Review
Clinical Neurology
Kasper P. Kepp, Nikolaos K. Robakis, Poul F. Hoilund-Carlsen, Stefano L. Sensi, Bryce Vissel
Summary: Results from recent clinical trials of anti-amyloid antibodies for Alzheimer's disease have challenged the amyloid cascade hypothesis and indicated a more complex etiology. The treatments have shown no or uncertain clinical effect on cognition, suggesting that amyloid may play a minor role in the disease. Multiple pathogenic factors may contribute to Alzheimer's disease, and evolving multi-factor disease models may lead to more effective treatment strategies.
Review
Biochemistry & Molecular Biology
Ernesto Fedele
Summary: In the past 30 years, most efforts to treat Alzheimer's disease (AD) have focused on clearing the beta-amyloid peptide (A beta) from the brain. However, clinical trial results suggest that A beta plays a minor role in the pathogenesis of AD. Additionally, A beta has been found to have various physiological functions, including memory formation, indicating that the loss of A beta function may contribute to AD. It is believed that AD could be the result of multiple molecular dysfunctions, and therefore, solely targeting A beta may overlook other important factors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Geriatrics & Gerontology
Tong Wu, Ding Lin, Yaqian Cheng, Senze Jiang, Muhammad Waheed Riaz, Nina Fu, Chenhao Mou, Menglu Ye, Ying Zheng
Summary: The amyloid cascade hypothesis has been a key focus in Alzheimer's disease therapeutic research. This review discusses the current hypothesis and pathogenesis, as well as drug development strategies targeting different stages in this hypothesis. Strategies like immunotherapy have shown promising results in clinical trials, but success rates remain low. The review also highlights common problems in drug development and emphasizes the importance of multidisciplinary cooperation and a better understanding of the amyloid cascade hypothesis.
Article
Psychology, Multidisciplinary
Samuel L. Warren, Edwina Reid, Paige Whitfield, Ahmed M. Helal, Eid G. Abo Hamza, Richard Tindle, Ahmed A. Moustafa, Mohamed S. Hamid
Summary: This study investigated the ability of commonly used neuropsychological tests to detect cognitive and functional decline in Alzheimer's disease (AD). The results showed that ADAS-13, RAVLT (learning), FAQ, ECog, and MoCA were predictive of the AD progression continuum, while TMT-B and RAVLT (immediate and forgetting) were not significant predictors. The study suggests using ECog (both versions), RAVLT (learning), ADAS-13, and MoCA to screen all stages of the AD continuum.
CURRENT PSYCHOLOGY
(2023)
Article
Neurosciences
Amanda E. Selwood, Vibeke S. Catts, Katya Numbers, Teresa Lee, Anbupalam Thalamuthu, Margaret J. Wright, Perminder S. Sachdev
Summary: This study aimed to examine the heritability of subjective cognitive complaints (SCCs) and their correlations with memory ability, personality, and mood. The results showed that SCCs had moderate heritability and were genetically, environmentally, and phenotypically correlated with memory performance, personality, and mood. Specifically, mood was environmentally related to SCCs, while memory performance had a genetic correlation with SCCs. The link between personality and SCCs was mediated by mood. These findings suggest that SCCs are influenced by both mood and memory performance, and these determinants are not mutually exclusive.
JOURNAL OF ALZHEIMERS DISEASE
(2023)
Article
Neurosciences
Hadeel Y. Tarawneh, Dona M. P. Jayakody, Shipra Verma, Vincent Dore, Ying Xia, Wilhelmina H. A. M. Mulders, Ralph N. Martins, Hamid R. Sohrabi
Summary: This study investigated whether auditory event-related potentials (AERPs) can be used to objectively identify older adults with subjective memory complaints (SMCs) who are at high risk of developing Alzheimer's disease (AD). The results suggest that P50 latencies may be a useful tool for identifying individuals at higher risk of developing measurable cognitive decline.
JOURNAL OF ALZHEIMERS DISEASE
(2023)
Review
Neurosciences
Russell H. Swerdlow
Summary: Viable hypotheses about Alzheimer's disease must consider its age-dependence, commonality, association with specific biological factors, connection with various changes in the body, and systemic features. Mitochondria and factors influenced by mitochondria may link these different characteristics. The mitochondrial cascade hypothesis provides a straightforward explanation and accumulating data support its validity. While alternative hypotheses may also explain mitochondria-related phenomena, the primary mitochondrial cascade hypothesis will continue to evolve and attract interest.
JOURNAL OF ALZHEIMERS DISEASE
(2023)
Article
Neurosciences
Philip S. Insel, Michael C. Donohue, David Berron, Oskar Hansson, Niklas Mattsson-Carlgren
Summary: The study revealed that changes in key pathological markers A beta and tau in Alzheimer's disease may occur several decades or years before A beta-positivity, while cognitive dysfunction may appear 4-6 years before A beta-positivity, providing potential windows for specific treatments.
Article
Geriatrics & Gerontology
Claudia Schwarz, Catharina Lange, Gloria S. Benson, Nora Horn, Katharina Wurdack, Mathias Lukas, Ralph Buchert, Miranka Wirth, Agnes Floeel
Summary: The severity of subjective cognitive complaints in memory and planning was positively correlated with amyloid-beta load in the frontal and parietal cortex, while higher levels of worry were associated with higher amyloid-beta load in the frontal cortex. Further research is needed to determine the direction of these associations and develop strategies to prevent amyloid deposition and cognitive decline.
FRONTIERS IN AGING NEUROSCIENCE
(2021)
Article
Mathematics, Applied
M. Bertsch, B. Franchi, L. Meacci, M. Primicerio, M. C. Tesi
Summary: The paper presents a conceptual mathematical model for Alzheimer's disease based on the amyloid cascade hypothesis, which suggests that the progression of AD is associated with toxic oligomers of beta-amyloid. The model uses ordinary differential equations to describe the evolution from monomeric amyloid to senile plaques, considering the degradation of neurons and toxic oligomers. Numerical simulations show that the model, under some simplifying assumptions, can effectively explain the development of Alzheimer's disease.
EUROPEAN JOURNAL OF APPLIED MATHEMATICS
(2021)
Article
Neurosciences
Xiaoqi Wang, Qiuhui Bi, Jie Lu, Piu Chan, Xiaochen Hu, Li Su, Frank Jessen, Hua Lin, Chunlei Han, Ni Shu, Hesheng Liu, Ying Han
Summary: The study found that individuals with multidomain subjective cognitive decline (md-SCD) had higher amyloid accumulation compared to individuals with single memory domain subjective cognitive decline (sd-SCD). Increased global amyloid load was associated with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores.
JOURNAL OF ALZHEIMERS DISEASE
(2022)
Article
Clinical Neurology
Johannes Levin, Jonathan Voglein, Yakeel T. Quiroz, Randall J. Bateman, Valentina Ghisays, Francisco Lopera, Eric McDade, Eric Reiman, Pierre N. Tariot, John C. Morris
Summary: The amyloid cascade hypothesis for Alzheimer's disease has faced challenges due to inconsistent clinical benefits of drugs targeting amyloid beta peptide. It is important to conduct intervention studies in cognitively unimpaired individuals at risk for dementia to further evaluate the hypothesis.
ALZHEIMERS & DEMENTIA
(2022)
Article
Neurosciences
Young Min Choe, Guk-Hee Suh, Boung Chul Lee, Ihn-Geun Choi, Jun Ho Lee, Hyun Soo Kim, Jaeuk Hwang, Jee Wook Kim
Summary: The study found that in older adults without dementia, subjective memory complaints (SMC) of feeling worse memory performance than others in a similar age group were associated with poor objective cognitive performance and this association was mediated by increased brain amyloid index (API).
FRONTIERS IN NEUROSCIENCE
(2022)
Review
Geriatrics & Gerontology
Mohammad Nasb, Weichu Tao, Ning Chen
Summary: Alzheimer's disease (AD) is a common neurodegenerative disease with both memory and non-memory impairments. It accounts for 60-70% of all dementia cases globally. Elucidating underlying mechanisms and developing interventional strategies are necessary due to the increasing number of AD patients. Hypotheses about AD, such as amyloid cascade, Tau hyperphosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic, and vascular hypotheses, are not mutually exclusive and all play a role in AD development. This article summarizes recent evidence on major pathological hypotheses of AD and their potential interplay, as well as the strengths and weaknesses of each hypothesis and their implications for effective treatments.
Article
Clinical Neurology
Emma M. Coomans, Jori Tomassen, Rik Ossenkoppele, Betty M. Tijms, Luigi Lorenzini, Mara ten Kate, Lyduine E. Collij, Fiona Heeman, Roos M. Rikken, Sophie M. van der Landen, Marijke E. den Hollander, Sandeep S. Golla, Maqsood Yaqub, Albert D. Windhorst, Frederik Barkhof, Philip Scheltens, Eco J. C. de Geus, Pieter Jelle Visser, Bart N. M. van Berckel, Anouk den Braber
Summary: The amyloid cascade hypothesis has played a significant role in Alzheimer's disease research and clinical trial designs. This study investigated the relationship between amyloid-beta and tau at the individual and twin-pair levels, aiming to rule out genetic and shared environmental effects as confounders. The findings suggest that the associations between amyloid-beta, tau, neurodegeneration, and cognition are unbiased by genetic factors, and the effects of amyloid-beta on neurodegeneration and cognitive decline are mediated by tau.
Article
Oncology
Marie Wood, Thomas J. George, Rami Manochakian, Maura Polansky, Allyson Baer, Anne Grupe, Yu Shyr, Cathy Wang, Leora Horn
Summary: This study investigated how oncology providers identify knowledge gaps and choose learning activities. The results show that learning needs and activity selection differ based on practice setting, professional role, and geographic location. Over 75% of learners prioritize convenience and content quality when choosing activities.
JOURNAL OF CANCER EDUCATION
(2021)
Article
Oncology
Rami Manochakian, Thomas J. George, Marie Wood, Maura Polansky, Allyson Baer, Anne Grupe, Yu Shyr, Cathy Wang, Leora Horn
Summary: The ASCO Learning Cohort Pilot Project successfully established a model for analyzing the learning process of oncology healthcare professionals and required unique infrastructure for its implementation. The research findings indicate that there is a certain relationship between participant demographic variables and learning preferences.
JOURNAL OF CANCER EDUCATION
(2021)
Article
Clinical Neurology
Michael C. Donohue, Fabian Model, Paul Delmar, Nicola Volye, Hong Liu-Seifert, Michael S. Rafii, Paul S. Aisen
ALZHEIMERS & DEMENTIA
(2020)
Article
Mathematical & Computational Biology
Rui Wang, Ante Bing, Cathy Wang, Yuchen Hu, Ronald J. Bosch, Victor DeGruttola
STATISTICS IN MEDICINE
(2020)
Article
Neurosciences
Philip S. Insel, Michael C. Donohue, David Berron, Oskar Hansson, Niklas Mattsson-Carlgren
Summary: The study revealed that changes in key pathological markers A beta and tau in Alzheimer's disease may occur several decades or years before A beta-positivity, while cognitive dysfunction may appear 4-6 years before A beta-positivity, providing potential windows for specific treatments.
Review
Oncology
Reem S. Chamseddine, Cathy Wang, Kanhua Yin, Jin Wang, Preeti Singh, Jingan Zhou, Mark E. Robson, Danielle Braun, Kevin S. Hughes
Summary: This systematic review identified 15 studies on penetrance of male breast cancer susceptibility genes, with pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 showing increased risk for MBC. Seven of these studies adjusted for ascertainment bias and their findings are considered applicable to the general population.
BREAST CANCER RESEARCH AND TREATMENT
(2022)
Article
Clinical Neurology
K. V. Papp, H. Rofael, A. E. Veroff, M. C. Donohue, S. Wang, C. Randolph, E. Grober, H. R. Brashear, G. Novak, K. Ernstrom, R. Raman, P. S. Aisen, R. Sperling, G. Romano, D. Henley
Summary: Cognitive composites are commonly used in Alzheimer's disease secondary prevention trials. This study found that individuals with A beta+ status performed worse on cognitive composites, but the effect size was generally small. Memory tests and speed of processing exhibited the largest A beta+/- effect sizes.
JPAD-JOURNAL OF PREVENTION OF ALZHEIMERS DISEASE
(2022)
Article
Anesthesiology
John J. Finneran, Engy T. Said, Brian P. Curran, Matthew W. Swisher, Jessica R. Black, Rodney A. Gabriel, Jacklynn F. Sztain, Wendy B. Abramson, Brenton Alexander, Michael C. Donohue, Adam Schaar, Brian M. Ilfeld
Summary: This study demonstrates that using an integrated timer and automated boluses can improve and prolong analgesia in foot or ankle surgery.
Article
Clinical Neurology
Michael S. Rafii, Reisa A. Sperling, Michael C. Donohue, Jin Zhou, Claire Roberts, Michael C. Irizarry, Shobha Dhadda, Gopalan Sethuraman, Lynn D. Kramer, Chad J. Swanson, David Li, Stephen Krause, Robert A. Rissman, Sarah Walter, Rema Raman, Keith A. Johnson, Paul S. Aisen
Summary: The AHEAD 3-45 Study aims to investigate the feasibility of intervention therapy before the clinical symptoms of Alzheimer's disease appear, and utilizes innovative approaches to accelerate the screening process for selecting suitable participants.
ALZHEIMERS & DEMENTIA
(2023)
Article
Clinical Neurology
Philip S. Insel, Christina B. Young, Paul S. Aisen, Keith A. Johnson, Reisa A. Sperling, Elizabeth C. Mormino, Michael C. Donohue
Summary: The rates of tau accumulation in cognitively unimpaired older adults are subtle and vary in magnitude and spatial patterns. The degree of regional accumulation also likely depends on the amyloid-beta-dependent accumulation. Therefore, it is important to evaluate the pattern and consistency of tau accumulation across multiple cohorts and its relationship with amyloid burden to design optimal tau endpoints for clinical trials.
Article
Clinical Neurology
Roos J. Jutten, Kathryn Papp, Suzanne Hendrix, Noel Ellison, Jessica B. Langbaum, Michael C. Donohue, Jason Hassenstab, Paul Maruff, Dorene M. Rentz, John Harrison, Jeffrey Cummings, Philip Scheltens, Sietske A. M. Sikkes
Summary: Using the right outcome measure is crucial in clinical trials. However, there has been relatively less progress in the evolution of clinical outcome assessments (COAs) for the early stages of Alzheimer's disease (AD). This paper aims to provide guidance for the design and evaluation of COAs for use in early AD trials and proposes a framework for assessing clinically meaningful changes. Recommendations are also given to facilitate the implementation of more effective cognitive outcome measures in AD trials.
ALZHEIMERS & DEMENTIA
(2023)
Article
Genetics & Heredity
Cathy Shyr, Amanda L. Blackford, Theodore Huang, Jianfeng Ke, Nofal Ouardaoui, Lorenzo Trippa, Sapna Syngal, Chinedu Ukaegbu, Hajime Uno, Khedoudja Nafa, Zsofia K. Stadler, Kenneth Offit, Christopher I. Amos, Patrick M. Lynch, Sining Chen, Francis M. Giardiello, Daniel D. Buchanan, John L. Hopper, Mark A. Jenkins, Melissa C. Southey, Aung Ko Win, Jane C. Figueiredo, Danielle Braun, Giovanni Parmigiani
Summary: This study evaluated the predictive performance of models for predicting the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, for individuals with a family history of colorectal cancer. MMRpro+ and PREMM5 showed good discrimination and predictive accuracy.
GENETICS IN MEDICINE
(2022)
Article
Clinical Neurology
Monica Rivera Mindt, Ozioma Okonkwo, Michael W. Weiner, Dallas P. Veitch, Paul Aisen, Miriam Ashford, Godfrey Coker, Michael C. Donohue, Kenneth M. Langa, Garrett Miller, Ronald Petersen, Rema Raman, Rachel Nosheny
Summary: The poor generalizability of clinical research data due to the enrollment of highly educated, non-Latinx White participants hampers the development of therapies for Alzheimer's disease (AD). Black and Latinx older adults have a greater risk for dementia, yet it is unclear how health-care disparities and sociocultural factors influence potential AD therapies and prognosis. Low enrollment of under-represented populations may be attributable to several factors including greater exclusion due to higher rates of comorbidities, lower access to AD clinics, and the legacy of unethical treatment in medical research. This perspective outlines solutions tested in the Brain Health Registry (BHR) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), including culturally-informed digital research methods, community-engaged research strategies, leadership from under-represented communities, and the reduction of exclusion criteria based on comorbidities. Our successes demonstrate that it is possible to increase the inclusion and engagement of under-represented populations into US-based clinical studies, thereby increasing the generalizability of their results.
ALZHEIMERS & DEMENTIA
(2023)
Article
Pharmacology & Pharmacy
Michael C. Donohue, Oliver Langford, Philip S. Insel, Christopher H. van Dyck, Ronald C. Petersen, Suzanne Craft, Gopalan Sethuraman, Rema Raman, Paul S. Aisen
Summary: Mixed model repeated measures (MMRM) is commonly used in clinical trials for analyzing continuous outcomes over time. However, categorizing time as a categorical variable can lead to bias and exclusion of valuable information. In this study, a constrained longitudinal data analysis with natural cubic splines is proposed as an alternative to MMRM, showing better precision and power in clinical trial datasets and simulation scenarios.
PHARMACEUTICAL STATISTICS
(2023)
Article
Clinical Neurology
Jennifer Ngolab, Michael Donohue, Alison Belsha, Jennifer Salazar, Paula Cohen, Sandhya Jaiswal, Veasna Tan, Devon Gessert, Shaina Korouri, Neelum T. Aggarwal, Jessica Alber, Ken Johnson, Gregory Jicha, Christopher Dyck, James Lah, Stephen Salloway, Reisa A. Sperling, Paul S. Aisen, Michael S. Rafii, Robert A. Rissman
Summary: The study compared retinal and cerebral amyloid deposits in clinically normal individuals with high and low amyloid levels. It found a greater number of retinal spots in individuals with high amyloid levels, and a positive correlation between retinal spots and brain amyloid. Larger sample sizes are needed to fully understand the relationship between amyloid PET and retinal amyloid deposition.
ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING
(2021)