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OVERTREATING ALZHEIMER’S DISEASE

M. Canevelli, N. Vanacore, A. Blasimme, G. Bruno, M. Cesari

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The management of frailty in older persons is not easy, implying interventions beyond the simple prescription of medications. Biological complexity, multimorbidity, polypharmacy, and social issues often hamper the possibility to directly translate the evidence coming from research into clinical practice. Frailty indeed represents the most relevant cause of the “evidence-based medicine issue” influencing clinical decisions in geriatric care. Today, patients with Alzheimer’s disease (AD) are much older and frailer than some decades ago. They also tend to have more drugs prescribed. In parallel, research on AD has evolved over the years, hypothesizing that anticipating the interventions to the earliest stages of the disease may provide beneficial effects (to date, still lacking). In this article, we argue that, by focusing exclusively on “the disease” and pushing to anticipate its detection (sometimes even before the appareance of its clinical manifestations) may overshadow the person’s values and priorities. Research should be developed for better integrating the concept of aging and frailty in the design of clinical trials in order to provide results that can be implemented in real life. On the other hand, clinicians should be less prone to the easy (but unsupported by evidence) pharmacological prescription.

CITATION:
M. Canevelli ; N. Vanacore ; A. Blasimme ; G. Bruno ; M. Cesari (2020): Overtreating Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.74

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PSYCHOMETRIC PROPERTIES OF THE CLINICAL DEMENTIA RATING – SUM OF BOXES AND OTHER COGNITIVE AND FUNCTIONAL OUTCOMES IN A PRODROMAL ALZHEIMER’S DISEASE POPULATION

F. McDougall, C. Edgar, M. Mertes, P.Delmar, P. Fontoura, D. Abi-Saab, C.J. Lansdall, M. Boada, R. Doody

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BACKGROUND: The Clinical Dementia Rating–Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population. OBJECTIVE: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD. SETTING: Data were gathered as part of a two-year clinical trial. PARTICIPANTS: Patients had biomarker confirmed prodromal AD. MEASUREMENTS: Clinical Dementia Rating (CDR), Functional Activities Questionnaire (FAQ), Alzheimer’s Disease Assessment Scale – Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR [words]). Assessments were conducted at least every 24 weeks. RESULTS: For the CDR-SB, test-retest reliability was good (intra-class correlation coefficient [ICC]=0.83); internal consistency was 0.65 at baseline but above 0.8 at later assessments. Relationships between the CDR-SB and other measures were as expected (higher correlations with more closely related constructs), and the CDR-SB differentiated between patients with different severities of dementia (-2.9 points difference between CDR-Global Score 0.5 and 1, P<.0001). Floor and ceiling effects on the CDR-SB total score were minimal; however, at baseline there were ceiling effects in the personal care domain. Further detail is provided on the psychometric properties of ADAS-Cog, MMSE, FCSRT-IR and FAQ in this population. CONCLUSION: The psychometric properties of the CDR-SB are adequate in prodromal AD and continued use is warranted in clinical trials. However, there remains scope for improvement in the assessment of functional constructs and development of novel measures should continue.

CITATION:
F. McDougall ; C. Edgar ; M. Mertes ; P.Delmar ; P. Fontoura ; D. Abi-Saab ; C.J. Lansdall ; M. Boada ; R. Doody (2020): Psychometric Properties of the Clinical Dementia Rating – Sum of Boxes and other Cognitive and Functional Outcomes in a Prodromal Alzheimer’s Disease Population. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.73

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CHINESE VERSION OF THE BAYLOR PROFOUND MENTAL STATUS EXAMINATION: A BRIEF STAGING MEASURE FOR PATIENTS WITH SEVERE ALZHEIMER’S DISEASE

X. Fu, W. Yu, M. Ke, X. Wang, J. Zhang, T. Luo, P.J. Massman, R.S. Doody, Y. Lü

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BACKGROUND: A specialized instrument for assessing the cognition of patients with severe Alzheimer’s disease (AD) is needed in China. Objectives: To validate the Chinese version of the Baylor Profound Mental Status Examination (BPMSE-Ch). Design: The BPMSE is a simplified scale which has proved to be a reliable and valid tool for evaluating patients with moderate to severe AD, it is worthwhile to extend the use of it to Chinese patients with AD. Setting: Patients were assessed from the Memory Clinic Outpatient. Participants: All participants were diagnosed as having probable AD by assessment. Measurements: The BPMSE was translated into Chinese and back translated. The BPMSE-Ch was administered to 102 AD patients with a Mini-Mental State Examination (MMSE) score below 17. We assessed the internal consistency, reliability, and construct validity between the BPMSE-Ch and MMSE, Severe Impairment Battery (SIB), Global Deterioration Scale (GDS-1), Geriatric Depression Scale(GDS-2), Instrumental Activities of Daily Living (IADL), Physical Self-Maintenance Scale (PSMS), Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR). Results: The BPMSE-Ch showed good internal consistency (α = 0.87); inter-rater and test-retest reliability were both excellent, ranging from 0.91 to 0.99. The construct validity of the measure was also supported by significant correlations with MMSE, SIB. Moreover, as expected, the BMPSE-Ch had a lower floor effect than the MMSE, but a ceiling effect existed for patients with MMSE scores above 11. Conclusions: The BPMSE-Ch is a reliable and valid tool for evaluating cognitive function in Chinese patients with severe AD.

CITATION:
X. Fu ; W. Yu ; M. Ke ; X. Wang ; J. Zhang ; T. Luo ; P.J. Massman ; R.S. Doody ; Y. Lü (2020): Chinese Version of the Baylor Profound Mental Status Examination: A Brief Staging Measure for Patients with Severe Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.72

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COST-EFFECTIVENESS OF DEMENTIA PREVENTION INTERVENTIONS

I. McRae, L. Zheng, S. Bourke, N. Cherbuin, K.J. Anstey

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Background: Assessment of cost-effectiveness of interventions to address modifiable risk factors associated with dementia requires estimates of long-term impacts of these interventions which are rarely directly available and must be estimated using a range of assumptions. OBJECTIVES: To test the cost-effectiveness of dementia prevention measures using a methodology which transparently addresses the many assumptions required to use data from short-term studies, and which readily incorporates sensitivity analyses. DESIGN: We explore an approach to estimating cost-effective prices which uses aggregate data including estimated lifetime costs of dementia, both financial and quality of life, and incorporates a range of assumptions regarding sustainability of short- term gains and other parameters. SETTING: The approach is addressed in the context of the theoretical reduction in a range of risk factors, and in the context of a specific small-scale trial of an internet-based intervention augmented with diet and physical activity consultations. MEASUREMENTS: The principal outcomes were prices per unit of interventions at which interventions were cost-effective or cost-saving. RESULTS: Taking a societal perspective, a notional intervention reducing a range of dementia risk-factors by 5% was cost-effective at $A460 per person with higher risk groups at $2,148 per person. The on-line program costing $825 per person was cost-effective at $1,850 per person even if program effect diminished by 75% over time. CONCLUSIONS: Interventions to address risk factors for dementia are likely to be cost-effective if appropriately designed, but confirmation of this conclusion requires longer term follow-up of trials to measure the impact and sustainability of short-term gains.

CITATION:
I. McRae ; L. Zheng ; S. Bourke ; N. Cherbuin ; K.J. Anstey (2020): Cost-Effectiveness of Dementia Prevention Interventions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.71

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A WEB-BASED MULTIDOMAIN LIFESTYLE INTERVENTION FOR OLDER ADULTS: THE EMIND RANDOMIZED CONTROLLED TRIAL

P. de Souto Barreto, K. Pothier, G. Soriano, M. Lussier, L. Bherer, S. Guyonnet, A. Piau, P.-J. Ousset, B. Vellas

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Importance/Objective: To describe the feasibility and acceptability of a 6-month web-based multidomain lifestyle training intervention for community-dwelling older people and to test the effects of the intervention on both function- and lifestyle-related outcomes. Design: 6-month, parallel-group, randomized controlled trial (RCT). Setting: Toulouse area, South-West, France. Participants: Community-dwelling men and women, ≥ 65 years-old, presenting subjective memory complaint, without dementia. Intervention: The web-based multidomain intervention group (MIG) received a tablet to access the multidomain platform and a wrist-worn accelerometer measuring step counts; the control group (CG) received only the wrist-worn accelerometer. The multidomain platform was composed of nutritional advices, personalized exercise training, and cognitive training. Main outcomes and measures: Feasibility, defined as the proportion of people connecting to ≥75% of the prescribed sessions, and acceptability, investigated through content analysis from recorded semi-structured interviews. Secondary outcomes included clinical (eg, cognitive function, mobility, health-related quality of life (HRQOL)) and lifestyle (eg, step count, food intake) measurements. Results: Among the 120 subjects (74.2 ±5.6 years-old; 57.5% women), 109 completed the study (n=54, MIG; n=55, CG). 58 MIG subjects connected to the multidomain platform at least once; among them, adherers of ≥75% of sessions varied across multidomain components: 37 people (63.8% of 58 participants) for cognitive training, 35 (60.3%) for nutrition, and three (5.2%) for exercise; these three persons adhered to all multidomain components. Participants considered study procedures and multidomain content in a positive way; the most cited weaknesses were related to exercise: too easy, repetitive, and slow progression. Compared to controls, the intervention had a positive effect on HRQOL; no significant effects were observed across the other clinical and lifestyle outcomes. Conclusions and Relevance: Providing multidomain lifestyle training through a web-platform is feasible and well-accepted, but the training should be challenging enough and adequately progress according to participants’ capabilities to increase adherence. Recommendations for a larger on-line multidomain lifestyle training RCT are provided.

CITATION:
P. de Souto Barreto ; K. Pothier ; G. Soriano ; M. Lussier ; L. Bherer ; S. Guyonnet ; A. Piau ; P.-J. Ousset ; B. Vellas (2020): A Web-Based Multidomain Lifestyle Intervention for Older Adults: The eMIND Randomized Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.70

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DOES TEA DRINKING PROMOTE HEALTH OF OLDER ADULTS: EVIDENCE FROM THE CHINA HEALTH AND NUTRITION SURVEY

J. Wang, Q. Wei, X. Wan

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Objective: This study selects the health indicators of older adults to analyze the impact of tea drinking on health. Design: This is a panel data. Setting: This study uses data from China Health and Nutrition Survey (CHNS), which covers nine provinces and ten waves, between 1997 and 2015. Participants: a total of 706 old adults are consistently surveyed in six surveys on issues such as health and nutrition. Measurements: Health of old adults is assessed by self-reported health (SRH), tea drinking is 0-1 dummy variable, and also analyze with the frequency of tea drinking. This study uses ordered probit model to analyze the influence of tea drinking on SRH. Results: Findings reveal a significant negative correlation between tea drinking and SRH of older adults. It is shows that the significant positive correlation exists between the tea drinking frequency and SRH, but the quadratic term of tea frequency shows the significant negative correlation. It means drinking tea benefits older adults in terms of improved health, but excessive consumption of tea is not healthy for them. The heterogeneity analyses reveal that there are no significant geographic, tea-drinking pattern or gender differences in the conclusion that tea drinking is good for older adults’ health. Conclusion: In this study, we find correlation between tea drinking and SRH of older adults, and tea drinking is beneficial toward the improvement of SRH, but drinking tea in excess is not good for older adults’ health.

CITATION:
J. Wang ; Q. Wei ; X. Wan (2020): Does Tea Drinking Promote Health of Older Adults: Evidence from the China Health and Nutrition Survey. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.67

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LONGITUDINAL COURSE OF AGITATION AND AGGRESSION IN PATIENTS WITH ALZHEIMER’S DISEASE IN A COHORT STUDY: METHODS, BASELINE AND LONGITUDINAL RESULTS OF THE A3C STUDY

A. De Mauleon, J. Delrieu, C. Cantet, B. Vellas, S. Andrieu, P.B. Rosenberg, C.G. Lyketsos, M. Soto Martin

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BACKGROUND: To present methodology, baseline results and longitudinal course of the Agitation and Aggression in patients with Alzheimer’s Disease Cohort (A3C) study. Objectives: The central objective of A3C was to study the course, over 12 months of clinically significant Agitation and Aggression symptoms based on validated measures, and to assess relationships between symptoms and clinical significance based on global ratings. Design: A3C is a longitudinal, prospective, multicenter observational cohort study performed at eight memory clinics in France, and their associated long-term care facilities. Setting: Clinical visits were scheduled at baseline, monthly during the first 3 months, at 6 months, at 9 months and at 12 months. The first three months intended to simulate a classic randomized control trial 12-week treatment design. Participants: Alzheimer’s Disease patients with clinically significant Agitation and Aggression symptoms lived at home or in long-term care facilities. Measurements: Clinically significant Agitation and Aggression symptoms were rated on Neuropsychiatric Inventory (NPI), NPI-Clinician rating (NPI-C) Agitation and Aggression domains, and Cohen Mansfield Agitation Inventory. Global rating of agitation over time was based on the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change. International Psychogeriatric Association “Provisional Diagnostic Criteria for Agitation”, socio-demographics, non-pharmacological approaches, psychotropic medication use, resource utilization, quality of life, cognitive and physical status were assessed. Results: A3C enrolled 262 AD patients with a mean age of 82.4 years (SD ±7.2 years), 58.4% women, 69.9% at home. At baseline, mean MMSE score was 10.0 (SD±8.0), Cohen Mansfield Agitation Inventory score was 62.0 (SD±15.8) and NPI-C Agitation and Aggression clinician severity score was 15.8 (SD±10.8). According to the International Psychogeriatric Association agitation definition, more than 70% of participants showed excessive motor activity (n=199, 76.3%) and/or a verbal aggression (n=199, 76.3%) while 115 (44.1%) displayed physical aggression. The change of the CMAI score and the NPI-C Agitation and Aggression at 1-year follow-up period was respectively -11.36 (Standard Error (SE)=1.32; p<0.001) and -6.72 (SE=0.77; p<0.001). Conclusion: Little is known about the longitudinal course of clinically significant agitation symptoms in Alzheimer’s Disease about the variability in different outcome measures over time, or the definition of a clinically meaningful improvement. A3C may provide useful data to optimize future clinical trials and guide treatment development for Agitation and Aggression in Alzheimer’s Disease.

CITATION:
A. De Mauleon ; J. Delrieu ; C. Cantet ; B. Vellas ; S. Andrieu ; P.B. Rosenberg ; C.G. Lyketsos ; M. Soto Martin (2020): Longitudinal Course of Agitation and Aggression in Patients with Alzheimer’s Disease in a Cohort study: Methods, Baseline and Longitudinal Results of the A3C Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.66

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MOLECULAR SUBTYPING OF MILD COGNITIVE IMPAIRMENT BASED ON GENETIC POLYMORPHISM AND GENE EXPRESSION

H.-T. Li, S.-X. Yuan, J.-S. Wu, X.-Z. Zhang, Y. Liu, X. Sun, For the Alzheimer’s Disease Neuroimaging Initiative

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Background: Alzheimer’s Disease (AD) is a neurodegenerative brain disease in the elderly. Recent studies have revealed the heterogeneous nature of AD. Mild Cognitive Impairment (MCI) is the prodromal stage of AD. Objectives: In this study, we identified subtypes of MCI based on genetic polymorphism and gene expression. Methods: We utilized the two types of omics data, namely genetic polymorphism and gene expression profiling, derived from 125 MCI patients’ peripheral blood samples from the ADNI-1 dataset. Similarity network fusion (SNF) algorithm was implemented to cluster MCI patient subtypes. And 185 MCI patients in ADNI-2 were utilized to evaluate the effectiveness of this method. Two MCI subtypes were identified by implementing the SNF algorithm. Results: We used Kaplan-Meier analysis and log-rank testing for the conversion from MCI to AD between two subtypes, and p-value is 4.58×10-3. In addition, we compared patients among two MCI subtypes by the following factors: the changes in Alzheimer’s Disease cognitive scales and MRI image; significantly enriched pathways based on differentially expressed genes. This study proved that MCI is a heterogeneous disease by concluding that AD development in two MCI subtypes is significantly different. Conclusions: MCI patients with different molecular characteristics have different risks converting to AD. In addition to evaluating statistics, genetic polymorphism and gene expression profiling from MCI patients’ peripheral blood are non-invasiveness and cost-effectiveness markers to identify MCI subtypes for clinical application.

CITATION:
H.-T. Li ; S.-X. Yuan ; J.-S. Wu ; X.-Z. Zhang ; Y. Liu ; X. Sun ; and For the Alzheimer’s Disease Neuroimaging Initiative (2020): Molecular Subtyping of Mild Cognitive Impairment based on Genetic Polymorphism and Gene Expression. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.65

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SUGAR IN BEVERAGE AND THE RISK OF INCIDENT DEMENTIA, ALZHEIMER’S DISEASE AND STROKE: A PROSPECTIVE COHORT STUDY

H. Miao, K. Chen, X. Yan, F. Chen

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Background: This study aimed to investigate the association between sugar in beverage and dementia, Alzheimer Disease (AD) dementia and stroke. Methods: This prospective cohort study were based on the US community-based Framingham Heart Study (FHS). Sugar in beverage was assessed between 1991 and 1995 (5th exam). Surveillance for incident events including dementia and stroke commenced at examination 9 through 2014 and continued for 15-20 years. Results: At baseline, a total of 1865 (63%) subjects consumed no sugar in beverage, whereas 525 (18%) subjects consumed it in 1-7 servings/week and 593 (29%) in over 7 servings/week. Over an average follow-up of 19 years in 1384 participants, there were 275 dementia events of which 73 were AD dementia. And 103 of 1831 participants occurred stroke during the follow-up nearly 16 years. After multivariate adjustments, individuals with the highest intakes of sugar in beverage had a higher risk of all dementia, AD dementia and stroke relative to individuals with no intakes, with HRs of 2.80(95%CI 2.24-3.50) for all dementia, 2.55(95%CI 1.55-4.18) for AD dementia, and 2.11(95%CI 1.48-3.00) for stroke. And the same results were shown in the subgroup for individuals with median intakes of sugar in beverage. Conclusion: Higher consumption of sugar in beverage was associated with an increased risk of all dementia, AD dementia and stroke.

CITATION:
H. Miao ; K. Chen ; X. Yan ; F. Chen (2020): Sugar in Beverage and the Risk of Incident Dementia, Alzheimer’s disease and Stroke: A Prospective Cohort Study . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.62

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APPLICATION OF DIGITAL COGNITIVE BIOMARKERS FOR ALZHEIMER’S DISEASE: IDENTIFYING COGNITIVE PROCESS CHANGES AND IMPENDING COGNITIVE DECLINE

J.R. Bock, J. Hara, D. Fortier, M.D. Lee, R.C. Petersen, W.R. Shankle, The Alzheimer’s Disease Neuroimaging Initiative

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Background: Recent Alzheimer’s disease (AD) trials have faced significant challenges to enroll pre-symptomatic or early stage AD subjects with biomarker positivity, minimal or no cognitive impairment, and likelihood to decline cognitively during a short trial period. Our previous study showed that digital cognitive biomarkers (DCB), generated by a hierarchical Bayesian cognitive process (HBCP) model, were able to distinguish groups of cognitively normal individuals with impending cognitive decline from those without. We generated DCBs using only baseline Auditory Verbal Learning Test’s wordlist memory (WLM) item response data from the Mayo Clinic Alzheimer’s Disease Patient Registry. Objectives: To replicate our previous findings, using baseline ADAS-Cog WLM item response data from the Alzheimer’s Disease Neuroimaging Initiative, and compare DCBs to traditional approaches for scoring word-list memory tests. Design: Classified decliner subjects (n = 61) as those who developed amnestic MCI or AD dementia within 3 years of normal baseline assessment and non-decliner (n = 442) as those who did not. Measures: Evaluated the relative value of DCBs compared to traditional measures, using three analytic approaches to group differences: 1) logistic regression of summary scores per ADAS-Cog WLM task; 2) Bayesian modeling of summary scores; and 3) HBCP modeling to generate DCBs from item-level responses. Results: The HBCP model produced posterior distributions of group differences, of which Bayes factor assessment identified three DCBs with notable group differences: Immediate Retrieval from Durable Storage, (BFds = 11.8, strong evidence); One-Shot Learning, (BFds = 4.5, moderate evidence); and Partial Learning (BFds = 2.9, weak evidence). In contrast, logistic regression of summary scores did not significantly discriminate between groups, and the Bayes factor assessment of modeled summary scores provided moderate evidence that the groups were equivalent (BFsd = 3.4, 3.1, 2.9, and 1.4, respectively). Conclusions: This study demonstrated DCBs’ ability to distinguish , at baseline, between impending cognitive decline and non-decline groups where individuals in both groups were classified as cognitively normal. This validated findings from our previous study, demonstrating DCBs’ advantages over traditional approaches. This study warrants further refinement of the HBCP DCBs to predict impending cognitive decline in individuals and other factors associated with AD, such as physical biomarker load.

CITATION:
J.R. Bock ; J. Hara ; D. Fortier ; M.D. Lee ; R.C. Petersen ; W.R. Shankle ; The Alzheimer’s Disease Neuroimaging Initiative (2020): Application of Digital Cognitive Biomarkers for Alzheimer’s Disease: Identifying Cognitive Process Changes and Impending Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.63

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EXECUTIVE FUNCTION PREDICTS THE VALIDITY OF SUBJECTIVE MEMORY COMPLAINTS IN OLDER ADULTS BEYOND DEMOGRAPHIC, EMOTIONAL, AND CLINICAL FACTORS

R.-Y. Chao, T.-F. Chen, Y.-L. Chang

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Background: Although evidence suggests that subjective memory complaints (SMCs) could be a risk factor for dementia, the relationship between SMCs and objective memory performance remains controversial. Old adults with or without mild cognitive impairment (MCI) may represent a highly heterogeneous group, based partly on the demonstrated variability in the level of executive function among those individuals. It is reasonable to speculate that the accuracy of the memory-monitoring ability could be affected by the level of executive function in old adults. Objective: This study investigated the effects of executive function level on the consistency between SMCs and objective memory performance while simultaneously considering demographic and clinical variables in nondemented older adults. Setting: Participants were recruited from both the memory clinics and local communities. Participants: Participants comprised 65 cognitively normal (CN) older adults and 54 patients with MCI. Measurements: Discrepancy scores between subjective memory evaluation and objective memory performance were calculated to determine the degree and directionality of the concordance between subjective and objective measures. Demographic, emotional, genetic, and clinical information as well as several executive function measurements were collected. Results: The CN and MCI groups exhibited similar degrees of SMC; however, the patients with MCI were more likely to overestimate their objective memory ability, whereas the CN adults were more likely to underestimate their objective memory ability. The results also revealed that symptoms of depression, group membership, and the executive function level together predicted the discrepancy between the subjective and objective measures of memory function; however, the executive function level retained its unique predictive ability even after the symptoms of depression, group membership, and other factors were controlled for. Conclusion: Although both noncognitive and cognitive factors were necessary for consideration, the level of executive function may play a unique role in understanding the equivocal relationship of the concurrence between subjective complaints and objective function measures. Through a comprehensive evaluation, high-risk individuals (i.e., CN individuals heightened self-awareness of memory changes) may possibly be identified or provided with the necessary intervention during stages at which objective cognitive impairment remains clinically unapparent.

CITATION:
R.-Y. Chao ; T.-F. Chen ; Y.-L. Chang (2020): Executive Function Predicts the Validity of Subjective Memory Complaints in Older Adults beyond Demographic, Emotional, and Clinical Factors. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.61

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MENTAL COMPONENT SCORE (MCS) FROM HEALTH-RELATED QUALITY OF LIFE PREDICTS INCIDENCE OF DEMENTIA IN U.S. MALES

X. Ding, E.L. Abner, F.A. Schmitt, J. Crowley, P. Goodman, R.J. Kryscio

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Background: The Medical Outcomes Study Questionnaire Short Form 36 health survey (SF-36) measures health-related quality of life (HRQoL) from the individual’s point of view and is an indicator of overall health status. Objective: To examine whether HRQoL shows differential changes over time prior to dementia onset and investigate whether HRQoL predicts incidence of dementia. Design: Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial, which recruited 7,547 non-demented men between 2002 and 2009. A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis Setting: Secondary data analysis of PREADViSE data. Participants: A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis. Measurements: Two summary T scores were generated for analysis: physical component score (PCS) and mental component score (MCS), each with a mean of 50 (standard deviation of 10); higher scores are better. Linear mixed models (LMM) were applied to determine if mean component scores varied over time or by eventual dementia status. Cox proportional hazards regression was used to determine if the baseline component scores were associated with dementia incidence, adjusting for baseline age, race, APOE-4 carrier status, sleep apnea, and self-reported memory complaint at baseline. Results: The mean baseline MCS score for participants who later developed dementia (mean± SD: 53.9±9.5) was significantly lower than for those participants who did not develop dementia during the study (mean±SD: 56.4±6.5; p = 0.005). Mean PCS scores at baseline (dementia: 49.3±7.9 vs. non-dementia: 49.8±7.8) were not significantly different (p = 0.5) but LMM analysis showed a significant time effect. For MCS, the indicator for eventual dementia diagnosis was significantly associated with poorer scores after adjusting for baseline age, race, and memory complaint. Adjusted for other baseline risk factors, the Cox model showed that a 10-unit increase in MCS was associated with a 44% decrease in the hazard of a future dementia diagnosis (95% CI: 32%-55%). Conclusion: The SF-36 MCS summary score may serve as a predictor for future dementia and could be prognostic in longitudinal dementia research.

CITATION:
X. Ding ; E.L. Abner ; F.A. Schmitt ; J. Crowley ; P. Goodman ; R.J. Kryscio (2020): Mental Component Score (MCS) from Health-Related Quality of Life Predicts Incidence of Dementia in U.S. Males. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.50

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JPAD Volume 8, N°01 - 2021

 

THIRTY-SIX-MONTH AMYLOID POSITRON EMISSION TOMOGRAPHY RESULTS SHOW CONTINUED REDUCTION IN AMYLOID BURDEN WITH SUBCUTANEOUS GANTENERUMAB

G. Klein, P. Delmar, G.A. Kerchner, C. Hofmann, D. Abi-Saab, A. Davis, N. Voyle, M. Baudler, P. Fontoura, R. Doody

J Prev Alz Dis 2021;1(8):3-6

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Previous findings from the positron emission tomography (PET) substudy of the SCarlet RoAD and Marguerite RoAD open-label extension (OLE) showed gantenerumab doses up to 1200 mg every 4 weeks administered subcutaneously resulted in robust beta-amyloid (Aβ) plaque removal over 24 months in people with prodromal-to-moderate Alzheimer’s disease (AD). In this 36-month update, we demonstrate continued reduction, with mean (standard error) centiloid values at 36 months of -4.3 (7.5), 0.8 (6.7), and 4.7 (8.0) in the SCarlet RoAD (double-blind pooled placebo and active groups), Marguerite RoAD double-blind placebo, and Marguerite RoAD double-blind active groups respectively, representing a change of -57.0 (10.3), -90.3 (9.0), and -74.9 (10.5) centiloids respectively. These results demonstrate that prolonged gantenerumab treatment, at doses up to 1200 mg, reduces amyloid plaque levels below the amyloid positivity threshold. The ongoing GRADUATE Phase III trials will evaluate potential clinical benefits associated with gantenerumab-induced amyloid-lowering in people with early (prodromal-to-mild) AD.

CITATION:
G. Klein ; P. Delmar ; G.A. Kerchner ; C. Hofmann ; D. Abi-Saab ; A. Davis ; N. Voyle ; M. Baudler ; P. Fontoura ; R. Doody (2020): Thirty-Six-Month Amyloid Positron Emission Tomography Results Show Continued Reduction in Amyloid Burden with Subcutaneous Gantenerumab. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.68

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SAFETY AND EFFICACY OF LEMBOREXANT IN PATIENTS WITH IRREGULAR SLEEP-WAKE RHYTHM DISORDER AND ALZHEIMER’S DISEASE DEMENTIA: RESULTS FROM A PHASE 2 RANDOMIZED CLINICAL TRIAL

M. Moline, S. Thein, M. Bsharat, N. Rabbee, M. Kemethofer-Waliczky, G. Filippov, N. Kubota, S. Dhadda

J Prev Alz Dis 2021;1(8):7-18

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BACKGROUND: Irregular sleep-wake rhythm disorder (ISWRD) is a common sleep disorder in individuals with Alzheimer’s disease dementia (AD-D). OBJECTIVES: This exploratory phase 2 proof-of-concept and dose-finding clinical trial evaluated the effects of lemborexant compared with placebo on circadian rhythm parameters, nighttime sleep, daytime wakefulness and other clinical measures of ISWRD in individuals with ISWRD and mild to moderate AD-D. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Sites in the United States, Japan and the United Kingdom. PARTICIPANTS: Men and women 60 to 90 years of age with documentation of diagnosis with AD-D and Mini-Mental State Exam (MMSE) score 10 to 26. INTERVENTION: Subjects were randomized to placebo or one of four lemborexant treatment arms (2.5 mg, 5 mg, 10 mg or 15 mg) once nightly at bedtime for 4 weeks. MEASUREMENTS: An actigraph was used to collect subject rest-activity data, which were used to calculate sleep-related, wake-related and circadian rhythm–related parameters. These parameters included least active 5 hours (L5), relative amplitude of the rest-activity rhythm (RA) and mean duration of sleep bouts (MDSB) during the daytime. The MMSE and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were used to assess for changes in cognitive function. RESULTS: Sixty-two subjects were randomized and provided data for circadian, daytime and nighttime parameters (placebo, n = 12; lemborexant 2.5 mg [LEM2.5], n = 12; lemborexant 5 mg [LEM5], n = 13, lemborexant 10 mg [LEM10], n = 13 and lemborexant 15 mg [LEM15], n = 12). Mean L5 showed a decrease from baseline to week 4 for LEM2.5, LEM5 and LEM15 that was significantly greater than with placebo (all p < 0.05), suggesting a reduction in restlessness. For RA, LS mean change from baseline to week 4 versus placebo indicated greater distinction between night and day with all dose levels of lemborexant, with significant improvements seen with LEM5 and LEM15 compared with placebo (both p < 0.05). The median percentage change from baseline to week 4 in MDSB during the daytime indicated a numerical decrease in duration for LEM5, LEM10 and LEM15, which was significantly different from placebo for LEM5 and LEM15 (p < 0.01 and p = 0.002, respectively). There were no serious treatment-emergent adverse events or worsening of cognitive function, as assessed by the MMSE and ADAS-Cog. Lemborexant was well tolerated. No subjects discontinued treatment. CONCLUSIONS: This study provides preliminary evidence of the potential utility of lemborexant as a treatment to address both nighttime and daytime symptoms in patients with ISWRD and AD-D.

CITATION:
M. Moline ; S. Thein ; M. Bsharat ; N. Rabbee ; M. Kemethofer-Waliczky ; G. Filippov ; N. Kubota ; S. Dhadda (2020): Safety and Efficacy of Lemborexant in Patients With Irregular Sleep-Wake Rhythm Disorder and Alzheimer’s Disease Dementia: Results From a Phase 2 Randomized Clinical Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.69

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ASSESSING THE IMPACT OF FACTORS THAT INFLUENCE THE KETOGENIC RESPONSE TO VARYING DOSES OF MEDIUM CHAIN TRIGLYCERIDE (MCT) OIL

A.G. Juby, D.R. Brocks, D.A. Jay, C.M.J. Davis, D.R. Mager

J Prev Alz Dis 2021;1(8):19-28

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Objectives, Design, Setting: The ketogenic effect of medium chain triglyceride (MCT) oil offers potential for Alzheimer’s disease prevention and treatment. Limited literature suggests a linear B-hyroxybutyrate (BHB) response to increasing MCT doses. This pharmacokinetic study evaluates factors affecting BHB response in three subject groups. Participants: Healthy subjects without cognitive deficits <65years, similarly healthy subjects >=65years, and those with Alzheimer’s Disease were assessed. Intervention: Different doses (0g,14g, 28g, 42g) of MCT oil (99.3% C8:0) were administered, followed by fasting during the study period. Measurements: BHB measured by finger prick sampling hourly for 5 hours after ingestion. Each subject attended four different days for each ascending dose. Data was also collected on body composition, BMI, waist/hip ratio, grip strength, gait speed, nutrient content of pre-study breakfast and side effects. Results: Twenty-five participants: eight healthy; average age of 44yr (25-61), nine healthy; 79yr (65-90) and eight with AD; 78.6yr (57-86) respectively. Compiled data showed the expected linear dose response relationship. No group differences, with baseline corrected area under the blood vs. time curve (r2=0.98) and maximum concentrations (r2=0.97). However, there was notable individual variability in maximum BHB response (42g dose: 0.4 -2.1mM), and time to reach maximum BHB response both, within and between individuals. Variability was unrelated to age, sex, sarcopenic or AD status. Visceral fat, BMI, waist/hip ratio and pretest meal CHO and protein content all affected the BHB response (p<0.001). Conclusion: There was a large inter-individual variability, with phenotype effects identified. This highlights challenges in interpreting clinical responses to MCT intake.

CITATION:
A.G. Juby ; D.R. Brocks ; D.A. Jay ; C.M.J. Davis ; D.R. Mager (2020): Assessing the Impact of Factors that Influence the Ketogenic Response to Varying Doses of Medium Chain Triglyceride (MCT) Oil. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.53

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LONG CHAIN OMEGA-3 FATTY ACID INTERVENTION IN AGEING ADULTS AT RISK OF DEMENTIA FOLLOWING REPEATED HEAD TRAUMA. LOW-LEVEL SUPPORT OR AN OPPORTUNITY FOR AN UNANSWERED QUESTION?

C.S. Patch, E.L Hill-Yardin, L. Ryan, E. Daly, A.J. Pearce

J Prev Alz Dis 2021;1(8):29-32

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Emerging evidence of brain injury on risk of neurodegenerative diseases such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE) have resulted in interest in therapeutic potential of omega-3 fatty acids (n-3FA). We conducted a systematic review of n-3FA therapeutic efficacy for ageing adults at risk of AD/CTE following a history of repeated head trauma. Databases for articles between 1980-June 2020 were examined for studies reporting on n-3 FAs in adults (≥ 45 years) with a history of repeated brain injury. Following an initial screen of 175 articles, 12 studies were considered but were eventually rejected, as they did not meet inclusion criteria. Our review could find no evidence to support, or disprove, effectiveness of n-3FA intervention in older adults with a history of head trauma. With animal studies showing neuro-restorative potential of n-3FA following brain injury, this review highlights the urgent need for human research in this area.

CITATION:
C.S. Patch ; E.L Hill-Yardin ; L. Ryan ; E. Daly ; A.J. Pearce (2020): Long Chain Omega-3 Fatty Acid Intervention in Ageing Adults at Risk of Dementia Following Repeated Head Trauma. Low-Level Support or an Opportunity for an Unanswered Question? . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.49

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COMPARATIVE EFFECTIVENESS OF BEHAVIORAL INTERVENTIONS TO PREVENT OR DELAY DEMENTIA: ONEYEAR PARTNER OUTCOMES

P.A. Amofa, D.E.C. Locke, M. Chandler, J.E. Crook, C.T. Ball, V. Phatak, G.E. Smith

J Prev Alz Dis 2021;1(8):33-40

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Background/Objective: Various behavioral interventions are recommended to combat the distress experienced by caregivers of those with cognitive decline, but their comparative effectiveness is poorly understood. Design/Setting: Caregivers in a comparative intervention study randomly had 1 of 5 possible interventions suppressed while receiving the other four. Caregivers in a full clinical program received all 5 intervention components. Care partner outcomes in the study group were compared to participants enrolled in a full clinical program. Participants: Two hundred and seventy-two dyads of persons with amnestic mild cognitive impairment (pwMCI) and care partners enrolled in the comparative intervention study. 265 dyads participated in the full clinical program. Intervention: Behavioral intervention components included: memory compensation training, computerized cognitive training, yoga, support group, and wellness education. Each was administered for 10 sessions over 2 weeks. Measurements: A longitudinal mixed-effect regression model was used to analyze the effects of the interventions on partner burden, quality of life (QoL), mood, anxiety, and self-efficacy at 12 months follow-up. Results: At 12 months, withholding wellness education or yoga had a significantly negative impact on partner anxiety compared to partners in the clinical program (ES=0.55 and 0.44, respectively). Although not statistically significant, withholding yoga had a negative impact on partner burden and mood compared to partners in the full clinical program (ES=0.32 and 0.36, respectively). Conclusion: Our results support the benefits of wellness education and yoga for improving partner’s burden, mood, and anxiety at one year. Our findings are the first to provide an exploration of the impact of multicomponent interventions in care partners of pwMCI.

CITATION:
P.A. Amofa ; D.E.C. Locke ; M. Chandler ; J.E. Crook ; C.T. Ball ; V. Phatak ; G.E. Smith (2020): Comparative Effectiveness of Behavioral Interventions to Prevent or Delay Dementia: One-Year Partner Outcomes. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.59

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PROSPECTIVE ASSOCIATIONS BETWEEN PLASMA AMYLOIDBETA 42/40 AND FRAILTY IN COMMUNITY-DWELLING OLDER ADULTS

W.-H. Lu, K.V. Giudici, Y. Rolland, S. Guyonnet, Y. Li, R.J. Bateman, P. de Souto Barreto, B. Vellas, for the MAPT/DSA Group

J Prev Alz Dis 2021;1(8):41-47

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Background: Brain amyloid-beta (Aβ) plaques, a hallmark of the pathophysiology of Alzheimer’s disease, have been associated with frailty. Whether the plasma Aβ markers show similar relationship with frailty is unknown. OBJECTIVES: To investigate the prospective associations between plasma Aβ42/40 ratio and overtime frailty in community-dwelling older adults. METHODS: From the 5-year Multidomain Alzheimer Preventive Trial (MAPT), we included 477 adults ≥70 years with available data on plasma Aβ42/40 ratio (lower is worse). Fried frailty phenotype (robust, pre-frail and frail) was assessed at the same time-point of plasma Aβ measures and after until the end of follow-up. The outcomes of interest were the change in the frailty phenotype over time (examined by mixed-effect ordinal logistic regressions) and incident frailty (examined by Cox proportional hazard models). RESULTS: Plasma Aβ42/40 did not show significant associations with incident frailty; however, after adjusting for Apolipoprotein E (APOE) ε4 genotype, people in the lower quartile of plasma Aβ42/40 (≤0.103) had higher risk of incident frailty (HR=2.63; 95% CI, 1.00 to 6.89), compared to those in the upper quartile (>0.123). Exploratory analysis found a significant association between the lower quartile of plasma Aβ42/40 and incident frailty among APOE ε4 non-carriers (HR=3.48; 95% CI, 1.19 to 10.16), but not among carriers. No associations between plasma Aβ42/40 and evolution of frailty were observed. CONCLUSION: No significant associations between plasma Aβ42/40 and frailty were found when APOE ε4 status was not accounted into the model. Nevertheless, APOE ε4 non-carriers with high Aβ burden might be more susceptible to develop frailty.

CITATION:
W.-H. Lu ; K.V. Giudici ; Y. Rolland ; S. Guyonnet ; Y. Li ; R.J. Bateman ; P. de Souto Barreto ; B. Vellas ; for the MAPT/DSA Group* (2020): Prospective Associations between Plasma Amyloid-Beta 42/40 and Frailty in Community-Dwelling Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.60

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INTEGRATING BIOMARKER OUTCOMES INTO CLINICAL TRIALS FOR ALZHEIMER’S DISEASE IN DOWN SYNDROME

M.S. Rafii, S. Zaman, B.L. Handen

J Prev Alz Dis 2021;1(8):48-51

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The NIH-funded Alzheimer’s Biomarker Consortium Down Syndrome (ABC-DS) and the European Horizon 21 Consortium are collecting critical new information on the natural history of Alzheimer’s Disease (AD) biomarkers in adults with Down syndrome (DS), a population genetically predisposed to developing AD. These studies are also providing key insights into which biomarkers best represent clinically meaningful outcomes that are most feasible in clinical trials. This paper considers how these data can be integrated in clinical trials for individuals with DS. The Alzheimer’s Clinical Trial Consortium - Down syndrome (ACTC-DS) is a platform that brings expert researchers from both networks together to conduct clinical trials for AD in DS across international sites while building on their expertise and experience.

CITATION:
M.S. Rafii ; S. Zaman ; B.L. Handen (2020): Integrating Biomarker Outcomes into Clinical Trials for Alzheimer’s Disease in Down Syndrome. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.35

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IS RELUCTANCE TO SHARE ALZHEIMER’S DISEASE BIOMARKER STATUS WITH A STUDY PARTNER A BARRIER TO PRECLINICAL TRIAL RECRUITMENT?

C.G. Cox, M.M. Ryan, D.L. Gillen, J.D. Grill

J Prev Alz Dis 2021;1(8):52-58

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Background: Preclinical Alzheimer’s disease clinical trials test candidate treatments in individuals with biomarker evidence but no cognitive impairment. Participants are required to co-enroll with a knowledgeable study partner, to whom biomarker information is disclosed. Objective: We investigated whether reluctance to share biomarker results is associated with viewing the study partner requirement as a barrier to preclinical trial enrollment. Design: We developed a nine-item assessment on views toward the study partner requirement and performed in-person interviews based on a hypothetical clinical trial requiring biomarker testing and disclosure. Setting: We conducted interviews on campus at the University of California, Irvine. Participants: Two hundred cognitively unimpaired older adults recruited from the University of California, Irvine Consent-to-Contact Registry participated in the study. Measurements: We used logistic regression models, adjusting for potential confounders, to examine potential associations with viewing the study partner requirement as a barrier to preclinical trial enrollment. Results: Eighteen percent of participants reported strong agreement that the study partner requirement was a barrier to enrollment. Ten participants (5%) agreed at any level that they would be reluctant to share their biomarker result with a study partner. The estimated odds of viewing the study partner requirement as a barrier to enrollment were 26 times higher for these participants (OR=26.3, 95% CI 4.0, 172.3), compared to those who strongly disagreed that they would be reluctant to share their biomarker result. Overall, participants more frequently agreed with positive statements than negative statements about the study partner requirement, including 76% indicating they would want their study partner with them when they learned biomarker results. Conclusions: This is one of the first studies to explore how potential preclinical Alzheimer’s disease trial participants feel about sharing their personal biomarker information with a study partner. Most participants viewed the study partner as an asset to trial enrollment, including having a partner present during biomarker disclosure.

CITATION:
C.G. Cox ; M.M. Ryan ; D.L. Gillen ; J.D. Grill (2020): Is Reluctance to Share Alzheimer’s Disease Biomarker Status with a Study Partner a Barrier to Preclinical Trial Recruitment?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.36

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THE COMPUTERIZED COGNITIVE COMPOSITE (C3) IN A4, AN ALZHEIMER’S DISEASE SECONDARY PREVENTION TRIAL

K.V. Papp, D.M. Rentz, P. Maruff, C.-K. Sun, R. Raman, M.C. Donohue, A. Schembri, C. Stark, M.A. Yassa, A.M. Wessels, R. Yaari, K.C. Holdridge, P.S. Aisen, R.A. Sperling, on behalf of the A4 Study Team

J Prev Alz Dis 2021;1(8):59-67

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Background: Computerized cognitive assessments may improve Alzheimer’s disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers. Objective: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3). Design: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD). Setting: Multi-center international study. Participants: Clinically normal (CN) older adults (65-85; n=4486) Measurements: Participants underwent florbetapir-Positron Emission Tomography for Aβ+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer’s Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/- groups (n=1323/3163) and PACC. Results: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen’s d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants. Conclusions: These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.

CITATION:
K.V. Papp ; D.M. Rentz ; P. Maruff ; C.-K. Sun ; R. Raman ; M.C. Donohue ; A. Schembri ; C. Stark ; M.A. Yassa ; A.M. Wessels ; R. Yaari ; K.C. Holdridge ; P.S. Aisen ; R.A. Sperling ; on behalf of the A4 Study Team ; (2020): The Computerized Cognitive Composite (C3) in A4, an Alzheimer’s Disease Secondary Prevention Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.38

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COMPARATIVE ANALYSIS OF DIFFERENT DEFINITIONS OF AMYLOID-Β POSITIVITY TO DETECT EARLY DOWNSTREAM PATHOPHYSIOLOGICAL ALTERATIONS IN PRECLINICAL ALZHEIMER

M. Milà-Alomà, G.Salvadó, M. Shekari, O. Grau-Rivera, A. Sala-Vila, G. Sánchez-Benavides, E.M. Arenaza-Urquijo, J.M. González-de-Echávarri, M. Simon, G. Kollmorgen, H. Zetterberg, K. Blennow, J.D. Gispert, M. Suárez-Calvet, J.L. Molinuevo, for the ALFA study

J Prev Alz Dis 2021;1(8):68-77

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Amyloid-β (Aβ) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early Aβ pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer’s continuum is critical. Here, we compare different Aβ classification approaches and we show their performance in detecting pathophysiological changes downstream Aβ pathology. We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer’s continuum. Participants underwent Aβ PET and CSF biomarkers assessment. We classified participants as Aβ -positive using five approaches: (1) CSF Aβ42 < 1098 pg/ml; (2) CSF Aβ42/40 < 0.071; (3) Aβ PET Centiloid > 12; (4) Aβ PET Centiloid > 30 or (5) Aβ PET Positive visual read. We assessed the correlations between Aβ biomarkers and compared the prevalence of Aβ positivity. We determined which approach significantly detected associations between Aβ pathology and tau/neurodegeneration CSF biomarkers. We found that CSF-based approaches result in a higher Aβ-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF Aβ-positive but PET Aβ-negative than CSF Aβ-negative but PET Aβ-positive. The CSF Aβ 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the Aβ-positive group. Altogether, we highlight the need for sensitive Aβ -classifications to study the preclinical Alzheimer’s continuum. Approaches that define Aβ positivity based on optimal discrimination of symptomatic Alzheimer’s disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer.

CITATION:
M. Milà-Alomà ; G.Salvadó ; M. Shekari ; O. Grau-Rivera ; A. Sala-Vila ; G. Sánchez-Benavides ; E.M. Arenaza-Urquijo ; J.M. González-de-Echávarri ; M. Simon ; G. Kollmorgen ; H. Zetterberg ; K. Blennow ; J.D. Gispert ; M. Suárez-Calvet ; J.L. Molinuevo ; for the ALFA study (2020): Comparative Analysis of Different Definitions of Amyloid-β Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.51

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POLYGENIC RISK SCORING IS AN EFFECTIVE APPROACH TO PREDICT THOSE INDIVIDUALS MOST LIKELY TO DECLINE COGNITIVELY DUE TO ALZHEIMER’S DISEASE

P. Daunt, C.G. Ballard, B. Creese, G. Davidson, J. Hardy, O. Oshota, R.J. Pither, A.M. Gibson, for the Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2021;1(8):78-83

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BACKGROUND: There is a clear need for simple and effective tests to identify individuals who are most likely to develop Alzheimer’s Disease (AD) both for the purposes of clinical trial recruitment but also for improved management of patients who may be experiencing early pre-clinical symptoms or who have clinical concerns. OBJECTIVES: To predict individuals at greatest risk of progression of cognitive impairment due to Alzheimer’s Disease in individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) using a polygenic risk scoring algorithm. To compare the performance of a PRS algorithm in predicting cognitive decline against that of using the pTau/Aß1-42 ratio CSF biomarker profile. DESIGN: A longitudinal analysis of data from the Alzheimer’s Disease Neuroimaging Initiative study conducted across over 50 sites in the US and Canada. SETTING: Multi-center genetics study. PARTICPANTS: 515 subjects who upon entry to the study were diagnosed as cognitively normal or with mild cognitive impairment. MEASUREMENTS: Use of genotyping and/or whole genome sequencing data to calculate polygenic risk scores and assess ability to predict subsequent cognitive decline as measured by CDR-SB and ADAS-Cog13 over 4 years RESULTS: The overall performance for predicting those individuals who would decline by at least 15 ADAS-Cog13 points from a baseline mild cognitive impairment in 4 years was 72.8% (CI:67.9-77.7) AUC increasing to 79.1% (CI: 75.6-82.6) when also including cognitively normal participants. Assessing mild cognitive impaired subjects only and using a threshold of greater than 0.6, the high genetic risk participant group declined, on average, by 1.4 points (CDR-SB) more than the low risk group over 4 years. The performance of the PRS algorithm tested was similar to that of the pTau/Aß1-42 ratio CSF biomarker profile in predicting cognitive decline. CONCLUSION: Calculating polygenic risk scores offers a simple and effective way, using DNA extracted from a simple mouth swab, to select mild cognitively impaired patients who are most likely to decline cognitively over the next four years.

CITATION:
P. Daunt ; C.G. Ballard ; B. Creese ; G. Davidson ; J. Hardy ; O. Oshota ; R.J. Pither ; A.M. Gibson ; for the Alzheimer’s Disease Neuroimaging Initiative (2020): Polygenic Risk Scoring is an Effective Approach to Predict Those Individuals Most Likely to Decline Cognitively Due to Alzheimer’s Disease . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.64

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A SYSTEMATIC REVIEW ON THE FEASIBILITY OF SALIVARY BIOMARKERS FOR ALZHEIMER’S DISEASE

M. Bouftas

J Prev Alz Dis 2021;1(8):84-91

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Early AD diagnosis is critical for ameliorating prognosis and treatment. The analysis of CSF biomarkers yields accurate results, but it necessitates a lumbar puncture procedure. Screening for peripheral biomarkers in saliva is advantageous since this medium is noninvasive and inexpensive to obtain. The objective of this systematic review is to analyze saliva biomarker studies which aim to diagnose AD. Titles, abstracts, and reference lists for publications from January 2004 to February 2020 were screened for by searching Google Scholar and PubMed. The inclusion criteria involved published studies that consisted of both AD and control groups. 88 studies were screened, and 20 publications fulfilled the inclusion criteria. These selected publications were scrutinized and included in this review. Aβ42, tau, certain metabolites, and oral microbiota might serve as reliable biomarkers for AD diagnosis. These results showcase the legitimate feasibility of proteomic, metabolomic, and microbiotic compounds in saliva for AD diagnostics in the near future. Supplemental studies must consider standardizing the analytical methods of measuring salivary biomarkers to establish coherence for the selection of valid AD biomarkers. Validation studies will require a large sample size of biomarker-diagnosed individuals for independent populations. This ensures accuracy and rigidity for receiver operating characteristic (ROC) curves that can be set for the most optimal salivary biomarkers in future clinical settings.

CITATION:
M. Bouftas (2020): A Systematic Review on the Feasibility of Salivary Biomarkers for Alzheimer’s Disease . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.57

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PHYSICAL FITNESS AND APOLIPOPROTEIN E GENOTYPE INFLUENCE CORTICAL NETWORKING AND INTELLIGENCE IN ADOLESCENTS

J. Park, Y. Kim, M. Woo

J Prev Alz Dis 2021;1(8):92-99

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Aims: This study examined the interactive effect of physical fitness and Apolipoprotein e4 on intelligence and cortical networking in adolescents. Methods: Participants were middle school students consisting of 10 and 8 high- and low-fit e4 carriers (e4+), respectively, and 14 and 10 high- and low-fit non-carriers (e4−), respectively. Inter- and intra-hemispheric coherences were calculated to examine cortico-cortical communication during intelligence test. Results: Coherence in low-fit e4+ was lower than in high-fit e4+, while coherence in low-fit e4- was similar to or higher than in high-fit e4-. Conclusion: the presence of the e4 allele can decrease neural networking 50-60 years before Alzheimer’s disease onset: however, physical fitness may compensate for the negative impact of genotype. Moreover, the beneficial effects of physical fitness may differ depending on functional states of the adolescent brain according to the presence of the e4 allele.

CITATION:
J. Park ; Y. Kim ; M. Woo (2020): Physical Fitness and Apolipoprotein E Genotype Influence Cortical Networking and Intelligence in Adolescents. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.56

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THE EFFECT OF BASELINE PERFORMANCE AND AGE ON COGNITIVE TRAINING IMPROVEMENTS IN OLDER ADULTS: A QUALITATIVE REVIEW

J.S. Shaw, S.M.H. Hosseini

J Prev Alz Dis 2021;1(8):100-109

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Findings that the brain is capable of plasticity up until old age have led to interest in the use of cognitive training as a potential intervention to delay the onset of dementia. However, individuals participating in training regimens differ greatly with respect to their outcomes, demonstrating the importance of considering individual differences, in particular age and baseline performance in a cognitive domain, when evaluating the effectiveness of cognitive training. In this review, we summarize existing literature on cognitive training in adults across the domains of episodic memory, working memory and the task-switching component of executive functioning to clarify the picture on the impact of age and baseline performance on cognitive training-related improvements. Studies targeting episodic memory induced greater improvements in younger adults with more intact cognitive abilities, explained in part by factors specific to episodic memory training. By contrast, older, lower baseline performance adults improved most in several studies targeting working memory in older individuals as well as in the majority of studies targeting executive functioning, suggesting the preservation of neural plasticity in these domains until very old age. Our findings can have important implications for informing the design of future interventions for enhancing cognitive functions in individuals at the prodromal stage of Alzheimer’s Disease and potentially delaying the clinical onset of Alzheimer’s Disease. Future research should more clearly stratify individuals according to their baseline cognitive abilities and assign specialized, skill-specific cognitive training regimens in order to directly answer the question of how individual differences impact training effectiveness.

CITATION:
J.S. Shaw ; S.M.H. Hosseini ; (2020): The Effect of Baseline Performance and Age on Cognitive Training Improvements in Older Adults: A Qualitative Review . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.55

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NUTRITION TO PREVENT OR TREAT COGNITIVE IMPAIRMENT IN OLDER ADULTS: A GRADE RECOMMENDATION

F. Buckinx, M. Aubertin-Leheudre

J Prev Alz Dis 2021;1(8):110-116

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Aging is associated with cognitive declines leading to mild cognitive impairments or Alzheimer disease. Nutrition appear to protect from aging. Some dietary factors could either increase or protect against cognitive declines. This article aimed to provide GRADE recommendations related to nutrition aspects able to prevent or to treat cognitive impairments. A comprehensive literature review was performed using Medline database. The GRADE approach was used to classify quality of the existing evidence (systematic review or meta-analysis).The GRADE process led us to formulate seven key nutritional recommendations to manage cognitive declines, but did not allow us to do it for protein, vitamin B or antioxidants. Thus, 1) adherence to a Mediterranean diet (GRADE 1B); 2) high-level of consumption of mono- or poly- unsaturated fatty acids combined to a low consumption of saturated fatty acids (GRADE 1B); 3) high consumption of fruits and vegetables (GRADE 1B); 4) higher vitamin D intake (GRADE 1C) than the recommended daily allowance. In addition, a ketogenic diet, a low consumption of whole-fat dairy products or a caloric restriction are promising nutritional habits although the evidence does not yet support widespread uptake (GRADE 2C). In conclusion, nutrition is an important modifiable factor to prevent or protect against cognitive decline. Nevertheless, more studies are required to determine specific guidelines such as duration and amounts of nutrients to help older adult to maintain a healthy cognitive life.

CITATION:
F. Buckinx ; M. Aubertin-Leheudre (2020): Nutrition to Prevent or Treat Cognitive Impairment in Older Adults: A GRADE Recommendation. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.40

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DEVELOPING A SKILLED WORKFORCE: IMPACT OF A POSTGRADUATE PROGRAMME ON DEMENTIA KNOWLEDGE, ATTITUDES AND TRAINING NEEDS

C. Scerri

J Prev Alz Dis 2021;1(8):117-118

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CITATION:
C. Scerri (2020): Developing a Skilled Workforce: Impact of a Postgraduate Programme on Dementia Knowledge, Attitudes and Training Needs. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2020.52

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