Alzheimer's - Dementia, Author Interviews, Lancet, Vaccine Studies / 01.03.2017 Interview with: Petr Novak, MD, PhD AXON Neuroscience Bratislava, Slovakia 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. (more…)
Alzheimer's - Dementia, Author Interviews, Genetic Research, PNAS / 12.10.2016 Interview with: Dr. Magdalena Sastre PhD Faculty of Medicine, Department of Medicine Senior Lecturer Imperial College London What is the background for this study? Response: Alzheimer’s disease is the most common neurodegenerative disorder, affecting over 45 million people around the world. Currently, there are no therapies to cure or stop the progression of the disease. Here, we have developed a gene therapy approach whereby we delivered a factor called PGC-1α, which regulates the expression of genes involved in metabolism, inflammation and oxidative stress in the brain of transgenic mice. This factor is also involved in the regulation of energy in the cells, because it controls the genesis of mitochondria and in the generation of amyloid-β, the main component of the neuritic plaques present in the brains of Alzheimer’s disease patients. We have found that the animals with Alzheimer’s pathology treated with PGC-1α develop less amyloid plaques in the brain, perform memory tasks as well as healthy mice and do not have neuronal loss in the brain areas affected by the disease. (more…)
Alzheimer's - Dementia, Author Interviews, Biomarkers / 01.09.2016 Interview with: Professor B. Paul Morgan Director, Systems Immunity Research Institute Institute of Infection and Immunity School of Medicine Cardiff University What is the background for this study? Response: Inflammation is a normal response of the body to infection or injury; however, it is well known that inflammation also has a dark side and when it escapes normal controls can cause disease. Some illnesses, like rheumatoid arthritis, have been known for many years to be caused by rogue inflammation and most of the drugs used to treat work by suppressing the inflammation (anti-inflammatories). More recently, it has become clear that inflammation is behind many other diseases that were previously thought of as diseases of ageing caused by wear and tear and lifestyle - these include heart disease and some brain diseases, notably Alzheimer's disease the commonest cause of dementia. Evidence that inflammation is one of the drivers of disease has come from many sources, including some where it was noticed that people on long-term anti-inflammatory drugs for other reasons appeared to be protected from developing Alzheimer's disease. A problem is that Alzheimer's disease, despite the name, is not a single disease but rather a group of conditions with similar symptoms, and inflammation is likely to be a cause in only some of the patients; further, most of the inflammation might be occurring very early in the disease, even before symptoms are obvious. So, there is an urgent need for a simple test or set of tests that can be used in individuals with the very earliest hints of Alzheimer's disease - mild memory loss - that will pick out those who have brain inflammation and are most likely to develop Alzheimer's disease. It might then be possible to treat this select group with anti-inflammatory drugs that will reduce brain inflammation and slow or stop progression of the disease. (more…)
Alzheimer's - Dementia, Author Interviews, Brigham & Women's - Harvard, Education / 30.08.2016 Interview with: Deborah Blacker MD, ScD Director of the Gerontology Research Unit Department of Psychiatry Massachusetts General Hospital What is the background for this study? What are the main findings Response: Many observational studies have found that those who are cognitively active have a lower risk of developing Alzheimer's disease or any type of dementia. However, we and others have been concerned that these findings might be spurious due to two potential biases:
  • 1) “confounding,” meaning that those who are cognitively active have lower rates of Alzheimer’s disease for another reason, in particular the effect of greater education, which is associated with both lower risk of Alzheimer’s and higher levels of cognitive activity; and
  • 2) “reverse causation,” meaning that theassociation could be due to a reduction in cognitive activity among those already in the long preclinical phase of cognitive decline before Alzheimer’s dementia (rather than the lack of cognitive activity causing the Alzheimer’s). Our study performed a systematic review of the literature on the association, and then a set of bias analyses to assess whether confounding or reverse causation could account for the observed associations.
Alzheimer's - Dementia, Author Interviews, Nutrition / 28.08.2016 Interview with: William B. Grant, Ph.D. Director, Sunlight, Nutrition, and Health Research Center San Francisco, CA What is the background for this study? What are the main findings? Response: The present study is the culmination of 20 years of investigating dietary links to Alzheimer's disease (AD). I am a physicist by training and spent my salaried career as an atmospheric scientist. In the 1990s while studying the effect of acid rain and ozone on eastern hardwood forests, I became familiar with the geographical ecological study approach. In this approach, populations are defined geographically, such as by state or country, and health outcomes are compared statistically with risk-modifying factors. Ecological studies are an efficient way to analyze the results of unplanned experiments. In 1996, I read that Japanese-American men living in Hawaii had two and a half times the prevalence of  Alzheimer's disease as native Japanese. I knew that AD patients often had higher concentrations of aluminum in their brains than other people, and that acid rain increased the concentration of aluminum in trees. It quickly occurred to me that the American diet must be the cause of the increased AD rate, and that by using the ecological approach, I could prove it. My first study, published in 1997, compared AD prevalence rates for 11 countries with macro-dietary factors of national diets. Total fat was found to have the highest correlation with AD, followed by total energy (calories), with fish reducing risk slightly, while countries such as China, Japan, and India, with large amounts of rice in the diet, had very low  Alzheimer's disease rates. This study was the first major study linking diet to risk of AD and led to observational studies that confirmed the findings five years later. (more…)
Alzheimer's - Dementia, Author Interviews, Neurological Disorders / 05.08.2016 Interview with: Auriel Willette, PhD Assistant Professor Departments of Food Science and Human Nutrition, and Psychology Iowa State University What is the background for this study? What are the main findings? Response: The Alzheimer's disease (AD) field continues to look for biological markers that can detect onset and progression of the disease, mainly memory decline and atrophy of medial temporal lobe where conscious memories are formed. The immune system has long been known to affect the onset and progression of Alzheimer's disease (AD), usually through a process called inflammation in the brain that causes damage to brain cells called neurons. We wished to examine all available immune system data in a large, well-established cohort across the AD spectrum and discover which immune markers best explained memory decline and medial temporal atrophy over 2 years. In essence, among dozens of candidate immune markers, we consistently found two to be most relevant: neuronal pentraxin 2 (NPTX2) and chitinase-3-like-protein-1 (C3LP1). NPTX2 is important for facilitating communication between neurons, whereas C3LP1 is related to activation of a part of the immune system that causes inflammation in the brain. To our surprise, higher NPTX2 levels at baseline were potently related to less memory loss and less medial temporal atrophy over 2 years. C3LP1, by contrast, was a relatively poor predictor. NPTX2 also better predicted levels of amyloid and tau in the brain, which are generally thought to help cause AD. Finally, we found that more years of education led to higher NPTX2 levels, suggesting that more formal learning leads to more stable, stronger connections between neurons that give rise to memory. (more…)
Author Interviews, Biomarkers, CT Scanning, McGill, MRI, Nature / 13.07.2016 Interview with: Dr. Yasser Iturria Medina PhD Post-doctoral fellow Montreal Neurological Institute What is the background for this study? What are the main findings? Response: We used over 200 peripheral molecular biomarkers, five different neuroimaging modalities and cognitive/clinical measurements to detect spatiotemporal abnormalities in subjects with dementia or with mild signs of cognitive deterioration. By means of a mathematical framework, we reordered all the biomarkers/descriptors considered, according to how much they change during the disease process. The results suggested that, contrary as suggested by more traditional clinical analyses, there are multiple early signs of neurodegeneration, at the molecular level and at the brain’s macroscopic and cognitive state. In particular, we observed notable early signs of generalized vascular dysregulation, which may be supporting the vascular hypothesis of Alzheimer’s disease. However, we still need to perform deeper analyzes, in order to clarify the complex causal mechanisms that trigger the disease. (more…)
Alzheimer's - Dementia, Author Interviews, Chemotherapy, Parkinson's / 13.07.2016 Interview with: Charbel Moussa MD. PhD Assistant Professor of Neurology Director- Laboratory for Dementia and Parkinsonism Clinical Research Director- National Parkinson's Foundation Center for Excellence Translational Neurotherapeutics Program Department of Neurology Georgetown University Medical Center Washington DC. What is the background for this study? What are the main findings? Response: We conducted a pilot open label proof-of-concept study to evaluate the safety and tolerability of Nilotinib in participants with advanced Parkinson’s disease (PD) with dementia (PDD) or dementia with Lewy bodies (DLB). Our primary objective is to demonstrate that low oral daily doses of 150mg or 300mg Nilotinib (compared to 600-800mg in cancer) are safe and tolerated. Our secondary objectives are that Nilotinib will cross the blood brain barier and may inhibit cerebral spinal fluid Abl. Based on preclinical data we also hypothesized that Nilotinib will increase DA levels. Motor and cognitive functions were also measured as exploratory clinical outcomes. Other exploratory outcomes are that Nilotinib may alter PD-related CSF biomarkers DJ-1 and α-synuclein. As most participants in this study had dementia we also explored the effects of Nilotinib on Alzheimer's Disease-related CSF biomarkers, including Aβ40 and Aβ42, total tau and phosphorylated tau (p-tau). (more…)
Alzheimer's - Dementia, Author Interviews, Cost of Health Care, Geriatrics / 22.06.2016 Interview with: Pei-Jung Lin, Ph.D. Assistant Professor Center for the Evaluation of Value and Risk in Health Institute for Clinical Research and Health Policy Studies Tufts Medical Center Boston, MA 02111 What is the background for this study? What are the main findings? Response: Alzheimer’s disease (AD) is a slow, progressive disease. Many people with AD may live for years with the disease left unrecognized or untreated, in part because the early symptoms are mild and often mistaken as part of normal aging. In this study, we found that Alzheimer’s patients may use more health care services and incur higher costs than those without dementia even before they receive a formal diagnosis. For example, total Medicare expenditures were 42% higher among Alzheimer’s patients than matched controls during the year prior to diagnosis ($15,091 vs. $10,622), and 192% higher in the first year immediately following diagnosis ($27,126 vs. $9,274). We also found similar trends among Medicare patients with mild cognitive impairment (MCI)— a prodromal stage of AD and associated with higher dementia risk. Our study suggests that an Alzheimer’s disease or MCI diagnosis appears to be prompted by other health problems such as cardiovascular and cerebrovascular diseases, pneumonia, renal failure, urinary tract infections, and blood and respiratory infections. This finding likely reflects a failure of ambulatory care related to the impact of cognitive impairment on other chronic conditions. (more…)
Alzheimer's - Dementia, Author Interviews / 01.06.2016 Interview with: Prof. Margitta Elvers, PhD Institute of Hemostasis, Hemotherapy and Transfusion Medicine University Clinic of the Heinrich-Heine-University Düsseldorf Düsseldorf Germany What is the background for this study? What are the main findings? Prof. Elvers: Platelets are the main players in hemostasis and thrombosis, but are also recognized to be involved in the pathology of different neurodegenerative diseases. It is well known that amyloid-beta is able to activate platelets and to induce platelet activation. In Alzheimer’s Disease (AD) patients, platelet activation is enhanced and a correlation between AD and vascular diseases such as stroke and atherosclerosis was shown in different studies However, a direct contribution of platelets to the progression of Alzheimer’s disease (AD) was an open question for many years. In the last years our group in Düsseldorf, Germany, provided strong evidence for platelets to play a relevant role in the progression of AD, because AD transgenic mice showed enhanced platelet signaling that translated into almost unlimited thrombus formation in vitro and accelerated carotid artery occlusion in vivo suggesting that these mice are at high risk of arterial thrombosis leading to cerebrovascular and unexpectedly to cardiovascular complications that might be also relevant in AD patients. In the recent study, we analyzed the contribution of platelets, which accumulate at vascular Abeta deposits, to cerebral amyloid angiopathy (CAA), a vascular dysfunction in most of  Alzheimer’s disease patients, characterized by deposits of Abeta in the wall of cerebral vessels. We found that synthetic monomeric Abeta is able to bind to integrin alphaIIbbeta3 via its RHDS (Arg-His-Asp-Ser) sequence thereby stimulating the release of adenosine diphosphate (ADP) and clusterin from platelets. ADP enhanced integrin activation via the ADP receptors P2Y1 and P2Y12 and further increased platelet clusterin release and Abeta fibril formation. Clopidogrel, an antiplatelet drug which irreversible inhibits P2Y12, inhibited Abeta aggregation in human and murine platelet cell cultures. Treatment of AD transgenic mice with clopidogrel for three months reduced clusterin plasma levels and the incidence of CAA. (more…)
ALS, Alzheimer's - Dementia, Author Interviews, Nature / 07.05.2016 Interview with: Ana Pereira, MD Instructor in Clinical Medicine Bruce McEwen's laboratory Rockefeller University What is the background for this study? Dr. Pereira: The neurons most susceptible to dying in Alzheimer’s disease are the ones that use glutamate as a neurotransmitter (chemical messengers that enable neurotransmission). Glutamate is the major excitatory neurotransmitter in the brain and its regulation is critical for learning and memory. When glutamate is not located in the correct place and amount, it causes several deleterious effects to neurons that can ultimately lead to cell death. Importantly, the glutamate transporter EAAT2 is the dominant regulator of glutamate levels and it is highly depressed in Alzheimer’s disease. Furthermore, glutamatergic dysregulation is implicated in several pathological mechanisms in Alzheimer’s disease including the release and toxicities of the proteins implicated in Alzheimer’s disease: amyloid-beta (which form amyloid plaques) and tau (which form neurofibrillary tangles). Better regulation of glutamatergic neural circuits is critically important to effectively treat age-related cognitive decline and Alzheimer’s disease. (more…)
Alzheimer's - Dementia, Author Interviews, Biomarkers / 27.04.2016 Interview with: Dr Anne Poljak Leader of the Proteomics Group Centre for Healthy Brain Ageing (CHeBA) UNSW, Australia What is the background for this study?  Dr Poljak: Amyloid-beta (Aβ) peptides are found in abundance in the plaque particles which build up in the Alzheimer’s brain and small blood vessels of the brain, and are therefore considered hallmark features of Alzheimer’s disease. However they are also found in blood which is a convenient body fluid for sampling purposes. We therefore wished to assay them in plasma samples from one of our longitudinal population based studies of older age individuals (70 – 90 years) – the Centre for Healthy Brain Ageing’s Sydney Memory and Ageing Study. Other research groups had previously measured these peptides in plasma, but there was controversy in the area because of differences in outcomes across laboratories. So one of the main questions was whether plasma levels of Aβ peptides have any relationship with what is happening in the brain, or are they a red-herring? We wanted to see how the levels we found would compare with the findings of others in relation to Alzheimer’s disease and mild cognitive impairment. A further question was how our plasma levels would relate to other clinical measures including cognition and brain volumetrics. One of the precautions we took was to use an assay kit with very well characterized antibodies, so we could be confident that our method was specific for the two full length Aβ peptides (Ab1-40 and Ab1-42). (more…)
Alzheimer's - Dementia, Author Interviews, JAMA, UCSF / 20.04.2016 Interview with: Jennifer S. Yokoyama, PhD Assistant Professor, Memory and Aging Center University of California, San Francisco What is the background for this study? Dr. Yokoyama: Alzheimer’s disease is a common neurodegenerative disease that occurs in older adults. Clinically, Alzheimer’s disease is primarily associated with changes in cognition (e.g., declines in memory, language and visuospatial functioning). Pathologically, Alzheimer’s disease is associated with misfolded amyloid beta and tau proteins and can only be definitively diagnosed at autopsy. It has long been appreciated that there is a link between the immune system and Alzheimer’s disease, and there are multiple sources of evidence that suggest that immune activity may be increased in patients with Alzheimer’s. Although there is strong evidence for an association between immune activity and Alzheimer’s disease there has always been a chicken-egg problem because we don’t know whether the Alzheimer’s disease process triggers the immune response or whether altered immune function promotes the Alzheimer’s disease process. Genetic information can offer important clues about the role of the immune system in Alzheimer’s disease. Each person has a unique genetic fingerprint, and different combinations of gene changes (“variants”) put individuals at higher or lower risk for different diseases. Genetic data enables us to test whether having a certain genetic variant puts people at greater risk for both Alzheimer’s disease and autoimmune diseases, immune system diseases in which the immune system is overactive (e.g., Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, Celiac's disease, and psoriasis). Rather than only responding to foreign objects such as bacteria and viruses, in autoimmune diseases the immune system also responds to the body’s own material, which do not ordinarily create an immune response, thereby leading to symptoms associated with higher levels of inflammation and other long-term problems. A variant that increases risk for both Alzheimer’s disease and autoimmune diseases would suggest a common biological pathway. What are the main findings? Dr. Yokoyama: In our study we tested whether there are genetic variants that put people at increased risk for both Alzheimer's disease and autoimmune diseases. We found eight genetic variants that influence people’s risk for both Alzheimer's disease and autoimmune disease. Some of these variants were associated with lower risk of autoimmune disease and Alzheimer’s disease, but two variants were associated with greater risk for both.   (more…)
Alzheimer's - Dementia, Author Interviews / 12.04.2016 Interview with: Dr. Sven Joubert, PhD Département de psychologie, Université de Montréal Centre de recherche Institut universitaire de gériatrie de Montréal (CRIUGM) Montréal, Canada What is the background for this study? What are the main findings? Dr. Joubert: Difficulties in recognizing familiar people in Alzheimer's disease have typically been attributed to the underlying memory impairment. There is evidence however that people with Alzheimer's disease also have difficulties in visual perception. The aim of this study was to determine if people with Alzheimer's were specifically impaired at face perception. In the current study, people with Alzheimer's along with healthy seniors were asked to process pictures of faces and cars at both upright and inverted orientation. Results showed that persons with Alzheimer's disease had a reduced face inversion effect, in other words they had a disproportionate impairment in processing upright relative to inverted faces. This reduced inversion effect in Alzheimer's disease, which was specific to faces, may reflect a reduced ability in "holistic" processing of faces, in other words the ability to form intergrated and individualized representations of faces based on their local features. (more…)
Alzheimer's - Dementia, Author Interviews, Blood Pressure - Hypertension, NIH / 03.02.2016 Interview with: Dr. Juan M. Saavedra, MD and Dr. Abdel Elkahloun PhD Comparative genomics and Cancer Genetics Branch National Human Genome Research Institute, National Institutes of Health, Bethesda, MD MedicalResearch: What is the background for this study? What are the main findings? Response: Alzheimer’s disease is the most frequent age-related dementia, a progressing, devastating illness without effective treatment. By the time it is diagnosed, major and irreversible cell injury has already occurred. It is therefore imperative to identify therapeutic agents effective against early, pre-symptomatic injury mechanisms and risk factors increasing vulnerability the disease. We focused on a class of compounds blocking receptors for Angiotensin II, the Angiotensin Receptor Blockers (ARBs). These compounds are commonly used for the treatment of hypertension, a major risk factor for Alzheimer’s disease. We and others have found that in addition to their cardiovascular benefits, ARBs are strongly neuroprotective. The present study was designed to explore in depth the neuroprotective effects of one member of the ARB class, candesartan. To this effect we cultured neurons extracted from the rat brain. These neurons were exposed to high concentrations of glutamate, a recently identified early injury mechanism in Alzheimer’s disease. We found that candesartan prevented glutamate-induced neuronal injury. We conducted in-depth examination of our results by genome-wide expression profile analysis. We found that candesartan normalized glutamate-induced alterations in expression of hundreds of genes, including many involved in neuronal inflammation, cardiovascular disease, diabetes and alterations in amyloid metabolism a hallmark for Alzheimer’s disease. This was evidence of direct neuroprotective effects of relevance for this disorder. When we compared our results with published databases obtained from autopsy samples from Alzheimer’s disease patients, we found impressive correlations. The expression of more than 400 genes altered by glutamate and normalized by candesartan in our cultures was similarly changed in the Alzheimer’s databases. The conclusion was that our cell culture results represented alterations found in the human condition. Our observations provide novel evidence of neuroprotection from early mechanisms of injury in Alzheimer’s disease and support testing candesartan in controlled clinical studies including individuals at the early stages of the illness, to unequivocally demonstrate their therapeutic effect. (more…)
Alcohol, Alzheimer's - Dementia, Author Interviews, BMJ / 11.12.2015 Interview with:

Professor, Frans Boch Waldorff General Practitioner Research Unit of General Practice Denmark

MedicalResearch: What is the background for this study? What are the main findings? Prof. Waldorff: While there are numerous studies focusing on alcohol as a risk factor for dementia and mortality in healthy subjects, virtually no attention has been paid to the effect of alcohol consumption in patients with Alzheimer’s disease (AD). Considering that AD is a neurodegenerative disorder and that alcohol has known neurotoxic effects, one could easily jump to the conclusion that alcohol is damaging for patients with AD. The aim of this study was to investigate whether the positive association between moderate alcohol intake and mortality shown in population-based studies on healthy subjects can be transferred to patients with mild AD. In our study we found that patients with mild  Alzheimer’s disease , moderate alcohol consumption (two to three units per day) was associated with a significantly lower risk of death compared with those who only had alcohol occasionally (one or less than one unit per day), and with those who had high alcohol intake (more than 3 units per day). Abstinence or high alcohol intake did not significantly raise mortality compared with those drinking only occasionally. (more…)
Alzheimer's - Dementia, Author Interviews, Journal Clinical Oncology, Prostate Cancer, Testosterone, University of Pennsylvania / 10.12.2015 Interview with: Kevin T. Nead, MD, MPhil Dept. of Radiation Oncology Perelman School of Medicine University of Pennsylvania MedicalResearch: What is the background for this study? What are the main findings? Dr. Nead: There are a growing number of studies suggesting that the use of  Androgen Deprivation Therapy (ADT)  may be associated with cognitive changes and some of these changes overlap with characteristic features of Alzheimer’s disease. In addition, low testosterone levels have been associated with Alzheimer’s disease risk and ADT lowers testosterone levels. Despite these findings, we could not identify any studies examining the association between ADT and Alzheimer’s disease risk. We therefore felt this study could make an important contribution in guiding future research to fully understand the relative risks and benefits of ADT. We examined electronic medical record data from Stanford University and Mt. Sinai hospitals to identify a cohort of 16,888 patients with prostate cancer. We found that men with prostate cancer who received Androgen Deprivation Therapy were more likely to develop Alzheimer’s disease than men who did not receive  Androgen Deprivation Therapy. We also found that this risk increased with a longer duration of ADT. These results were consistent using multiple statistical approaches and separately at both Stanford and Mr. Sinai. (more…)
Alzheimer's - Dementia, Author Interviews, Nature, UCSF / 03.12.2015 Interview with: Elsa Suberbielle, DVM, PhD Research Scientist Gladstone Institute of Neurological Diseases San Francisco, CA 94158 Medical Research: What is the background for this study? Dr. Suberbielle: BRCA1 is a key protein involved in DNA repair, and mutations that impair its function increase the risk for breast and ovarian cancer. Research into DNA repair mechanisms in dividing cells recently was recently rewarded by the Nobel Prize in Chemistry. In such cells, BRCA1 helps repair a type of DNA damage known as double-strand breaks that can occur when cells are injured. In neurons, though, such breaks can occur even under normal circumstances, for example, after increased brain activity, as shown by the team of Gladstone scientists in an earlier study. The researchers speculated that in brain cells, cycles of DNA damage and repair facilitate learning and memory, whereas an imbalance between damage and repair disrupts these functions. Medical Research: What are the main findings? Dr. Suberbielle In a new study published in Nature Communications, Researchers from the Gladstone Institutes demonstrates that Alzheimer’s disease is associated with a depletion of BRCA1 in neurons and that BRCA1 depletion can cause cognitive deficits. The researchers experimentally reduced BRCA1 levels in the neurons of mice. Reduction of the DNA repair factor led to an accumulation of DNA damage and to neuronal shrinkage. It also caused learning and memory deficits. Because Alzheimer’s disease is associated with similar neuronal and cognitive problems, the scientists wondered whether they might be mediated by depletion of BRCA1. They therefore analyzed neuronal BRCA1 levels in post-mortem brains of Alzheimer’s patients. Compared with non-demented controls, neuronal BRCA1 levels in the patients were reduced by 65-75%. To determine the causes of this depletion, the investigators treated neurons grown in cell culture with amyloid-beta proteins, which accumulate in Alzheimer brains. These proteins depleted BRCA1 in the cultured neurons, suggesting that they may be an important cause of the faulty DNA repair seen in Alzheimer brains. Further supporting this conclusion, the researchers demonstrated that accumulation of amyloid-beta in the brains of mice also reduced neuronal BRCA1 levels. They are now testing whether increasing BRCA1 levels in these mouse models can prevent or reverse neurodegeneration and memory problems. (more…)
Alzheimer's - Dementia, Author Interviews, Cleveland Clinic, JAMA / 22.09.2015

Jeffrey L. Cummings, M.D., Sc.D. Director, Lou Ruvo Center for Brain Health Camille and Larry Ruvo Chair for Brain Health Cleveland Clinic Las Vegas, NV Interview with: Jeffrey L. Cummings, M.D., Sc.D. Director, Lou Ruvo Center for Brain Health Camille and Larry Ruvo Chair for Brain Health Cleveland Clinic  Las Vegas, NV 89106  Medical Research: What is the background for this study? What are the main findings? Dr. Cummings: Agitation is a common problem in Alzheimer’s disease (AD); approximately 70% of patients with AD will experience periods of agitation.  This difficult behavior challenges patients and caregivers, adversely affects quality of life, and may precipitate institutionalization.  There are not drugs approved for treatment of agitation in Alzheimer’s disease. The study reported in JAMA showed that a drug based on a combination of dextromethorphan and quinidine (DM/Q) produced statistically significant and clinically meaningful reduction in agitation in Alzheimer’s disease patients.  The study met its primary outcome (decline in the Neuropsychiatric Inventory agitation scale in drug compared to placebo) and many of its secondary outcomes (e.g, decreases in caregiver stress).  The agent was safe and well tolerated. (more…)
Author Interviews, Cognitive Issues, UCSF / 22.08.2015

Jin-Tai Yu MD, PhD Memory and Aging Center, Department of Neurology University of California San Francisco San Francisco, CA 94158 Interview with: Jin-Tai Yu MD, PhD Memory and Aging Center, Department of Neurology University of California San Francisco San Francisco, CA 94158 Medical Research: What is the background for this study? What are the main findings? Response: The number of dementia cases in the whole world was estimated to be 35.6 million in 2010 and this number was expected to almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050. The global prevalence of dementia was 5-7% and Alzheimer’s disease accounts for roughly 60%. This data means that we are facing an increasing number of global populations of this specific neurodegenerative disease and also the heavy burden brought by it. Data from the website of global clinical trials ( showed that a total of 1,732 clinical trials for Alzheimer’s disease were under way. However, the previous results are not so optimistic, possibly due to the complex etiological mechanisms. In one word, we had currently no effective drugs for this disease. Figuring out how to effectively prevent its occurrence is increasingly attracting people’s attentions.Therefore, we have done the most extensive and comprehensive systematic review and meta-analysis to date, which employs a full-scale search of observational studies to calculate effect sizes and grade the evidence strength of various modifiable risk factors for this disease. We hope these results will be informative and instructive. (more…)
Alzheimer's - Dementia, Author Interviews, Diabetes, Diabetologia / 14.08.2015

Laura Ekblad, MD, researcher Turku PET Interview with: Laura Ekblad, MD, researcher Turku PET Centre Medical Research: What is the background for this study? What are the main findings? Dr. Ekblad: The background for our study is that the metabolic syndrome and diabetes have been shown to increase the risk for cognitive decline and dementia. Also, insulin resistance is thought to play a pivotal role in the pathophysiology of Alzheimer´s disease. In addition, intranasal insulin administration is being studied as a promising treatment for Alzheimer´s disease. Previous studies indicate that both gender and APOE epsilon 4 genotype modulate the effects of insulin on cognition. Our main findings are that insulin resistance is associated with poorer verbal fluency, but only in women. Our population-based study consisted of adults from 30-97 years of age and we had nearly 6000 participants. Age did not modulate the association of insulin resistance and cognition, which means that our results apply even to young adults. We also found that insulin resistance associated with poorer verbal fluency only in non-carriers of the APOE epsilon 4 genotype. (more…)
Cost of Health Care / 13.08.2015

Noam Y. Kirson, Ph.D.  Vice President Analysis Group, Inc. Economic, Financial, and Strategy Consulting Boston, MA Interview with: Noam Y. Kirson, Ph.D.  Vice President Analysis Group, Inc. Economic, Financial, and Strategy Consulting Boston, MA 02199 Medical Research: What is the background for this study? What are the main findings? Dr. Kirson: Developments in diagnostic technology now support ruling out Alzheimer’s disease (AD) among patients presenting with symptoms of cognitive decline, possibly facilitating earlier and more accurate diagnosis of non-Alzheimer’s dementias. Our study assessed potential economic benefits of timely rule out of Alzheimer’s disease among U.S. Medicare beneficiaries eventually diagnosed with vascular dementia (VD) or Parkinson’s disease (PD) by estimating excess medical costs among those previously misdiagnosed withAlzheimer’s. We found that approximately one in six beneficiaries with VD and one in twelve beneficiaries with PD had a prior Alzheimer’s disease diagnosis. Further, we found that VD and PD patients previously diagnosed with Alzheimer’s disease incurred substantially higher medical costs in periods leading up to and including their VD/PD diagnoses, compared with matched counterparts with no prior AD diagnosis during the same timeframe. Perhaps most interestingly, excess costs declined – and eventually dissipated – following the confirmed VD/PD diagnoses. (more…)
Alzheimer's - Dementia, Author Interviews, Diabetes, JAMA, Nutrition / 31.07.2015

Auriel A. Willette, M.S., Ph.D. Food Science and Human Nutrition Neuroscience Interdepartmental Graduate Program Gerontology Interdepartmental Graduate Program Iowa State University, Interview with: Auriel A. Willette, M.S., Ph.D. Food Science and Human Nutrition Neuroscience Interdepartmental Graduate Program Gerontology Interdepartmental Graduate Program Iowa State University, Ames Medical Research: What is the background for this study? What are the main findings? Response: Obesity is a major health concern around the world. Obesity causes insulin resistance, defined in this case as the inability of insulin to bind to its receptor and mediate glucose metabolism. Other researchers and I have recently found that higher insulin resistance is associated with less glucose metabolism in the brains of patients with Alzheimer's disease. This relationship is found primarily in medial temporal lobe, an area necessary for generating new memories of facts and events. This is important because Alzheimer's disease is characterized by progressive decreases in glucose metabolism over time, and partly drives worse memory performance. Insulin resistance in midlife also increases the risk of developing Alzheimer's disease. We wanted to determine if insulin resistance is linked to similar effects in cognitively normal, late middle-aged participants decades before Alzheimer's disease typically occurs. If so, insulin resistance might be an important biological marker to track from middle-age onwards. Thus, we examined the association between insulin resistance, regional glucose metabolism using FDG-PET, and memory function in 150 middle-aged participants, many of whom had a mother or father with Alzheimer's disease. We found that higher insulin resistance was strongly associated with less glucose metabolism throughout many brain regions, predominantly in areas that are affected by Alzheimer's disease. The strongest statistical effects were found in left medial temporal lobe, which again is important for generating new memories. This relationship, in turn, predicted worse memory performance, both immediately after learning a list of words and a 20-minute delay thereafter. The take-home message is that insulin resistance has an Alzheimer's-like association with glucose metabolism in middle-aged, cognitively normal people at risk for Alzheimer's, an association which is related to worse memory. (more…)
Alzheimer's - Dementia, Author Interviews, NYU / 21.07.2015

Fernando Goni, PhD MS Adjunct associate professor Department of Neurology, Center for Cognitive Neurology NYU School of Medicine NYU Langone Medical Interview with: Fernando Goni, PhD MS Adjunct associate professor Department of Neurology, Center for Cognitive Neurology NYU School of Medicine NYU Langone Medical Center Medical Research: What is the background for this study? What are the main findings? Dr. Goni: It has been established that most neurodegenerative diseases including Alzheimer's, Lewy Body and other dementias, Parkinson's and prion diseases develop and progress along similar paths. In each disease, a particular protein undergoes a change in its shape from a soluble, physiologically functional protein to a protein that has lost the ability to perform its required tasks in the brain, starting off a chain reaction of binding to each other with little control. These aggregates become toxic to brain cells. We raised antibodies in mice against the common beta-sheet structures present in toxic oligomers of many neurodegenerative diseases including amyloid and tau in Alzheimer's; oligomeric forms of prions and oligomerized alpha-synuclein in Parkinson's. From that response, we produced monoclonal antibodies of the same characteristics. At least three of the monoclonals recognize pathological structures in histological samples of human brains from Alzheimer's disease, Parkinson's disease and GSS (human prionosis). They also recognized in vitro the oligomeric forms particular for each disease. In old animals of a mouse model of Alzheimer's, that already had pathology, the monoclonal antibodies could rescue behavior and reduced significantly the oligomers of Tau and Abeta. (more…)
Alzheimer's - Dementia, Author Interviews, JAMA, Medical Imaging, UCSF / 20.05.2015

Rik Ossenkoppele PhD. Postdoctoral researcher UCSF Memory and Aging Interview with: Rik Ossenkoppele PhD. Postdoctoral researcher UCSF Memory and Aging Center MedicalResearch: What is the background for this study? Dr. Ossenkoppele: Since 2004, several PET tracers have been developed that measure fibrillar amyloid-β plaques, a neuropathological hallmark of Alzheimer’s disease (AD). Through visual assessment by a nuclear medicine physician or quantitative cut-points, the presence or absence of amyloid-β pathology can be determined in the living human brain. The FDA, in support of the clinical application of amyloid imaging, has recently approved three of these PET tracers. A proportion of patients with other types of dementia then Alzheimer’s disease that harbor cerebral amyloid-β pathology, however, potentially limits the clinical utility of amyloid imaging. When ordering clinical amyloid PET scans and correctly interpreting the significance of amyloid PET results, clinicians need to understand the prevalence of amyloid-positivity across different types of dementia. It is also important to be aware of the relationships of amyloid-positivity prevalence and demographic (e.g. age and sex), cognitive and genetic (e.g. presence of the AD-risk allele apolipoprotein E [APOE] ε4) factors. Most amyloid PET studies to date come from single centers with modest sample sizes. We therefore conducted a meta-analysis with individual participant data from 29 cohorts worldwide, including 1359 patients with clinically diagnosed Alzheimer’s disease and 538 patients with non-AD dementia. We also included 1849 healthy controls with amyloid PET data, and an independent sample of 1369 AD patients with autopsy data from the NACC database. MedicalResearch: What are the main findings? Dr. Ossenkoppele: In patients clinically diagnosed with Alzheimer’s disease, the prevalence of amyloid-positivity decreased from 93% at age 50 to 79% at age 90. The drop in amyloid-positivity was most prominent in older Alzheimer’s disease patients who did not carry an APOE ε4 allele (~1/3 of these patients had a negative amyloid PET scan). This most likely reflects a mix of 1) clinical misdiagnoses (i.e. non-AD pathology causing an AD phenotype), 2) false negative PET scans (i.e. abundance of cerebral amyloid pathology that is not detected by PET), and 3) possibly elder patients need less amyloid pathology (sub-threshold levels for PET) to reach the stage of dementia due to age-related reductions in cognitive resilience (“cognitive reserve theory”) or simultaneous presence of multiple pathologies (“double-hit theory”). The relatively high rate of amyloid-negative Alzheimer’s disease patients highlights the necessity of biomarker-informed patient selection for Alzheimer’s disease clinical trials. In most patients clinically diagnosed with non-AD, the prevalence of amyloid-positivity increased with aging and was ~18% higher in APOE ε4 carriers. Presence of amyloid pathology in non-AD dementia may reflect 1) clinical misdiagnosis (i.e. AD pathology is the causative pathology), or 2) comorbid pathologies, where amyloid may be secondary to other pathologies that are actually driving the clinical presentation. Interestingly, patients with a clinical diagnosis of non-AD dementia who harbored cerebral amyloid pathology showed lower Mini-Mental State Examination scores (measure of global cognition), suggesting that amyloid-β is not just an innocent bystander. (more…)
Alzheimer's - Dementia, Author Interviews, Johns Hopkins, Medical Imaging / 20.03.2015

Arnold Bakker, Ph.D. Assistant Professor Division of Psychiatric Neuroimaging Department of Psychiatry and Behavioral Sciences The Johns Hopkins University School of Medicine Baltimore, MD Interview with: Arnold Bakker, Ph.D. Assistant Professor Division of Psychiatric Neuroimaging Department of Psychiatry and Behavioral Sciences The Johns Hopkins University School of Medicine Baltimore, MD 21287 Medical Research: What is the background for this study? What are the main findings? Dr. Bakker: Patients who are at increased risk for developing dementia due to Alzheimer’s disease show hyperactivity in an area of the brain called the hippocampus, which is critically important for memory function. This study investigated the functional significance of this hyperactivity and determined if, similar to animal studies, treatment with low dose levetiracetam would reduce this increased activation and improve memory function in these patients. Results showed that this overactivity is a dysfunctional condition that contributes to the memory impairment such that treatment with very low doses of levetiracetam both reduces this overactivity and improves memory function in these patients. (more…)
Alzheimer's - Dementia, Author Interviews, Karolinski Institute, Lancet / 13.03.2015 Interview with: Miia Kivipelto MD, PhD, Professor Deputy Head, Senior Geriatrician Aging Research Center and Alzheimer Disease Research Center Karolinska Institutet Clinical Trials Unit, Memory Clinic Karolinska University Hospital Stockholm, Sweden Medical Research: What is the background for this study? What are the main findings? Dr. Kivipelto: Epidemiological studies have linked several modifiable risk factors to cognitive impairment and dementia but evidence from randomized controlled trials (RCT) has been lacking showing the efficacy of the interventions. Because cognitive impairment, dementia and Alzheimer’s disease are complex, multi-factorial disorders, multidomain interventions targeting several risk factors and disease mechanisms simultaneously could be needed for optimum preventive effect. The FINGER study is the first large, long-term RCT indicating that multi-domain intervention can improve and maintain cognitive functioning in at risk elderly people from the general population. We observed a significant intervention effects on the primary outcome (overall cognition), main secondary outcomes (executive functioning and processing speed) as well as on complex memory tasks and risk of cognitive decline. The multidomain lifestyle intervention was feasible and safe. (more…)
Alzheimer's - Dementia, Author Interviews, Brigham & Women's - Harvard, JAMA, Memory / 24.02.2015

Dr. Rebecca E. Amariglio Ph.D. Massachusetts Alzheimers Disease Research Center Massachusetts General Interview with: Dr. Rebecca E. Amariglio Ph.D. Massachusetts Alzheimers Disease Research Center Massachusetts General Hospital Medical Research: What is the background for this study? What are the main findings? Dr. Amariglio: As the field of Alzheimer’s disease moves towards early detection and treatment, new tests that can measure very subtle changes in cognitive functioning are needed. A new instrument developed by the Alzheimer’s Disease Cooperative Study that measures subjective report of memory changes of both the study participant and a study partner (usually a family member) was associated with cognitive decline over four years.  Specifically, greater report of memory concerns was associated with worse memory performance over time. (more…)
Author Interviews, Genetic Research, UCSD / 18.02.2015

Dr. Rahul S. Desikan MD, PhD Department of Radiologoy University of California, San Diego School of Interview with: Dr. Rahul S. Desikan MD, PhD Department of Radiologoy University of California, San Diego School of Medicine Medical Research: What is the background for this study? What are the main findings? Dr. Desikan: The MAPT gene encodes the tau protein, which plays an integral role in Alzheimer's disease (AD) neurodegeneration. Though a number of studies have investigated this issue, the role of the MAPT gene in Alzheimer's disease is still unclear. In contrast, a number of studies have found a robust association between MAPT and increased risk for other 'tauopathies' like Parkinson's disease (PD). In our study, rather than evaluating all possible genetic loci, we only assessed shared genetic variants between Alzheimer's disease and PD. By using this type of approach, we were able to increase our statistical power for gene discovery in Alzheimer's disease. We found genetic overlap between Alzheimer's disease and Parkinson's disease at a locus on chromosome 17 within the MAPT region. Our findings demonstrate that this MAPT associated locus increases risk for Alzheimer's disease, correlates with gene expression of MAPT and is associated with brain atrophy of the entorhinal cortex and hippocampus on longitudinal MRI scans. (more…)