Medicine and Health Sciences Commons^™

Alzheimer’S Disease Genetic Risk And Cognitive Reserve In Relationship To Long-Term Cognitive Trajectories Among Cognitively Normal Individuals, Corinne Pettigrew, Jurijs Nazarovs, Anja Soldan, Vikas Singh, Jiangxia Wang, Timothy Hohman, Logan Dumitrescu, Julia Libby, Brian Kunkle, Alden L. Gross, Sterling Johnson, Qiongshi Lu, Corinne Engelman, Colin L. Masters, Paul Maruff, Simon M. Laws, John C. Morris, Jason Hassenstab, Carlos Cruchaga, Susan M. Resnick, Melissa H. Kitner-Triolo, Yang An, Marilyn Albert

Research outputs 2022 to 2026

Background:

Both Alzheimer’s disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition.

Methods:

Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by …

How Does Apolipoprotein E Genotype Influence The Relationship Between Physical Activity And Alzheimer’S Disease Risk? A Novel Integrative Model, Jaisalmer De Frutos Lucas, Kelsey R. Sewell, Alejandra García-Colomo, Shaun Markovic, Kirk I. Erickson, Belinda M. Brown

Research outputs 2022 to 2026

Background:

Wide evidence suggests that physical activity (PA) confers protection against Alzheimer’s disease (AD). On the other hand, the apolipoprotein E gene (APOE) ε₄ allele represents the greatest genetic risk factor for developing AD. Extensive research has been conducted to determine whether frequent PA can mitigate the increased AD risk associated with APOE ε₄. However, thus far, these attempts have produced inconclusive results. In this context, one possible explanation could be that the influence of the combined effect of PA and APOE ε₄ carriage might be dependent on the specific outcome measure utilised.

Main body:

In …

Using Digital Assessment Technology To Detect Neuropsychological Problems In Primary Care Settings, David J Libon, Emily Frances Matusz, Stephanie Cosentino, Catherine C Price, Rod Swenson, Meagan Vermeulen, Terrie Beth Ginsberg, Adaora Obiageli Okoli-Umeweni, Leonard Powell, Robert Nagele, Sean Tobyne, Joyce Rios Gomes-Osman, Alvaro Pascual-Leone

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

INTRODUCTION: Screening for neurocognitive impairment and psychological distress in ambulatory primary and specialty care medical settings is an increasing necessity. The Core Cognitive Evaluation™ (CCE) is administered/scored using an iPad, requires approximately 8 min, assesses 3- word free recall and clock drawing to command and copy, asks questions about lifestyle and health, and queries for psychological distress. This information is linked with patients' self- reported concerns about memory and their cardiovascular risks.

METHODS: A total of 199 ambulatory patients were screened with the CCE as part of their routine medical care. The CCE provides several summary indices, and scores on …

Tolfenamic Acid Derivatives: A New Class Of Transcriptional Modulators With Potential Therapeutic Applications For Alzheimer’S Disease And Related Disorders, Juanetta Hill, Karim E. Shalaby, Syed W. Bihaqi, Bothaina H. Alansi, Benjamin Barlock, Keykavous Parang, Richard Thompson, Khalid Ourarhni, Nasser H. Zawia

Pharmacy Faculty Articles and Research

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs …

Alcohol As A Modifiable Risk Factor For Alzheimer’S Disease—Evidence From Experimental Studies, Devaraj V. Chandrashekar, Ross A. Steinberg, Derick Han, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment and memory loss. Epidemiological evidence suggests that heavy alcohol consumption aggravates AD pathology, whereas low alcohol intake may be protective. However, these observations have been inconsistent, and because of methodological discrepancies, the findings remain controversial. Alcohol-feeding studies in AD mice support the notion that high alcohol intake promotes AD, while also hinting that low alcohol doses may be protective against AD. Chronic alcohol feeding to AD mice that delivers alcohol doses sufficient to cause liver injury largely promotes and accelerates AD pathology. The mechanisms by which alcohol can …

The Effects Of A Blood–Brain Barrier Penetrating Erythropoietin In A Mouse Model Of Tauopathy, Joshua Yang, Weijun Ou, Nataraj Jagadeesan, Juste Simanauskaite, Jiahong Sun, Demi M. Castellanos, David H. Cribbs, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for Alzheimer’s disease (AD) but has limited blood–brain barrier (BBB) permeability. EPO fused to a chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the brain via TfR-mediated transcytosis across the BBB. We previously showed that cTfRMAb-EPO is protective in a mouse model of amyloidosis, but its effects on tauopathy are not known. Given that amyloid and tau pathology are characteristics of AD, the effects of cTfRMAb-EPO were studied in a tauopathy mouse model (PS19). Six-month-old PS19 mice were injected intraperitoneally with either saline (PS19-Saline; n = 9) or cTfRMAb-EPO (PS19-cTfRMAb-EPO, 10 mg/kg; …

Early Visual Alterations In Individuals At-Risk Of Alzheimer’S Disease: A Multidisciplinary Approach, Inés López-Cuenca, Alberto Nebreda, Alejandra García-Colomo, Elena Salobrar-García, Jaisalmer De Frutos-Lucas, Ricardo Bruña, Ana I. Ramírez, Federico Ramirez-Toraño, Juan J. Salazar, Ana Barabash, Pedro Gil, Fernando Maestú, José M. Ramírez, Rosa De Hoz

Research outputs 2022 to 2026

Background: The earliest pathological features of Alzheimer’s disease (AD) appear decades before the clinical symptoms. The pathology affects the brain and the eye, leading to retinal structural changes and functional visual alterations. Healthy individuals at high risk of developing AD present alterations in these ophthalmological measures, as well as in resting-state electrophysiological activity. However, it is unknown whether the ophthalmological alterations are related to the visual-related electrophysiological activity. Elucidating this relationship is paramount to understand the mechanisms underlying the early deterioration of the system and an important step in assessing the suitability of these measures as early biomarkers of disease. …

Estimating Dementia Risk In An African American Population Using The Dctclock, Marissa Ciesla, Jeff Pobst, Joyce Gomes-Osman, Melissa Lamar, Lisa L Barnes, Russell Banks, Ali Jannati, David Libon, Rodney Swenson, Sean Tobyne, David Bates, John Showalter, Alvaro Pascual-Leone

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

The prevalence of Alzheimer's disease (AD) and related dementias (ADRD) is increasing. African Americans are twice as likely to develop dementia than other ethnic populations. Traditional cognitive screening solutions lack the sensitivity to independently identify individuals at risk for cognitive decline. The DCTclock is a 3-min AI-enabled adaptation of the well-established clock drawing test. The DCTclock can estimate dementia risk for both general cognitive impairment and the presence of AD pathology. Here we performed a retrospective analysis to assess the performance of the DCTclock to estimate future conversion to ADRD in African American participants from the Rush Alzheimer's Disease Research …

Ketone Bodies Mediate Alterations In Brain Energy Metabolism And Biomarkers Of Alzheimer’S Disease, Matin Ramezani, Malika Fernando, Shaun Eslick, Prita R. Asih, Sina Shadfar, Ekanayaka M. S. Bandara, Heidi Hillebrandt, Silochna Meghwar, Maryam Shahriari, Pratishtha Chatterjee, Rohith Thota, Cintia B. Dias, Manohar L. Garg, Ralph N. Martins

Research outputs 2022 to 2026

Alzheimer’s disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta () plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including A , phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and …

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

Research outputs 2022 to 2026

Background: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid- (A ) and tau in Alzheimer’s Disease (AD). However, its association with longitudinal cognition and comparative performance to PET A 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 A (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 …

Utility Of Dna Methylation As A Biomarker In Ageing And Alzheimer’S Disease, Lidija Milicic, Tenielle Porter, Michael Vacher, Simon M. Laws

Research outputs 2022 to 2026

Epigenetic mechanisms such as DNA methylation have been implicated in a number of diseases including cancer, heart disease, autoimmune disorders, and neurodegenerative diseases. While it is recognized that DNA methylation is tissue-specific, a limitation for many studies is the ability to sample the tissue of interest, which is why there is a need for a proxy tissue such as blood, that is reflective of the methylation state of the target tissue. In the last decade, DNA methylation has been utilized in the design of epigenetic clocks, which aim to predict an individual’s biological age based on an algorithmically defined set …

Sixteen-Year Longitudinal Evaluation Of Blood-Based Dna Methylation Biomarkers For Early Prediction Of Alzheimer's Disease, Fernanda Schäfer Hackenhaar, Maria Josefsson, Annelie Nordin Adolfsson, Mattias Landfors, Karolina Kauppi, Tenielle Porter, Lidija Milicic, Simon M. Laws, Magnus Hultdin, Rolf Adolfsson, Sofie Degerman, Sara Pudas, Australian Imaging Biomarkers And Lifestyle Study

Research outputs 2022 to 2026

BACKGROUND: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer's disease (AD) prediction. OBJECTIVE: Testing long-term predictive ability ( > 15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers. METHODS: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse Partial Least Squares …

Tackling Dementia Together Via The Australian Dementia Network (Adnet): A Summary Of Initiatives, Progress And Plans, Sharon L. Naismith, Johannes C. Michaelian, Cherry Santos, Inga Mehrani, Joanne Robertson, Kasey Wallis, Xiaoping Lin, Stephanie A. Ward, Ralph Martins, Colin L. Masters, Michael Breakspear, Susannah Ahern, Jurgen Fripp, Peter R. Schofield, Perminder S. Sachdev, Christopher C. Rowe

Research outputs 2022 to 2026

In 2018, the Australian Dementia Network (ADNeT) was established to bring together Australia's leading dementia researchers, people with living experience and clinicians to transform research and clinical care in the field. To address dementia diagnosis, treatment, and care, ADNeT has established three core initiatives: the Clinical Quality Registry (CQR), Memory Clinics, and Screening for Trials. Collectively, the initiatives have developed an integrated clinical and research community, driving practice excellence in this field, leading to novel innovations in diagnostics, clinical care, professional development, quality and harmonization of healthcare, clinical trials, and translation of research into practice. Australia now has a national …

Precision Medicine Approach To Alzheimer’S Disease: Rationale And Implications, Dale E. Bredesen, Kat Toups, Ann Hathaway, Deborha Gordon, Henrianna Chung, Cyrus Raji, Alan Boyd, Benjamin D. Hill, Sharon Hausman-Cohen, Mouna Attarha, Won Jong Chwa, Alexei Kurakin, Michael Jarrett

University Faculty and Staff Publications

The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer’s disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review …