Diseases Commons^™

Cerebrospinal Fluid Proteomics Define The Natural History Of Autosomal Dominant Alzheimer’S Disease, Erik C. B. Johnson, Shijia Bian, Rafi U. Haque, E. Kathleen Carter, Caroline M. Watson, Brian A. Gordon, Lingyan Ping, Duc M. Duong, Michael P. Epstein, Eric Mcdade, Nicolas R. Barthélemy, Celeste M. Karch, Chengjie Xiong, Carlos Cruchaga, Richard J. Perrin, Aliza P. Wingo, Thomas S. Wingo, Jasmeer P. Chhatwal, Gregory S. Day, James M. Noble, Sarah B. Berman, Ralph Martins, Neill R. Graff-Radford, Peter R. Schofield, Takeshi Ikeuchi, Hiroshi Mori, Johannes Levin, Martin Farlow, James J. Lah, Christian Haass, Mathias Jucker, John C. Morris, Tammie L. S. Benzinger, Blaine R. Roberts, Randall J. Bateman, Anne M. Fagan, Nicholas T. Seyfried, Allan I. Levey, Dominantly Inherited Alzheimer Network

Research outputs 2022 to 2026

Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid- (A ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of A plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale …

Mid-Life Leukocyte Telomere Length And Dementia Risk: An Observational And Mendelian Randomization Study Of 435,046 Uk Biobank Participants, Rui Liu, Luke C. Pilling, David Melzer, Lihong Wang, Kevin J. Manning, David C. Steffens, Jack Bowden, Richard H. Fortinsky, George A. Kuchel, Taeho G. Rhee, Breno S. Diniz, Chia-Ling Kuo

Health Science Faculty Publications

Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European-ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data ( …

Plasma Glial Fibrillary Acidic Protein In Autosomal Dominant Alzheimer's Disease: Associations With Aβ-Pet, Neurodegeneration, And Cognition, Pratishtha Chatterjee, Lisa Vermunt, Brian A. Gordon, Steve Pedrini, Lynn Boonkamp, Nicola J. Armstrong, Chengjie Xiong, Abhay K. Singh, Yan Li, Hamid R. Sohrabi, Kevin Taddei, Mark Molloy, Tammie L. S. Benzinger, John C. Morris, Celeste Karch, Sarah Berman, Jasmeer Chhatwal, Carlos Cruchaga, Neill R. Graff-Radford, Gregory S. Day, Martin Farlow, Nick Fox, Alison Goate, Jason Hassenstab, Jae-Hong Lee, Johannes Levin, Eric Mcdade, Hiroshi Mori, Richard Perrin, Raquel Sanchez-Valle, Peter R. Schofield, Allan Levey, Mathias Jucker, Colin L. Masters, Anne M. Fagan, Randall J. Bateman, Ralph N. Martins, Charlotte Teunissen, Dominantly Inherited Alzheimer Network

Research outputs 2022 to 2026

Background: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. Methods: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (A ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished A -positive from A -negative ADAD …

First Presentation With Neuropsychiatric Symptoms In Autosomal Dominant Alzheimer's Disease: The Dominantly Inherited Alzheimer's Network Study, Antoinette O'Connor, Helen Rice, Josephine Barnes, Natalie S. Ryan, Kathy Y. Liu, Ricardo Francisco Allegri, Sarah Berman, John M. Ringman, Carlos Cruchaga, Martin R. Farlow, Jason Hassenstab, Jae-Hong Lee, Richard J. Perrin, Chengjie Xiong, Brian Gordon, Allan I. Levey, Alison Goate, Neil Graff-Radford, Johannes Levin, Mathias Jucker, Tammie Benzinger, Eric Mcdade, Hiroshi Mori, James M. Noble, Peter R. Schofield, Ralph N. Martins, Stephen Salloway, Jasmeer Chhatwal, John C. Morris, Randall Bateman, Rob Howard, Suzanne Reeves, Nick C. Fox

Research outputs 2022 to 2026

Behavioural changes and neuropsychiatric symptoms (NPS) commonly occur in Alzheimer’s disease (AD) but may not be recognised as AD-related when they are the presenting feature. NPS are important as they are associated with greater functional impairment, poorer quality of life, accelerated cognitive decline and worsened caregiver burden.1 Autosomal dominant AD (ADAD), although < 1% of total AD cases, provides a valuable opportunity to study the clinical heterogeneity of AD. The young age at onset reduces the prevalence of age-related comorbid pathologies and the near 100% penetrance of pathogenic mutations reduces the likelihood of misdiagnosis.2 Anxiety and depression commonly occur in ADAD family members, with increased levels of depression having been found among predementia female mutation carriers.3 Subsequent studies, however, have shown that anxiety and/or depression are common regardless of mutation status, occurring in almost one in three at-risk individuals, with one study reporting a higher rate of depression in non-carriers (17%) than asymptomatic carriers (5%).4 5 Despite the high frequency of NPS in ADAD families, relatively little is known about the proportion of ADAD cases who present with predominantly behavioural symptoms. Our aims were to assess the first reported clinical change in symptomatic ADAD, to compare presentations across genotypes, and to compare cognitive performance between behavioural and cognitive-led presentations.

The Treatment Of Depression In Alzheimer's Disease Using Neuromodulation: A Literature Review, Aaron Marbn, Shane Ragland, Thalia Adrian, Clara Alvarez Villalba, Samuel Neuhut

East Florida Division GME Research Day 2023

Please see supplemental content for full abstract with references.

INTRODUCTION: An estimated 44 million individuals live with Alzheimer's Dementia globally, a number expected to triple by 2050.1 Depression is a commonly observed comorbidity in individuals with Alzheimer's disease. Traditional antidepressant medications often pose challenges due to their side effects and limited efficacy in this population. As a result, alternative therapeutic approaches are being explored, with Transcranial Magnetic Stimulation (TMS) emerging as a promising intervention for treating depression in Alzheimer's patients. TMS is a non-invasive brain stimulation technique that utilizes magnetic fields to modulate neural activity in targeted brain regions …

Discovery Of A Missense Mutation (Q222k) Of The Apoe Gene From The Australian Imaging, Biomarker And Lifestyle Study, Blaine R. Roberts, Scott B. Laffoon, Anne M. Roberts, Tenielle Porter, Chris Fowler, Colin L. Masters, Edward A. Dratz, Simon M. Laws

Research outputs 2022 to 2026

After age, polymorphisms of the Apolipoprotein E (APOE) gene are the biggest risk factor for the development of Alzheimer's disease (AD). During our investigation to discovery biomarkers in plasma, using 2D gel electrophoresis, we found an individual with and unusual apoE isoelectric point compared to APOE ϵ2, ϵ3, and ϵ4 carriers. Whole exome sequencing of APOE from the donor confirmed a single nucleotide polymorphism (SNP) in exon 4, translating to a rare Q222K missense mutation. The apoE ϵ4 (Q222K) mutation did not form dimers or complexes observed for apoE ϵ2 ϵ3 proteins.

Plasma Aβ42/40 Ratio, P-Tau181, Gfap, And Nfl Across The Alzheimer's Disease Continuum: A Cross-Sectional And Longitudinal Study In The Aibl Cohort, Pratishtha Chatterjee, Steve Pedrini, James D. Doecke, Rohith Thota, Victor L. Villemagne, Vincent Doré, Abhay K. Singh, Penghao Wang, Stephanie Rainey-Smith, Christopher Fowler, Kevin Taddei, Hamid R. Sohrabi, Mark P. Molloy, David Ames, Paul Maruff, Christopher C. Rowe, Colin L. Masters, Ralph N. Martins, Aibl Research Group

Research outputs 2022 to 2026

Introduction:

Plasma amyloid beta (Aβ)1-42/Aβ1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking.

Methods:

Plasma Aβ1-42, Aβ1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aβ-PET (positron emission tomography)–negative cognitively unimpaired (CU Aβ−, n = 81) and mild cognitive impairment (MCI Aβ−, n = 26) participants were compared with Aβ-PET–positive participants across the AD continuum (CU Aβ+, n = …

Impaired Muscle Function, Including Its Decline, Is Related To Greater Long-Term Late-Life Dementia Risk In Older Women, Simone Radavelli-Bagatini, Helen Macpherson, David Scott, Robin M. Daly, Jonathan M. Hodgson, Simon M. Laws, Kun Zhu, Richard L. Prince, Joshua R. Lewis, Marc Sim

Research outputs 2022 to 2026

Background: Impaired muscle function has been identified as a risk factor for declining cognitive function and cardiovascular health, both of which are risk factors for late-life dementia (after 80 years of age). We examined whether hand grip strength and timed-up-and-go (TUG) performance, including their change over 5 years, were associated with late-life dementia events in older women and whether any associations provided independent information to Apolipoprotein E ℇ4 (APOE ℇ4) genotype. Methods: Grip strength and TUG were assessed in community-dwelling older women (mean ± SD; age 75.0 ± 2.6 years) at baseline (n = 1225) and 5 years (n = …

Longitudinal Trajectories Of Basal Forebrain Volume In Normal Aging And Alzheimer's Disease, Ying Xia, Paul Maruff, Vincent Doré, Pierrick Bourgeat, Simon M. Laws, Christopher Fowler, Stephanie R. Rainey-Smith, Ralph N. Martins, Victor L. Villemagne, Christopher C. Rowe, Colin L. Masters, Elizabeth J. Coulson, Jurgen Fripp

Research outputs 2022 to 2026

Dysfunction of the cholinergic basal forebrain (BF) system and amyloid- (A ) deposition are early pathological features in Alzheimer's disease (AD). However, their association in early AD is not well-established. This study investigated the nature and magnitude of volume loss in the BF, over an extended period, in 516 older adults who completed A -PET and serial magnetic resonance imaging scans. Individuals were grouped at baseline according to the presence of cognitive impairment (CU, CI) and A status (A −, A +). Longitudinal volumetric changes in the BF and hippocampus were assessed across groups. The results indicated that high A …

A Potential Role For Sirtuin-1 In Alzheimer's Disease: Reviewing The Biological And Environmental Evidence, Mehrane Mehramiz, Tenielle Porter, Eleanor K. O'Brien, Stephanie R. Rainey-Smith, Simon M. Laws

Research outputs 2022 to 2026

Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer's disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing the involvement …