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02/2019 journal articles

Editorials

IMPLICATIONS FOR BACE1 INHIBITOR CLINICAL TRIALS: ADULT CONDITIONAL BACE1 KNOCKOUT MICE EXHIBIT AXONAL ORGANIZATION DEFECTS IN THE HIPPOCAMPUS

R. Vassar

J Prev Alz Dis 2019;6(2):78-84

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BACE1 is the rate-limiting enzyme for the production of the Aβ peptide that forms amyloid plaques in Alzheimer’s disease (AD). Small molecule inhibitors of BACE1 are being tested in clinical trials for AD, but the safety and efficacy of BACE1 inhibition has yet to be fully explored. Knockout of the Bace1 gene in the germline of mice causes multiple neurological phenotypes, suggesting that BACE1 inhibition could be toxic. However, these phenotypes could be the result of BACE1 deficiency during development rather than due to the lack of BACE1 function in the adult. To address this problem, we generated tamoxifen-inducible conditional BACE1 knockout mice in which the Bace1 gene may be deleted in the whole body of the adult at will. Importantly, the adult conditional BACE1 knockout mice largely lack phenotypes, indicating that many BACE1 functions are not required in the adult organism. However, a germline phenotype was observed after BACE1 knockout in the adult: reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle comprised of axons of dentate gyrus granule cells. The infrapyramidal bundle abnormality correlated with reduced proteolytic processing of the neural cell adhesion protein CHL1 that is involved in axonal guidance. We conclude that BACE1 inhibition in the adult mouse brain does not lead to the phenotypes associated with BACE1 deficiency during embryonic and postnatal development. However, adult conditional BACE1 knockout mice also suggest that BACE1 inhibitor drugs may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory. Here, I review the adult conditional BACE1 knockout results and consider their implications for BACE1 inhibitor clinical trials.

CITATION:
R. Vassar (2019): Implications for BACE1 Inhibitor Clinical Trials: Adult Conditional BACE1 Knockout Mice Exhibit Axonal Organization Defects in the Hippocampus. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.3

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Original Research

ASSESSMENT OF CLINICAL MEANINGFULNESS OF ENDPOINTS IN THE GENERATION PROGRAM BY THE INSIGHTS TO MODEL ALZHEIMER’S PROGRESSION IN REAL LIFE (IMAP) STUDY

A. Graf, V. Risson, A. Gustavsson, V. Bezlyak, A. Caputo, P.N. Tariot, J.B. Langbaum, C. Lopez Lopez, V. Viglietta

J Prev Alz Dis 2019;6(2):85-89

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We are launching the Insights to Model Alzheimer’s Progression in Real Life study in parallel with the Alzheimer Prevention Initiative Generation Program. This is a 5-year, multinational, prospective, longitudinal, non-interventional cohort study that will collect data across the spectrum of Alzheimer’s disease. The primary objective is to assess the ability of the Alzheimer’s Prevention Initiative Cognitive Composite Test Score and Repeatable Battery for the Assessment of Neuropsychological Status to predict clinically meaningful outcomes such as diagnosis of mild cognitive impairment or dementia due to Alzheimer’s disease, and change in Clinical Dementia Rating – Global Score. This study is the first large-scale, prospective effort to establish the clinical meaningfulness of cognitive test scores that track longitudinal decline in preclinical Alzheimer’s disease. This study is also expected to contribute to our understanding of the relationships among outcomes in different stages of Alzheimer’s disease as well as models of individual trajectories during the course of the disease.

CITATION:
A. Graf ; V. Risson ; A. Gustavsson ; V. Bezlyak ; A. Caputo ; P.N. Tariot ; J.B. Langbaum ; C. Lopez Lopez ; V. Viglietta (2018): Assessment of Clinical Meaningfulness of Endpoints in the Generation Program by the Insights to Model Alzheimer’s Progression in Real Life (iMAP) Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.49

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UTILIZATION OF OBSERVATIONAL DATA AS A PROXY COHORT FOR COMPARISON PURPOSES WITH OPEN-LABEL STUDY RESULTS: AN EXAMPLE FROM ALZHEIMER’S DISEASE

C. Reed, M. Happich, J. Raskin, A. Tockhorn-Heidenreich, M. Belger

J Prev Alz Dis 2019;6(2):90-99

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Background: Randomized placebo-controlled trials in the development of disease-modifying treatments for Alzheimer’s disease are typically of short duration (12–18 months), and health economic modeling requires extrapolation of treatment effects beyond the trial period. OBJECTIVES: To investigate whether observational data can be used to extrapolate data from open-label trials, we compared outcomes (cognition, function, behavior) over 36 months for patients with mild Alzheimer’s disease dementia in the GERAS observational study (proxy for placebo control) with those of the mild Alzheimer’s disease population on active treatment (solanezumab) in two 18-month randomized placebo-controlled trials (EXPEDITION and EXPEDITION2) and the additional 18-month open-label extension study (EXPEDITION-EXT). DESIGN & SETTING: Analysis of longitudinal data from patients with mild Alzheimer’s disease dementia in the GERAS observational study (conducted in France, Germany and the United Kingdom) and the EXPEDITION program (conducted in Europe, North America, South America, Asia and Australia). PARTICIPANTS: European and North American community-living patients, aged ≥55 years, with probable Alzheimer’s disease dementia and their caregivers. Mild Alzheimer’s disease dementia was defined as a Mini-Mental State Examination score of 20–26 in EXPEDITION and 21–26 in GERAS. INTERVENTION: Active treatment in both randomized placebo-controlled trials and the open-label extension study was intravenous solanezumab 400 mg every 4 weeks. Patients in GERAS were receiving treatment as part of standard care. MEASUREMENTS: Between-group differences for changes from baseline over 36 months in cognitive function, ability to perform activities of daily living, and behavioral and psychological symptoms of dementia were assessed using models stratified by propensity score. RESULTS: At baseline, patients and caregivers participating in GERAS were significantly older than those in the EXPEDITION studies, and the GERAS patient cohort had fewer years of education and a shorter time since diagnosis of Alzheimer’s disease. The baseline mean Mini-Mental State Examination score of the GERAS cohort was significantly higher (indicating better cognition) than that of patients receiving placebo or active treatment in the pooled EXPEDITION studies Baseline functional ability scores were significantly lower for the GERAS cohort, indicating poorer functioning. Propensity score stratification achieved a good balance in the baseline variables between GERAS and the two EXPEDITION arms. Over 18 months, least squares mean changes from baseline in outcome measures were similar in the GERAS cohort and the pooled placebo groups from the randomized controlled trials. Also, the 18-month results for the comparison between the GERAS cohort and the pooled active treatment groups from the randomized controlled trials were generally similar to those reported for the comparison with the control group in the randomized trial. Comparison of active treatment (EXPEDITION-EXT) and observational study (GERAS, as proxy control) results over 36 months of the open-label trial showed a significantly smaller decline in activities of daily living (instrumental and basic) in the active treatment group, reflecting better functioning, but no between-group differences at 36 months for cognitive function or behavioral and psychological symptoms of dementia. CONCLUSIONS: Comparing results from clinical trials and observational studies (real-world data) may be a useful methodological approach for informing long-term outcomes in Alzheimer’s disease drug development and could be used to inform health economic modeling. Further research using this methodological approach is needed.

CITATION:
C. Reed ; M. Happich ; J. Raskin ; A. Tockhorn-Heidenreich ; M. Belger (2019): Utilization of Observational Data as a Proxy Cohort for Comparison Purposes with Open-Label Study Results: An Example from Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.4

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MRI CLINICAL RATINGS AND COGNITIVE FUNCTION IN A CROSS-SECTIONAL POPULATION STUDY OF DEMENTIA: THE CACHE COUNTY MEMORY STUDY

Y.H.W. Tsui-Caldwell, T.J. Farrer, Z. McDonnell, Z. Christensen, C. Finuf, E.D. Bigler, J.T. Tschanz, M.C. Norton, K.A. Welsh-Bohmer

J Prev Alz Dis 2019;6(2):100-107

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BACKGROUND: White matter integrity in aging populations is associated with increased risk of cognitive decline, dementia diagnosis, and mortality. Population-based data can elucidate this association. Objectives: To examine the association between white matter integrity, as measured by a clinical rating scale of hyperintensities, and mental status in older adults including advanced aging. Design: Scheltens Ratings Scale was used to qualitatively assess white matter (WM) hyperintensities in participants of the Cache County Memory Study (CCMS), an epidemiological study of Alzheimer’s disease in an exceptionally long-lived population. Further, the relation between Mini-Mental State Exam (MMSE) and WM hyperintensities were explored. Method: Participants consisted of 415 individuals with dementia and 22 healthy controls. Results: CCMS participants, including healthy controls, had high levels of WM pathology as measured by Scheltens Ratings Scale score. While age did not significantly relate to WM pathology, higher Scheltens Ratings Scale scores were associated with lower MMSE findings (correlation between -0.14 & -0.22; p < .05). Conclusions: WM pathology was common in this county-wide population sample of those ranging in age from 65 to 106. Increased WM burden was found to be significantly associated with decreased overall MMSE performance.

CITATION:
Y.H.W. Tsui-Caldwell ; T.J. Farrer ; Z. McDonnell ; Z. Christensen ; C. Finuf ; E.D. Bigler ; J.T. Tschanz ; M.C. Norton ; K.A. Welsh-Bohmer (2019): MRI Clinical Ratings and Cognitive Function in a Cross-Sectional Population Study of Dementia: The Cache County Memory Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.1

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SHIFT IN HOSPITALIZATIONS FOR ALZHEIMER’S DISEASE TO RELATED DEMENTIAS IN FRANCE BETWEEN 2007 AND 2017

M. Rochoy, E. Chazard, S. Gautier, R. Bordet

J Prev Alz Dis 2019;6(2):108-111

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INTRODUCTION: Alzheimer’s disease (AD) is the first cause of dementia. Diagnostic criteria have evolved: proposals to revise the NINCDS–ADRDA criteria were published in 2007. Our aim was to analyze the evolution in the coding of AD in the French nationwide exhaustive hospital discharge database (PMSI) between 2007 and 2017. METHODS: We analyzed evolution of International Classification of Diseases and Related Health Problems, 10th edition (ICD-10) coding for AD and AD dementia in the PMSI database from 2008 to 2017 (285,748,938 inpatient stays). RESULTS: We observed a 44% decrease in the number of inpatient stays with a principal diagnosis of AD or AD dementia from 2007 (46,313 inpatient stays) to 2017 (25,856 inpatient stays) in France. Over the same period, we observed a 49% increase in the number of inpatient stays with a principal diagnosis of related dementias (other organic mental disorders or other degenerative disorders). Overall, the number of inpatient stays for dementia remained stable despite the increase in the total number of inpatient stays: 95,377 in 2007 (0.409% of inpatient stays) and 99,190 in 2017 (0.344%). CONCLUSION: We therefore note a shift from AD and AD dementia to other dementia diagnoses since 2007. This study suggests a more accurate use of AD related ICD-10 codes since the revised criteria in 2007.

CITATION:
M. Rochoy ; E. Chazard ; S. Gautier ; R. Bordet (2019): Shift in Hospitalizations for Alzheimer’s Disease to Related Dementias in France between 2007 and 2017. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.5

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Review Articles

FACTORS ASSOCIATED WITH ALZHEIMER’S DISEASE: AN OVERVIEW OF REVIEWS

M. Rochoy, V. Rivas, E. Chazard, E. Decarpentry, G. Saudemont, P.-A. Hazard, F. Puisieux, S. Gautier, R. Bordet

J Prev Alz Dis 2019;6(2):121-134

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Alzheimer’s disease (AD) is a frequent pathology, with a poor prognosis, for which no curative treatment is available in 2018. AD prevention is an important issue, and is an important research topic. In this manuscript, we have synthesized the literature reviews and meta-analyses relating to modifiable risk factors associated with AD. Smoking, diabetes, high blood pressure, obesity, hypercholesterolemia, physical inactivity, depression, head trauma, heart failure, bleeding and ischemic strokes, sleep apnea syndrome appeared to be associated with an increased risk of AD. In addition to these well-known associations, we highlight here the existence of associated factors less described: hyperhomocysteinemia, hearing loss, essential tremor, occupational exposure to magnetic fields. On the contrary, some oral antidiabetic drugs, education and intellectual activity, a Mediterranean-type diet or using Healthy Diet Indicator, consumption of unsaturated fatty acids seemed to have a protective effect. Better knowledge of risk factors for AD allows for better identification of patients at risk. This may contribute to the emergence of prevention policies to delay or prevent the onset of AD.

CITATION:
M. Rochoy ; V. Rivas ; E. Chazard ; E. Decarpentry ; G. Saudemont ; P.-A. Hazard ; F. Puisieux ; S. Gautier ; R. Bordet (2019): Factors Associated with Alzheimer’s Disease: An Overview of Reviews. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.7

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BIOLOGICAL AND COGNITIVE MARKERS OF PRESENILIN1 E280A AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE: A COMPREHENSIVE REVIEW OF THE COLOMBIAN KINDRED

J.T. Fuller, A. Cronin-Golomb, J.R. Gatchel, D.J. Norton, E. Guzmán-Vélez, H.I.L. Jacobs, B. Hanseeuw, E. Pardilla-Delgado, A. Artola, A. Baena, Y. Bocanegra, K.S. Kosik, K. Chen, P.N. Tariot, K. Johnson, R.A. Sperling, E.M. Reiman, F. Lopera, Y.T. Quiroz

J Prev Alz Dis 2019;6(2):112-120

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The study of individuals with autosomal dominant Alzheimer’s disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer’s disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world’s largest single-mutation autosomal dominant Alzheimer’s disease kindred — a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene — will provide new directions for Alzheimer’s research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer’s disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers’ estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities — such as cortical thinning and hyperactivation in memory networks — as well as differences in biofluid and in vivo measurements of Alzheimer’s-related pathological proteins distinguish Presenilin1 E280A mutation carriers from non-carriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer’s disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer’s disease to the larger sporadic Alzheimer’s disease population.

CITATION:
J.T. Fuller ; A. Cronin-Golomb ; J.R. Gatchel ; D.J. Norton ; E. Guzmán-Vélez ; H.I.L. Jacobs ; B. Hanseeuw ; E. Pardilla-Delgado ; A. Artola ; A. Baena ; Y. Bocanegra ; K.S. Kosik ; K. Chen ; P.N. Tariot ; K. Johnson ; R.A. Sperling ; E.M. Reiman ; F. Lopera ; Y.T. Quiroz (2019): Biological and Cognitive Markers of Presenilin1 E280A Autosomal Dominant Alzheimer’s Disease: A Comprehensive Review of the Colombian Kindred. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.6

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Brief Report

IMPLEMENTING A MEMORY CLINIC MODEL TO FACILITATE RECRUITMENT INTO EARLY PHASE CLINICAL TRIALS FOR MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE

L. Park, C. Kouhanim, S. Lee, Z. Mendoza, K. Patrick, L. Gertsik, C. Aguilar, D. Gullaba, S. Semenova, S. Jhee

J Prev Alz Dis 2019;6(2):135-138

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Background: The recruitment challenges for MCI and AD subjects into clinical trials are well known, and this is particularly true for early phase studies. Currently, only 10-20% of all patients who are referred for research from the community are trial eligible (Grill and Karlawish, 2011). Due to the limited and specific study objectives in early phase study designs, these rates drop to approximately one patient every two months. Barriers to research recruitment are multi-factorial, involving patient centered factors, issues related to caregiver/study partner participation, and aspects related to the involvement of their treating physicians. To address this challenge, we implemented a Memory Clinic within PAREXEL’s Early Phase Clinical Pharmacology Unit. Our objective was to significantly facilitate recruitment into AD clinical trials by providing resources and education to patients, their treating physicians, and caregivers in the community. Method: The Clinic’s primary goals were to increase research visibility and partnerships with local organizations and referring physicians. Members of the research team co-sponsored community outreach events with local organizations, thereby increasing awareness about the services of this memory clinic. Secondly, physician outreach was expanded to include those who were not previously amenable to clinical trial referrals. Finally, Memory Clinic patients were given clinical evaluations, free of charge and the results were discussed with the patients and their caregivers. If the patients were interested in hearing more about possible research opportunities, they were referred to the early phase unit for a screening visit. Results: We found that new referrals for research participation significantly increased as a result of this new paradigm. In 2016, 12 patients diagnosed with MCI or AD per protocol, were referred to a research study and 3 were randomized. In 2017, 98 patients were referred and 16 were enrolled In addition, our referral network increased with 30 physicians over a 20 mile radius. Collaborations with national non-profit organizations also increased, thereby increasing public awareness about the importance of research participation in the development of new treatments for Alzheimer’s Disease. Conclusions: In summary, community engagement and providing referring physicians with a clinical service improved recruitment significantly for our phase 1 unit. Resource education, staff training, and dedicated medical professionals can significantly improve awareness about clinical research participation and provide additional participants over and above traditional recruitment methods and trial registry enrollment in a large urban area.

CITATION:
L. Park ; C. Kouhanim ; S. Lee ; Z. Mendoza ; K. Patrick ; L. Gertsik ; C. Aguilar ; D. Gullaba ; S. Semenova ; S. Jhee (2019): Implementing a Memory Clinic Model to facilitate recruitment into early phase clinical trials for Mild Cognitive Impairment and Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.8

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Short Communication

REPORT FROM THE FIRST CLINICAL TRIALS ON ALZHEIMER’S DISEASE (CTAD) ASIA-CHINA 2018 : BRINGING TOGETHER GLOBAL LEADERS

J.K. Chhetri, P. Chan, B. Vellas, J. Touchon, S. Gauthier

J Prev Alz Dis 2019;6(2):144-147

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Population of older adults in Asia, and particularly in China is increasing rapidly. Older population are at increased risk of Alzheimer’s disease (AD) and other dementias. Soon, the Chinese population with AD will represent almost half of the world’s AD population. There is a desperate need of disease modifying therapies to delay or slow the progression of AD, to tackle this emerging healthcare emergency. In this context, the first CTAD Asia-China conference was held in China to bring together Western and Asian leaders in AD. This meeting focused largely on how to develop successful trials in China, utilizing past experiences from the West.

CITATION:
J.K. Chhetri ; P. Chan ; B. Vellas ; J. Touchon ; S. Gauthier (2019): Report from the First Clinical Trials on Alzheimer’s Disease (CTAD) Asia-China 2018 : Bringing together Global Leaders. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2019.2

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Brief Report

CROSS-SECTIONAL CHARACTERIZATION OF ALBUMIN GLYCATION STATE IN CEREBROSPINAL FLUID AND PLASMA FROM ALZHEIMER’S DISEASE PATIENTS

M. Costa, A. Mestre, R. Horrillo, A. M. Ortiz, A. Pérez, A. Ruiz, M. Boada, S. Grancha

J Prev Alz Dis 2019;6(2):139-143

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We determined albumin post-translational modifications (PTMs) by mass spectrometry (MS) in plasma and cerebrospinal fluid (CSF) from 31 Alzheimer’s disease (AD) patients (with 27 samples of paired plasma-CSF from the same patients). Results were cross-sectionally compared with healthy controls. For percentage of relative intensity of glycated isoforms, plasma albumin was globally more glycated in AD patients than in healthy controls (P<0.01). MS results in plasma were confirmed by a quantitative enzymatic assay (Lucica GA-L) for albumin early-glycation detection. In CSF there were no global glycation differences detected by MS, although a different pattern of glycated isoforms was observed. Oxidized+glycated and cysteinylated+glycated isoforms were increased in both plasma and CSF of AD patients in comparison with healthy controls (P<0.001). Furthermore, AD patients showed higher glycation in plasma than in CSF (P<0.01). Our data support the role of glycation and oxidative stress in AD.

CITATION:
M. Costa ; A. Mestre ; R. Horrillo ; A. M. Ortiz ; A. Pérez ; A. Ruiz ; M. Boada ; S. Grancha (2018): Cross-Sectional Characterization of Albumin Glycation State in Cerebrospinal Fluid and Plasma from Alzheimer’s Disease Patients. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.48

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