Familial History Improves Predictive Value of TOMM40 Gene in Alzheimer’s Disease

MedicalResearch.com Interview with:

Auriel Willette, M.S., Ph.D. Assistant Professor Departments of Food Science and Human Nutrition and Psychology Iowa State University

Dr. Willette

Auriel Willette, M.S., Ph.D.
Assistant Professor
Departments of Food Science and Human Nutrition and Psychology
Iowa State University

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Translocase of Outer Mitochondrial Membrane 40 (TOMM40) is a gene that regulates the width of the outer mitochondrial pore, facilitating the transport of ribosomal pre-proteins into the inner mitochondrial matrix for translational modification into functional proteins. In 2010, Dr. Allen Roses, who discovered the Apolipoprotein E (APOE) gene, Dr. Michael Lutz, and other colleagues found that a variation in poly-T length at locus rs10524523 (‘523) within intron 6 predicted Alzheimer’s disease onset. Specifically, a “long” versus “short” poly-T length was related to earlier age of onset by 8 years.

However, several multi-cohort studies either failed to replicate the findings or found the opposite relationship, where a “long” or “very long” poly-T length was related to later age of onset. The literature has remained mixed to this day.

We were interested in testing factors that might change the relationship between TOMM40 and both cognitive decline and risk for having Alzheimer’s disease. It is known that a family history (FH) of Alzheimer’s disease has been associated with mitochondrial dysfunction. We reasoned, then, that FH may interact with TOMM40 to modulate how it was related to our outcomes of interest. We investigated this hypothesis in two separate cohorts: the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a late middle-aged cohort, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a well-characterized sample of aged participants from across the Alzheimer’s spectrum.

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Salivary Biomarker May Lead To Spit Test For Early Diagnosis of Alzheimer’s Disease

MedicalResearch.com Interview with:

Ali Yilmaz, PhD Beaumont Research Institute Beaumont Health, Royal Oak, MI

Dr. Yilmaz

Ali Yilmaz, PhD
Beaumont Research Institute
Beaumont Health, Royal Oak, MI

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of β-amyloid plaques and tau tangles. Mild cognitive impairment (MCI) is progressive degree of impairment that is greater than might be attributed to normal age-related cognitive decline, but is not so severe as to merit a diagnosis of dementia. MCI is thought to be a transitional state between normal aging and AD sufferers phenotypically converting to AD at a rate of 10% per year. Currently there is no cure and few reliable diagnostic biomarkers for AD. As we live longer there is an ever increasing demand for valid and reliable biomarkers of Alzheimer’s disease; not only because it will help clinicians recognize the disease in its earliest symptomatic stages but will also be important for developing novel treatment of AD. Using 1D H NMR metabolomics, we biochemically profiled saliva samples collected from healthy-controls (n = 12), mild cognitive impairment (MCI) sufferers (n = 8), and Alzheimer’s disease (AD) patients (n = 9). We accurately identified significant concentration changes in 22 metabolites in the saliva of MCI and AD patients compared to controls.

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Depressive Symptoms Not Found To Increase Risk of Dementia

MedicalResearch.com Interview with:

Archana Singh-Manoux, PhD Research Professor (Directeur de Recherche) Epidemiology of ageing & age-related diseases INSERM U1018, France Honorary Professor University College London, UK

Dr. Archana Singh-Manoux

Archana Singh-Manoux, PhD
Research Professor (Directeur de Recherche)
Epidemiology of ageing & age-related diseases
INSERM  France
Honorary Professor
University College London, UK 

MedicalResearch.com: What is the background for this study?

Response: Depressive symptoms are common in dementia patients. Previous studies, based on older adults, show depressive symptoms in late life to be associated with an increased risk of dementia. These studies do not allow conclusions to be drawn on the causal nature of the association between depressive symptoms and dementia.

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Alzheimer’s Disease: Tramiprosate Envelopes Amyloid Protein To Prevent Misfolding Into Aggregates

MedicalResearch.com Interview with:

Dr. Petr Kocis Vice President Preclinical Development Alzheon, Inc. University of Oxford

Dr. Kocis

Dr. Petr Kocis PhD
Vice President Preclinical Development
Alzheon, Inc.
University of Oxford

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Researchers widely accept that amyloid plaques are the hallmark of Alzheimer’s disease. However, for many years, drug development has focused on the solid amyloid plaque as a primary disease culprit. Recent advances show that it is more likely that early stage soluble beta amyloid oligomers play a key role in the pathogenic process of Alzheimer’s disease.

A paper recently published by Alzheon, a company developing medicines for Alzheimer’s disease and other neurological disorders, suggests a new therapeutic mechanism for targeting toxic amyloid beta oligomers with a small molecule, tramiprosate, the active agent in the drug candidate, ALZ-801. ALZ-801 is a Phase 3-ready drug candidate that is an optimized prodrug of tramiprosate, with a substantially improved pharmacokinetic and safety profile compared to tramiprosate.

Alzheon scientists discovered that tramiprosate acts to inhibit the production of neurotoxic beta amyloid oligomers by ‘enveloping’ the amyloid peptide to prevent its misfolding into soluble amyloid aggregates. Beta amyloid oligomers are believed to be key drivers of the pathogenic process in Alzheimer’s disease (AD). This novel enveloping mechanism of tramiprosate prevents the self-assembly of misfolded proteins into beta amyloid oligomers that lead to amyloid aggregation and, subsequently, cause neuronal toxicity and clinical progression in Alzheimer’s disease. These results were published in the medical journal, CNS Drugs, and the paper is available through Open Access here. [“Elucidating the Aß42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data”]

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Can Greebles Help Identify People At Risk of Alzheimer’s Disease?

MedicalResearch.com Interview with:
Emily Mason, Ph.D.

Postdoctoral Associate
Department of Neurological Surgery
University of Louisville

MedicalResearch.com: What is the background for this study? What are the main findings?

Family History of Alzheimer’s Disease is Associated with Impaired Perceptual Discrimination of Novel Objects

Family History of Alzheimer’s Disease is Associated with Impaired Perceptual Discrimination of Novel Objects

Response: Alzheimer’s disease is a devastating neurodegenerative disease that currently affects one in eight Americans over the age of 65. Unfortunately, there is still no treatment that will halt or reverse the pathology associated with Alzheimer’s disease. One of the reasons for this may be that we still don’t fully understand what is happening in the very earliest stages of the disease. Previous studies have shown that one of the pathological hallmarks of the disease, called “tau tangles,” begins to accumulate in a specific area of the brain called the medial temporal lobe decades before people are typically diagnosed with Alzheimer’s disease. We wondered if we could use cognitive tests targeted to structures in the medial temporal lobe to pick up very subtle behavioral changes in people who were at increased risk for Alzheimer’s disease. We examined people who were in their 40s and 50s, which is a time when if any differences could be detected, it’s possible that pathology may be reversible.

Using a cognitive task called “odd man out” that can be easily implemented using a computer, we found that subjects at risk for Alzheimer’s disease tended to do worse in identifying differences between objects called Greebles. These objects are highly visually similar, and most people have never seen them before. Those two things make this task very difficult. We believe that this study lays some of the groundwork in developing cognitive tests targeted at relatively young subjects who may be in the very earliest stages of the disease.

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Neither Vitamin E or Selenium Found To Prevent Dementia

MedicalResearch.com Interview with:

Richard J. Kryscio, Ph.D. Statistics and Chair, Biostatistics and Sanders-Brown Center on Aging Sanders-Brown Center on Aging University of Kentucky

Dr. Richard Kryscio

Richard J. Kryscio, Ph.D.
Statistics and Chair, Biostatistics and Sanders-Brown Center on Aging
Sanders-Brown Center on Aging
University of Kentucky 

MedicalResearch.com: What is the background for this study?

Response: At the time the trial was initiated (2002), there was ample evidence that oxidative stress is an important mechanism in brain aging. Research showed that protein oxidation is linked to the brain’s response to the abnormal proteins seen in Alzheimer disease (amyloid beta plaques in particular) leading to inflammation, DNA repair problems, reduced energy production, and other cellular changes that are identified mechanisms in the Alzheimer brain.

Both vitamin E and selenium are antioxidants. Antioxidants, either through food or supplements, are believed to reduce oxidative stress throughout the body. In the brain, they may reduce the formation of amyloid beta plaques, reduce brain inflammation, and improve other brain processes. Studies in humans support these hypotheses. The Rotterdam study in the Netherlands, as an example, showed that initial blood levels of vitamin E could predict dementia risk. Those people with higher vitamin E levels were 25% less likely to develop dementia. Also, selenium deficiency results in cognitive difficulties and several population-based studies have shown an association between selenium level and cognitive decline (lower selenium levels are linked to thinking changes in the elderly).
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No Decrease In Incidence of Dementia Over Past Decades

MedicalResearch.com Interview with:

Emma van Bussel MD, MSc Academic Medical Center | University of Amsterdam Amsterdam | The Netherlands

Dr. Emma van Bussel

Emma van Bussel MD, MSc
Academic Medical Center | University of Amsterdam
Amsterdam | The Netherlands 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Dementia forms a high social and economic burden on society. Since there is a growing number of older people, the occurrence of dementia is expected to increase over the years to come. For future planning of care, it is important to have reliable predictions on new dementia cases for the population at large. Studies in Western countries suggested that the incidence per 1000 person years is declining.

We studied the incidence trend of dementia in the Netherlands in primary care registry data, in a population of over 800,000 older people (60 years and over) for the years 1992 to 2014. Our results indicate a small increase of 2.1% (95% CI 0.5% to 3.8%) per year in dementia incidence over the past decades. The trend did not change in the years after 2003, when a national program was developed to support dementia care and research, compared to the years prior to 2003.

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Safety and Immunogenicity of the Tau Vaccine AADvac1 in Patients with Alzheimer’s Disease

MedicalResearch.com Interview with:

Petr Novak, MD, PhD AXON Neuroscience Bratislava, Slovakia

Dr. Petr Novak

Petr Novak, MD, PhD
AXON Neuroscience
Bratislava, Slovakia

MedicalResearch.com: What is the background for this study?

Response: Alzheimer’s disease is a complex, multifactorial disorder, with many-faceted neuropathology. A hallmark finding is the co-existence of neurofibrillary pathology (such as neurofibrillary tangles) composed of tau protein, and amyloid-β pathology (plaques) [1].

Neurofibrillary pathology is closely correlated with cognitive impairment in Alzheimer’s disease [2], while support for the role amyloid in the disease pathogenesis comes from the ability of certain mutations to induce AD in an autosomal-dominant fashion [3].

The field has explored various anti-amyloid therapies to great extent, and continues to do so with undiminished effort [4]; meanwhile, there is a noticeable paucity of investigated therapies aimed at neurofibrillary tau protein pathology, despite the ability of tau protein dysfunction to cause a multitude of neurodegenerative disorders, collectively named “tauopathies” [5].

AADvac1 is the first tau-targeted immunotherapy investigated in humans [6], a pioneering effort to target the component of AD neuropathology that is proximal to neuronal damage and cognitive loss, and thus to halt or slow the progression of Alzheimer’s disease.

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Stopping Warfarin in Dementia Patients with Atrial Fib Associated With Increased Risk of Stroke and Death

MedicalResearch.com Interview with:

Ariela Orkaby, MD, MPH Geriatrics & Preventive Cardiology Associate Epidemiologist Division of Aging, Brigham and Women's Hospital Instructor in Medicine, Harvard Medical School

Dr. Ariela Orkaby

Ariela Orkaby, MD, MPH
Geriatrics & Preventive Cardiology
Associate Epidemiologist
Division of Aging, Brigham and Women’s Hospital
Instructor in Medicine, Harvard Medical School

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Atrial Fibrillation is a common heart rhythm that affects 1 in 25 adults over age 60 and 1 in 10 adults over age 80. The feared consequence of atrial fibrillation is stroke, leading to the prescription of blood thinning medications (anticoagulants such as warfarin) to prevent strokes. However, there is an underutilization of these life-saving medications in older adults, and particularly in those who have dementia. In part, this is due to a lack of research and inclusion of older adults with dementia in prior studies.

In this study, we used clinical Veterans Administration data, linked to Medicare, to follow 2,572 individuals over age 65 who had atrial fibrillation and until a diagnosis of dementia. The average age was 80 years, and 99% were male. We found that only 16% remained on warfarin. We used statistical methods to account for reasons why a patient would or would not be treated with warfarin and found that those who continued to take warfarin had a significantly lower risk of stroke (HR 0.74, 95% Confidence interval 0.54- 0.99, p=0.47) and death (HR 0.72, 95% CI 0.60-0.87, p<0.01) compared to those who did not continue to take warfarin, without an increased risk of bleeding.

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Excessive Sleeping May Be Early Marker of Dementia

MedicalResearch.com Interview with:

Dr. Matthew P. Pase Sidney Sax NHMRC Fellow, Department of Neurology Boston University School of Medicine Investigator, Framingham Heart Study;  Senior Research Fellow, Swinburne University of Technology. Boston MA 02118

Dr. Matthew Pase

Dr. Matthew P. Pase
Sidney Sax NHMRC Fellow, Department of Neurology
Boston University School of Medicine

Investigator, Framingham Heart Study;
Senior Research Fellow, Swinburne University of Technology.
Boston MA 02118

MedicalResearch.com: What is the background for this study?

Response: Sleep disturbances are common in dementia. However, most studies have focused on patients who already have dementia and so it is unclear whether disturbed sleep is a symptom or a cause of dementia.

We studied 2,457 older participants enrolled in the Framingham Heart Study, a large group of adults sampled from the community in Framingham, Massachusetts. We asked participants to indicate how long they typically slept each night. Participants were then observed for the following 10-years to determine who developed dementia, including dementia due to Alzheimer’s disease. Over the 10 years, we observed 234 cases of dementia. Information on sleep duration was then examined with respect to the risk of developing dementia.
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Role Identified for Neuronal Protein in Dementia of Frontotemporal Lobar Degeneration

MedicalResearch.com Interview with:
Shinsuke Ishigaki

Department of Neurology
Department of Therapeutics for Intractable Neurological Disorders
Nagoya University Graduate School of Medicine
Nagoya,Japan

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Frontotemporal lobar degeneration (FTLD) is a pathological process that
has been characterized by personality changes, abnormal behaviors,
language impairment, and progressive dementia. The genetic and
pathological similarities in fused in sarcoma (FUS), transactive
response (TAR) DNA-binding protein 43 (TDP-43), and C9orf72 in relation
to FTLD and amyotrophic lateral sclerosis (ALS) have recently lead to
the recognition that the two conditions represent points on a spectrum
of a single disease entity. Additionally, Frontotemporal lobar degeneration has also been classified as a tauopathy, characterized by an accumulation of phosphorylated
microtubule-associated protein tau (tau) in affected neurons.

Our study demonstrated a biological link between FUS/SFPQ and the regulation of
tau isoforms involved in the early phase of Frontotemporal lobar degeneration.

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Living Near Major Roads Associated With Increased Dementia Risk

MedicalResearch.com Interview with:

Hong Chen, PhD Scientist, Environmental Health Assessment Public Health Ontario | Santé publique Ontario Assistant Professor, Dalla Lana School of Public Health, University of Toronto Adjunct Scientist, Institute for Clinical Evaluative Sciences (ICES) Toronto, ON

Dr. Hong Chen

Hong Chen, PhD
Scientist, Environmental Health Assessment
Public Health Ontario | Santé publique Ontario
Assistant Professor, Dalla Lana School of Public Health
University of Toronto
Adjunct Scientist, Institute for Clinical Evaluative Sciences
Toronto, ON

MedicalResearch.com: What is the background for this study?

Response: Over the past several decades, there is unequivocal evidence that living close to major roadways may lead to various adverse health outcomes, such as cardio-respiratory related mortality and mortality. In the past decade, concern is growing that exposures associated with traffic such as air pollution and noise may also have an adverse impact on brain health. Several experimental studies show that air pollutants and diesel exhaust induce oxidative stress and neuroinflammation, activate microglia (which act as the first and main form of immune defense in the central nervous system), and stimulate neural antibodies. There are also a small number of epidemiological studies linking traffic-related noise and air pollution to cognitive decline and increased incidence of Parkinson’s disease and Alzheimer’s disease.

Studies also showed that living near roads was associated with reduced white matter hyperintensity volume and cognition, but its effect on the incidence of dementia, Parkinson’s disease, and multiple sclerosis is unknown. Given hundreds of millions of people worldwide live close to major roads, we conducted this population-based cohort study to investigate the association between residential proximity to major roadways and the incidence of these three neurological diseases in Ontario, Canada.

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