03/2023 journal articles
EDITORIAL: WHAT IS REASONABLE AND NECESSARY FOR ALZHEIMER PATIENTS FROM RANDOMIZED CLINICAL TRIALS TO CLINICAL PRACTICE?
L.T. Middleton, J. Touchon, B. Vellas
J Prev Alz Dis 2023;3(10):331-332Show summaryHide summary
L.T. Middleton ; J. Touchon ; B. Vellas ; (2023): What Is Reasonable and Necessary for Editorial: Alzheimer Patients from Randomized Clinical Trials to Clinical Practice? . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.69
VIEWPOINT «COMPOUNDED INTEREST» IN ALZHEIMER’S DISEASE: DO NEW AMYLOID-TARGETING TREATMENTS JUSTIFY THEIR USE
J Prev Alz Dis 2023;3(10):333-335Show summaryHide summary
C. Sampaio ; (2023): Viewpoint«Compounded Interest» in Alzheimer’s Disease: Do New Amyloid-Targeting Treatments Justify Their Use. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.70
VIEWPOINT: BALANCING THE CONFLICTING GOALS FOR TREATMENT OF ALZHEIMER’S DISEASE WITH MONOCLONAL ANTIBODIES
D.R. Scrase, N. Budhwar
J Prev Alz Dis 2023;3(10):336-338Show summaryHide summary
The recent conflicting recommendations on coverage and use of monoclonal antibody treatments for Alzheimer’s Disease (AD) in the United States provide an opportunity to better define the concepts of safety, efficacy, reasonableness, and necessity. The translation of current science into clinical practice may require additional studies that enroll patients like those seen by primary care providers. Regarding recently published clinical trials as a step forward toward an AD cure is critical, as is wide collaboration between researchers and clinicians, and public and private sectors, to ensure that new effective therapies can be easily provided in clinical practice settings.
D.R. Scrase ; N. Budhwar ; (2023): Viewpoint: Balancing the Conflicting Goals for Treatment of Alzheimer’s Disease with Monoclonal Antibodies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.71
VIEWPOINT: CLINICIANS’ PERSPECTIVES ON HOW DISEASE MODIFYING DRUGS FOR ALZHEIMER’S DISEASE IMPACT SPECIALTY CARE
S. Gauthier, Z. Ismail, Z. Goodarzi, K.P. Ng, P. Rosa-Neto
J Prev Alz Dis 2023;3(10):339-341Show summaryHide summary
Clinicians specialized in the diagnosis and management of persons living with early-stage Alzheimer’s disease need to enable access, for those meeting criteria, to the new class of disease modifying drugs (DMDs). These drugs act on amyloid β42 and delay progression of symptoms. Thus, there will be interest from patients and families. Over the short term, the use of antibodies administered intravenously with serial MRIs to detect amyloid-related imaging abnormalities (ARIA) may require participation in structured phase 4 studies or in registries with third party funding for support staff and MRI scans. In the mid term, the availability of oral anti-amyloid therapy, likely with lower risk of ARIA, may transform clinical practice to a model of screening suitable patients using plasma biomarkers, with a subsequent rapid referral to a specialized memory clinic. Eventually, the biological profile of patients for amyloid, tau, and inflammation will determine which type of DMD to use. We are optimistic that clinicians will gain confidence with the use DMDs and answer the increasing needs of our aging population.
S. Gauthier ; Z. Ismail ; Z. Goodarzi ; K.P. Ng ; P. Rosa-Neto ; (2023): Viewpoint: The Comparative Effectiveness of Monotherapy and Combination Therapies: Impact of Angiotensin Receptor Blockers on the Onset of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.8
VIEWPOINT: WHEN IT COMES TO LECANEMAB (AND DONANEMAB), HOW MIGHT WE THINK ABOUT ‘REASONABLE AND NECESSARY’?
J Prev Alz Dis 2023;3(10):342-343Show summaryHide summary
L.S. Schneider ; (2023): Viewpoint: When It Comes to Lecanemab (and Donanemab), How Might We Think about ‘Reasonable and Necessary’?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.73
VIEWPOINT: WHAT IS REASONABLE AND NECESSARY FOR PEOPLE LIVING WITH AD AFTER THE FDA APPROVES A TREATMENT?
R.S. Doody, S. Skerjanec
J Prev Alz Dis 2023;3(10):344-345Show summaryHide summary
R.S. Doody ; S. Skerjanec ; ; (2023): Viewpoint: What Is Reasonable and Necessary for People Living with AD after the FDA Approves a Treatment?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.74
VIEWPOINT: DEFINING FDA APPROVED TREATMENTS AS REASONABLE AND NECESSARY: PERSPECTIVES OF INDIVIDUALS LIVING WITH ALZHEIMER’S DISEASE AND CARE PARTNERS
M.C. Carrillo, M. Moreno
J Prev Alz Dis 2023;3(10):346-348Show summaryHide summary
M.C. Carrillo ; M. Moreno ; (2023): Viewpoint: Defining FDA Approved Treatments as Reasonable and Necessary: Perspectives of Individuals Living with Alzheimer’s Disease and Care Partners. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.75
VIEWPOINT: AMYLOID-TARGETING NEW THERAPIES FOR ALZHEIMER’S DISEASE: A HEALTH ECONOMICS PERSPECTIVE
L. Jönsson, A. Wimo
J Prev Alz Dis 2023;3(10):349-352Show summaryHide summary
L. Jönsson ; A. Wimo ; (2023): Viewpoint: Amyloid-targeting New Therapies for Alzheimer’s Disease: A Health Economics Perspective. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.76
EDITORIAL: CLINICAL IMPLEMENTATION OF LECANEMAB: CHALLENGES, QUESTIONS AND SOLUTIONS
J Prev Alz Dis 2023;3(10):353-355Show summaryHide summary
T. Iwatsubo (2023): Editorial: Clinical Implementation of Lecanemab: Challenges, Questions and Solutions . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.41
EDITORIAL: APPROPRIATE USE RECOMMENDATIONS FOR LECANEMAB
J Prev Alz Dis 2023;3(10):356Show summaryHide summary
M.S. Rafii ; (2023): Appropriate Use Recommendations for Lecanemab . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.34
EDITORIAL: LECANEMAB: APPROPRIATE USE RECOMMENDATIONS – A COMMENTARY FROM A EUROPEAN PERSPECTIVE
L. Frölich, F. Jessen
J Prev Alz Dis 2023;3(10):357-358Show summaryHide summary
L. Frölich ; F. Jessen ; (2023): Editorial: Lecanemab: Appropriate Use Recommendations – A Commentary from a European Perspective . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.44
EDITORIAL: IMPLICATIONS OF EMERGING USES OF GENETIC TESTING FOR ALZHEIMER’S DISEASE
D. Blasco, J.S. Roberts
J Prev Alz Dis 2023;3(10):359-361Show summaryHide summary
D. Blasco ; J.S. Roberts ; (2023): Editorial: Implications of Emerging Uses of Genetic Testing for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.46
LECANEMAB: APPROPRIATE USE RECOMMENDATIONS
J. Cummings, L. Apostolova, G.D. Rabinovici, A. Atri, P. Aisen, S. Greenberg, S. Hendrix, D. Selkoe, M. Weiner, R.C. Petersen, S. Salloway, For the Alzheimer’s Disease and Related Disorders Therapeutics Work Group
J Prev Alz Dis 2023;3(10):362-377Show summaryHide summary
Lecanemab (Leqembi®) is approved in the United States for the treatment of Alzheimer’s disease (AD) to be initiated in early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) with confirmed brain amyloid pathology. Appropriate Use Recommendations (AURs) are intended to help guide the introduction of new therapies into real-world clinical practice. Community dwelling patients with AD differ from those participating in clinical trials. Administration of lecanemab at clinical trial sites by individuals experienced with monoclonal antibody therapy also differs from the community clinic-based administration of lecanemab. These AURs use clinical trial data as well as research and care information regarding AD to help clinicians administer lecanemab with optimal safety and opportunity for effectiveness. Safety and efficacy of lecanemab are known only for patients like those participating in the phase 2 and phase 3 lecanemab trials, and these AURs adhere closely to the inclusion and exclusion criteria of the trials. Adverse events may occur with lecanemab including amyloid related imaging abnormalities (ARIA) and infusion reactions. Monitoring guidelines for these events are detailed in this AUR. Most ARIA with lecanemab is asymptomatic, but a few cases are serious or, very rarely, fatal. Microhemorrhages and rare macrohemorrhages may occur in patients receiving lecanemab. Anticoagulation increases the risk of hemorrhage, and the AUR recommends that patients requiring anticoagulants not receive lecanemab until more data regarding this interaction are available. Patients who are apolipoprotein E ε4 (APOE4) gene carriers, especially APOE4 homozygotes, are at higher risk for ARIA, and the AUR recommends APOE genotyping to better inform risk discussions with patients who are lecanemab candidates. Clinician and institutional preparedness are mandatory for use of lecanemab, and protocols for management of serious events should be developed and implemented. Communication between clinicians and therapy candidates or those on therapy is a key element of good clinical practice for the use of lecanemab. Patients and their care partners must understand the potential benefits, the potential harms, and the monitoring requirements for treatment with this agent. Culture-specific communication and building of trust between clinicians and patients are the foundation for successful use of lecanemab.
J. Cummings ; L. Apostolova ; G.D. Rabinovici ; A. Atri ; P. Aisen ; S. Greenberg ; S. Hendrix ; D. Selkoe ; M. Weiner ; R.C. Petersen ; S. Salloway ; For the Alzheimer’s Disease and Related Disorders Therapeutics Work Group ; ; (2023): Editorial: Lecanemab: Appropriate Use Recommendations . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.30
COMMENTARY: CLINICAL EFFICACY IN INDIVIDUAL PATIENTS TREATED WITH LECANEMAB
S. Gauthier, J. Therriault, P. Rosa-Neto
J Prev Alz Dis 2023;3(10):378-379Show summaryHide summary
S. Gauthie ; J. Therriault ; P. Rosa-Neto ; (2023): Commentary: Clinical Efficacy in Individual Patients Treated with Lecanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.58
EDITORIAL: EXPANDING THE ATN FRAMEWORK TO FURTHER PERSONALIZE THERAPIES
S. Gauthier, P. Rosa-Neto
J Prev Alz Dis 2023;3(10):380Show summaryHide summary
S. Gauthier ; P. Rosa-Neto ; (2023): Editorial: Expanding the atn Framework to Further Personalize Therapies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.51
ADDING THE TOPOGRAPHICAL INFORMATION FROM TAU-PET TO THE A/T/(N) FRAMEWORK: STEPS TOWARDS STAGING AD IN VIVO
J. Therriault, S. Gauthier, P. Rosa-Neto
J Prev Alz Dis 2023;3(10):381-386Show summaryHide summary
Biomarkers have revolutionized the study and clinical diagnosis of Alzheimer’s disease (AD). While amyloid-β accumulation begins decades before the onset of clinical dementia in AD, tau pathology is more closely associated in both space and time to neurodegeneration and to clinical dysfunction. Correspondingly, tau-PET may prove useful in determining the severity of AD. Building on the biological research framework for AD, we review here methods and rationale to stage the severity of AD in vivo using the topographical distribution of tau-PET. We discuss how tau-PET can be used to detect early and subthreshold tau accumulation in medial temporal cortices prior to the onset of cognitive symptoms. Furthermore, tau-PET can be used to monitor the severity of AD as tau-PET spreads to association cortices and finally primary sensory cortices. We discuss the utility of tau-PET to monitor the progression of AD, the flexibility of potential approaches, and applications for clinical trials. In this regard, topographical information from tau-PET is a useful addition to the A/T/(N) framework.
J. Therriault ; S. Gauthier ; P. Rosa-Neto ; (2023): Adding the Topographical Information from Tau-PET to the A/T/(N) Framework: Steps Towards Staging AD in Vivo. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.52
WHITE MATTER HYPERINTENSITY AS A VASCULAR CONTRIBUTION TO THE AT(N) FRAMEWORK
K.P. Ng, J.Y. Shen, H.J. Chiew, A.S.L. Ng, N. Kandiah, P. Rosa-Neto, S. Gauthier
J Prev Alz Dis 2023;3(10):387-400Show summaryHide summary
The AT(N) framework enables the classification of an individual within the biological Alzheimer’s disease (AD) continuum by pairing the cognitive stage with the biomarker status of amyloid-beta (Aβ, A), tau (T) and neurodegeneration (N). AD is a multifactorial disease that may involve different pathogenic mechanisms such as cerebrovascular disease (CVD). Therefore, biomarkers of these mechanisms can be added to the AT(N) framework to enhance the biomarker characterization of individuals within the AD continuum. In AD, white matter hyperintensities (WMH) which are postulated to develop as a result of chronic ischemia from small vessel CVD are shown to play a role in the aetiology. However, the interplay of WMH with Aβ and tau pathophysiology in AD remains unclear. In this review, we summarized the studies that evaluated the associations between WMH and AD pathophysiology (Aβ and tau). We found that the evidence supporting the association of WMH with Aβ was mixed, and this may be explained by the relative contributions of WMH due to its differential load and anatomical distribution. More studies are also needed to determine the association of WMH with tau pathology. Future longitudinal studies with harmonized methodologies to quantify WMH and account for the anatomical differences of WMH are required to validate the relationship between WMH and AT(N) biomarkers. This will allow a clearer understanding of the utility of WMH as a vascular biomarker in the AT(N) framework. Novel CVD biomarkers will also have the potential to further elucidate the contributions of CVD to the AD pathophysiology.
K.P. Ng ; J.Y. Shen ; H.J. Chiew ; A.S.L. Ng ; N. Kandiah ; P. Rosa-Neto ; S. Gauthier ; (2023): White Matter Hyperintensity as a Vascular Contribution to the AT(N) Framework. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.53
NEUROINFLAMMATION BIOMARKERS IN THE AT(N) FRAMEWORK ACROSS THE ALZHEIMER’S DISEASE CONTINUUM
A. Bieger, A. Rocha, B. Bellaver, L. Machado, L. Da Ros, W.V. Borelli, J. Therriault, A.C. Macedo, T.A. Pascoal, S. Gauthier, P. Rosa-Neto, E.R. Zimmer
J Prev Alz Dis 2023;3(10):401-417Show summaryHide summary
In the past years, neuroinflammation has been widely investigated in Alzheimer’s disease (AD). Evidence from animal, in vivo and post-mortem studies has shown that inflammatory changes are a common feature of the disease, apparently happening in response to amyloid-beta and tau accumulation. Progress in imaging and fluid biomarkers now allows for identifying surrogate markers of neuroinflammation in living individuals, which may offer unprecedented opportunities to better understand AD pathogenesis and progression. In this context, inflammatory mediators and glial proteins (mainly derived from microglial cells and astrocytes) seem to be the most promising biomarkers. Here, we discuss the biological basis of neuroinflammation in AD, revise the proposed neuroinflammation biomarkers, describe what we have learned from anti-inflammatory drug trials, and critically discuss the potential addition of these biomarkers in the AT(N) framework.
A. Bieger ; A. Rocha ; B. Bellaver ; L. Machado ; L. Da Ros ; W.V. Borelli ; J. Therriault ; A.C. Macedo ; T.A. Pascoal ; S. Gauthier ; P. Rosa-Neto ; E.R. Zimmer ; (2023): Neuroinflammation Biomarkers in the AT(N) Framework Across the Alzheimer’s Disease Continuum. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.54
CAN WE USE BLOOD BIOMARKERS AS ENTRY CRITERIA AND FOR MONITORING DRUG TREATMENT EFFECTS IN CLINICAL TRIALS? A REPORT FROM THE EU/US CTAD TASK FORCE
D. Angioni, O. Hansson, R.J. Bateman, C. Rabe, M. Toloue, J.B. Braunstein, S. Agus, J.R. Sims, T. Bittner, M.C. Carrillo, H. Fillit, C.L. Master, S. Salloway, P. Aisen, M. Weiner, B. Vellas, S. Gauthier, and the EU/US/CTAD Task force
J Prev Alz Dis 2023;3(10):418-425Show summaryHide summary
In randomized clinical trials (RCTs) for Alzheimer’s Disease (AD), cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are currently used for the detection and monitoring of AD pathological features. The use of less resource-intensive plasma biomarkers could decrease the burden to study volunteers and limit costs and time for study enrollment. Blood-based markers (BBMs) could thus play an important role in improving the design and the conduct of RCTs on AD. It remains to be determined if the data available on BBMs are strong enough to replace CSF and PET biomarkers as entry criteria and monitoring tools in RCTs.
D. Angioni ; O. Hansson ; R.J. Bateman ; C. Rabe ; M. Toloue ; J.B. Braunstein ; S. Agus ; J.R. Sims ; T. Bittner ; M.C. Carrillo ; H. Fillit ; C.L. Masters ; S. Salloway ; P. Aisen ; M. Weiner ; B. Vellas ; S. Gauthier (2023): Can We Use Blood Biomarkers as Entry Criteria and for Monitoring Drug Treatment Effects in Clinical Trials? A Report from the EU/US CTAD Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.68
DIAGNOSTIC BIOMARKERS OF AMYLOID AND TAU PATHOLOGY IN ALZHEIMER’S DISEASE: AN OVERVIEW OF TESTS FOR CLINICAL PRACTICE IN THE UNITED STATES AND EUROPE
L. Iaccarino, S.C. Burnham, G. Dell’Agnello, S.A. Dowsett, S. Epelbaum
J Prev Alz Dis 2023;3(10):426-442Show summaryHide summary
Amyloid and tau biomarkers for Alzheimer’s disease are widely recognized diagnostic tools for the identification of Alzheimer’s disease pathology antemortem and are recommended by the most recent clinical and research guidelines. Approved biomarkers include positron emission tomography (PET)- and fluid-based markers derived from cerebrospinal fluid and, more recently, plasma. These biomarkers are still infrequently used in clinical practice, potentially due to challenges in access to and understanding of individual assay information and methodology. We provide an overview of the diagnostic biomarkers for amyloid and tau pathology that are currently available in the US and/or EU for clinical use. Available performance data from both labels/instructions for use and the scientific literature (with focus on autopsy or PET as standard of truth) are summarized to help healthcare providers navigate the biomarker landscape. All available PET amyloid and tau biomarkers demonstrate high accuracy in identifying amyloid and tau Alzheimer’s disease pathology, respectively, at autopsy. Among cerebrospinal fluid biomarkers, all showed accurate prediction of Alzheimer’s disease pathology, either based on autopsy or PET findings; greater accuracy was evident for concentration ratios (Aβ42/40 or P-tau181/Aβ42) versus individual biomarker concentrations. Among plasma biomarkers, Aβ42/40 and P-tau181 demonstrated high agreement with PET findings. Overall, we conclude that commercially available PET, cerebrospinal fluid and plasma assays accurately identify Alzheimer’s disease amyloid and tau pathology. The recent development of fully automated tests for fluid-based biomarkers improves test reliability. The continued development of plasma biomarkers holds promise for the future management of patients with Alzheimer’s disease.
L. Iaccarino ; S.C. Burnham ; G. Dell’Agnello ; S.A. Dowsett ; S. Epelbaum ; (2023): Diagnostic Biomarkers of Amyloid and Tau Pathology in Alzheimer’s Disease: An Overview of Tests for Clinical Practice in the United States and Europe. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.43
ADULT RENAL DYSFUNCTION AND RISK OF DEMENTIA OR COGNITIVE DECLINE: BRAIN-KIDNEY AXIS HYPOTHESIS BASED ON A SYSTEMATIC REVIEW AND META-ANALYSIS
H.-C. Chi, Y. Liu, C.-C. Tan, Y.-C. Zhang, L. Tan, W. Xu
J Prev Alz Dis 2023;3(10):443-452Show summaryHide summary
OBJECTIVE: The brain-kidney axis was proposed to emphasize roles of kidney functioning in modulating neurodegeneration. We aimed to evaluate the associations of renal diseases and blood markers with risk of dementia or cognitive decline among non-demented adults.
METHODS: The PubMed, EMBASE, and Cochrane library were searched until February 1st, 2022, to include longitudinal studies. Multivariate adjusted effects were pooled by random-effects models. The robust error meta-regression models were used for dose–response analyses. The credibility of meta-analyses was graded and an innovative index (Sdifference) was developed to evaluate the evidence tendency.
RESULTS: A total of 41 longitudinal studies (6,480,136 participants, mean age range: 58.5-83.5 years) were included, of which 33 were for meta-analyses. Though with low level of evidence, five indicators of kidney were associated with increased risk of dementia or cognitive decline, including acute kidney injury (hazard ratio [HR] = 2.24, p = 0.0001), chronic kidney disease (HR = 1.29, p = 0.0001), higher serum creatinine (HR = 1.35, p = 0.0001), higher urine albumin creatine ratio (UACR, HR = 1.23, p = 0.0001), and lower estimated glomerular filtration rate (eGFR, HR = 1.18, p = 0.0001). A linear relationship was revealed for eGFR (p = 0.0217) or UACR (p = 0.0006). Heterogeneity is a main concern to jeopardize the evidence robustness, especially for eGFR (Sdifference = 0.05).
CONCLUSION: Some renal indicators were associated with a higher risk of dementia, though the evidence base warrants further strengthening. Renal function management might serve as a promising target for dementia prediction and prevention.
H.-C. Chi ; Y. Liu ; C.-C. Tan ; Y.-C. Zhang ; L. Tan ; W. Xu ; (2023): Adult Renal Dysfunction and Risk of Dementia or Cognitive Decline: Brain-Kidney Axis Hypothesis Based on a Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.35
OUTREACH, SCREENING, AND RANDOMIZATION OF APOE Ε4 CARRIERS INTO AN ALZHEIMER’S PREVENTION TRIAL: A GLOBAL PERSPECTIVE FROM THE API GENERATION PROGRAM
T. Walsh, L. Duff, M.-E. Riviere, P.N. Tariot, K. Doak, M. Smith, B. Borowsky, C. Lopez Lopez, P.C. Arratia, F. Liu, I. Scholten, D. Gordon, J. Arbuckle, A. Graf, M. Quinn, J. Ricart, J.B. Langbaum
J Prev Alz Dis 2023;3(10):453-463Show summaryHide summary
BACKGROUND: Alzheimer’s disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study’s inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease.
OBJECTIVES: Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer’s Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique.
DESIGN AND SETTING: The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring.
PARTICIPANTS: Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid.
METHODS AND MEASUREMENTS: Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype.
RESULTS: At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening.
CONCLUSIONS: It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.
T. Walsh ; L. Duff ; M.-E. Riviere ; P.N. Tariot ; K. Doak ; M. Smith ; B. Borowsky ; C. Lopez Lopez ; P.C. Arratia ; F. Liu ; I. Scholten ; D. Gordon ; J. Arbuckle ; A. Graf ; M. Quinn ; J. Ricart ; J.B. Langbaum (2023): Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer’s Prevention Trial: A global Perspective from the API Generation Program. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.27
COMBINED EVIDENCE FOR A LONG-TERM, CLINICAL SLOWING EFFECT OF MULTINUTRIENT INTERVENTION IN PRODROMAL ALZHEIMER’S DISEASE: POST-HOC ANALYSIS OF 3-YEAR DATA FROM THE LIPIDIDIET TRIAL
S.B. Hendrix, H. Soininen, A. Solomon, P.J. Visser, A.M.J. van Hees, D.S. Counotte, J. Nicodemus-Johnson, S.P. Dickson, K. Blennow, M. Kivipelto, T. Hartmann, on behalf of the LipiDiDiet clinical study group
J Prev Alz Dis 2023;3(10):464-470Show summaryHide summary
The LipiDiDiet randomized clinical trial is evaluating the long term effects of a multinutrient intervention (Fortasyn Connect) compared with control in participants with prodromal AD. In this post-hoc analysis we used the Alzheimer’s Disease Composite Score (ADCOMS) as a measure of cognition and global function, together with a global statistical test (GST) and Bayesian hierarchical modelling (BHM) to evaluate the totality of evidence for an effect of the intervention over 36 months. The analysis includes 67 participants (39 active, 28 control) with change from baseline data after 36 months intervention. All outcome measures showed a statistically significant effect for the intervention: ADCOMS (P =0.045), GST (P <0.001), and BHM (P =0.008 based on 3 outcomes and P <0.001 including all primary and secondary quantitative clinical outcomes). Fortasyn Connect was associated with significantly less clinical decline over 36 months, suggesting the long-lasting beneficial effects of the multinutrient in prodromal AD.
S.B. Hendrix ; H. Soininen ; A. Solomon ; P.J. Visser ; A.M.J. van Hees ; D.S. Counotte ; J. Nicodemus-Johnson ; S.P. Dickson ; K. Blennow ; M. Kivipelto ; T. Hartmann ; on behalf of the LipiDiDiet clinical study group ; (2023): Combined Evidence for a Long-Term, Clinical Slowing Effect of Multinutrient Intervention in Prodromal Alzheimer’s Disease: Post-Hoc Analysis of 3-Year Data from the LipiDiDiet Trial . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.29
COHORT EFFECTS IN ALZHEIMER’S DISEASE TRIALS: AN EMPIRICAL ASSESSMENT UTILIZING DATA FROM THE ALZHEIMER’S DISEASE COOPERATIVE STUDY
A.I. Birnbaum, J.D. Grill, D.L. Gillen
J Prev Alz Dis 2023;3(10):471-477Show summaryHide summary
BACKGROUND: Cohort effects in study populations can impact clinical trial conclusions and generalizability, particularly in trials with planned interim analyses. Long recruitment windows may exacerbate these risks in Alzheimer’s disease (AD) trials.
OBJECTIVES: To investigate the presence of cohort effects mild-to-moderate AD trials.
DESIGN: Retrospective analysis using pooled participant-level data from nine randomized, placebo-controlled trials conducted by the Alzheimer’s Disease Cooperative Study (ADCS).
SETTING: Trials were multicenter studies conducted by an academic trial network.
PARTICIPANTS: The trials enrolled participants with mild, mild-to-moderate, or moderate AD who were over age 50 and had mini mental state exam scores between 12 and 26.
INTERVENTIONS/EXPOSURE: We defined a participant’s site-standardized enrollment time as the number of days between their screening date and the first screening date among randomized participants at their site within their study.
MAIN OUTCOMES(S) AND MEASURES(S): Our primary outcome was the 12-month change in the AD assessment scale – cognitive subscale (ADAS-Cog). Secondary outcomes were participant demographics and time to study discontinuation.
RESULTS: The pooled sample consisted of N=2,754 at baseline with N=2,191 participants completing a 12-month visit. We found no meaningful differences in the distributions of sex, race and ethnicity, age, years of education or baseline ADAS-Cog score across enrollment time. We found a significant association between enrollment time and 12-month change in ADAS-Cog, with participants enrolling 100 days later tending to experience an increase on the ADAS-Cog of 0.16 points greater (reflecting greater cognitive decline; 95% CI: (0.021, 0.294), p = 0.02), after controlling for potential confounding factors.
CONCLUSION: We found minimal evidence of clinically relevant cohort effects in ADCS trials. Our results reinforce the original findings of these trials.
A.I. Birnbaum ; J.D. Grill ; D.L. Gillen ; (2023): Cohort Effects in Alzheimer’s Disease Trials: An Empirical Assessment Utilizing Data from the Alzheimer’s Disease Cooperative Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.45
VALIDATION OF THE COGDRISK INSTRUMENT AS PREDICTIVE OF DEMENTIA IN FOUR GENERAL COMMUNITY-DWELLING POPULATIONS
S. Kootar, M.H. Huque, R. Eramudugolla, D. Rizzuto, M.C. Carlson, M.C. Odden, O.L. Lopez, C. Qiu, L. Fratiglioni, S.D. Han, D.A. Bennett, R. Peters, K.J. Anstey
J Prev Alz Dis 2023;3(10):478-487Show summaryHide summary
BACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research.
OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer’s disease (AD) using cohort studies.
DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model.
RESULTS: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project.
CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.
S. Kootar ; M.H. Huque ; R. Eramudugolla ; D. Rizzuto ; M.C. Carlson ; M.C. Odden ; O.L. Lopez ; C. Qiu ; L. Fratiglioni ; S.D. Han ; D.A. Bennett ; R. Peters ; K.J. Anstey ; (2023): Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.38
USEFULNESS OF COMMUNITY PHARMACY FOR EARLY DETECTION OF COGNITIVE IMPAIRMENT IN OLDER PEOPLE USING THE IQCODE QUESTIONNAIRE
L.F. Agüera Ortiz, G. García-Ribas, F. Jordano Luna, M.C. Porras Álvarez, N. Sánchez Marcos, B. Soler López, Grupo de estudio NEURAXCARE
J Prev Alz Dis 2023;3(10):488-496Show summaryHide summary
BACKGROUND: People with cognitive impairment (CI) need to be identified early because of the risk of progression to dementia.
OBJECTIVES: The primary objective of the study was to analyze the usefulness of the community pharmacy for early detection of CI in older people through their caregivers. As secondary objective the risk factors related to IQ-CODE classification of risk of CI were identified.
DESIGN: A cross-sectional observational study was designed.
SETTING: Caregivers were selected by pharmacists from Spanish community pharmacies.
PARTICIPANTS: Subjects with a close relationship to persons over 70 years of age who were not previously diagnosed with CI and who did not live in a nursing home or were hospitalized participated in the study.
MEASUREMENTS: The proportion of older people who were classified as “at risk of CI” was assessed using the Informant Questionnaire on Cognitive Decline in the Elderly (IQ-CODE), which was completed by the caregiver.
RESULTS: A total of 197 pharmacists selected 910 caregivers with an average age of 53 years, 75.5% of whom were women. In 324 people over the age of 70 (38.5%), “risk of CI” was observed, increasing with age. The risk of CI was 4.3 times higher in older people who complained of memory loss (p<0.001), 2.5 times higher if they had had a stroke in the last two years (p=0.007), 1.9 times higher if they were smokers (p=0.045) and 1.6 times higher if they were diabetic (p=0.028).
CONCLUSION: Detection of risk of CI from the community pharmacy showed prevalence figures consistent with the CI figures observed in the Spanish primary care setting, demonstrating the capacity of the community pharmacy to contribute to early detection of CI.
L.F. Agüera Ortiz ; G. García-Ribas ; F. Jordano Luna ; M.C. Porras Álvarez ; N. Sánchez Marcos ; B. Soler López ; Grupo de estudio NEURAXCARE ; (2023): Usefulness of Community Pharmacy for Early Detection of Cognitive Impairment in Older People Using the IQ-CODE Questionnaire. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.39
PHYSICAL ACTIVITY IS ASSOCIATED WITH SLOWER COGNITIVE DECLINE IN OLDER ADULTS WITH TYPE 2 DIABETES
Y. Rabinowitz, R. Ravona-Springer, A. Heymann, E. Moshier, Y. Berman, J. Schwartz, M. Sano, D. Aisenberg, M. Schnaider-Beeri
J Prev Alz Dis 2023;3(10):497-502Show summaryHide summary
BACKGROUND: Physical activity is associated with slower cognitive decline in old age. Type 2 diabetes (T2d) is a risk factor for dementia and cognitive decline. Physical activity protects against several T2d complications. Yet, little is known about the contribution of physical activity to cognitive health among the elderly with T2d.
OBJECTIVES: To examine the association between physical activity and cognitive decline in older adults with T2d. Design: This is a prospective longitudinal study using data from the Israel Diabetes and Cognitive Decline (IDCD) study. Setting: ICDC study (N=1,213), is a population-based cohort of adults over the age of 65, diagnosed with type 2 diabetes, who were cognitively normal at baseline and followed up every 18 months.
PARTICIPANTS: Participants with at least one follow-up assessment who were in the same physical activity group consistently and had complete demographic data.
MEASUREMENTS: Physical activity was measured using Minnesota Leisure Time Activity Questionnaire, cognitive functioning was measured using a broad neuropsychological assessment measuring Executive Functioning, Attention/Working Memory, Semantic Categorization and Episodic Memory.
RESULTS: Participants were classified into physical activity groups based on self-reported physical activity at baseline and all follow ups: “active” - participation in recreational physical activity (n=286); “non-active”- the only physical activity was walking from place to place (n=93) and “sedentary” (n=19). Linear mixed effects models were applied to adjust for key demographic and cardiovascular risk factors. Participants were 72.4 (SD 4.6) years old, had 13.3 (SD 3.6) years of education, and 163 (41%) were female. In the fully adjusted model, compared to the non-active group the active group had significantly slower rate of decline in Global Cognition (p=0.005), Executive Functioning (p=.014), and Attention/Working Memory (p=.01). There were no significant group differences for Semantic Categorization (p=.17) and Episodic Memory (p=.88).
CONCLUSIONS: Among initially cognitively normal and independent older adults with T2d, a physically active lifestyle was associated with a slower rate of cognitive decline. Future research should examine whether promoting physical activity may prevent or delay onset of dementia in this high-risk population.
Y. Rabinowitz ; R. Ravona-Springer ; A. Heymann ; E. Moshier ; Y. Berman ; J. Schwartz ; M. Sano ; D. Aisenberg ; M. Schnaider-Beeri ; (2023): Physical Activity Is Associated with Slower Cognitive Decline in Older Adults with Type 2 Diabetes. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.26
PUSHING THROUGH THE BARRIERS: PEER ADVICE TO INCREASE PHYSICAL ACTIVITY AND REDUCE DEMENTIA RISK FROM PARTICIPANTS IN A MASSIVE OPEN ONLINE ALZHEIMER’S FOCUSED COURSE
M.R. Abela, H. Maxwell, A. Bindoff, J. Alty, M. Farrow, K. Lawler
J Prev Alz Dis 2023;3(10):503-512Show summaryHide summary
BACKGROUND: Engagement in physical activity is associated with reduced dementia risk but insufficient physical activity is a global trend.
OBJECTIVES: We aimed to explore what advice might be offered to others to increase physical activity and to identify enablers and barriers to physical activity for adults interested in dementia prevention and participating in a massive open online course.
PARTICIPANTS: Two thousand, one hundred and thirty-two participants contributed to an online discussion forum.
DESIGN: Analysis was conducted using Topic modelling analysis followed by thematic analysis.
RESULTS: The themes generated from the discussion posts included time constraints, poor health and lack of motivation as barriers to physical activity, and social interaction, incidental activities, and dog ownership as enablers. Peer advice was frequently suggested around scheduling physical activity into the day and joining a friend or organised activity.
CONCLUSION: This online discussion forum uniquely captured ideas from a large, diverse group of participants. Future research may benefit from further examining the role of discussion forums and peer advice in dementia risk reduction initiatives.
M.R. Abela ; H. Maxwell ; A. Bindoff ; J. Alty ; M. Farrow ; K. Lawler ; (2023): Pushing through the Barriers: Peer Advice to Increase Physical Activity and Reduce Dementia Risk from Participants in a Massive Open Online Alzheimer’s Focused Course. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.42
ASSOCIATION OF CIRCULATING CAPRYLIC ACID WITH RISK OF MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE IN THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI) COHORT
L. Fan, X. Zhu, A.R. Borenstein, X. Huang, M.J. Shrubsole, L.L. Dugan, Q. Dai
J Prev Alz Dis 2023;3(10):513-522Show summaryHide summary
OBJECTIVE: Medium-chain fatty acids (MCFAs) can rapidly cross the blood-brain barrier and provide an alternative energy source for the brain. This study aims to determine 1) whether plasma caprylic acid (C8:0) is associated with risk of incident mild cognitive impairment (MCI) among baseline cognitively normal (CN) participants, and incident Alzheimer’s Disease (AD) among baseline MCI participants; and 2) whether these associations differ by sex, comorbidity of cardiometabolic diseases, apolipoprotein E (APOE) ε4 alleles, and ADAS-Cog 13.
METHODS: Within the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, plasma C8:0 was measured at baseline in 618 AD-free participants aged 55 to 91. Logistic regression models were used to estimate odds ratios (ORs) and 95% CIs with incident MCI and AD as dependent variables, separately.
RESULTS: The inverse association between circulating C8:0 and risk of incident MCI was of borderline significance. The inverse association between circulating levels of C8:0 and risk of incident MCI was significant among CN participants with ≥1 cardiometabolic diseases [OR (95% CI): 0.75 (0.58-0.98) (P=0.03)], those with one copy of APOE ε4 alleles [OR (95% CI): 0.43 (0.21-0.89) (P=0.02)], female [OR (95% CI): 0.60 (0.38-0.94) (P=0.02)], and ADAS-Cog 13 above the median [OR (95%CI): 0.69 (0.50-0.97)(P=0.03)] after adjusting for all covariates.
CONCLUSION: The inverse associations were present only among subgroups of CN participants, including female individuals, those with one or more cardiometabolic diseases, or one APOE ε4 allele, or higher ADAS-Cog 13 scores. If confirmed, this finding will facilitate precision prevention of MCI, in turn, AD among CN older adults.
L. Fan ; X. Zhu ; A.R. Borenstein ; X. Huang ; M.J. Shrubsole ; L.L. Dugan ; Q. Dai ; (2023): Association of Circulating Caprylic Acid with Risk of Mild Cognitive Impairment and Alzheimer’s Disease in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.37
ASSOCIATION BETWEEN NEUROPSYCHOLOGICAL PERFORMANCE AND CSF PROFILE IN SUBJECTIVE COGNITIVE DECLINE: TOWARDS THE DIAGNOSIS OF PRECLINICAL AD
E. Chipi, G. Bellomo, N. Salvadori, C. Montanucci, L. Gaetani, F. Paolini Paoletti, L. Parnetti
J Prev Alz Dis 2023;3(10):523-529Show summaryHide summary
BACKGROUND: In the perspective of novel treatments with disease-modifying drugs, a timely diagnosis of Alzheimer’s’ disease (AD) at preclinical phase represents a major issue. To this purpose, in clinical setting, there is the need to detect the earliest cognitive symptoms not yet fulfilling Mild Cognitive Impairment criteria, in order to proceed to biomarker assessment for diagnostic definition. In terms of cognitive performance, Subjective Cognitive Decline (SCD) is still a controversial entity, due to the difficulty of reliably measuring subtle deficits.
OBJECTIVES: To evaluate the possibility to predict the presence of AD-like CSF pattern in SCD individuals, according to their neuropsychological performance assessed by means of both traditional and computerized measures.
DESIGN: Retrospective study.
SETTING: Clinical setting (Centre for Memory Disturbances, Section of Neurology, University Hospital of Perugia, Italy).
PARTICIPANTS: 74 consecutive SCD subjects who underwent an in-depth (paper-pencil and computerized) neuropsychological assessment and CSF analysis for AD biomarkers (Aβ42/Aβ40 ratio, phospho-tau, total tau).
MEASUREMENTS: Neuropsychological assessment was composed of traditional tests assessing five cognitive domains (verbal memory, attention, executive functions, language, visuo-spatial abilities) and computerized tasks from CAmbridge Neuropsychological Test Automated Battery (CANTAB) (Pattern Recognition Memory, Paired Associates Learning and Spatial Working Memory). According to their performance at traditional tests, SCD individuals were categorized into cognitively normal (CN) and subtle impaired (SI); with respect to CANTAB, they were defined as CANTAB- in presence of normal performance, and CANTAB+ in presence of at least one pathological score. The subgroup with completely normal performance was defined as CN/CANTAB-, and the subgroup with impairment in both measures as SI/CANTAB+. Differences in prevalence of A/T/N profile according to cognitive profiles were assessed by Fisher’s exact text for count data.
RESULTS: None of CN/CANTAB- subjects showed A+/T+ status. SI/CANTAB+ subjects showed a significantly high prevalence of A+/T+ profile (14/35, 40%, p=0.03 vs CN/CANTAB-).
CONCLUSION: The neuropsychological profile may be of help in identifying SCD subjects requiring biomarker assessment. If confirmed in larger cohorts, the combination of traditional and computerized tests (namely, CANTAB) might represent a feasible strategy in clinical setting for carrying out biomarker assessment in individuals before the MCI stage. Detection of AD in these subjects would give them the highest chances to halt disease progression by means of disease modifying treatments.
E. Chipi ; G. Bellomo ; N. Salvadori ; C. Montanucci ; L. Gaetani ; F. Paolini Paoletti ; L. Parnetti ; (2023): Association between Neuropsychological Performance and CSF Profile in Subjective Cognitive Decline: Towards the Diagnosis of Preclinical AD. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.33
REPRODUCTIVE MARKERS IN ALZHEIMER’S DISEASE PROGRESSION: THE FRAMINGHAM HEART STUDY
H. Ding, Y. Li, T.F.A. Ang, Y. Liu, S. Devine, R. Au, P.M. Doraiswamy, C. Liu
J Prev Alz Dis 2023;3(10):530-535Show summaryHide summary
BACKGROUND: Reproductive status, such as the age of menarche or menopause, may be linked to cognitive abilities and risk for incident Alzheimer’s disease (AD) but the evidence is conflicting. It is also not fully known if these factors interact with cortical beta-amyloid deposition.
OBJECTIVES: To study the relationship between reproductive risks, sex hormone markers and risk for decline in specific cognitive domains in women.
DESIGN, SETTING AND PARTICIPANTS participants: We analyzed the association of reproductive markers (age at menarche, number of births, age at menopause, sex hormone-binding globulin, estradiol, estrone, total testosterone, free testosterone) with incident AD and annualized cognitive decline in the community-based longitudinal Framingham Heart Study (FHS) Offspring women 60 years and older (n=772, mean age 68 years, mean follow-up 10.7 ± 3 years). We used the Cox proportional hazards regression model and linear regression model, adjusting for covariates.
OUTCOME MEASURES: Incident AD dementia as well as the annualized change in memory, language, attention and executive functions.
RESULTS: Older age at menopause was associated with a lower risk of incident AD dementia (p = 0.047, 6% lower risk per older year) after adjusting for baseline age, education, hormone therapy status, and MMSE score. Older age at menopause was significantly associated with a slower annualized decline in memory (beta = 0.085, p = 0.00059). The lower level of plasma Aβ42 was also associated with a higher risk of incident AD (HR = 0.97, 95% CI = 0.95, 0.99; p = 0.0039) but there was no significant interaction effect with age at menarche, age at menopause or plasma sex hormone levels.
CONCLUSION: Younger age at menopause is a risk factor for late-life memory decline and incident AD. This risk appears to be independent of Aβ42 pathology. Further studies to understand the biological and social mechanisms underlying the differential effects of reproductive risks are warranted.
H. Ding ; Y. Li ; T.F.A. Ang ; Y. Liu ; S. Devine ; R. Au ; P.M. Doraiswamy ; C. Liu ; (2023): Reproductive Markers in Alzheimer’s Disease Progression: The Framingham Heart Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.28
A GENETIC VALIDATION OF THE NEURODEGENERATION BIOMARKERS TAU-A AND TAU-C - A MENDELIAN RANDOMIZATION STUDY
T.M. Axelsen, C. Bager, A. Bihlet, M.A. Karsdal, K. Henriksen, M.H.E. Tang
J Prev Alz Dis 2023;3(10):536-542Show summaryHide summary
BACKGROUND: Disease modifying treatments for dementia are only just surfacing, and their development is still significantly hindered by the lack of validated tools for identification of subjects with subclinical disease. Much interest has been taken in developing accessible non-invasive serum biomarkers of neurodegeneration. Recent studies have identified caspase-3-cleaved tau (Tau-C), and ADAM-10 cleaved tau (Tau-A) as possible markers of preclinical neurodegenerative disease.
OBJECTIVES: To explore if serum levels of Tau-A and Tau-C change as a consequence of neurodegeneration.
DESIGN AND SETTING: Cohort study with measurement of biomarkers and genome sequencing at baseline with follow-up after an average of 14 years.
PARTICIPANTS: Postmenopausal Danish women from the Prospective Epidemiological Risk Factor (PERF) cohort (n=4968)
METHODS: Genotyping data was used to perform a Mendelian randomization analysis of serum levels of Tau-A and Tau-C in relation to a diagnosis of dementia at follow-up. A dementia diagnosis was defined as a composite of an all-cause dementia diagnosis derived from the Danish National Health registries, a self-reported diagnosis of dementia and/or cognitive test scores suggestive of dementia. Serum levels of Tau-A and Tau-C were measured blinded in samples from baseline in a CAP certified lab. The association with dementia was assessed using bi-directional one- and two- sample Mendelian randomization.
RESULTS: A lead single nucleotide polymorphism (SNP) was identified for Tau-A (rs10414043) and Tau-C (rs429358), respectively were identified. Both were located in the APOE/C1 cluster on chromosome 19. APOE and EPOC1 variants were associated with lower levels of Tau-A and Tau-C levels – effect size -0.13, 95%CI [-0.17 - -0.09] log2 (ng/mL), p=7.05e-11 for rs10414043 association with Tau-A and effect size -0.12, 95%CI [-0.15 - -0.08] log2 (ng/mL), p=2e-11 for rs429358 association with Tau-C. When incorporating genetic data from a larger genetic study we found that Alzheimer’s disease was marginally associated with a decreased Tau-A and Tau-C levels (Odds Ratio 0.97, 95%CI [0.93 – 1.00]. No association was found in the forward Mendelian randomization analysis.
CONCLUSIONS: By combining genotype data with serum measurements of the novel biomarkers Tau-A and Tau-C, we conclude that Tau-A and Tau-C levels change because of neurodegeneration. We also conclude that lower serum-values of the biomarkers are associated with the presence of genetic variants commonly found in individuals suffering from late-onset Alzheimer’s Dementia. These findings add to the growing data pointing towards Tau-A and Tau-C as valuable biomarkers for neurodegeneration.
T.M. Axelsen ; C. Bager ; A. Bihlet ; M.A. Karsdal ; K. Henriksen ; M.H.E. Tang ; (2023): A Genetic Validation of the Neurodegeneration Biomarkers Tau-A and Tau-C - A Mendelian Randomization Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.36
ASSOCIATION BETWEEN LONGITUDINAL CEREBROSPINAL FLUID ALZHEIMER’S BIOMARKERS AND THE LIFESTYLE FOR BRAIN HEALTH (LIBRA) INDEX: FINDINGS FROM THE EUROPEAN PREVENTION OF ALZHEIMER’S DEMENTIA COHORT STUDY (EPAD LCS)
T.S. Saunders, M. Protsiv, N.D. Jenkins, A. Solomon, K. Blennow, C. Ritchie, G. Muniz-Terrera
J Prev Alz Dis 2023;3(10):543-550Show summaryHide summary
BACKGROUND: In the absence of preventative pharmacological interventions for Alzheimer’s Disease dementia, there is a growing interest in modifiable risk factors associated with AD. Such risk factors are thought to contribute up to 40% of the risk of dementia. The Lifestyle for Brain Health (LIBRA) index, a dementia risk score which focuses exclusively on modifiable factors, has been found to be associated with increased risk of dementia and cognitive decline. It is currently unclear how the LIBRA index relates to cerebrospinal fluid (CSF) biomarkers of Alzheimer’s Disease.
OBJECTIVES: To examine the association between LIBRA index scores and trajectories of phospho-tau 181 and total tau in the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS), and to examine whether these trajectories differ between participants with high and low CSF amyloid-beta 1-42 (Aβ42).
DESIGN: Analysis of CSF biomarker and LIBRA index scores from the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study.
SETTING: The European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study is a multi-centre, pan-European study.
MEASUREMENTS: Cerebrospinal fluid samples were taken by lumbar puncture and analysed using electrochemiluminescence. LIBRA index scores were calculated from self-reported variables, questionnaires, and physiological measurements.
RESULT: In the total sample (n = 1715; mean age = 66.0, 56.4% female), there were no significant associations between LIBRA scores (mean = 0.73 points) and rate of change in cerebrospinal fluid biomarkers. In participants with high Aβ, reflecting less deposition in the brain, (n = 1134), LIBRA scores were significantly associated with the rate of change in total tau, where higher LIBRA scores (denoting higher dementia risk) were associated with increases in t-tau. There were no significant associations between LIBRA scores and change in cerebrospinal biomarkers in participants with low Aβ.
CONCLUSION: We found an association between modifiable risk factors and total tau accumulation in participants without dementia and without Aβ accumulation. This suggests that increasing levels of total tau may be driven by factors other than Aβ accumulation and highlights the need for developing and examining tau-targeting drugs in Alzheimer’s Disease development.
T.S. Saunders ; M. Protsiv ; N.D. Jenkins ; A. Solomon ; K. Blennow ; C. Ritchie ; G. Muniz-Terrera (2023): Association between Longitudinal Cerebrospinal Fluid Alzheimer’s Biomarkers and the Lifestyle for Brain Health (LIBRA) Index: Findings from the European Prevention of Alzheimer’s Dementia Cohort Study (EPAD LCS). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.31
UNDERSTANDING ONLINE REGISTRY FACILITATORS AND BARRIERS EXPERIENCED BY BLACK BRAIN HEALTH REGISTRY PARTICIPANTS: THE COMMUNITY ENGAGED DIGITAL ALZHEIMER’S RESEARCH (CEDAR) STUDY
M.T. Ashford, D. Zhu, J. Bride, E. McLean, A. Aaronson, C. Conti, C. Cypress, P. Griffin, R. Ross, T. Duncan, X. Deng, A. Ulbricht, J. Fockler, M.R. Camacho, D. Flenniken, D. Truran, S.R. Mackin, C. Hill, M.W. Weiner, D. Byrd, R.W. Turner II, H. Cham, M. Rivera Mindt, R.L. Nosheny
J Prev Alz Dis 2023;3(10):551-561Show summaryHide summary
BACKGROUND: Failure of Alzheimer’s disease and related diseases (ADRD) research studies to include and engage Black participants is a major issue, which limits the impact and generalizability of research findings. Little is known about participation of Black adults in online ADRD-related research registries.
OBJECTIVES: As part of the Community Engaged Digital Alzheimer’s Research (CEDAR) Study, this study aims to increase our understanding of facilitators and barriers of Black adults to participating in ADRD-related online registries, as well as to understand their preferences for communication channels.
DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: We invited all Black participants enrolled in the Brain Health Registry (BHR) to complete a cross-sectional online survey. The survey consisted of rating scales and open-text questions asking about their attitudes towards brain health research, reasons for joining and continuing to participate in BHR, difficulties with participating, and preferences for modes of contact and website usage.
RESULTS: Of all invited Black BHR participants (N=3,636), 198 (5.5%) completed the survey. The mean age was 58.4 (SD=11.3), mean years of education were 16.3 (SD=2.4), and 85.5% identified as female. Reported facilitators for joining and continuing to participate in BHR were personal interest (e.g., learning more about own brain health) and altruism (e.g., helping research). Among additional registry features which could encourage return, receiving feedback or scores about BHR tasks was rated the highest. Of those who found BHR participation difficult (21%), the most frequent reason was time burden. The most preferred way of receiving study information was via email. Participants reported that the websites that they used the most were YouTube and Facebook.
DISCUSSION: The results of our study can inform the development of culturally-responsive registry features and engagement efforts to improve inclusion and participation of Black adults in online ADRD research. Providing participants with feedback about their registry performance and reducing the number of registry tasks are among the recommended strategies.
M.T. Ashford ; D. Zhu ; J. Bride ; E. McLean ; A. Aaronson ; C. Conti ; C. Cypress ; P. Griffin ; R. Ross ; T. Duncan ; X. Deng ; A. Ulbricht ; J. Fockler ; M.R. Camacho ; D. Flenniken ; D. Truran ; S.R. Mackin ; C. Hill ; M.W. Weiner ; D. Byrd ; R.W. Turner II ; H. Cham ; M. Rivera Mindt ; R.L. Nosheny (2023): Understanding Online Registry Facilitators and Barriers Experienced by Black Brain Health Registry Participants: The Community Engaged Digital Alzheimer’s Research (CEDAR) Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.25
SUBJECTIVE COGNITIVE COMPLAINTS: COMPARING THE RELATION BETWEEN SELF-REPORTED VERSUS INFORMANTREPORTED SUBJECTIVE COGNITIVE COMPLAINTS AND COGNITIVE PERFORMANCES IN COGNITIVELY UNIMPAIRED, MILD COGNITIVE IMPAIRMENT AND POPULATIONS WITH DEMENTIA
S.-W. Peng, C.-Y. Wang, S.-Y. Lin, Y.-L. Lee, Y.-C. Lin, Y.-J. Lin, P.-N. Wang
J Prev Alz Dis 2023;3(10):562-570Show summaryHide summary
BACKGROUND: Subjective cognitive decline is proposed to be associated with future mild cognitive impairment and dementia. A better understanding of the roles of self-reported and informant-reported subjective cognitive complaints can provide a more delicate picture in dementia recognition and early diagnosis.
OBJECTIVES: To evaluate the accuracy of self-reported and informant-reported subjective cognitive complaints and the relation of subjective cognitive complaints and neuropsychological function in cognitively unimpaired, mild cognitive impairment and populations with dementia.
DESIGN: We conducted a cross-sectional survey and evaluate the relations between subjective cognitive complaint scores and cognitive function in the different diagnostic groups.
SETTING: We recruited individuals diagnosed with cognitively unimpaired or mild cognitive impairment or dementia with Alzheimer’s clinical syndrome from a memory clinic in a tertiary medical center in Taiwan.
PARTICIPANTS: Participants, age greater than 50 years old, were enrolled in this study. Participants’ informants were also enrolled for the cognitive questionnaire assessment.
MEASUREMENTS: Participants’ and informants’ subjective cognitive complaint scores were collected based on a 12-item questionnaire. Neuropsychological assessments of global cognitive function, memory, language, executive function, visuospatial function and calculation were performed. The relations between subjective cognitive complaint scores and cognitive function in the different diagnostic groups were assessed by linear regression model.
RESULTS: There were 1536 individuals and 1028 informants enrolled in this study. Self-reported subjective cognitive complaint scores from early and late mild cognitive impairment and dementia with Alzheimer’s clinical syndrome participants showed no significant differences, but informants’ subjective cognitive complaint scores showed a significant increase. Informant-reported subjective cognitive complaint scores related to neuropsychological tests in population with dementia. Neither self-reported nor informant-reported subjective cognitive complaint scores related to neuropsychological tests in cognitively unimpaired and mild cognitive impairment populations.
CONCLUSIONS: Self-reported subjective cognitive complaints alone may not be sufficient to demonstrate clinical significance in different stages of cognitive impairment. Incorporating informant-reported subjective cognitive complaints, along with considering individual’s anxiety and depressive status, are crucial in assessing cognitive statuses in clinical practice.
S.-W. Peng ; C.-Y. Wang ; S.-Y. Lin ; Y.-L. Lee ; Y.-C. Lin ; Y.-J. Lin ; P.-N. Wang (2023): Subjective Cognitive Complaints: Comparing the Relation between Self-Reported Versus Informant-Reported Subjective Cognitive Complaints and Cognitive Performances in Cognitively Unimpaired, Mild Cognitive Impairment and Populations with Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.47
CHINESE PRECLINICAL ALZHEIMER’S DISEASE STUDY (C-PAS): DESIGN AND CHALLENGE FROM PET ACCEPTANCE
L. Cui, L. Huang, F.-F. Pan, Y. Wang, Q. Huang, Y.-H. Guan, C-Y.Z. Lo, Y.-H. Guo, A.S. Chan, F. Xie, Q.-H. Guo
J Prev Alz Dis 2023;3(10):571-580Show summaryHide summary
BACKGROUND: Large-scale preclinical Alzheimer’s disease study based on β-amyloid positron emission tomography (PET) has not been conducted in China.
OBJECTIVES: Establish a cohort on Alzheimer’s disease spectrum, especially the preclinical stages, and determine the factors influencing the acceptance of β-amyloid PET scan screening in China.
SETTING: Shanghai, China.
PARTICIPANTS: A total of 4386 participants were screened and 2451 participants who met enrollment criteria were eventually included in this report.
MEASUREMENTS: The multidimensional data was collected, including comprehensive assessments, PET and magnetic resonance imaging scans, genetics, and plasma biomarkers.
RESULTS: There were 571 participants in the normal cognition group, 625 participants in the subjective cognitive decline group, 155 participants in the objectively defined subtle cognitive decline group, 501 participants in the mild cognitive impairment group, 471 participants in Alzheimer’s disease group, and 128 participants with cognitive impairment from other known causes. Significant differences in demographics, florbetapir PET, APOE, and neuropsychological tests were found among the groups. Eight hundred and seventeen participants (33.3%) completed the florbetapir PET scanning. Non-demented individuals with higher age, lower education years, male, with a family history of dementia, and higher self-report depression prefer to undergo PET scans. Acceptance of PET scans did not correlate with objectively assessed cognitive impairment.
CONCLUSIONS: The Chinese Preclinical Alzheimer’s Disease Study was designed to establish a large-scale cohort with comprehensive data collection. Our findings may help to understand the factors affecting the acceptance of β-amyloid PET in urban areas of China and help us address the low acceptance challenge.
L. Cui ; L. Huang ; F.-F. Pan ; Y. Wang ; Q. Huang ; Y.-H. Guan ; C-Y.Z. Lo ; Y.-H. Guo ; A.S. Chan ; F. Xie ; Q.-H. Guo ; (2023): Chinese Preclinical Alzheimer’s Disease Study (C-PAS): Design and Challenge from PET Acceptance. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.49
NEUROPROTECTIVE EFFECTS OF IVIG AGAINST ALZHEIMER’ S DISEASE VIA REGULATION OF ANTIGEN PROCESSING AND PRESENTATION BY MHC CLASS I MOLECULES IN 3XTG-AD MICE
Z. Fei, B. Pan, R. Pei, S. Ye, Z. Wang, L. Ma, R. Zhang, C. Li, X. Du, H. Cao
J Prev Alz Dis 2023;3(10):581-594Show summaryHide summary
BACKGROUND: The results of clinical trials for Alzheimer’s disease (AD) patients treated with Intravenous immunoglobulin (IVIG) revealed inconsistency in efficacy.
Objective: To explore the neuroprotective effects and possible mechanisms of different IVIG in 3xTg-AD mice.
METHODS: 3-month-old 3xTg-AD mice were administered intraperitoneally with different IVIG (A/B/C) for 3 months and then the therapeutic effects were observed and tested at 9 months of age. The bioavailability of IVIG and Aβ40/42 concentrations in parietotemporal cortex was measured by ELISA. Behavioral tests were performed to examine cognitive functions. Immunohistochemistry was utilized to examine the deposition of Aβ, the phosphorylation of tau, the levels of GFAP and Iba-1 in the hippocampus. Proteomics, Luminex assay and parallel reaction monitoring were performed to identify and verify the proteins that showed a marked change in the hippocampus.
RESULTS: IVIG-C was more effective than IVIG-A and IVIG-B in counteracting cognitive deficits, ameliorating Aβ deposits and tau phosphorylation, attenuating the activation of microglia and astrocytes in the hippocampus and inhibiting the secretion of pro-inflammatory factors. IVIG-C affected innate immunity and suppressed the activation of antigen processing and presentation by MHC class I molecule (APP-MHC-I).
CONCLUSION: The efficacy of different IVIG on AD was significantly different, and only IVIG-C has been confirmed to possess significant neuroprotective effects, which are related to the inhibition of APP-MHC-I. IVIG may be a potential therapeutic for AD but further research is needed to evaluate the functional of IVIG before clinical trials of AD treatment.
Z. Fei ; B. Pan ; R. Pei ; S. Ye ; Z. Wang ; L. Ma ; R. Zhang ; C. Li ; X. Du ; H. Cao (2023): Neuroprotective Effects of IVIG against Alzheimer’ s Disease via Regulation of Antigen Processing and Presentation by MHC Class I Molecules in 3xTg-AD Mice. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.56
‘TIME SAVED’ AS A DEMONSTRATION OF CLINICAL MEANINGFULNESS AND ILLUSTRATED USING THE DONANEMAB TRAILBLAZER-ALZ STUDY FINDINGS
S.P. Dickson, A.M. Wessels, S.A. Dowsett, C. Mallinckrodt, J.D. Sparks, S. Chatterjee, S. Hendrix
J Prev Alz Dis 2023;3(10):595-599Show summaryHide summary
In Alzheimer’s disease (AD) clinical trials, disease-modifying therapies are expected to slow the rate of disease progression. Treatment effects are evaluated using a validated clinical scale as the difference between treatment and placebo in mean change from baseline to endpoint. Understanding the clinical relevance of this metric is not necessarily intuitive. Expressing active treatment-placebo difference as a time metric (i.e., months saved with treatment) has potential to provide a metric that is more easily and consistently interpreted. Using data from the TRAILBLAZER-ALZ study, time component tests (TCTs) were employed to determine the time saved with donanemab (an amyloid lowering drug) treatment. At study endpoint (Week 76), disease progression was delayed by 5.3 months and 5.2 months as measured by the Integrated Alzheimer’s Disease Rating Scale (iADRS) and the Clinical Dementia Rating Sum of Boxes (CDR-SB), respectively.
S.P. Dickson ; A.M. Wessels ; S.A. Dowsett ; C. Mallinckrodt ; J.D. Sparks ; S. Chatterjee ; S. Hendrix (2023): ‘Time Saved’ As a Demonstration of Clinical Meaningfulness and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.50
TEN YEARS AFTER THE NATIONAL ALZHEIMER’S PLAN: DEMENTIA REMAINS A HIDDEN SYNDROME IN FRANCE
J.-F. Dartigues, J.A. Avila-Funes, L. Letenneur, C. Meillon, C. Helmer, H. Amieva, K. Pérès
J Prev Alz Dis 2023;3(10):600-606Show summaryHide summary
Ten years after the implementation of the French Plan on Alzheimer’s Disease (2008-2012), the present study aimed at describing the situation of the persons living with dementia in terms of diagnosis and high-risk situations (living alone, continuing driving, inability to handle budget and to manage medication). Among the 115 dementia cases followed-up in the AMI population-based cohort on aging in 2018 (i.e. ten years after the launch of the Plan), the prevalence of under-diagnosis was similar to the one estimated ten years earlier (53.0% vs. 55.6%). Almost all cases (95.3%) were concerned by high-risk situations (61.2% were unable to handle finances, 48.2% were living alone, 27.1% continued driving). Being diagnosed as demented was not associated with a lower frequency of high-risk situations, excepting for driving (16.7% vs. 37.2%). Ten years after the beginning of the French Alzheimer’s Plan, dementia remains a hidden syndrome, with a frequent inadequate management of high-risk situations.
J.-F. Dartigues ; J.A. Avila-Funes ; L. Letenneur ; C. Meillon ; C. Helmer ; H. Amieva ; K. Pérès ; (2023): Ten Years after the National Alzheimer’s Plan: Dementia Remains a Hidden Syndrome in France. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.24
ASSOCIATIONS BETWEEN PARTICIPANT CHARACTERISTICS AND PARTICIPANT FEEDBACK ABOUT AN UNSUPERVISED ONLINE COGNITIVE ASSESSMENT IN A RESEARCH REGISTRY
M.T. Ashford, J. Eichenbaum, C. Jin, J. Neuhaus, A. Aaronson, A. Ulbricht, M.R. Camacho, J. Fockler, D. Flenniken, D. Truran, R.S. Mackin, P. Maruff, M.W. Weiner, R.L. Nosheny
J Prev Alz Dis 2023;3(10):607-614Show summaryHide summary
BACKGROUND: This study aims to understand whether and how participant characteristics (age, gender, education, ethnocultural identity) are related to their feedback about taking a remote, unsupervised, online cognitive assessment.
METHODS: The Brain Health Registry is a public online registry which includes cognitive assessments. Multivariable ordinal regressions assessed associations between participant characteristics and feedback responses of older (55+) participants (N=11,553) regarding their Cogstate Brief Battery assessment experience.
RESULTS: Higher age, secondary education or less, Latino identity, and female gender were associated with a poorer assessment experience; higher age and a non-White identity were associated with experiencing the assessment instructions as less clear; and higher age, non-White identity, and secondary education or less were associated with rating additional human support with the assessment as more useful.
DISCUSSION: Our findings highlight the importance of improving the design and instructions of unsupervised, remote, online cognitive assessments to better suit the needs of diverse communities.
M.T. Ashford ; J. Eichenbaum ; C. Jin ; J. Neuhaus ; A. Aaronson ; A. Ulbricht ; M.R. Camacho ; J. Fockler ; D. Flenniken ; D. Truran ; R.S. Mackin ; P. Maruff ; M.W. Weiner ; R.L. Nosheny (2023): Background: This study aims to understand whether and how participant characteristics (age, gender, education, ethnocultural identity) are related to their feedback about taking a remote, unsupervised, online cognitive assessment. Methods: The Brain Health Registry is a public online registry which includes cognitive assessments. Multivariable ordinal regressions assessed associations between participant characteristics and feedback responses of older (55+) participants (N=11,553) regarding their Cogstate Brief Battery assessment experience. Results: Higher age, secondary education or less, Latino identity, and female gender were associated with a poorer assessment experience; higher age and a non-White identity were associated with experiencing the assessment instructions as less clear; and higher age, non-White identity, and secondary education or less were associated with rating additional human support with the assessment as more useful. Discussion: Our findings highlight the importance of improving the design and instructions of unsupervised, remote, online cognitive assessments to better suit the needs of diverse communities. . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.40