended to decline faster over time at an accelerated rate. Conclusions: These findings yield new insights about the complex and diverse roles of these nutritional biomarkers on the trajectory of cognitive function in old age.

CITATION:
H. Murayama ; S. Shinkai ; M. Nishi ; Y. Taniguchi ; H. Amano ; S. Seino ; Y. Yokoyama ; H. Yoshida ; Y. Fujiwara ; H. Ito (2016): Albumin, Hemoglobin, and the Trajectory of Cognitive Function in Community-Dwelling Older Japanese: A 13-Year Longitudinal Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.113

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FACEHBI: A PROSPECTIVE STUDY OF RISK FACTORS, BIOMARKERS AND COGNITION IN A COHORT OF INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE. STUDY RATIONALE AND RESEARCH PROTOCOLS

O. Rodriguez-Gomez, A. Sanabria, A. Perez-Cordon, D. Sanchez-Ruiz, C. Abdelnour, S. Valero, I. Hernandez, M. Rosende-Roca, A. Mauleon, L. Vargas, M. Alegret, A. Espinosa, G. Ortega, M. Guitart, A. Gailhajanet, O. Sotolongo-Grau, S. Moreno-Grau, S. Ruiz, M. Tarragona, J. Serra, E. Martin, E. Peleja, F. Lomeña, F. Campos, A. Vivas, M.Gomez-Chiari, M.A. Tejero, J. Giménez, P. Pesini, M. Sarasa, G.Martinez, A. Ruiz, L. Tarraga, M.Boada

J Prev Alz Dis 2017;2:100-108

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Background: Long-term longitudinal studies with multimodal biomarkers are needed to delve into the knowledge of preclinical AD. Subjective cognitive decline has been proposed as a risk factor for the development of cognitive impairment. Thus, including individuals with SCD in observational studies may be a cost-effective strategy to increase the prevalence of preclinical AD in the sample. Objectives: To describe the rationale, research protocols and baseline characteristics of participants in the Fundació ACE Healthy Brain Initiative (FACEHBI). Design: FACEHBI is a clinical trial (EudraCT: 2014-000798-38) embedded within a long-term observational study of individuals with SCD. Setting: Participants have been recruited at the memory clinic of Fundació ACE (Barcelona) from two different sources: patients referred by a general practitioner and individuals from an Open House Initiative. Participants: 200 individuals diagnosed with SCD with a strictly normal performance in a comprehensive neuropsychological battery. Measurements: Individuals will undergo an extensive neuropsychological protocol, risk factor assessment and a set of multimodal biomarkers including florbetaben PET, structural and functional MRI, diffusion tensor imaging, determination of amyloid species in plasma and neurophthalmologic assessment with optical coherence tomography. Results: Two hundred individuals have been recruited in 15 months. Mean age was 65.9 years; mean MMSE was 29.2 with a mean of 14.8 years of education. Conclusions: FACEHBI is a long-term study of cognition, biomarkers and lifestyle that has been designed upon an innovative symptom-based approach using SCD as target population. It will shed light on the pathophysiology of preclinical AD and the role of SCD as a risk marker for the development of cognitive impairment.

CITATION:
O. Rodriguez-Gomez ; A. Sanabria ; A. Perez-Cordon ; D. Sanchez-Ruiz ; C. Abdelnour ; S. Valero ; I. Hernandez ; M. Rosende-Roca ; A. Mauleon ; L. Vargas ; M. Alegret ; A. Espinosa ; G. Ortega ; M. Guitart ; A. Gailhajanet ; O. Sotolongo-Grau ; S. Moreno-Grau ; S. Ruiz ; M. Tarragona ; J. Serra ; E. Martin ; E. Peleja ; F. Lomeña ; F. Campos ; A. Vivas ; M.Gomez-Chiari ; M.A. Tejero ; J. Giménez ; P. Pesini ; M. Sarasa ; G.Martinez ; A. Ruiz ; L. Tarraga ; M. Boada (2016): FACEHBI: A Prospective Study of Risk Factors, Biomarkers and Cognition in a Cohort of Individuals with Subjective Cognitive Decline. Study Rationale and Research Protocols. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.122

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Review Articles

DEFINING DISEASE MODIFYING THERAPY FOR ALZHEIMER’S DISEASE

J. Cummings, N. Fox

J Prev Alz Dis 2017;2:109-115

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Background: Disease-modifying therapies (DMTs) are urgently needed to treat the growing number of individuals with Alzheimer’s disease (AD) or at immanent risk for AD. A definition of DMT is required to facilitate the process of DMT drug development. Process: This is a review of the state of the science with regard to definition and development of DMTs. Results: A DMT is as an intervention that produces an enduring change in the clinical progression of AD by interfering in the underlying pathophysiological mechanisms of the disease process that lead to cell death. Demonstration of DMT efficacy is garnered through clinical trial designs and biomarkers. Evidence of disease modification in the drug development process is based on trial designs such as staggered start and delayed withdrawal showing an enduring effect on disease course or on combined clinical outcomes and correlated biomarker evidence of an effect on the underlying pathophysiological processes of the disease. Analytic approaches such as showing change in slope of cognitive decline, increasing drug-placebo difference over time, and delay of disease milestones are not conclusive by themselves but support the presence of a disease modifying effect. Neuroprotection is a related concept whose demonstration depends on substantiating disease modification. No single type of evidence in itself is sufficient to prove disease modification – consistency, robustness, and variety of sources of data will all contribute to convincing stakeholders that an agent is a DMT. Conclusion: DMT is defined by its enduring effect on processes leading to cell death. A variety of types of data can be used to support the hypothesis that disease modification has occurred.

CITATION:
J. Cummings ; N. Fox (2017): Defining Disease Modifying Therapy for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.12

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EU/US/CTAD TASK FORCE: LESSONS LEARNED FROM RECENT AND CURRENT ALZHEIMER’S PREVENTION TRIALS

P. Aisen, J. Touchon, R. Amariglio, S. Andrieu, R. Bateman, J. Breitner, M. Donohue, B. Dunn, R. Doody, N. Fox, S. Gauthier, M. Grundman, S. Hendrix, C. Ho, M. Isaac, R. Raman, P. Rosenberg, R. Schindler, L. Schneider, R.A. Sperling, P. Tariot, K. Welsh-Bohmer, M. Weiner, B. Vellas, and Task Force Members

J Prev Alz Dis 2017;2:116-124

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At a meeting of the EU/US/Clinical Trials in Alzheimer’s Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.

CITATION:
P. Aisen ; J. Touchon ; R. Amariglio ; S. Andrieu ; R. Bateman ; J. Breitner ; M. Donohue ; B. Dunn ; R. Doody ; N. Fox ; S. Gauthier ; M. Grundman ; S. Hendrix ; C. Ho ; M. Isaac ; R. Raman ; P. Rosenberg ; R. Schindler ; L. Schneider ; R. Sperling ; P. Tariot ; K. Welsh-Bohmer ; M. Weiner ; B. Vellas ; and Task Force Members (2017): EU/US/CTAD Task Force: Lessons Learned from Recent and Current Alzheimer’s Prevention Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.13

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ETHICAL ISSUES IN THE DEVELOPMENT OF READINESS COHORTS IN ALZHEIMER’S DISEASE RESEARCH

R. Milne, E. Bunnik, K. Tromp, S. Bemelmans, S. Badger, D.Gove, M. Maman, M. Schermer, L. Truyen, C. Brayne, E. Richard

J Prev Alz Dis 2017;2:125-131

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There is growing interest in the development of novel approaches to secondary prevention trials in Alzheimer’s disease to facilitate screening and recruitment of research participants and to reduce the time and costs associated with clinical trials. Several international research collaborations are setting up research infrastructures that link existing research cohorts, studies or patient registries to establish ‘trial-ready’ or ‘readiness’ cohorts. From these cohorts, individuals are recruited into clinical trial platforms. In setting up such research infrastructures, researchers must make ethically challenging design decisions in at least three areas: re-contacting participants in existing research studies, obtaining informed consent for participation in a readiness cohort, and disclosure of Alzheimer’s disease-related biomarkers. These ethical considerations have been examined by a dedicated workgroup within the European Prevention of Alzheimer’s Dementia (EPAD) project, a trans-European longitudinal cohort and adaptive proof-of-concept clinical trial platform. This paper offers recommendations for the ethical management of re-contact, informed consent and risk disclosure which may be of value to other research collaborations in the process of developing readiness cohorts for prevention trials in Alzheimer’s disease and other disease areas.

CITATION:
R. Milne ; E. Bunnik ; K. Tromp ; S. Bemelmans ; S. Badger ; D. Gove ; M. Maman ; M. Schermer ; L. Truyen ; C. Brayne ; E. Richard (2017): Ethical Issues in the Development of Readiness Cohorts in Alzheimer’s Disease Research. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.5

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