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01/2021 journal articles

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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