Ahead of print articles
HIGH-FAT DIET-INDUCED DIABETIC CONDITIONS EXACERBATE COGNITIVE IMPAIRMENT IN A MOUSE MODEL OF ALZHEIMER’S DISEASE VIA A SPECIFIC TAU PHOSPHORYLATION PATTERN
Y. Ito, S. Takeda, T. Nakajima, A. Oyama, H. Takeshita, K. Miki, Y. Takami, Y. Takeya, M. Shimamura, H. Rakugi, R. Morishita
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BACKGROUND: Epidemiological evidence has demonstrated a clear association between diabetes mellitus and increased risk of Alzheimer’s disease (AD). Cerebral accumulation of phosphorylated tau aggregates, a cardinal neuropathological feature of AD, is associated with neurodegeneration and cognitive decline. Clinical and experimental studies indicate that diabetes mellitus affects the development of tau pathology; however, the underlying molecular mechanisms remain unknown.
OBJECTIVE: In the present study, we used a unique diabetic AD mouse model to investigate the changes in tau phosphorylation patterns occurring in the diabetic brain.
DESIGN: Tau-transgenic mice were fed a high-fat diet (n = 24) to model diabetes mellitus. These mice developed prominent obesity, severe insulin resistance, and mild hyperglycemia, which led to early-onset neurodegeneration and behavioral impairment associated with the accumulation of hyperphosphorylated tau aggregates.
RESULTS: Comprehensive phosphoproteomic analysis revealed a unique tau phosphorylation signature in the brains of mice with diabetic AD. Bioinformatic analysis of the phosphoproteomics data revealed putative tau-related kinases and cell signaling pathways involved in the interaction between diabetes mellitus and AD.
CONCLUSION: These findings offer potential novel targets that can be used to develop tau-based therapies and biomarkers for use in AD.
Y. Ito ; S. Takeda ; T. Nakajima ; A. Oyama ; H. Takeshita ; K. Miki ; Y. Takami ; Y. Takeya ; M. Shimamura ; H. Rakugi ; R. Morishita ; (2023): High-Fat Diet-Induced Diabetic Conditions Exacerbate Cognitive Impairment in a Mouse Model of Alzheimer’s Disease Via a Specific Tau Phosphorylation Pattern. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.85
ORAL HEALTH AS A RISK FACTOR FOR ALZHEIMER DISEASE
S.M. Pruntel, B.C. van Munster, J.J. de Vries, A. Vissink, A. Visser
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In patients with Alzheimer’s disease pathophysiological changes of the brain that initiate the onset of Alzheimer’s disease include accumulation of amyloid-β plaques and phosphorylation of tau-tangles. A rather recently considered risk factor for the onset of Alzheimer’s disease is poor oral health. The aim of this systematic review of the literature was to assess the potential association(s) of oral health as a risk factor for the onset of Alzheimer’s disease. After a systematic search of Pubmed, Embase and Web of Science. A total of 1962 studies were assessed, of which 17 studies demonstrated possible associations between oral health diseases and Alzheimer’s disease. 4 theories could be distinguished that describe the possible links between oral health and the development or onset of Alzheimer’s disease; 1) role of pathogens, 2) role of inflammatory mediators, 3) role of APOE alleles and 4) role of Aβ peptide. The main common denominator of all the theories is the neuroinflammation due to poor oral health. Yet, there is insufficient evidence to prove a link due to the diversity of the designs used and the quality of the study design of the included studies. Therefore, further research is needed to find causal links between oral health and neuroinflammation that possibly can lead to the onset of Alzheimer’s disease with the future intention to prevent cognitive decline by better dental care.
S.M. Pruntel ; B.C. van Munster ; J.J. de Vries ; A. Vissink ; A. Visser ; (2023): Oral Health as a Risk Factor for Alzheimer Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.82
ARE POPULATION-LEVEL APPROACHES TO DEMENTIA RISK REDUCTION UNDER-RESEARCHED? A RAPID REVIEW OF THE DEMENTIA PREVENTION LITERATURE
S. Walsh, L. Wallace, I. Kuhn, O. Mytton, L. Lafortune, W. Wills, N. Mukadam, C. Brayne
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Dementia is forecast to become increasingly prevalent, particularly in low- and middle-income countries, and is associated with high human and economic costs. Primary prevention of dementia -preventing risk factors leading to disease development - is an emerging global public health priority. Primary prevention can be achieved in two ways: individual-level or population-level. In this rapid review, we quantify the proportion of contributing interventional evidence to the dementia primary prevention literature that is concerned with either approach. We searched Medline, the National Institute for Health and Care Excellence, Cochrane, the World Health Organization, and Google to identify systematic reviews that described primary prevention interventions for dementia. We used search terms related to dementia risk reduction, intervention/policy, and review. We analysed reference lists of included dementia prevention reviews to identify contributing primary prevention evidence, and categorised these as either individual-level or population-level. Additionally, we examined search strategies to investigate the likelihood of reviews identifying available population-level interventions. We included twelve of the 527 articles retrieved. Population-level evidence was summarised by only two reviews. In these two reviews, <2.5% of the interventions described where population-level interventions. Most search strategies were weighted towards identifying individual-level evidence. Existing systematic reviews of dementia primary prevention interventions include almost no population-level evidence. Correction of this imbalance is needed to ensure that dementia prevention policies can achieve meaningful reductions in the prevalence of, and inequalities in, dementia.
S. Walsh ; L. Wallace ; I. Kuhn ; O. Mytton ; L. Lafortune ; W. Wills ; N. Mukadam ; C. Brayne (2023): Are Population-Level Approaches to Dementia Risk Reduction Under-Researched? A Rapid Review of the Dementia Prevention Literature. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.57
BURDEN OF ILLNESS IN PEOPLE WITH ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW OF EPIDEMIOLOGY, COMORBIDITIES AND MORTALITY
K.L. Lanctôt, J. Hviid Hahn-Pedersen, C.S. Eichinger, C. Freeman, A. Clark, L.R.S. Tarazona, J. Cummings
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BACKGROUND: Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide, and an updated quantification of its impact on morbidity, disability, and mortality is warranted. We conducted a systematic literature review, focusing on the past decade, to characterize AD and assess its impact on affected individuals.
METHODS: Searches of Embase, MEDLINE, and the Cochrane Library were conducted on August 7, 2020 and updated on November 10, 2021. Observational studies from any country reporting incidence, prevalence, comorbidities, and/or outcomes related to disability and mortality/life expectancy, in people with mild cognitive impairment (MCI) due to AD, or mild, moderate, or severe AD dementia, were considered relevant.
RESULTS: Data were extracted from 88 studies (46 incidence/prevalence; 44 comorbidities; 25 mortality-/disability-related outcomes), mostly from Europe, the USA, and Asia. AD dementia diagnosis was confirmed using biomarkers in only 6 studies. Estimated 5-year mortality in AD was 35%, and comorbidity prevalence estimates varied widely (hypertension: 30.2–73.9%; diabetes: 6.0–24.3%; stroke: 2.7–13.7%). Overall, people with AD dementia were more likely to have cardiovascular disease or diabetes than controls, and 5-year mortality in people with AD dementia was double that in the age- and year-matched general population (115.0 vs 60.6 per 1,000 person-years).
CONCLUSIONS: AD is associated with excess morbidity and mortality. Future longitudinal studies of population aging, incorporating biomarker assessment to confirm AD diagnoses, are needed to better characterize the course of MCI due to AD and AD dementia.
K.L. Lanctôt ; J. Hviid Hahn-Pedersen ; C.S. Eichinger ; C. Freeman ; A. Clark ; L.R.S. Tarazona ; J. Cummings (2023): Burden of Illness in People with Alzheimer’s Disease: A Systematic Review of Epidemiology, Comorbidities and Mortality. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.61
LIFESTYLE AND SOCIOECONOMIC TRANSITION AND HEALTH CONSEQUENCES OF ALZHEIMER’S DISEASE AND OTHER DEMENTIAS IN GLOBAL, FROM 1990 TO 2019
Y. Cui, W. Yang, J. Shuai, Y. Ma, Y. Yan
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Background: Previous studies only focused on changes in the global age-specific incidence and mortality for Alzheimer’s disease and other dementias, failed to distinguish between cohort and period effects, and did not discuss risk factors separately.
Methods: In this study, Alzheimer’s disease disability-adjusted life years (DALYs) data to estimate the burden by gender, age, locations, and social-demographic status for 21 regions from 1990 to 2019. Additionally, trend analysis was performed using the age-period-cohort (APC) model and Join-point model.
Results: In most regions, indicators (incidence, mortality, and DALYs) increased steadily with socio-demographic index(SDI) increased. The age effects for Alzheimer’s disease and other dementias showed a significant increase from 40 to 95 years. The cohort effects rate ratios (RRs) had a rapid reduction attributed to smoking, high fasting plasma glucose, and high body mass index (BMI).
Conclusions: Countries in middle-low and low SDI regions have higher levels of risk factor exposure. As a result, rapid and effective government responses are necessary to control dementia risk factors and reduce the disease burden in these countries.
Y. Cui ; W. Yang ; J. Shuai ; Y. Ma ; Y. Yan ; (2023): Lifestyle and Socioeconomic Transition and Health Consequences of Alzheimer’s Disease and Other Dementias in Global, from 1990 to 2019. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.63
EXPECTANCY DOES NOT PREDICT 18-MONTH TREATMENT OUTCOMES WITH COGNITIVE TRAINING IN MILD COGNITIVE IMPAIRMENT
J.N. Motter, S.N. Rushia, M. Qian, C. Ndouli, A. Nwosu, J.R. Petrella, P.M. Doraiswamy, T.E. Goldberg, D.P. Devanand
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Background: Computerized cognitive training (CCT) has emerged as a potential treatment option for mild cognitive impairment (MCI). It remains unclear whether CCT’s effect is driven in part by expectancy of improvement.
OBJECTIVES: This study aimed to determine factors associated with therapeutic expectancy and the influence of therapeutic expectancy on treatment effects in a randomized clinical trial of CCT versus crossword puzzle training (CPT) for older adults with MCI.
DESIGN: Randomized clinical trial of CCT vs CPT with 78-week follow-up.
SETTING: Two-site study - New York State Psychiatric Institute and Duke University Medical Center.
PARTICIPANTS: 107 patients with MCI.
INTERVENTION: 12 weeks of intensive training with CCT or CPT with follow-up booster training over 78 weeks.
MEASUREMENTS: Patients rated their expectancies for CCT and CPT prior to randomization.
RESULTS: Patients reported greater expectancy for CCT than CPT. Lower patient expectancy was associated with lower global cognition at baseline and older age. Expectancy did not differ by sex or race. There was no association between expectancy and measures of everyday functioning, hippocampus volume, or apolipoprotein E genotype. Expectancy was not associated with change in measures of global cognition, everyday functioning, and hippocampus volume from baseline to week 78, nor did expectancy interact with treatment condition.
CONCLUSIONS: While greater cognitive impairment and increased age was associated with low expectancy of improvement, expectancy was not associated with the likelihood of response to treatment with CPT or CCT.
J.N. Motter ; S.N. Rushia ; M. Qian ; C. Ndouli ; A. Nwosu ; J.R. Petrella ; P.M. Doraiswamy ; T.E. Goldberg ; D.P. Devanand ; (2023): Expectancy Does Not Predict 18-month Treatment Outcomes with Cognitive Training in Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.62
JPAD Volume 10, N°04 - 2023
EDITORIAL: THE STATE OF ALZHEIMER’S RESEARCH AND THE PATH FORWARD
H.M. Fillit, B. Vellas, Y. Hara
J Prev Alz Dis 2023;4(10):617-619Show summaryHide summary
H.M. Fillit ; B. Vellas ; Y. Hara ; (2023): Editorial: The State of Alzheimer’s Research and the Path Forward. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.102
GEROSCIENCE AND ALZHEIMER’S DISEASE DRUG DEVELOPMENT
J. Cummings, A.M. Leisgang Osse, J. Kinney
J Prev Alz Dis 2023;4(10):620-632Show summaryHide summary
Age is the most important risk factor for Alzheimer’s disease (AD). The acceptable age range for participation in AD clinical trials is 50 to 90, and this 40-year span incorporates enormous age-related change. Clinical trial participants tend to be younger and healthier than the general population. They are also younger than the general population of AD patients. Drug development from a geroscience perspective would take greater account of effects of aging on clinical trial outcomes. The AD clinical trial pipeline has diversified beyond the canonical targets of amyloid beta protein and tau. Many of these interventions apply to age-related disorders. Anti-inflammatory agents and bioenergetic and metabolic therapies are among the well represented classes in the pipeline and are applicable to AD and non-AD age-related conditions. Drug development strategies can be adjusted to better inform outcomes of trials regarding aged individuals. Inclusion of older individuals in the multiple ascending dose trials of Phase 1, use of geriatric-related clinical outcomes and biomarkers in Phase 2, and extension of these Phase 2 learnings to Phase 3 will result in a more comprehensive understanding of AD therapies and their relationship to aging. Clinical trials can employ a more comprehensive geriatric assessment approach and biomarkers more relevant to aging at baseline and as exploratory outcomes. Greater attention to the role of aging and its influence in AD clinical trials can result in better understanding of the generalizability of clinical trial findings to the older AD population.
J. Cummings ; A.M. Leisgang Osse ; J. Kinney ; (2023): Geroscience and Alzheimer’s Disease Drug Development. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.103
TRANSLATING THE BIOLOGY OF AGING INTO NEW THERAPEUTICS FOR ALZHEIMER’S DISEASE: SENOLYTICS
M. Riessland, M.E. Orr
J Prev Alz Dis 2023;4(10):633-646Show summaryHide summary
The recent FDA-approval for amyloid lowering therapies reflects an unwavering commitment from the Alzheimer’s disease (AD) research community to identify treatments for this leading cause of dementia. The clinical benefits achieved by reducing amyloid, though modest, provide evidence that disease modification is possible. Expanding the same tenacity to interventions targeting upstream drivers of AD pathogenesis could significantly impact the disease course. Advanced age is the greatest risk factor for developing AD. Interventions targeting biological aging offer the possibility of disrupting a foundational cause of AD. Senescent cells accumulate with age and contribute to inflammation and age-related diseases like AD. Senolytic drugs that clear senescent cells improve healthy aging, halt AD disease progression in animal models and are undergoing clinical testing. This review explores the biology of aging, the role of senescent cells in AD pathology, and various senotherapeutic approaches such as senolytics, dampening the SASP (senescence associated secretory phenotype), senescence pathway inhibition, vaccines, and prodrugs. We highlight ongoing clinical trials evaluating the safety and efficacy of the most advanced senolytic approach, dasatinib and quercetin (D+Q), including an ongoing Phase II senolytic trial supported by the Alzheimer’s Drug Discovery Foundation (ADDF). Challenges in the field of senotherapy for AD, including target engagement and biomarker development, are addressed. Ultimately, this research pursuit may lead to an effective treatment for AD and provide the field with another disease-modifying therapy to be used, alone or in combination, with other emerging treatment options.
M. Riessland ; M.E. Orr (2023): Translating the Biology of Aging into New Therapeutics for Alzheimer’s Disease: Senolytics. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.104
FIBRIN-TARGETING IMMUNOTHERAPY FOR DEMENTIA
A.B. Kantor, K. Akassoglou, J.B. Stavenhagen
J Prev Alz Dis 2023;4(10):647-660Show summaryHide summary
Blood-brain barrier (BBB) disruption is an early event in the development of Alzheimer’s disease. It precedes extracellular deposition of amyloid-β in senile plaques and blood vessel walls, the intracellular accumulation of neurofibrillary tangles containing phosphorylated tau protein, microglial activation, and neuronal cell death. BBB disruption allows the coagulation protein fibrinogen to leak from the blood into the brain, where it is converted by thrombin cleavage into fibrin and deposits in the parenchyma and CNS vessels. Fibrinogen cleavage by thrombin exposes a cryptic epitope termed P2 which can bind CD11b and CD11c on microglia, macrophages and dendritic cells and trigger an inflammatory response toxic to neurons. Indeed, genetic and pharmacological evidence demonstrates a causal role for fibrin in innate immune cell activation and the development of neurodegenerative diseases. The P2 inflammatory epitope is spatially and compositionally distinct from the coagulation epitope on fibrin. Mouse monoclonal antibody 5B8, which targets the P2 epitope without interfering with the clotting process, has been shown to reduce neurodegeneration and neuroinflammation in animal models of Alzheimer’s disease and multiple sclerosis. The selectivity and efficacy of this anti-human fibrin-P2 antibody in animal models supports the development of a monoclonal antibody drug targeting fibrin P2 for the treatment of neurodegenerative diseases. THN391 is a humanized, affinity-matured antibody which has a 100-fold greater affinity for fibrin P2 and improved development properties compared to the parental 5B8 antibody. It is currently in a Phase 1 clinical trial.
A.B. Kantor ; K. Akassoglou ; J.B. Stavenhagen (2023): Fibrin-Targeting Immunotherapy for Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.105
OPPORTUNITIES FOR CELLULAR REJUVENATION IN ALZHEIMER’S DISEASE: HOW EPIGENETIC REPROGRAMMING AND CHAPERONE-MEDIATED AUTOPHAGY ARE ENABLING NEXT GENERATION THERAPEUTIC APPROACHES
J Prev Alz Dis 2023;4(10):661-668Show summaryHide summary
Age remains the largest risk factor in the development of neurodegenerative diseases such as Alzheimer’s disease (AD). Numerous cellular hallmarks of aging contribute to the advancement of the pathologies associated with neurodegenerative disease. Not all cellular hallmarks of aging are independent and several fall into the broader category of cellular rejuvenation, which captures returning cells to a more youthful, improved functional state. Cellular rejuvenation is quickly becoming a hot topic in the development of novel therapeutic modalities for a range of diseases. Therapeutic approaches utilizing cellular rejuvenation technologies are rapidly advancing and will represent the next phase of AD therapeutics. This review focuses on two important processes, epigenetic reprogramming, and chaperone-mediated autophagy (CMA) that play a critical role in aging and in neurodegenerative diseases and the potential therapeutic approaches (gene therapy, small molecule) towards targeting these mechanisms. In aging and in AD, epigenetic changes on DNA (e.g., hypermethylation on CpG islands) lead to alterations in gene expression. Partial epigenetic reprogramming utilizes transcription factors to remove the epigenetic marks and to rejuvenate cells to a more youthful state. During aging and in neurodegenerative disorders, CMA becomes impaired resulting in a buildup of proteins known to be associated with neurodegenerative pathologies. The protein buildups lead to aggregates that preclude proteostasis leading to cell toxicity. Small-molecule CMA activators restore proteostasis and limit toxicity enabling cellular rejuvenation.
S. Rosenzweig-Lipson (2023): Opportunities for Cellular Rejuvenation in Alzheimer’s Disease: How Epigenetic Reprogramming and Chaperone-Mediated Autophagy Are Enabling Next Generation Therapeutic Approaches. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.106
ASURE CLINICAL TRIAL PROTOCOL: A RANDOMIZED, PLACEBOCONTROLLED, PROOF-OF-CONCEPT STUDY AIMING TO EVALUATE SAFETY AND TARGET ENGAGEMENT FOLLOWING ADMINISTRATION OF TW001 IN EARLY ALZHEIMER’S DISEASE PATIENTS
M. Oosthoek, A. Lili, A. Almeida, O. van Loosbroek, R. van der Geest, I. de Greef-van der Sandt, P. van Bokhoven, S.A.M. Sikkes, C.E. Teunissen, E.G.B. Vijverberg
J Prev Alz Dis 2023;4(10):669-674Show summaryHide summary
BACKGROUND: Alzheimer’s disease (AD) is a neurodegenerative disease with complex disease etiology and pathological processes. These include formation of plaques and tangles, aberrant lipid processing, neuroinflammation, cerebrovascular dysregulation, ion channel and mitochondrial dysfunction, and oxidative stress. Disease-modifying therapies focusing on all these different facets are needed. TW001 is an oral formulation with the radical scavenger edaravone as its active ingredient, targeting oxidative stress.
OBJECTIVES: This manuscript describes the trial design for Phase IIA Alzheimer Study Using oRal Edaravone (ASURE).
METHODS: ASURE is a randomized, placebo-controlled, proof-of-concept study aiming to evaluate safety and target engagement following administration of TW001 in early AD patients. Patients should have a biomarker confirmed diagnosis to be included in the trial and will be treated for 90 days. The primary endpoints include safety and effect of TW001 on oxidative stress biomarkers. Exploratory endpoints focus on a panel of AD(-related) fluid-based biomarkers and EEG. In addition, a recently developed cognitive functional composite (CFC) score will measure early signs of cognitive and functional effects of TW001.
RESULTS: This article outlines the design of the clinical study, no results are included.
CONCLUSIONS: The ASURE trial design is discussed, with a particular focus on fluid biomarkers, EEG, and CFC as endpoints. By testing multiple measures related to pathology, pharmacodynamics, EEG as proxy for cognition, and cognitive functional scores, it is expected that small changes will be detectable in trials of shorter duration. Moreover, the wide range of endpoints allows to make well-informed decisions for designing pivotal studies later.
M. Oosthoek ; A. Lili ; A. Almeida ; O. van Loosbroek ; R. van der Geest ; I. de Greef-van der Sandt ; P. van Bokhoven ; S.A.M. Sikkes ; C.E. Teunissen ; E.G.B. Vijverberg ; (2023): ASURE Clinical Trial Protocol: A Randomized, Placebo-Controlled, Proof-of-Concept Study Aiming to Evaluate Safety and Target Engagement following Administration of TW001 in Early Alzheimer’s Disease Patients. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.107
MODULATION OF MITOCHONDRIAL FUNCTION AS A THERAPEUTIC STRATEGY FOR NEURODEGENERATIVE DISEASES
E. Trushina, T.K.O. Nguyen, S. Trushin
J Prev Alz Dis 2023;4(10):675-685Show summaryHide summary
Despite recent FDA approval of anti-amyloid antibodies for Alzheimer’s Disease, strategies that target early molecular mechanisms and could delay or change the disease trajectory are still needed. Mitochondria emerge as a signaling organelle that could modulate multiple molecular mechanisms to enhance cellular bioenergetics and promote neuronal survival. Approaches to enhance mitochondrial function could promote healthy aging delaying the onset of age-related diseases such as Alzheimer’s Disease. Some of these strategies have been recently tested in clinical trials. Emerging evidence demonstrates that in response to mild energetic stress, mitochondria could orchestrate a robust adaptive stress response activating multiple neuroprotective mechanism. The objective of this review is to highlight recent development of mitochondria-targeting therapeutics for neurodegenerative diseases, mitochondria complex I inhibitors in particular.
E. Trushina ; T.K.O. Nguyen ; S. Trushin ; (2023): Modulation of Mitochondrial Function as a Therapeutic Strategy for Neurodegenerative Diseases. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.108
NEUROINFLAMMATION, ITS ROLE IN ALZHEIMER’S DISEASE AND THERAPEUTIC STRATEGIES
M. Kiraly, J.F. Foss, T. Giordano
J Prev Alz Dis 2023;4(10):686-698Show summaryHide summary
Neuroinflammation precedes the clinical onset of various neurodegenerative diseases, including Alzheimer’s disease (AD), by years or frequently even decades (1-3). In terms of the underlying physiology, there is a great need for understanding and controlling interactions between the central nervous system (CNS) and the immune system in an attempt to develop approaches to prevent or delay the disease’s progression. Nerve cells have limited motion capability, whereas immune cells can migrate freely via circulation. This difference raises a variety of questions in the context of senile plaque formation and phagocytosis. Broad-scale unbiased genomic studies bring several genetic variants such as sialic acid binding Ig-like lectin 3 (CD33), triggering receptor expressed on myeloid cells 2 (TREM2) or complement receptor type 1 (CR1) into the focus of researchers’ attention as potential risk factors for neuroinflammation. In addition, advanced proteomic analyses have been revealing links between these genetic contributors and complex, malfunctioning signaling pathways (including the upregulation of factors like tumor necrosis factor TNF-α, tumor growth factor TGF-β and interleukin IL-1α) that promote proinflammatory mechanisms via intracellular signaling and trafficking, synaptic function, and cell metabolism/ proliferation. In AD, the brain’s microglia and astrocytes, which are normally responsible for maintaining the homeostasis of synaptic transmission and its remodeling by pruning, are the initiators of neuroinflammation and toxic tau and amyloid-β (Aβ) accumulation. Thus, they drive the CNS into a state of sustained or even self-accelerated deterioration. Here we aim to review the cell types and mediators involved in neuroinflammation and AD, the symptom manifestation in clinical settings, and potential candidates for improving diagnosis and treatment.
M. Kiraly ; J.F. Foss ; T. Giordano ; ; (2023): Neuroinflammation, Its Role in Alzheimer’s Disease and Therapeutic Strategies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.109
TARGETING ENDOGENOUS MECHANISMS OF BRAIN RESILIENCE FOR THE TREATMENT AND PREVENTION OF ALZHEIMER’S DISEASE
H.R.C. Shanks, K.M. Onuska, S.M. Massa, T.W. Schmitz, F.M. Longo
J Prev Alz Dis 2023;4(10):699-705Show summaryHide summary
Alzheimer’s disease is a neurodegenerative disorder which contributes to millions of cases of dementia worldwide. The dominant theoretical models of Alzheimer’s disease propose that the brain passively succumbs to disruptions in proteostasis, neuronal dysfunction, inflammatory and other processes, ultimately leading to neurodegeneration and dementia. However, an emerging body of evidence suggests that the adult brain is endowed with endogenous mechanisms of resilience which may enable individuals to remain cognitively intact for years despite underlying pathology. In this brief review, we discuss evidence from basic neuroscience and clinical research which demonstrates the existence of endogenous molecular signaling pathways that can promote resilience to neurodegeneration. The p75 neurotrophin receptor provides one such pathway of resilience due to its role as a fundamental signaling switch which determines neuronal survival or degeneration. We highlight a series of preclinical studies targeting the p75 neurotrophin receptor in mouse models which demonstrate resilience to amyloid. We briefly discuss the design and goals of a recent clinical trial of p75 neurotrophin receptor modulation in patients with mild to moderate Alzheimer’s disease. Unique challenges for developing therapeutics and biomarkers which are optimized for targeting and detecting endogenous mechanisms of resilience are also discussed. Altogether, this review motivates further trial work of therapeutics modulating the p75 neurotrophin receptor and other deep biology targets.
H.R.C. Shanks ; K.M. Onuska ; S.M. Massa ; T.W. Schmitz ; F.M. Longo ; (2023): Targeting Endogenous Mechanisms of Brain Resilience for the Treatment and Prevention of Alzheimer’s Disease . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.110
METFORMIN IN THE PREVENTION OF ALZHEIMER’S DISEASE AND ALZHEIMER’S DISEASE RELATED DEMENTIAS
M. Tahmi, J.A. Luchsinger
J Prev Alz Dis 2023;4(10):706-717Show summaryHide summary
Metformin is a safe and effective medication for Type 2 diabetes (T2D) that has been proposed to decrease the risk of aging related disorders including Alzheimer’s Disease (AD) and AD related disorders (ADRD). This review seeks to summarize findings from human and non-human studies examining the association of metformin with AD/ADRD related outcomes. Studies in animal models suggest that metformin could decrease the risk of AD/ADRD through multiple mechanisms including neuroprotective effects, decreasing neuroinflammation, and decreasing AD pathology. However, there are non-human studies that suggest that metformin could increase the risk of AD/ADRD. Observational human studies are also conflicting, but those with better study designs suggest that metformin use in persons with T2D is associated with a lower risk of dementia. However, these observational studies are limited by the use of administrative data to ascertain metformin use and/or cognitive outcomes. There are few clinical trials in persons without T2D that have small sample sizes and short durations but suggest that metformin could prevent AD/ADRD. There are ongoing studies including large clinical trials with long duration that are testing the effect of metformin on AD/ADRD outcomes in persons without T2D at risk for dementia.
M. Tahmi ; J.A. Luchsinger ; (2023): Metformin in the Prevention of Alzheimer’s Disease and Alzheimer’s Disease Related Dementias. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.113
MULTIMODAL PRECISION PREVENTION - A NEW DIRECTION IN ALZHEIMER’S DISEASE
M. Barbera, D. Perera, A. Matton, F. Mangialasche, A. Rosenberg, L. Middleton, T. Ngandu, A. Solomon, M. Kivipelto
J Prev Alz Dis 2023;4(10):718-728Show summaryHide summary
At least 40% of all dementia has been linked to modifiable risk factors suggesting a clear potential for preventative approaches targeting these factors. Despite the recent promising findings from anti-amyloid monoclonal antibodies, a limited proportion of patients are expected to be eligible for these novel AD treatments. Given the heterogeneous nature of AD and the complex multi-level pathological processes leading to dementia (involving, e.g., shared risk factors, interaction of different pathology mechanisms, and their putative synergistic effects on cognition), targeting a single pathology may not be sufficient to halt or significantly impact disease progression. With exponentially increasing numbers of patients world-wide, in parallel to the unprecedented population ageing, new multimodal therapy approaches targeting several modifiable risk factors and disease mechanisms simultaneously are urgently required. Developing the next generation of combination therapies with lifestyle intervention and pharmacological treatments, implementing the right interventions for the right people at the right time, and defining accessible and sustainable strategies worldwide are crucial. Here, we summarize the state-of-the-art multimodal lifestyle-based approaches, especially findings and lessons learned from the FINGER trial, for prevention and risk reduction of cognitive impairment and dementia. We also discuss some emerging underlying biological mechanisms and the current development of precision prevention approaches. We present an example of a novel trial design combining healthy lifestyle changes with a repurposed putative disease-modifying drug and place this study in the context of the World-Wide FINGERS, the first interdisciplinary network of multimodal trials dedicated to the prevention and risk reduction of cognitive impairment and dementia.
M. Barbera ; D. Perera ; A. Matton ; F. Mangialasche ; A. Rosenberg ; L. Middleton ; T. Ngandu ; A. Solomon ; M. Kivipelto (2023): Multimodal Precision Prevention - A New Direction in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.114
THE CRITICAL ROLE OF BIOMARKERS FOR DRUG DEVELOPMENT TARGETING THE BIOLOGY OF AGING
M. Owen, N. Bose, L. Nisenbaum, K.A. Partrick, H.M. Fillit
J Prev Alz Dis 2023;4(10):729-742Show summaryHide summary
Alzheimer’s disease is a devastating neurodegenerative disorder that poses a significant societal burden. Approval of anti-amyloid antibody therapies is a significant milestone for treatment that was enabled by the inclusion of biomarkers. The use of biomarkers in clinical trials for Alzheimer’s disease has enabled selective participant recruitment, improved treatment monitoring, and supported more rigorous trial designs. This review discusses emerging biomarkers associated with the biology of aging and their application in Alzheimer’s disease clinical trials. Aging is the primary risk factor for sporadic Alzheimer’s disease and is associated with biological processes implicated in disease development and progression. Novel therapies targeting these underlying biological aging processes are currently undergoing clinical development. Biomarkers that capture the biology of aging are integral to accelerating the development of these therapies. Current progress in biomarker development demonstrates efforts to capture the full spectrum of aging biology. Further work is needed to expand the range of biomarkers that enable comprehensive assessment of brain pathology and aid in prognosis, diagnosis, and measuring treatment response. Establishing a comprehensive arsenal of biomarkers will support strategic decision making and increase the likelihood of positive clinical trials and drug registration for the next generation of Alzheimer’s disease drugs targeting the biology of aging.
M. Owen ; N. Bose ; L. Nisenbaum ; K.A. Partrick ; H.M. Fillit ; (2023): The Critical Role of Biomarkers for Drug Development Targeting the Biology of Aging . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.111
COMMENTARY: FUTURE OF ALZHEIMER’S DISEASE TREATMENT: COMBINATION THERAPY AND PRECISION MEDICINE
H.M. Fillit, L.K. Nisenbaum, A.H. Burstein
J Prev Alz Dis 2023;4(10):743-745Show summaryHide summary
H.M. Fillit ; L.K. Nisenbaum ; A.H. Burstein ; ; (2023): Commentary: Future of Alzheimer’s Disease Treatment: Combination Therapy and Precision Medicine. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.112
EDITORIAL: DIETARY CHOLESTEROL AND DEMENTIA RISK
L.T. Middleton, E. Riboli
J Prev Alz Dis 2023;4(10):746-747Show summaryHide summary
L.T. Middleton ; E. Riboli ; (2023): Editorial: Dietary Cholesterol and Dementia Risk. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.66
HIGH INTAKE OF DIETARY CHOLESTEROL DECREASES THE RISK OF ALL-CAUSE DEMENTIA AND AD DEMENTIA: A RESULTS FROM FRAMINGHAM OFFSPRING COHORT
M. Wang, Y. Wang, Y. Zhang, W. Zhang, Y. Wang, R. Fan, Y. Wen
J Prev Alz Dis 2023;4(10):748-755Show summaryHide summary
BACKGROUND: Dietary cholesterol has been confirmed to be associated with high risks of diabetes, hypertension, and stroke, but whether it is detrimental to cognitive health is highly debated. This study aimed to investigate the associations between dietary cholesterol and all-cause dementia and AD dementia.
METHODS: This prospective study analyzed Framingham Offspring Study cohort (FOS) participants who were dementia-free at baseline and had detailed information on daily diet (measured by food frequency questionnaires) and demographic characteristics. Surveillance for incident dementia commenced at examination 5 (1991–1995) through 2018 and continued for approximately 30 years.
RESULTS: A total of 3249 subjects were included with a mean age of 54.7 years (SD: 9.8). During a median follow-up of 20.2 years (interquartile range: 14.2-24.8), a total of 312 incident dementia events occurred, including 211 (67.7%) cases of AD dementia. After multivariate adjustments for established dementia risk factors, participants with the highest intake of dietary cholesterol had a lower risk of all-cause dementia (HR: 0.70; 95% CI: 0.57-0.93) and AD dementia (HR: 0.68; 95% CI: 0.60-0.88) relative to individuals with the lowest intake. However, the associations were not significant for the group with a medium intake of dietary cholesterol.
CONCLUSION: High intake of dietary cholesterol was associated with a decreased risk of all-cause dementia and AD dementia. The findings of this observational study need to be confirmed by other studies to highlight the role of dietary cholesterol in the development of neurodegenerative diseases.
M. Wang ; Y. Wang ; Y. Zhang ; W. Zhang ; Y. Wang ; R. Fan ; Y. Wen ; (2023): High Intake of Dietary Cholesterol Decreases the Risk of All-Cause Dementia and AD Dementia: A Results from Framingham Offspring Cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.59
PREFERENCES ABOUT FUTURE ALZHEIMER’S DISEASE TREATMENTS ELICITED THROUGH AN ONLINE SURVEY USING THE THRESHOLD TECHNIQUE
S. Roldan Munoz, S.T. de Vries, G. Lankester, F. Pignatti, B.C. van Munster, I. Radford, L. Guizzaro, P.G.M. Mol, H. Hillege, D. Postmus
J Prev Alz Dis 2023;4(10):756-764Show summaryHide summary
BACKGROUND: Treatments aiming at slowing down the progression of Alzheimer’s disease (AD) may soon become available. However, information about the risks that people are willing to accept in order to delay the progression of the disease is limited.
OBJECTIVE: To determine the trade-offs that individuals are willing to make between the benefits and risks of hypothetical treatments for AD, and the extent to which these trade-offs depend on individuals’ characteristics and beliefs about medicines.
DESIGN: Online, cross-sectional survey study.
SETTING: Population in the UK. Public link to the survey available at the websites of Alzheimer’s Research UK and Join Dementia Research.
Participants: Everyone self-reported ≥18 years old was eligible to participate. A total of 4384 people entered the survey and 3658 completed it.
MEASUREMENTS: The maximum acceptable risks (MARs) of participants for moderate and severe adverse events in exchange for a 2-year delay in disease progression. The risks were expressed on ordinal scales, from <10% to ≥50%, above a pre-existing risk of 30% for moderate adverse events and 10% for severe adverse events. We obtained the population median MARs using log-normal survival models and quantified the effects of individuals’ characteristics and beliefs about medicines in terms of acceleration factors.
RESULTS: For the moderate adverse events, 26% of the participants had a MAR ≥50%, followed by 25% of the participants with a MAR of 10 to <20%, giving an estimated median MAR of 25.4% (95% confidence interval [CI] 24.5 to 26.3). For the severe adverse events, 43% of the participants had a MAR <10%, followed by 25% of the participants with a MAR of 10 to <20%, resulting in an estimated median MAR of 12.1% (95%CI 11.6 to 12.5). Factors that were associated with the individuals’ MARs for one or both adverse events were age, gender, educational level, living alone, and beliefs about medicines. Whether or not individuals were living with memory problems or had experience as a caregiver had no effect on the MARs for any of the adverse events.
CONCLUSION: Trade-offs between benefits and risks of AD treatments are heterogeneous and influenced by individuals’ characteristics and beliefs about medicines. This heterogeneity should be acknowledged during the medicinal product decision-making in order to fulfil the needs of the various subpopulations.
S. Roldan Munoz ; S.T. de Vries ; G. Lankester ; F. Pignatti ; B.C. van Munster ; I. Radford ; L. Guizzaro ; P.G.M. Mol ; H. Hillege ; D. Postmus ; (2023): Preferences about Future Alzheimer’s Disease Treatments Elicited through an Online Survey Using the Threshold Technique. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.84
INITIAL EXPERIENCES WITH AMYLOID-RELATED IMAGING ABNORMALITIES IN PATIENTS RECEIVING ADUCANUMAB FOLLOWING ACCELERATED APPROVAL
M.D. Howe, K.J. Britton, H.E. Joyce, G.J. Pappas, M.A. Faust, B.C. Dawson, M.C. Riddle, S.P. Salloway
J Prev Alz Dis 2023;4(10):765-770Show summaryHide summary
Aducanumab is the first FDA-approved amyloid-lowering immunotherapy for Alzheimer’s disease. There is little real-world data to guide management of amyloid-related imaging abnormalities (ARIA), a potentially serious side-effect which requires surveillance with magnetic resonance imaging. We report our experiences in managing ARIA in patients receiving aducanumab at the Butler Hospital Memory and Aging Program during the year following FDA approval. We followed the Appropriate Use Recommendations for aducanumab to guide patient selection, detection, and management of ARIA (1). ARIA-E occurred in 6 out of 24 participants treated; all APOE-ε4 carriers. Treatment was discontinued in 4 cases of moderate-severe ARIA-E, temporarily held in 1 moderate case, and dosed through in 1 mild case (mean duration = 3 months, range, 1-6 months). No participants required hospitalization or high dose corticosteroids. Participants on anticoagulation were excluded and no macrohemorrhages occurred. These data support the measured approaches to treatment outlined in the Appropriate Use Recommendations.
M.D. Howe ; K.J. Britton ; H.E. Joyce ; G.J. Pappas ; M.A. Faust ; B.C. Dawson ; M.C. Riddle ; S.P. Salloway (2023): Initial Experiences with Amyloid-Related Imaging Abnormalities in Patients Receiving Aducanumab Following Accelerated Approval. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.96
LECANEMAB CLARITY AD: QUALITY-OF-LIFE RESULTS FROM A RANDOMIZED, DOUBLE-BLIND PHASE 3 TRIAL IN EARLY ALZHEIMER’S DISEASE
S. Cohen, C.H. van Dyck, M. Gee, T. Doherty, M. Kanekiyo, S. Dhadda, D. Li, S. Hersch, M. Irizarry, L.D. Kramer
J Prev Alz Dis 2023;4(10):771-777Show summaryHide summary
BACKGROUND: Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to amyloid-beta protein protofibrils. In phase 3 development, lecanemab has been shown to reduce markers of amyloid in early Alzheimer’s disease and reduce decline on clinical endpoints of cognition and function at 18 months.
OBJECTIVES: To describe the health-related quality-of-life (HRQoL) results from Clarity AD which were exploratory outcomes in this trial.
DESIGN: Clarity AD was an 18-month, multi-center, double-blind, phase 3 trial.
SETTING: Early Alzheimer’s disease.
PARTICIPANTS: Individuals 50-90 years of age with a diagnosis of mild cognitive impairment or mild dementia due to Alzheimer’s disease and positron emission tomography or cerebrospinal fluid evidence of cerebral amyloid accumulation.
INTERVENTION: Placebo or lecanemab 10-mg/kg IV biweekly.
MEASUREMENTS: HRQoL was measured at baseline and every 6 months using the European Quality of Life–5 Dimensions (EQ-5D-5L; by subject) and Quality of Life in AD (QOL-AD; by subject and proxy). Study partner burden was measured using the Zarit Burden Interview (ZBI).
RESULTS: A total of 1795 participants were enrolled (lecanemab:898; placebo:897). At month 18, adjusted mean change from baseline in EQ-5D-5L and QOL-AD by subject showed 49% and 56% less decline, respectively. QOL-AD rated by study partner as proxy resulted in 23% less decline. ZBI adjusted mean change from baseline at 18 months resulted in 38% less increase of care partner burden. Individual HRQoL test items and dimensions also showed lecanemab benefit.
CONCLUSIONS: Lecanemab was associated with a relative preservation of HRQoL and less increase in caregiver burden, with consistent benefits seen across different quality of life scales and within scale subdomains. These benefits provide valuable patient reported outcomes which, together with previously reported benefits of lecanemab across multiple measures of cognition, function, disease progression, and biomarkers, demonstrate that lecanemab treatment may offer meaningful benefits to patients, care partners, and society.
S. Cohen ; C.H. van Dyck ; M. Gee ; T. Doherty ; M. Kanekiyo ; S. Dhadda ; D. Li ; S. Hersch ; M. Irizarry ; L.D. Kramer ; (2023): Lecanemab Clarity AD: Quality-of-Life Results from a Randomized, Double-Blind Phase 3 Trial in Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.123
SAFETY, TOLERABILITY, PHARMACOKINETICS AND QUANTITATIVE ELECTROENCEPHALOGRAPHY ASSESSMENT OF ACD856, A NOVEL POSITIVE ALLOSTERIC MODULATOR OF TRK-RECEPTORS FOLLOWING MULTIPLE DOSES IN HEALTHY SUBJECTS
K. Önnestam, B. Nilsson, M. Rother, E. Rein-Hedin, J. Bylund, P. Anderer, M. Kemethofer, M.M. Halldin, J. Sandin, M. Segerdahl
J Prev Alz Dis 2023;4(10):778-789Show summaryHide summary
BACKGROUND: ACD856 is a positive allosteric modulator of tropomyosin receptor kinase (Trk) receptors which has shown to have pro-cognitive and anti-depressant-like effects in various animal models. It is currently in clinical development for the treatment of Alzheimer’s disease and other disorders where cognition is impaired and is also considered for indications such as depression or other neuropsychiatric diseases. ACD856 has a novel mechanism of action modulating the activity of the Trk-receptors, resulting in increased stimulation of the neurotrophin signaling pathways. Previous studies applying single intravenous and oral doses of ACD856 indicate that ACD856 is safe and well-tolerated by healthy volunteer subjects, and that it has suitable safety and pharmacokinetic properties for further clinical development.
OBJECTIVES: To investigate the safety and tolerability of 7 days of treatment with multiple ascending oral doses of ACD856 in healthy subjects, and to characterize its pharmacokinetic (PK) properties. In addition, pharmacodynamic effects of ACD856 using quantitative electroencephalography (qEEG) as an indicator for central target engagement were assessed.
DESIGN: This was a prospective, phase I, double-blind, parallel-group, placebo-controlled, randomized study of the safety, tolerability, PK and pharmacodynamics of multiple ascending oral doses of ACD856 in healthy subjects. ACD856 or placebo were administered in 3 ascending dose cohorts of 8 subjects. Within each cohort, subjects were randomized to receive either ACD856 (n=6) or placebo (n=2).
SETTING: The study was conducted at a First-in-Human unit in Sweden.
PARTICIPANTS: Twenty-four healthy male and female subjects.
INTERVENTION: The study medication was administered as an oral solution, with ACD856 or the same contents without the active ingredient (placebo). The dose levels ranged from 10 mg to 90 mg. ACD856 was administered once daily for 7 days, targeting steady state.
MEASUREMENTS: Safety and tolerability assessments included adverse events, laboratory, vital signs, 12-lead electrocardiogram (ECG), physical examination, assessment of stool frequency and questionnaires to assess symptoms of anxiety, depression, as well as suicidal ideation and behavior. In addition, cardiodynamic ECGs were extracted to evaluate cardiac safety. PK parameters were calculated based on measured concentrations of ACD856 in plasma, urine, and cerebrospinal fluid (CSF) samples. Metabolite profiling, characterization and analysis was performed based on and urine samples. qEEG was recorded for patients in the two highest dose cohorts (30 and 90 mg/day) as a pharmacodynamic assessment to explore central target engagement.
RESULTS: Treatment with ACD856 was well tolerated with no serious adverse events. No treatment emergent or dose related trends were observed for any of the safety assessments. ACD856 was rapidly absorbed and reached maximum plasma exposure at 30 to 45 minutes after administration. Steady state was reached before Day 6, with an elimination half-life at steady state of approximately 20 hours. At steady state, ACD856 exhibited accumulation ratios for Cmax and AUC of approximately 1.6 and 1.9 respectively. The exposure, Cmax and AUC0-24, increased proportionally with the dose. There was no unchanged ACD856 detected in urine. The metabolic pattern in urine and plasma was similar, and in alignment with the metabolites observed in preclinical toxicology studies. The level of ACD856 measured in CSF at steady state increased with dose, indicating Central Nervous System (CNS) exposure at relevant levels for pharmacodynamic effects. ACD856 demonstrated significant dose-dependent treatment-associated changes on qEEG parameters. Specifically, increase of the relative theta power and decrease of the fast alpha and beta power was observed, leading to an acceleration of the delta+theta centroid and an increase in the theta/beta ratio.
CONCLUSIONS: ACD856 was well tolerated at the tested dose levels (10-90 mg/daily for 7 days) in healthy subjects. The compound has a robust pharmacokinetic profile, with rapid absorption and dose-dependent exposure. ACD856 was shown to pass the blood-brain-barrier, reach relevant exposure in the CNS and to induce dose-dependent treatment-related changes on qEEG parameters, indicating central target engagement.
K. Önnestam ; B. Nilsson ; M. Rother ; E. Rein-Hedin ; J. Bylund ; P. Anderer ; M. Kemethofer ; M.M. Halldin ; J. Sandin ; M. Segerdahl ; (2023): Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.89
A RANDOMIZED PROSPECTIVE SURVEY TARGETING KNOWLEDGE, BARRIERS, FACILITATORS AND READINESS TO PARTICIPATION IN DEMENTIA RESEARCH
M. Sajatovic, L.K. Herrmann, C. Knebusch, K. Sarna, A.J. Lerner, E. Fuentes-Casiano, C.J. Burant
J Prev Alz Dis 2023;4(10):790-799Show summaryHide summary
BACKGROUND: While the U.S. National Institute on Aging has developed a strategy for recruitment of minority populations in dementia research, including increasing awareness and engagement, minority populations remain under-represented, and the evidence-base is limited. We tested a conceptually driven communication approach targeting barriers and facilitators to research participation vs. standard education.
METHODS: In this 2-phase project, input from the minority advisory board of the Cleveland Alzheimer’s Disease Research Center informed development of 2 brief health communication videos which differentially focused on research barriers and facilitators (POWER) versus an education control (Phase 1). In Phase 2, a randomized prospective survey compared POWER vs. an active comparator control on pre/post video change in dementia knowledge, cumulative barriers, and facilitators to dementia research, and change in research readiness measured by the Transtheoretical behavior change model. Changes in outcomes were evaluated using two group by two time points repeated measure analysis of variance (RMANOVA) controlling for age, gender, race, and education.
RESULTS: The pre-video sample (n=242) had mean age of 57.6 (SD17.2) years, mostly female (n=181, 74.8%), 42.6% non-white. The analyzable sample who completed both pre and post assessments comprised n=102 in the POWER and n=105 in the control group. Non-white participants made up 41.1% of the analyzable POWER (n=51) and 44.1% (n= 52) of controls. Adjusted for age, gender, race and education, controls had a greater increase in dementia knowledge (p=0.004). There was a significant reduction in barriers for POWER (p=.044) vs. control. There were no differences in research facilitators and research readiness between POWER vs. control. Among African Americans (n=59, 28.5% of the analyzable sample) there was a trend for improved dementia knowledge (p=.059) favoring control and in research readiness (p=.051), favoring POWER.
CONCLUSIONS: Targeting barriers and attitudes towards research could inform development of approaches with potential to improve dementia research participation across diverse communities.
M. Sajatovic ; L.K. Herrmann ; C. Knebusch ; K. Sarna ; A.J. Lerner ; E. Fuentes-Casiano ; C.J. Burant ; (2023): A Randomized Prospective Survey Targeting Knowledge, Barriers, Facilitators and Readiness to Participation in Dementia Research. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.124
PROTOCOL OF A PHASE II RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF S-ADENOSYL METHIONINE IN PARTICIPANTS WITH MILD COGNITIVE IMPAIRMENT OR DEMENTIA DUE TO ALZHEIMER’S DISEASE
S. Holper, R. Watson, L. Churilov, P. Yates, Y.Y. Lim, K.J. Barnham, N. Yassi
J Prev Alz Dis 2023;4(10):800-809Show summaryHide summary
Background: S-adenosyl methionine (SAMe) is a pivotal metabolite in multiple pathways required for neuronal homeostasis, several of which are compromised in Alzheimer’s disease (AD). Correction of the SAMe deficiency that is characteristic of the AD brain may attenuate or prevent pathological processes driving AD-associated neurodegeneration including aberrant tau hyperphosphorylation and DNA hypomethylation.
Objectives: The primary aim is to test the hypothesis that daily treatment with 400 mg oral SAMe for 180 days will lead to a greater reduction from baseline in plasma levels of p-tau181 compared to placebo in patients with mild cognitive impairment or dementia due to AD.
Design, Setting, Participants: This is a phase II, randomized, multi-center, double-blind, placebo-controlled trial among 60 participants with mild cognitive impairment or dementia due to AD. Participants will be randomized in a 1:1 ratio to receive either SAMe or matching placebo, to be taken as an adjunct to their AD standard of care.
Measurements and Results: The primary outcome is change in plasma p-tau181 concentration between baseline and following 180 days of treatment, which will be compared between the active and placebo group. Secondary outcomes are the safety of SAMe administration (incidence of serious adverse events), change from baseline in cognitive performance (as measured by the Repeatable Battery for the Assessment of Neuropsychological Status), and epigenetic changes in DNA methylation.
Conclusion: Demonstration of effective and safe lowering of plasma p-tau181 with SAMe in this phase II trial would pave the way for an exciting field of translational research and a larger phase III trial.
S. Holper ; R. Watson ; L. Churilov ; P. Yates ; Y.Y. Lim ; K.J. Barnham ; N. Yassi ; (2023): Protocol of a Phase II Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial of S-Adenosyl Methionine in Participants with Mild Cognitive Impairment or Dementia Due to Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.55
BASELINE FINDINGS OF PREVENTE4: A DOUBLE-BLIND PLACEBO CONTROLLED CLINICAL TRIAL TESTING HIGH DOSE DHA IN APOE4 CARRIERS BEFORE THE ONSET OF DEMENTIA
H.N. Yassine, I.C. Arellanes, A. Mazmanian, L. De La Cruz, J. Martinez, L. Contreras, N. Kono, B.S. Liu, D. Badie, M.A. Bantugan, A. Grindon, T. Urich, L. D’Orazio, B.A. Emmanuel, H.C. Chui, W.J. Mack, M.G. Harrington, M.N. Braskie, L.S. Schneider
J Prev Alz Dis 2023;4(10):810-820Show summaryHide summary
INTRODUCTION: Lower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known.
METHODS: PreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function.
RESULTS: 365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365).
CONCLUSIONS: Findings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.
H.N. Yassine ; I.C. Arellanes ; A. Mazmanian ; L. De La Cruz ; J. Martinez ; L. Contreras ; N. Kono ; B.S. Liu ; D. Badie ; M.A. Bantugan ; A. Grindon ; T. Urich ; L. D’Orazio ; B.A. Emmanuel ; H.C. Chui ; W.J. Mack ; M.G. Harrington ; M.N. Braskie ; L.S. Schneider ; (2023): Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.77
REDUCING THE EFFECTS OF AGEING ON COGNITION WITH THERAPEUTIC INTERVENTION OF AN ORAL MULTI-NUTRIENT: THE REACTION PILOT TRIAL STUDY DESIGN
C.J. Camargo, S. Merritt, M. Modjeski, D.S. Counotte, K. Fernández McInerney
J Prev Alz Dis 2023;4(10):821-827Show summaryHide summary
BACKGROUND: Clinical benefits have been reported with a specific multinutrient intervention (Souvenaid) in Alzheimer’s disease and mild cognitive impairment due to Alzheimer’s disease. The effects of Souvenaid in age-related cognitive decline are not established.
OBJECTIVE: To assess the feasibility of using virtual assessments to study the effects of a multinutrient on cognitive ageing.
DESIGN: This is a randomized, double-blind, placebo-controlled, parallel group virtual pilot trial performed over 6 months in a single-centre. Participants are randomly allocated (1:1) to receive the specific multinutrient (Souvenaid) or an isocaloric, same tasting, placebo.
SETTING: Trial visits are done virtually using secure online video communication.
PARTICIPANTS: English or Spanish speaking people aged 55−89 years from all ethnic groups and considered to have age-related cognitive decline are eligible.
MEASUREMENTS: Neuropyschological tests are done at baseline and after 6 months of intervention. Participants are contacted monthly by telephone to monitor safety, assess motivation and promote compliance. The primary outcome is feasibility determined by assessing recruitment rate, recruitment time, adherence rate and retention rate. A comprehensive set of neuropyschological measures will provide a broad assessment of cognitive function, including verbal memory, processing speed, and attention and executive function. Self-reported questionnaires are used to assess quality of life.
CONCLUSIONS: This pilot trial will provide data to guide inform selection of participants and outcome measures in future studies in age-related cognitive decline.
C.J. Camargo ; S. Merritt ; M. Modjeski ; D.S. Counotte ; K. Fernández McInerney (2023): Reducing the Effects of Ageing on Cognition with Therapeutic Intervention of an Oral Multi-Nutrient: The REACTION Pilot Trial Study Design. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.81
TWO-YEAR PROGNOSTIC UTILITY OF PLASMA P217+TAU ACROSS THE ALZHEIMER’S CONTINUUM
A. Feizpour, V. Doré, J.D. Doecke, Z.S. Saad, G. Triana-Baltzer, R. Slemmon, P. Maruff, N. Krishnadas, P. Bourgeat, K. Huang, C. Fowler, S.R. Rainey-Smith, A.I. Bush, L. Ward, J. Robertson, R.N. Martins, C.L. Masters, V.L. Villemagne, J. Fripp, H.C. Kolb, C.C. Rowe
J Prev Alz Dis 2023;4(10):828-836Show summaryHide summary
Background: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-β (Aβ) and tau in Alzheimer’s Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aβ and tau in predicting cognitive decline are unknown.
Objectives: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on Aβ (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET Aβ (A+) and tau (T+) with and without p217+tau pre-screening.
Design: A prospective observational cohort study.
Setting: Participants of the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT).
Participants: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals.
Measurements: Baseline p217+tau Simoa® assay, 18F-MK6240 tau-PET and 18F-NAV4694 Aβ-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years.
Results: In CI, p217+tau was a significant predictor of change in MMSE (β = -0.55, p < 0.001) and CDR-SB (β =0.61, p < 0.001) with an effect size similar to Aβ Centiloid (MMSE β = -0.48, p = 0.002; CDR-SB β = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: β = -0.62, p < 0.001; CDR-SB: β = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (β = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU.
Conclusions: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing.
A. Feizpour ; V. Doré ; J.D. Doecke ; Z.S. Saad ; G. Triana-Baltzer ; R. Slemmon ; P. Maruff ; N. Krishnadas ; P. Bourgeat ; K. Huang ; C. Fowler ; S.R. Rainey-Smith ; A.I. Bush ; L. Ward ; J. Robertson ; R.N. Martins ; C.L. Masters ; V.L. Villemagne ; J. Fripp ; H.C. Kolb ; C.C. Rowe (2023): Two-Year Prognostic Utility of Plasma p217+tau across the Alzheimer’s Continuum. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.83
PLASMA OLIGOMER Β-AMYLOID AND WHITE MATTER MICROSTRUCTURAL INTEGRITY IN COGNITIVELY NORMAL OLDER ADULTS ACCORDING TO CEREBRAL AMYLOID DEPOSITION
S.-M. Wang, D.W. Kang, Y.H. Um, S.-H. Kim, C.U. Lee, P. Scheltens, H.K. Lim
J Prev Alz Dis 2023;4(10):837-846Show summaryHide summary
BACKGROUND: Multimer detection system-oligomeric amyloid-β (MDS-OAβ) measure plasma OAβ level, which is associated with earlier Alzheimer’s disease (AD) pathology. However, no study has investigated MDS-OAβ differences in cognitive normal older adults (CN) with or without cerebral Aβ burden and its correlation with Aβ deposition and white matter (WM) integrity.
OBJECTIVE: To investigate associations among cerebral Aβ burden, MDS-OAβ, and WM integrity in CN.
DESIGN: This is a single center, cross-sectional study which used data from Catholic Aging Brain Imaging (CABI) database.
SETTING: CABI database contains brain scans of patients who visited the outpatient clinic at Catholic Brain Health Center, Yeouido St. Mary’s Hospital, The Catholic University of Korea, between 2017 and 2022.
PARTICIPANTS: A total 34 amyloid-PET negative CN and 23 amyloid-PET positive CN were included.
MEASUREMENTS : Plasma Aβ level using MDS-OAβ, cerebral Aβ deposition level using global standardized uptake value ratio (SUVR) values, WM integrity using fractional anisotropy (FA) and mean diffusivity (MD), and cortical thickness from structural MRI were utilized.
RESTULS: The amyloid-PET positive group showed higher MDS-OAβ level than the amyloid-PET negative group (0.997 ± 0.19 vs. 0.79 ± 0.28, P <0.005), but they did not differ in WM integrity or cortical thickness. The MDS-OAβ positive group showed higher global cerebral Aβ deposition or mean global SUVR values (0.609 ± 0.135 vs. 0.533 ± 0.121 vs. P <0.05), lower regional FA of left forceps minor and the right superior longitudinal fasciculus (family-wise error rate, p <0.05), and lower cortical thickness of left fusiform (p <0.05, Monte Carlo simulation) than the MDS-OAβ negative group. MDS-OAβ was positively associated with global cerebral Aβ deposition (r=0.278, P <0.05) and negatively associated (r = - 0.324, P < 0.05) with regional WM integrity.
CONCLUSIONS: In this study, MDS-OAβ value demonstrated earlier and different AD pathology than cerebral Aβ retention according to amyloid-PET. Longitudinal studies are needed to elucidate the causal relationships of plasma OAβ and cerebral Aβ with WM integrity disturbance and cortical atrophy during the AD trajectory.
S.-M. Wang ; D.W. Kang ; Y.H. Um ; S.-H. Kim ; C.U. Lee ; P. Scheltens ; H.K. Lim ; (2023): Plasma Oligomer β-Amyloid and White Matter Microstructural Integrity in Cognitively Normal Older Adults According to Cerebral Amyloid Depositio. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.87
THE COMMUNITY ENGAGED DIGITAL ALZHEIMER’S RESEARCH (CEDAR) STUDY: A DIGITAL INTERVENTION TO INCREASE RESEARCH PARTICIPATION OF BLACK AMERICAN PARTICIPANTS IN THE BRAIN HEALTH REGISTRY
M.R. Mindt, M.T. Ashford, D. Zhu, H. Cham, A. Aaronson, C. Conti, X. Deng, R. Alaniz, J. Sorce, C. Cypress, P. Griffin, D. Flenniken, M. Camacho, J. Fockler, D. Truran, R.S. Mackin, C. Hill, M.W. Weiner, D. Byrd, R.W. Turner II, R.L. Nosheny
J Prev Alz Dis 2023;4(10):847-856Show summaryHide summary
BACKGROUND: Although Black/African American older adults bear significant inequities in prevalence, incidence, and outcomes of Alzheimer’s disease and related dementias, they are profoundly under-included in Alzheimer’s Disease research. Community-Engaged Research (e.g., equitable community/science partnerships) is an evidence-based approach for improving engagement of underrepresented populations into Alzheimer’s Disease research, but has lacked scalability to the national level. As internet use among older adults from underrepresented populations continues to grow, internet-based research shows promise as a feasible, valid approach to engagement and longitudinal assessment. The Community Engaged Digital Alzheimer’s Research (CEDAR) study utilizes a community-engaged research approach to increase the engagement and research participation of Black/African American adults in the Brain Health Registry (BHR) and Alzheimer Disease clinical research.
OBJECTIVES: To describe the methods and evaluate the feasibility of the CEDAR culturally-informed digital platform within BHR.
DESIGN: All Black/African American participants in BHR were invited to enroll in CEDAR and to consider serving on a newly convened Community-Scientific Partnership Board to guide the study. The community board guided the development a culturally-informed cadre of engagement materials and strategies to increase research participation. Engagement strategies included incentives for study task completion, culturally-informed communications (e.g., landing page, emails and social media), resources about brain health, and video and written testimonials by CEDAR participants.
SETTING: BHR, an Internet-based registry and cohort.
PARTICIPANTS: BHR participants self-identifying as Black/African American were invited to enroll. All participants who signed an online informed consent document were enrolled.
MEASUREMENTS: We report the number of participants invited, enrolled, completed tasks, and volunteered to join the community board. We compared the demographics, cognitive profile, and baseline BHR task completion rates between CEDAR participants and all those invited to join the study.
RESULTS: Of 3738 invited, 349 (9.34%) enrolled in CEDAR. 134 (37% of CEDAR participants) volunteered to join the community board, of which 19 were selected for the community board. Compared to those invited, the CEDAR cohort had a higher percentage of female participants (84.5%) and a lower percentage of participants who identify as belonging to more than one ethnocultural group (21.8%). Compared to those did not enroll in CEDAR, those enrolled in CEDAR had a higher percentage of participants completing all BHR tasks (22%) and a higher percentage of participants completing at least one cognitive test (76%). Those enrolled in CEDAR also had a higher percentage of participants having an enrolled study partner (18%).
CONCLUSIONS: A culturally-informed Community-Engaged Research approach, including a remotely-convened community board, to engagement of Black/African American participants in an online research registry is feasible. This approach can be adapted for use in various clinical studies and other settings. Future studies will evaluate the effectiveness of the engagement strategies.
M.R. Mindt ; M.T. Ashford ; D. Zhu ; H. Cham ; A. Aaronson ; C. Conti ; X. Deng ; R. Alaniz ; J. Sorce ; C. Cypress ; P. Griffin ; D. Flenniken ; M. Camacho ; J. Fockler ; D. Truran ; R.S. Mackin ; C. Hill ; M.W. Weiner ; D. Byrd ; R.W. Turner II ; R.L. Nosheny ; (2023): The Community Engaged Digital Alzheimer’s Research (CEDAR) Study: A Digital Intervention to Increase Research Participation of Black American Participants in the Brain Health Registry. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.32
DEVELOPMENT OF A MOBILE-FIRST REGISTRY TO RECRUIT HEALTHY VOLUNTEERS AND MEMBERS OF UNDERREPRESENTED COMMUNITIES FOR ALZHEIMER’S DISEASE PREVENTION STUDIES
R. Aggarwal, E. Sidnam-Mauch, D. Neffa-Creech, A. Plant, E. Williams, E. Shami, U. Menon, S. George, J.B. Langbaum
J Prev Alz Dis 2023;4(10):857-864Show summaryHide summary
BACKGROUND: Web-based participant recruitment registries can be useful tools for accelerating enrollment into studies, but existing Alzheimer’s disease (AD)-focused recruitment registries have had limited success enrolling individuals from underrepresented racial and ethnic groups. Designing these registries to meet the needs of individuals from these communities, including designing mobile-first, may facilitate improvement in the enrollment of underrepresented groups.
OBJECTIVES: Evaluate the usability of a prototype mobile-first participant recruitment registry for AD prevention studies; assess users’ perceptions of and willingness to sign up for the registry.
DESIGN AND SETTING: Quantitative usability testing and an online survey; online setting.
PARTICIPANTS: We recruited 1,358 adults ages 45-75 who self-reported not having a diagnosis of mild cognitive impairment, AD, or other forms of dementia (Study 1: n=589, Study 2: n=769). Black/African American and Hispanic/Latino participants were specifically recruited, including those with lower health literacy.
METHODS AND MEASUREMENTS: Study 1 measures the prototype’s usability through observed task success rates, task completion times, and responses to the System Usability Scale. Study 2 uses an online survey to collect data on perceptions of and willingness to sign up for the mobile-first registry.
RESULTS: Study 1 findings show the prototype mobile-first recruitment registry website demonstrates high usability and is equally usable for Black / African American, Hispanic/Latino, and White user groups. Survey results from Study 2 indicate that users from underrepresented communities understand the registry’s purpose and content and express willingness to sign up for the registry on a mobile device.
CONCLUSIONS: Designing mobile-first participant recruitment registries based on feedback from underrepresented communities may result in more sign-ups by individuals from minoritized communities.
R. Aggarwal ; E. Sidnam-Mauch ; D. Neffa-Creech ; A. Plant ; E. Williams ; E. Shami ; U. Menon ; S. George ; J.B. Langbaum ; (2023): Development of a Mobile-First Registry to Recruit Healthy Volunteers and Members of Underrepresented Communities for Alzheimer’s Disease Prevention Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.86
UNDERSTANDING BARRIERS AND FACILITATORS TO SIGNING UP FOR A MOBILE-RESPONSIVE REGISTRY TO RECRUIT HEALTHY VOLUNTEERS AND MEMBERS OF UNDERREPRESENTED COMMUNITIES FOR ALZHEIMER’S DISEASE PREVENTION STUDIES
D. Neffa-Creech, R. Aggarwal, C. Stowell, U. Menon, S. George, A. Plant, J.B. Langbaum
J Prev Alz Dis 2023;4(10):865-874Show summaryHide summary
Background: Alzheimer’s disease (AD) disproportionately affects Black/African American and Hispanic/Latino adults, yet they are underrepresented in AD studies. Recruitment challenges for these populations limit generalizability of findings.
Objectives: This study explores barriers and facilitators to signing up for an AD participant recruitment registry website intended to optimize recruitment of these adults. The registry is geared toward recruitment on smartphones and tablets (mobile devices), as research suggests that mobile-first approaches may be more successful within these populations.
Design: In 2020, we conducted four focus groups (n = 39) and an online survey (n = 1010) with Black/African American and Hispanic/Latino adults. The survey also included Whites as a comparison group.
Setting: Focus groups were in-person at research facilities in New Orleans, Louisiana, and Los Angeles, California. The online survey was distributed by a survey panel company to participants nationwide.
Participants: Black/African American (n = 360), Hispanic/Latino (n = 359), or White (n = 330) individuals, 45-75 years old, who self-reported not having mild cognitive impairment (MCI), dementia, or AD.
Measurements: Barriers and facilitators explored in the focus groups and survey were related to health and AD (e.g., AD-related concerns and past participation/willingness to participate in health or AD studies); current use of mobile devices (e.g., comfort using devices and receptivity to the AD recruitment registry); and participant characteristics and beliefs (e.g., demographics, health literacy level, and trust in government and the scientific community).
Results: The focus groups and survey revealed similar findings. Participants commonly use mobile devices to go online and perform health-related activities. They were aware of AD, expressed concerns with developing it, and were willing to participate in AD-related studies (motivated by personal connection to AD, altruism, and compensation). When presented with the AD recruitment registry, most provided positive feedback (e.g., easy to use and informative) and shared an interest in joining. Barriers to joining the registry with a mobile device included complex or multistep enrollment processes, beliefs that studies are primarily for those with a specific disease, and confusion about how studies can prevent AD among those low-risk for AD. The focus groups also revealed that Black/African American participants expressed more hesitation than Hispanic/Latinos in joining the registry due to greater distrust in the government and scientific community.
Conclusions: Recruiting more Black/African American and Hispanic/Latino participants into AD studies is vitally important. This mixed methods study suggests that adults in these underrepresented groups are motivated to prevent AD and willing to sign up for an AD participant recruitment registry using mobile devices. Most barriers to joining a registry can be addressed through slight modifications to the registry’s design and functionality and by adding content. These findings can help enhance the appeal of joining AD recruitment registries to ultimately enroll more diverse, representative groups of participants and increase the generalizability of AD study findings.
D. Neffa-Creech ; R. Aggarwal ; C. Stowell ; U. Menon ; S. George ; A. Plant ; J.B. Langbaum ; (2023): Understanding Barriers and Facilitators to Signing Up for a Mobile-Responsive Registry to Recruit Healthy Volunteers and Members of Underrepresented Communities for Alzheimer’s Disease Prevention Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.67
PROTOCOL FOR THE BRAIN HEALTH SUPPORT PROGRAM STUDY OF THE CANADIAN THERAPEUTIC PLATFORM TRIAL FOR MULTIDOMAIN INTERVENTIONS TO PREVENT DEMENTIA (CANTHUMBS UP): A PROSPECTIVE 12-MONTH INTERVENTION STUDY
H.H. Feldman, S. Belleville, H.B. Nygaard, M. Montero-Odasso, J. Durant, J.-L. Lupo, C. Revta, S. Chan, M. Cuesta, P.J. Slack, S. Winer, P.W.H. Brewster, S.M. Hofer, A. Lim, A. Centen, D.M. Jacobs, N.D. Anderson, J.D. Walker, M.R. Speechley, G.Y. Zou, H. Chertkow, for the Canadian Consortium on Neurodegeneration in Aging (CCNA), CAN-THUMBS UP Study Group
J Prev Alz Dis 2023;4(10):875-885Show summaryHide summary
BACKGROUND/OBJECTIVES: CAN-THUMBS UP is designed as a comprehensive and innovative fully remote program to 1) develop an interactive and compelling online Brain Health Support Program intervention, with potential to positively influence dementia literacy, self-efficacy and lifestyle risk factors; 2) enroll and retain a community-dwelling Platform Trial Cohort of individuals at risk of dementia who will participate in the intervention; 3) support an open platform trial to test a variety of multidomain interventions that might further benefit individuals at risk of dementia. This manuscript presents the Brain Health Support Program Study protocol.
DESIGN/SETTING: Twelve-month prospective multi-center longitudinal study to evaluate a fully remote web-based educational intervention. Participants will subsequently be part of a Platform Trial Cohort and may be eligible to participate in further dementia prevention clinical trials.
PARTICIPANTS: Three hundred fifty older adults who are cognitively unimpaired or have mild cognitive impairment, with at least 1 well established dementia risk factor.
INTERVENTION: Participants engage in the Brain Health Support Program intervention for 45-weeks and complete pre/post intervention measures. This intervention is designed to convey best available evidence for dementia prevention, consists of 181 chapters within 8 modules that are progressively delivered, and is available online in English and French. The program has been developed as a collaborative effort by investigators with recognized expertise in the program’s content areas, along with input from older-adult citizen advisors.
MEASUREMENTS: This study utilizes adapted remote assessments with accessible technologies (e.g. videoconferencing, cognitive testing via computer and mobile phone, wearable devices to track physical activity and sleep, self-administered saliva sample collection). The primary outcome is change in dementia literacy, as measured by the Alzheimer’s Disease Knowledge Scale. Secondary outcomes include change in self-efficacy; engagement using the online program; user satisfaction ratings; and evaluation of usability and acceptance. Exploratory outcomes include changes in attitudes toward dementia, modifiable risk factors, performance on the Neuropsychological Test Battery, performance on self-administered online cognitive assessments, and levels of physical activity and sleep; success of the national recruitment plan; and the distribution of age adjusted polygenic hazard scores.
CONCLUSIONS: This fully remote study provides an accessible approach to research with all study activities being completed in the participants’ home environment. This approach may reduce barriers to participation, provide an easier and less demanding participant experience, and reach a broader geography with recruitment from all regions of Canada. CAN-THUMBS UP represents a Canadian contribution to the global World-Wide FINGERS program (alz.org/wwfingers).
H.H. Feldman ; S. Belleville ; H.B. Nygaard ; M. Montero-Odasso ; J. Durant ; J.-L. Lupo ; C. Revta ; S. Chan ; M. Cuesta ; P.J. Slack ; S. Winer ; P.W.H. Brewster ; S.M. Hofer ; A. Lim ; A. Centen ; D.M. Jacobs ; N.D. Anderson ; J.D. Walker ; M.R. Speechley ; G.Y. Zou ; H. Chertkow ; for the Canadian Consortium on Neurodegeneration in Aging (CCNA), CAN-THUMBS UP Study Group ; (2023): Protocol for the Brain Health Support Program Study of the Canadian Therapeutic Platform Trial for Multidomain Interventions to Prevent Dementia (CAN-THUMBS UP): A Prospective 12-Month Intervention Study . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.65
GENOTYPIC EFFECTS OF THE TOMM40’523 VARIANT AND APOE ON LONGITUDINAL COGNITIVE CHANGE OVER 4 YEARS: THE TOMMORROW STUDY
H. Zou, S. Luo, H. Liu, M.W. Lutz, D.A. Bennett, B.L. Plassman, K.A. Welsh-Bohmer
J Prev Alz Dis 2023;4(10):886-894Show summaryHide summary
BACKGROUND: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD.
OBJECTIVES: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance.
DESIGN: A phase 3, double-blind, placebo-controlled, randomized clinical trial.
SETTING: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA.
PARTICIPANTS: Cognitively normal older adults aged 65 to 83.
INTERVENTION: Pioglitazone tablet.
MEASUREMENTS: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40’523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40’523 genotypes.
RESULTS: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40’523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40’523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers.
CONCLUSIONS: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.
H. Zou ; S. Luo ; H. Liu ; M.W. Lutz ; D.A. Bennett ; B.L. Plassman ; K.A. Welsh-Bohmer ; (2023): Genotypic Effects of the TOMM40’523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.115
SOCIAL DETERMINANTS OF HEALTH AMONG OLDER ADULTS WITH DEMENTIA IN URBAN AND RURAL AREAS
M.M. Bartley, H. Baer-Benson, D.R. Schroeder, J.L. St. Sauver, N. Khera, J.M. Griffin
J Prev Alz Dis 2023;4(10):895-902Show summaryHide summary
BACKGROUND: Social determinants of health (SDOH) may influence health in people living with dementia. Little is known about SDOH differences in urban compared to rural dwelling people living with dementia.
OBJECTIVES: To explore urban-rural differences in SDOH in people living with mild cognitive impairment (MCI) and dementia.
DESIGN: Descriptive study.
SETTING/PARTICIPANTS: People ≥55 years with MCI or dementia empaneled to Community Internal Medicine at Mayo Clinic (Rochester, MN, USA) who completed SDOH questions between June 1, 2019 and June 30, 2021 were included.
MEASUREMENTS: SDOH questions addressed education, depression, alcohol use, financial strain, food insecurity, physical activity, social connections, stress and transportation. SDOH data were compared by location based on Rural-Urban Commuting Areas Codes.
RESULTS: Of 3552 persons with MCI (n=1495) or dementia (n=2057), 62% lived in urban areas, 19% in large rural, 10% in small rural and 9% in isolated areas. Approximately 60% were physically inactive, 20% socially isolated and 30% had stress concerns. Rural patients experienced greater financial strain (p=0.003).
CONCLUSION: Social isolation, stress and physical inactivity are common in people living with MCI and dementia across urban and rural areas. Targeted interventions to improve physical and psychosocial health could have great impact in this population.
M.M. Bartley, ; H. Baer-Benson, ; D.R. Schroeder, ; J.L. St. Sauver, ; N. Khera ; J.M. Griffin ; (2023): Social Determinants of Health among Older Adults with Dementia in Urban and Rural Areas. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1007/s42414-023-0002-2
ASSOCIATION OF LONELINESS WITH COGNITIVE FUNCTIONS
K.T. Kyaw, A. Levine
J Prev Alz Dis 2023;4(10):903-908Show summaryHide summary
Introduction: Observational studies suggest psychosocial factors such as social support and loneliness are associated with vulnerability for cognitive decline in older adults. However, because of racial/ethnic homogeneity in prior studies focused on identifying these associations in predominantly White cohorts, less is known about the generalizability of these putative psychosocial mechanisms in a diverse population. Thus, we evaluated whether lower levels of loneliness were associated with better cognitive performance in our sample. Methods: We conducted a cross-sectional study using 541 participants from (Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) Dementia Cohort. Participants’ self-reported loneliness as exposure. Cognitive performance is measured using a neuropsychological battery as the outcome. Raw scores were converted into Z scores, and global cognitive function was created. Generalized estimated equation and robust regression analysis).
Results: Better global cognitive function is associated with a lower level of loneliness at (β = -0.0131, 95 % CI -0.1990, -0.0071) after adjustment for age, gender, and education. Lower levels of loneliness were associated with varying cognitive domains after adjustment for age, gender, and education; and persisted after additional adjustments of vascular risk factors.
Conclusions: Self-reported lower loneliness was associated with higher levels of cognitive performance in a rural South African cohort of Black older adults. Although these findings and the potential of reverse causality need to be further validated, our results suggest that an intervention study may be merited to assess whether reducing loneliness lessens vulnerability to cognitive decline.
K.T. Kyaw ; A. Levine ; (2023): Association of Loneliness with Cognitive Functions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.60