01/2023 journal articles
EDITORIAL: ACCELERATING INNOVATIONS FOR ENHANCED BRAIN HEALTH. CAN ARTIFICIAL INTELLIGENCE ADVANCE NEW PATHWAYS FOR DRUG DISCOVERY FOR ALZHEIMER’S AND OTHER NEURODEGENERATIVE DISORDERS?
A.S. Khachaturian, A. Dengel, V. Dockal, P. Hrobon, M. Tolar
J Prev Alz Dis 2023;1(10):1-4Show summaryHide summary
A.S. Khachaturian ; A. Dengel ; V. Dočkal ; P. Hroboň ; M. Tolar (2023): Editorial: Accelerating Innovations for Enhanced Brain Health. Can Artificial Intelligence Advance New Pathways for Drug Discovery for Alzheimer’s and other Neurodegenerative Disorders?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.1
EDITORIAL: CHANGE ON CLINICAL TRIAL OUTCOME ASSESSMENTS: THE SEARCH FOR MEANINGFULNESS
J Prev Alz Dis 2023;1(10):5-6Show summaryHide summary
J. Cummings (2022): Editorial: Change on Clinical Trial Outcome Assessments: The Search for Meaningfulness. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.103
EDITORIAL: USEFULNESS OF ANCHOR BASED METHODS FOR DETERMINING CLINICALLY MEANINGFUL CHANGE IN MCI DUE TO AD
S.B. Hendrix, S.P. Dickson
J Prev Alz Dis 2023;1(10):7-8Show summaryHide summary
S.B. Hendrix ; S.P. Dickson ; (2022): Editorial: Usefulness of Anchor Based Methods for Determining Clinically Meaningful Change in MCI due to AD. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.104
ESTABLISHING CLINICALLY MEANINGFUL CHANGE ON OUTCOME ASSESSMENTS FREQUENTLY USED IN TRIALS OF MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE
C.J. Lansdall, F. McDougall, L.M. Butler, P. Delmar, N. Pros, S. Qin, L. McLeod, X. Zhou, G.A. Kerchner, R.S. Doody
J Prev Alz Dis 2023;1(10):9-18Show summaryHide summary
Background: Consensus is lacking on what constitutes a meaningful score change for individual patients on clinical outcome assessments (COAs) that are commonly used in clinical trials of Alzheimer’s disease. Such thresholds are one important approach to help contextualize trial results and demonstrate meaningful treatment benefit.
Objectives: To estimate meaningful within-patient change thresholds for the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE) among participants with mild cognitive impairment (MCI).
Design: Retrospective anchor- and distribution-based analyses of data from the ADC-008 (NCT00000173) study were used to estimate thresholds for meaningful within-patient change on the target measures.
Setting: Analyses were conducted using data from ADC-008 a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study among participants with the amnestic subtype of MCI, which was conducted by the Alzheimer’s Disease Cooperative Study (ADCS) between March 1999 and January 2004 in the United States and Canada.
Participants: Analyses were based on 769 eligible participants who completed the baseline assessment from 69 ADCS sites in the United States and Canada.
Measurements: The target outcome measures for this analysis included the CDR-SB, the ADAS-Cog, and the MMSE. The anchor measures for this analysis included the Global Deterioration Scale and the MCI–Clinical Global Impression of Change.
Results: Focusing on the 12-month time point, within-patient increases of 1–2.5 points in the CDR-SB and increases of 2–5 points on the 11-item ADAS-Cog and 13-item ADAS-Cog, on average, reflect minimal-to-moderate levels of deterioration, respectively.
Conclusions: These thresholds may be useful to aid the interpretation of Alzheimer’s disease clinical trial data by illustrating meaningful within-patient progression over the course of a clinical trial via supplementary progressor analyses, which may in turn be informative for treatment decisions. Estimates generated via these methods are specifically intended to evaluate within-patient change and are not intended to assess the magnitude and meaningfulness of differences between group-level changes over time.
C.J. Lansdall ; F. McDougall ; L.M. Butler ; P. Delmar ; N. Pross ; S. Qin ; L. McLeod ; X. Zhou ; G.A. Kerchner ; R.S. Doody ; (2022): Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.102
ACU193, A MONOCLONAL ANTIBODY THAT SELECTIVELY BINDS SOLUBLE ASS OLIGOMERS: DEVELOPMENT RATIONALE, PHASE 1 TRIAL DESIGN, AND CLINICAL DEVELOPMENT PLAN
E. Siemers, J. Hitchcock, K. Sundell, R. Dean, J. Jerecic, E. Cline, K. Iverson, J. Moore, C. Edgar, R. Manber, N. Fuin, T. Poppe, R. Barton
J Prev Alz Dis 2023;1(10):19-24Show summaryHide summary
Background: Alzheimer’s disease is a large and growing unmet medical need. Clinical trial designs need to assess disease-related outcomes earlier to accelerate the development of better treatments for Alzheimer’s disease. ACU193 is a monoclonal antibody that selectively targets amyloid β oligomers, thought to be the most toxic species of Aβ that accumulates early in AD and contributes to downstream pathological effects. Nonclinical data indicate that ACU193 can reduce the toxic effects of amyloid β oligomers. ACU193 is currently being investigated in a phase 1 clinical trial designed with the properties described in this report. This phase 1 trial is designed to provide data to enable a go/no-go decision regarding the initiation of a subsequent phase 2/3 study.
Objectives: To design a phase 1 study that assesses target engagement and incorporates novel measures to support more rapid development of a potential disease-modifying treatment for Alzheimer’s disease.
Design: The INTERCEPT-AD trial for ACU193 is an ongoing randomized, placebo-controlled phase 1a/b study that assesses safety, tolerability, pharmacokinetics, target engagement, clinical measures, and several Alzheimer’s disease biomarkers, including novel digital and imaging biomarkers.
Setting: For INTERCEPT-AD, brief inpatient stays for patients in the single ascending dose portion of the study, with the remainder of the evaluations being performed as outpatients at multiple clinical trial sites in the U.S.
Participants: Patients with early Alzheimer’s disease (mild cognitive impairment or mild dementia with a positive florbetapir positron emission tomography scan).
Intervention: ACU193 administered intravenously at doses of 2– 60 mg/kg.
Measurements: Safety assessments including magnetic resonance imaging for the presence of amyloid-related imaging abnormalities, clinical assessments for Alzheimer’s disease including the Alzheimer’s Disease Rating Scale-cognition and Clinical Dementia Rating scale, pharmacokinetics, a measure of target engagement, and digital and imaging biomarkers, including a computerized cognitive test battery and a measure of cerebral blood flow using arterial spin labelling magnetic resonance imaging.
Results: A phase 1 study design was developed for ACU193 that allows collection of data that will enable a go/no-go decision for initiation of a subsequent adaptive phase 2/3 study.
Conclusions: A phase 1a/b trial and an overall clinical development plan for an Alzheimer’s disease treatment can be designed that maintains patient safety, allows informed decision-making, and achieves an accelerated timeline by using novel biomarkers and adaptive study designs.
E. Siemers ; J. Hitchcock ; K. Sundell ; R. Dean ; J. Jerecic ; E. Cline ; K. Iverson ; J. Moore ; C. Edgar ; R. Manber ; N. Fuin ; T. Poppe ; R. Barton ; (2022): ACU193, a Monoclonal Antibody that Selectively Binds Soluble Aß Oligomers: Development Rationale, Phase 1 Trial Design, and Clinical Development Plan. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.93
BUNTANETAP, A NOVEL TRANSLATIONAL INHIBITOR OF MULTIPLE NEUROTOXIC PROTEINS, PROVES TO BE SAFE AND PROMISING IN BOTH ALZHEIMER’S AND PARKINSON’S PATIENTS
C. Fang, P. Hernandez, K. Liow, E. Damiano, H. Zetterberg, K. Blennow, D. Feng, M. Chen, M. Maccecchini
J Prev Alz Dis 2023;1(10):25-33Show summaryHide summary
Background: Previously we reported the clinical safety and pharmacological activity of buntanetap (known as Posiphen or ANVS401) in healthy volunteers and mild cognitive impaired (MCI) patients (21). The data supported continued clinical evaluation of buntanetap for treating Alzheimer’s Disease (AD). Neurodegenerative diseases such as AD and Parkinson’s disease (PD) share several pathological manifestations, including increased levels of multiple neurotoxic protein aggregates. Therefore, a treatment strategy that targets toxic species common to both disorders can potentially provide better clinical outcomes than attacking one neurotoxic protein alone. To test this hypothesis, we recently completed a clinical study in early AD and early PD participants and report the data here.
OBJECTIVES: We evaluated safety, pharmacokinetics, biomarkers, and efficacy of buntanetap in treating early AD and PD patients.
DESIGN: Double-blind, placebo-controlled, multi-center study.
SETTING: 13 sites in the US participated in this clinical trial. The registration number is NCT04524351 at ClinicalTrials.gov.
PARTICIPANTS: 14 early AD patients and 54 early PD patients.
INTERVENTION: AD patients were given either 80mg buntanetap or placebo QD. PD patients were given 5mg, 10mg, 20mg, 40mg, 80mg buntanetap or placebo QD.
MEASUREMENTS: Primary endpoint is safety and tolerability; secondary endpoint is pharmacokinetics of buntanetap in plasma; exploratory endpoints are 1) biomarkers in cerebrospinal fluid (CSF) in both AD and PD patients 2) psychometric tests specific for AD (ADAS-Cogs & WAIS coding test) or PD (MDS-UPDRS & WAIS coding test).
RESULTS: Buntanetap was safe and well tolerated. Biomarker data indicated a trend in lowering levels of neurotoxic proteins and inflammatory factors and improving axonal integrity and synaptic function in both AD and PD cohorts. Psychometric tests showed statistically significant improvements in ADAS-Cog11 and WAIS coding in AD patients and MDS-UPDRS and WAIS coding in PD patients.
CONCLUSIONS: Buntanetap is well tolerated and safe at doses up to 80mg QD in both AD and PD patients. Cmax and AUC increase with dose without evidence for a plateau up to 80mg QD. The drug shows promising evidence in exploratory biomarker and efficacy measures. Further evaluation of buntanetap in larger, longer-term clinical trials for the treatment of AD and PD are warranted.
C. Fang ; P. Hernandez ; K. Liow ; E. Damiano ; H. Zetterberg ; K. Blennow ; D. Feng ; M. Chen ; M. Maccecchini ; (2022): Buntanetap, a Novel Translational Inhibitor of Multiple Neurotoxic Proteins, Proves to Be Safe and Promising in Both Alzheimer’s and Parkinson’s Patients. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.84
US ADULTS’ LIKELIHOOD TO PARTICIPATE IN DEMENTIA PREVENTION DRUG TRIALS: RESULTS FROM THE NATIONAL POLL ON HEALTHY AGING
C.G. Cox, M.A. Davis, J.D. Grill, J.S. Roberts
J Prev Alz Dis 2023;1(10):34-40Show summaryHide summary
Background: Recruitment to dementia prevention clinical trials is challenging, and participants are not representative of US adults at risk. A better understanding of the general public’s interest in dementia prevention research participation is needed to inform future recruitment strategies.
Objective: To examine US adults’ characteristics associated with self-reported likelihood to participate in dementia prevention clinical trials.
Design: We conducted a cross-sectional survey using the October 2018 wave of the University of Michigan National Poll on Healthy Aging.
Setting: The National Poll on Healthy Aging is a nationally representative survey of adults using KnowledgePanel (Ipsos Public Affairs LLC), a probability-based panel of the civilian, noninstitutionalized US population.
Participants: We analyzed data from 1,028 respondents, ages 50 to 64 years, who completed a web survey module on brain health.
Measurements: We used logistic regression models to examine associations between sociodemographic and dementia-related factors (e.g., family history) and self-reported likelihood to participate in a dementia prevention clinical trial of a new medicine (“very” or “somewhat likely” vs. “not likely” survey responses). Among respondents not likely to participate, we examined frequency of reasons endorsed for this decision, stratified by age, sex, and race and ethnicity.
Results: Of the 1,028 respondents, half were female, 68% Non-Hispanic White, 13% Hispanic, and 12% Non-Hispanic Black. Twelve percent of respondents reported being very likely to participate in a dementia prevention trial, 32% somewhat likely, and 56% not likely. Factors associated with higher likelihood to participate were higher perceived risk of dementia [OR, 2.17 (95% CI, 1.61, 2.93)], a positive family history of dementia [OR, 1.75 (95% CI, 1.27, 2.43)], and having discussed dementia prevention with a doctor [OR, 2.20 (95% CI, 1.10, 4.42)]. There were no differences in likelihood to participate by sociodemographic characteristics. Among 570 respondents not likely to participate, 39% said they did not want to be a guinea pig, 23% thought dementia would not affect them, 22% thought there would be too high a chance for harm, 15% indicated study participation would take too much time, and 5% reported fear of learning information about oneself. There were no differences across age, sex, and racial and ethnic groups.
Conclusions: In this study, perceived risk of dementia, family history, and discussion of prevention with a doctor were associated with likelihood to participate in a dementia prevention clinical trial, whereas sociodemographic factors including race and ethnicity were not. Findings suggest that recruitment interventions focused on increasing knowledge of dementia risk and prevention trials and involving healthcare providers may be effective tools to improve enrollment rates, regardless of target community.
C.G. Cox ; M.A. Davis ; J.D. Grill ; J.S. Roberts ; (2022): US Adults’ Likelihood to Participate in Dementia Prevention Drug Trials: Results from the National Poll on Healthy Aging. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.86
THE USE OF EPISODIC MEMORY TESTS FOR SCREENING IN CLINICAL TRIALS FOR EARLY ALZHEIMER’S DISEASE: A COMPARISON OF THE FREE AND CUED SELECTIVE REMINDING TEST (FCSRT) AND THE REPEATABLE BATTERY FOR THE ASSESSMENT OF NEUROPSYCHOLOGICAL STATUS (RBANS)
E. Teng, P.T. Manser, M. Shah, K. Pickthorn, N. Hu, S. Djakovic, H. Swendsen, M. Blendstrup, G. Faccin, S. Ostrowitzki, K.M. Sink
J Prev Alz Dis 2023;1(10):41-49Show summaryHide summary
Background: Screening procedures for early Alzheimer’s disease (AD) trials seek to efficiently identify participants who fulfill clinical and biomarker criteria for AD and enrich for those most likely to experience significant clinical progression during the study. Episodic memory performance is often assessed in screening, but the utility of different memory tests for optimizing screening efficiency and/or rates of clinical progression remains uncertain.
Objectives: Cross-study comparisons of the effects of inclusion criteria based on performance on the Free and Cued Selective Reminding Test (FCSRT) or the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) on screen-failure rates for episodic memory and β-amyloid (Aβ) positivity (by CSF or PET) and on subsequent rates of clinical disease progression in randomized participants across three clinical trials in early (prodromal-to-mild) AD.
Design: Secondary analyses of cross-sectional and longitudinal clinical trial data.
Setting: Multi-center international clinical trials.
Participants: Individuals with prodromal-to-mild AD screened and/or randomized in clinical trials for crenezumab (CREAD, CREAD2) or semorinemab (Tauriel). Cross-sectional analyses of screening data for episodic memory impairment included participants from CREAD2 (n=2897) and Tauriel (n=887) and for Aβ positivity included participants from CREAD (n=1138), CREAD2 (n=1119), and Tauriel (n=483). Longitudinal analyses of rates of clinical progression included participants from CREAD (n=779), CREAD2 (n=773), and Tauriel (n=331).
Measurements: Cross-sectional analyses examined eligibility rates per cutoffs defined for the FCSRT (CREAD, CREAD2) or RBANS (Tauriel) and per Aβ positivity using CSF and/or PET biomarkers. Longitudinal analyses examined rates of clinical progression on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL).
Results: Lower rates of study eligibility per episodic memory criteria were seen with the FCSRT (CREAD2) relative to the RBANS (Tauriel), but similar rates of eligibility per Aβ positivity criteria were seen amongst participants with episodic memory impairment per the cutoffs used on either assessment. Similar rates of clinical decline over 18 months on the CDR-SB, ADAS-Cog13, and ADCS-ADL were observed in study populations enriched using the FCSRT (CREAD, CREAD2) or the RBANS (Tauriel).
Conclusions: Cutoffs for episodic memory impairment on the FCSRT used in the CREAD and CREAD2 studies are more stringent than those on the RBANS used in the Tauriel study, resulting in lower rates of eligibility. However, given that study enrichment with either test yields similar rates of Aβ positivity and clinical progression, considerations beyond these factors may drive the decision of which assessment to use for screening in early AD clinical trials.
E. Teng ; P.T. Manser ; M. Shah ; K. Pickthorn ; N. Hu ; S. Djakovic ; H. Swendsen ; M. Blendstrup ; G. Faccin ; S. Ostrowitzki ; K.M. Sink ; (2022): The Use of Episodic Memory Tests for Screening in Clinical Trials for Early Alzheimer’s Disease: A Comparison of the Free and Cued Selective Reminding Test (FCSRT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.101
PHARMACOLOGICAL INVENTIONS FOR ALZHEIMER TREATMENT IN THE UNITED STATES OF AMERICA: A REVISION PATENT FROM 2010 – 2020
N. Navarro-Gómez, M. Valdes-Gonzalez, B.B. Garrido-Suárez, G. Garrido
J Prev Alz Dis 2023;1(10):50-68Show summaryHide summary
Alzheimer’s disease (AD) is the most common form of dementia. There is currently no cure, and the available pharmacological treatment focuses on treating the symptoms. This study aimed to analyze the pharmacological treatments for AD protected in the US Patent Office. The Matheo Patent software was used to search for patents granted in the 2010-2020 period in the USPTO database. The search strategy «Alzheimer» was used in title and abstract and the International Patent Classification (IPC) codes A61P* and A61K*. The selected patents were divided into six categories according to therapeutic target. Complementary information from scientific databases was used to determine the stage of investigation and efficacy of the patented molecules. In the analyzed period, 58 patents were granted: 10 directed to Aβ peptide metabolism and deposition, three to tau, seven to inflammation, nine to cholinergic, two to glutamatergic and 27 to other targets. More than 80.0% belong to holders from the USA, France, and Japan. The molecules Elenbecestat and LY3202626 decreased the burden of Aβ plaques without significant cognitive improvement, Donanemab is in Phase 3 clinical trial, and the FDA has designated it Breakthrough Therapy. CPC-201 and PXT864 demonstrated, in Phase 2, good tolerability and improvement of AD symptoms. Most of the inventions are focused on treating the earliest phase of AD. The most advanced treatments in their research are those focused on treating Aβ accumulation. More studies are needed to prove the efficacy of the patented molecules.
N. Navarro-Gómez ; M. Valdes-Gonzalez ; B.B. Garrido-Suárez ; G. Garrido ; (2023): Pharmacological Inventions for Alzheimer Treatment in the United States of America: A Revision Patent from 2010 – 2020. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.2
GENDER-SPECIFIC DESIGN AND EFFECTIVENESS OF NONPHARMACOLOGICAL INTERVENTIONS AGAINST COGNITIVE DECLINE – SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
A.E. Zülke, S.G. Riedel-Heller, F. Wittmann, A. Pabst, S. Röhr, M. Luppa
J Prev Alz Dis 2023;1(10):69-82Show summaryHide summary
Background: The number of people living with dementia worldwide is increasing rapidly. Preventive approaches constitute a promising strategy to counter the dementia epidemic, and growing numbers of lifestyle interventions are conducted around the globe. Gender differences with respect to modifiable risk factors for dementia have been reported, however, little is known about gender-specific effectiveness of lifestyle trials against cognitive decline and dementia. A systematic review and meta-analysis was conducted to assess evidence on gender-specific design and effectiveness of randomized controlled trials against cognitive decline.
Methods: Systematic literature searches were conducted in MEDLINE, PsycINFO, Web of Science, Cochrane Central and ALOIS. Studies assessing global and/or domain-specific cognitive function in older adults free from dementia were eligible for the systematic review. We assessed between-group effect sizes using random-effects meta-analysis. Methodological quality of included studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN)-checklist.
Results: The systematic review and meta-analysis included 34 and 31 studies, respectively. Effects of lifestyle-interventions on global cognition were non-significant overall (g = .27; 95% CI: -.01; .56) and in male subsamples (g = -.05; 95% CI: -.55; .45), and small for female subsamples (g = .38; 95% CI: .05; .72). Small beneficial effects were found for memory (overall: g = .38; 95% CI = .17; .59). Stratified by gender, significant effects were observed only in women (g = .39; 95% CI = .13; .65; men: g = .37; 95% CI: .00; .73). Aspects of gender in study design and conduct were discussed in a small minority of studies. Comparable results were observed for executive function and verbal fluency. Methodological quality was deemed high in 17.6% of studies, acceptable and low quality in 52.9% and 29.4%, respectively.
Discussion: We found evidence for small differences in the effectiveness of lifestyle interventions on global cognition and memory in favor of women. However, small numbers of trials 1) targeting men and 2) reporting gender-specific results for older adults with mild cognitive impairment warrant further attention. Assessing differences in modifiable risk factors for dementia in men and women and systematically addressing aspects of gender in trial conduction and recruitment in future studies might increase knowledge on gender-specific effectiveness of lifestyle trials against cognitive decline.
A.E. Zülke ; S.G. Riedel-Heller ; F. Wittmann ; A. Pabst ; S. Röhr ; M. Luppa ; (2022): Gender-Specific Design and Effectiveness of Non-Pharmacological Interventions against Cognitive Decline – Systematic Review and Meta-Analysis of Randomized Controlled Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.80
SOCIOECONOMIC STATUS AND RISKS OF COGNITIVE IMPAIRMENT AND DEMENTIA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF 39 PROSPECTIVE STUDIES
A.-Y. Wang, H.-Y. Hu, Y.-N. Ou, Z.-T. Wang, Y.-H. Ma, L. Tan, J.-T. Yu
J Prev Alz Dis 2023;1(10):83-94Show summaryHide summary
Background: In recent decades, increased attention has been paid to the impact of socioeconomic status (SES) on cognition function and dementia, however, an ongoing debate continues to exist. The objective of our study was to explore the potential effect of SES on the risks of cognitive dysfunction and dementia.
Methods: PubMed, Cochrane Library, and EMBASE were searched for prospective studies from inception to 9 January 2022. Meta-analyses using random-effect models were performed, and then subgroup analyses stratified by study characteristics for specific outcomes were conducted.
Results: Thirty-nine prospective studies (1,485,702 individuals) were eligible for inclusion, of which 25 reported the incidence of dementia and 14 reported cognitive decline. Primary results of the meta-analyses found an elevated combined risk of cognitive impairment and dementia (relative risk [RR] = 1.31, 95% confidence interval [CI] = 1.16-1.49) in low-SES participants compared with high-SES participants. We also found an elevated risk of all-cause dementia (RR = 1.40, 95% CI = 1.12-1.74) in low-SES participants. Further subgroup analyses stratified by education, occupation, and income showed that low education subgroup (RR = 1.21, 95% CI = 1.04-1.41) and low-income subgroup (RR = 1.22, 95% CI = 1.10-1.35) had an increased combined risks of cognitive impairment and dementia, but only individuals with lower education had a higher risk of dementia (RR = 1.66, 95% CI = 1.20-2.32).
Conclusions: Low SES substantially increased the risk of dementia and cognitive dysfunction, suggesting that public health strategies could reduce the dementia burden by reducing social inequalities.
A.-Y. Wang ; H.-Y. Hu ; Y.-N. Ou ; Z.-T. Wang ; Y.-H. Ma ; L. Tan ; J.-T. Yu ; (2022): Socioeconomic Status and Risks of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of 39 Prospective Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.81
PROGRAMMED DEATH OF MICROGLIA IN ALZHEIMER’S DISEASE: AUTOPHAGY, FERROPTOSIS, AND PYROPTOSIS
Z. Qiu, H. Zhang, M. Xia, J. Gu, K. Guo, H. Wang, C. Miao
J Prev Alz Dis 2023;1(10):95-103Show summaryHide summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Increasing evidence has demonstrated that the damage of cell plays an important role in AD. Cell death is a critical phenomenon for physiological functions, which promotes AD pathogenesis. Programmed cell death, including necroptosis, pyroptosis, autophagy, and ferroptosis, have been discovered that have unique biological functions and pathophysiological characteristics. Here, we review the available evidence detailing the mechanisms of programmed microglial death, including pyroptosis, autophagy, and ferroptosis. We also highlight the role of programmed death of microglia during the process of AD and focus on the connection between the disease and cell death.
Z. Qiu ; H. Zhang ; M. Xia ; J. Gu ; K. Guo ; H. Wang ; C. Miao ; (2023): Programmed Death of Microglia in Alzheimer’s Disease: Autophagy, Ferroptosis, and Pyroptosis . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.3
AGE- AND SEX-DIFFERENT ASSOCIATIONS BETWEEN COGNITIVE PERFORMANCE AND INFLAMMATORY BIOMARKERS IN COMMUNITY DWELLING OLDER ADULTS: TOWARDS PRECISION PREVENTIVE STRATEGIES
B.-A. Chen, W.-J. Lee, C.-P. Chung, L.-N. Peng, L.-K. Chen
J Prev Alz Dis 2023;1(10):104-111Show summaryHide summary
Background: Studies have demonstrated associations between inflammatory biomarkers and cognitive function in people with dementia or stroke, but little is known regarding these associations in healthy middle-aged and older populations.
OBJECTIVES: This study aims to examine associations between inflammatory biomarkers (both vascular and systemic) and cognitive performance in stroke- and dementia-free middle-aged and older adults without apolipoprotein E4 (ApoE ε4) allele carriers.
DESIGN: A cross-sectional study.
SETTING: Social Environment and Biomarkers of Aging Study (SEBAS) 2006.
PARTICIPANTS: A total of 983 participants aged 53 years and older.
MEASUREMENTS: Composite cognitive function assessment, including the Short Portable Mental Status Questionnaire, the Rey Auditory Verbal Learning Test, and the Wechsler Adult Intelligence Scale. Overnight venous blood sampling for 6 inflammatory biomarkers (C-reactive protein, interleukin-6, fibrinogen, homocysteine, intercellular adhesion molecule-1 and E-selectin) and ApoE genotyping.
RESULTS: Among 983 participants (mean age: 65.8±9.5 years), 808 were non-ApoE e4 allele carriers and were stroke- and dementia-free. Higher log fibrinogen was associated with poorer cognitive function after adjustment for potential confounding factors in non-ApoE e4 allele carriers and stroke- and dementia-free populations (unstandardized coefficients β= -1.553, P value= 0.003). In participants aged 65 years or older, both of elevated fibrinogen and homocysteine were associated with poorer cognitive function (β= -2.288, P value= 0.015; β= -1.331, P value= 0.012, respectively). Elevated log CRP was significantly associated with lower cognitive function only in women (β= -0.514, P value= 0.024).
CONCLUSION: Higher serum levels of fibrinogen were negatively associated with cognitive function, which was independent of ApoE genotyping and prior cerebrovascular events in dementia-free community-dwelling older adults. Further studies are needed to validate the roles of fibrinogen in the pathophysiology of dementia and elucidate the underlying mechanisms.
B.-A. Chen ; W.-J. Lee ; C.-P. Chung ; L.-N. Peng ; L.-K. Chen ; (2022): Age- and Sex-Different Associations between Cognitive Performance and Inflammatory Biomarkers in Community Dwelling Older Adults: towards Precision Preventive Strategies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.83
ASSOCIATIONS OF STAGES OF OBJECTIVE MEMORY IMPAIRMENT WITH CEREBROSPINAL FLUID AND NEUROIMAGING BIOMARKERS OF ALZHEIMER’S DISEASE
K.K. Petersen, A. Ezzati, R.B. Lipton, B.A. Gordon, J. Hassenstab, J.C. Morris, E. Grober
J Prev Alz Dis 2023;1(10):112-119Show summaryHide summary
Objective: To investigate cerebrospinal fluid (CSF) and neuroimaging correlates of Stages of Objective Memory Impairment (SOMI) based on Free and Cued Selective Reminding Test (FCSRT) performance, and to evaluate the effect of APOE ε4 status on this relationship.
Methods: Data from 586 cognitively unimpaired individuals who had FCSRT, CSF, and volumetric magnetic resonance imaging (MRI) measures available was used. We compared CSF measures of β-amyloid (Aβ42/Aβ40 ratio), phosphorylated tau (p-Tau181), total tau (t-Tau), hippocampal volume, and PIB-PET mean cortical binding potential with partial volume correction (MCBP) among SOMI groups in the whole sample and in subsamples stratified by APOE ε4 status.
Results: Participants had a mean age of 67.4 (SD=9.1) years, had 16.1 (SD=2.6) years of education, 57.0% were female, and 33.8% were APOE ε4 positive. In the entire sample, there was no significant difference between SOMI stages in Aβ42/Aβ40 ratio, p-Tau181, t-Tau, or PIB-PET MCBP when adjusted for age, sex, and education. However, higher SOMI stages had smaller hippocampal volume (F=3.29, p=0.020). In the stratified sample based on APOE ε4 status, in APOE ε4 positive individuals, higher SOMI stages had higher p-Tau181 (F=2.94, p=0.034) higher t-Tau (F=3.41, p=0.019), and smaller hippocampal volume (F=5.78, p<0.001). There were no significant differences in CSF or imaging biomarkers between SOMI groups in the APOE ε4 negative subsample.
Conclusion: Cognitively normal older individuals with higher SOMI stages have higher in-vivo tau and neurodegenerative pathology only in APOE ε4 carriers. These original results indicate the potential usefulness of the SOMI staging system in assessing of tau and neurodegenerative pathology.
K.K. Petersen ; A. Ezzati ; R.B. Lipton ; B.A. Gordon ; J. Hassenstab ; J.C. Morris ; E. Grober ; (2022): Associations of Stages of Objective Memory Impairment with Cerebrospinal Fluid and Neuroimaging Biomarkers of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.98
SYSTEMATIC AND COMPARATIVE ANALYSIS OF THE BURDEN OF ALZHEIMER´S DISEASE AND OTHER DEMENTIAS IN MEXICO. RESULTS AT THE NATIONAL AND SUBNATIONAL LEVELS, 1990- 2019
M. Agudelo-Botero, L. Giraldo-Rodríguez, M.E. Rojas-Russell
J Prev Alz Dis 2023;1(10):120-129Show summaryHide summary
INTRODUCTION: Dementias, including Alzheimer´s disease (AD), are one of the leading causes of disability and mortality in older people. It is a growing health problem in low- and middle-income countries, where epidemiological information is scarce and deficient. The aim of this study was to analyze the burden of AD and other dementias in Mexico from 1990 to 2019 by sex, subnational level, and age groups.
METHODS: A secondary analysis was conducted using data from the 2019 Global Burden of Disease, Injury, and Risk Factors Study (GBD). Data on prevalence, incidence, mortality, years of life lost (YLL), years lived with disability (YLD), and disability-adjusted life years (DALY) due to AD and other dementias were obtained. A joinpoint regression analysis was performed to describe the changes in the trend of age-standardized DALY rates by AD and other dementias during the analysis period.
RESULTS: AD and other dementias ranked second among neurological disorders producing the most DALY in Mexico. Between 1990 and 2019, prevalence and incidence increased by almost 203%. In 2019, the age-standardized rate per 100,000 inhabitants was: 512 for prevalence, 79.3 for incidence, 73.3 for YLD, 256.9 for YLL and 272.2 for DALY. Likewise, five states concentrated 39% of AD and other dementias cases: Ciudad de México, Estado de México, Veracruz, Jalisco and Puebla. Differences were also observed by sex and age groups.
DISCUSSION: Given that the number of older adults in Mexico will significantly rise over the next few decades, AD and other dementias represent one of the most important health challenges. The fact that epidemiological and demographic transformations take place in Mexico in a very diverse way makes it difficult for the country to adequately plan for the growing demands of both people with AD and other dementias and their families.
M. Agudelo-Botero ; L. Giraldo-Rodríguez ; M.E. Rojas-Russell ; (2022): Systematic and Comparative Analysis of the Burden of Alzheimer´s Disease and Other Dementias in Mexico. Results at the National and Subnational Levels, 1990-2019. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.92
DEMOGRAPHIC ANALYSIS OF INDUSTRY-SPONSORED ALZHEIMER’S DISEASE TRIAL POPULATIONS IN THE UNITED STATES
J Prev Alz Dis 2023;1(10):130-132Show summaryHide summary
The Food and Drug Administration has that “sponsors should enroll participants who reflect the characteristics of clinically relevant populations”. Recent reports have noted that global Alzheimer’s Disease trials have enrolled predominantly White subjects. However, a thorough analysis of industry-sponsored, United States-only Alzheimer’s trials has yet to be performed. A search of the clinicaltrials.gov database and PubMed identified 101 industry-sponsored Alzheimer’s trials, performed solely in the United States, with gender data. The percentage of male (46%) vs. female (54%) subjects was higher than expected compared to real-world data. There were 50 Alzheimer’s trials with race data. There was a significant overrepresentation of White subjects (92%) compared to all other race groups. These data suggest that significant modifications of subject recruitment methods are needed to increase the enrollment of underrepresented populations into Alzheimer’s trials of potential new therapeutic agents in the United States.
S.J. Peroutka ; ; (2022): Demographic Analysis of Industry-Sponsored Alzheimer’s Disease Trial Populations in the United States. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.90
RISK ESTIMATES OF DEMENTIA AND ALZHEIMER’S DISEASE AMONG DIFFERENT WHOLE GRAIN FOOD CONSUMPTION CATEGORIES: A PILOT STUDY
K. Wang, Q. Zhou
J Prev Alz Dis 2023;1(10):133-136Show summaryHide summary
Objectives: Whole grains (WG) have been widely recognized as healthy foods but few prospective studies have examined WG foods consumption and all-cause dementia and Alzheimer’s disease (AD) dementia. This pilot study aimed to investigate the relationship between WG and dementia.
Methods: 2958 subjects from the Framingham Offspring cohort were included with the Food Frequency Questionnaire (FFQ) to assess their diet intake. And multivariate Cox proportional regression was conducted to examine the relations.
Results: After an average follow-up of 12.6 years, 322 all-cause dementia were documented, including 247 AD dementia. In the fully adjusted model, participants in the highest vs. the lowest quintiles of WG consumption had lower risks of all-cause dementia (HR, 0.72; 95% CI, 0.53-0.84; P for trend <0.001) and AD dementia (HR, 0.64; 95% CI, 0.47-0.80; P for trend <0.001).
Conclusions: High consumption of WG foods is associated with decreased risks of all-cause dementia and AD dementia.t disease mortality. Our findings are from a preliminary study and need to be confirmed in comprehensive settings and integrated statistical methods.
K. Wang ; Q. Zhou ; (2022): Risk Estimates of Dementia and Alzheimer’s Disease among Different Whole Grain Food Consumption Categories: A Pilot Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.91
PREVENTION OF ALZHEIMER’S DISEASE AND COGNITIVE DECLINE WITH DIET & LIFESTYLE: PROCEEDINGS OF THE A. G. LEVENTIS FOUNDATION CONFERENCE
M.S. Hershey, M. Sotos-Prieto, S. Andrieu, A. Hofman, P. Magiatis, M.A. Martinez-Gonzalez, M. Yannakoulia, S. Kales, N. Scarmeas
J Prev Alz Dis 2023;1(10):137-143Show summaryHide summary
The A. G. Leventis Foundation International Conference, “Prevention of Alzheimer’s Disease and Cognitive Decline with Diet & Lifestyle”, was held on May 11-12th, 2022 in Nicosia, Cyprus. This conference examined the role of diet and lifestyle for the prevention and treatment of Alzheimer’s Disease and other forms of cognitive decline. Speakers from leading academic institutions presented evidence on healthy dietary patterns, with a particular focus on the traditional Mediterranean diet (MedDiet), in association with cognitive outcomes, mainly cognitive decline, dementia, and Alzheimer’s disease, from both observational and interventional studies. Moreover, future directions for the potential use of olive oil, rich in polyphenols, for its therapeutic use as a nutraceutical, as well as nutritional interventions with high-quality dietary patterns (i.e. MedDiet) that support existing primarily observational evidence for the prevention of cognitive decline, as well as challenges in designing rigorous clinical trials are summarized and discussed within the conference proceedings.
M.S. Hershey ; M. Sotos-Prieto ; S. Andrieu ; A. Hofman ; P. Magiatis ; M.A. Martinez-Gonzalez ; M. Yannakoulia ; S. Kales ; N. Scarmeas ; (2022): Prevention of Alzheimer’s Disease and Cognitive Decline with Diet & Lifestyle: Proceedings of the A. G. Leventis Foundation Conference. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.99
EMBRYO SELECTION FOR A CARRIER OF AN EARLY-ONSET ALZHEIMER’S DISEASE-ASSOCIATED MUTATION IN THE PSEN1 GENE
O.H. Valdés-Martínez, S.M. García-Luna, L.C. Oceguera-Palao, L. Villarreal-Pineda, L.H. Sordia-Hernández, B. de la Fuente Cortez, A. Morales-Martínez
J Prev Alz Dis 2023;1(10):144-147Show summaryHide summary
Alzheimer’s disease (AD) is the most common neurodegenerative dementia. It manifests as early-onset or late-onset AD. Early-onset AD represents about 5.5% of the total cases and occurs in patients under age 65. The EOAD progresses more aggressively and has a shorter life expectancy due to a greater pathogenic load. We present two asymptomatic siblings, a 30-year-old male and a 34- year-old female, who are heterozygous carriers of a pathogenic variant c.428T>C (Ile143Thr) in the presenilin 1 (PSEN1) gene. During genetic counseling, assisted reproduction techniques (ART) coupled with embryo biopsy and a preimplantation genetic test for monogenic disorders (PGT-M) were recommended to provide reproductive care for the patients and their partners. ART and preimplantation genetic testing (PGT) have made it possible to have chromosomally normal and genetically unaffected offspring, allowing patients with genetic diseases to become parents.
O.H. Valdés-Martínez ; S.M. García-Luna ; L.C. Oceguera-Palao ; L. Villarreal-Pineda ; L.H. Sordia-Hernández ; B. de la Fuente Cortez ; A. Morales-Martínez ; (2023): Embryo Selection for a Carrier of an Early-Onset Alzheimer’s Disease-Associated Mutation in the PSEN1 Gene. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.4
LETTER TO THE EDITOR: AMBAR: A THERAPEUTICAL APPROACH FOR ALZHEIMER’S DISEASE PATIENTS REGARDLESS OF AMYLOID STATUS
M. Costa, M. Boada
J Prev Alz Dis 2023;1(10):148-149Show summaryHide summary
M. Costa ; M. Boada ; (2022): Letter to the Editor: AMBAR: A Therapeutical Approach for Alzheimer’s Disease Patients Regardless of Amyloid Status. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.100
ERRATUM TO: CEREBRAL PHOSPHO-TAU ACTS SYNERGISTICALLY WITH SOLUBLE AΒ42 LEADING TO MILD COGNITIVE IMPAIRMENT IN AAV-AD RATS
B. Souchet, M. Audrain, Y. Gu, M.F. Lindberg, N.S. Orefice, E. Rey, N. Cartier, N. Janel, L. Meijer, J. Braudeau
J Prev Alz Dis 2023;1(10):150Show summaryHide summary
B. Souchet ; M. Audrain ; Y. Gu ; M.F. Lindberg ; N.S. Orefice ; E. Rey ; N. Cartier ; N. Janel ; L. Meijer ; J. Braudeau ; (2022): Erratum to: Cerebral phospho-tau acts synergistically with soluble Aβ42 leading to Mild Cognitive Impairment in AAV-AD rats. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2022.74
ERRATUM TO: ALZHEIMER’S DISEASE COMPOSITE SCORE: A POST-HOC ANALYSIS USING DATA FROM THE LIPIDIDIET TRIAL IN PRODROMAL ALZHEIMER’S DISEASE
S.B. Hendrix, H. Soininen, A.M.J. van Hees, N. Ellison, P.J. Visser, A. Solomon, A. Attali, K. Blennow, M. Kivipelto, T. Hartmann
J Prev Alz Dis 2023;1(10):151Show summaryHide summary
S.B. Hendrix ; H. Soininen ; A.M.J. van Hees ; N. Ellison ; P.J. Visser ; A. Solomon ; A. Attali ; K. Blennow ; M. Kivipelto ; T. Hartmann ; (2022): Erratum to: Alzheimer’s Disease Composite Score: a Post-Hoc Analysis Using Data from the LipiDiDiet Trial in Prodromal Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1007/s42414-019-0001-5