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David G. Morgan, PhD

Speaker – MiniSymposium 1

Dr. David G. Morgan is a Distinguished Professor of Molecular Pharmacology and Physiology for the Morsani College of Medicine and at the University of South Florida.

Dr. Morgan’s research interests are aging and brain function, focusing on drugs to treat Alzheimer’s dementia. His doctoral research at Northwestern investigated the neurochemistry of memory and his postdoctoral studies addressed aging-related changes in rodent and human brain.

Morgan became a faculty member at the University of Southern California in 1986 where his research projects focused on astrocytes and microglia in aged brain, including Alzheimer’s tissues. After moving to South Florida in 1992, Morgan participated in the development of a transgenic mouse model of Alzheimer’s disease (APP+PS1). He has developed methods to measure the damage that occurs in the brains of these mice and studied how this damage causes memory deficits in the mice.

His work focuses largely on the neuro-immune interactions associated with the Alzheimer phenotype, and the role of astrocytes and microglia in the disease process. He is presently testing safer NSAID drugs, amyloid dissolving agents, amyloid immunotherapy and gene therapy to treat the Alzheimer-like changes in transgenic mouse models of the disease. This work is supported by multiple grants from the NIH, private foundations and contracts from industrial partners. An antibody against the amyloid peptide that was characterized in his laboratory has entered clinical testing in AD patients through Pfizer Inc.

Morgan regularly sits on review panels for NIH and other agencies evaluating grants to develop new drugs to treat Alzheimer’s and other neurodegenerative disorders. In addition to his research activities, Morgan has consulted with both major pharmaceutical companies and small biotechnology companies regarding the development of therapeutics for Alzheimer’s disease, and advised capital investment organizations regarding the most promising therapeutic approaches to curing Alzheimer’s disease.

Innate Immune Activation in Neurodegenerative Disease: Differential Effects on Amyloid and Tau Pathology

David G. Morgan

University of South Florida, Tampa, USA

In the 1980s, several teams (McGeer, EIkelenboom, Rogers) noted the significant increase in markers of innate immune system activation (“inflammation”) present within the brains of Alzheimer’s disease victims at autopsy. Since that time a major debate has been the degree to which this activation was itself pathogenic, causing at least some of the neurodegeneration, or increased primarily in response to the ongoing pathology and degeneration. Early attempts to address this question used mouse models of amyloid deposition. These models do develop some innate immune system activation, but lack the severe neuron loss and brain atrophy characteristic of Alzheimer’s dementia. In at least some instances, activation of innate immune representatives in the brain (microglia and astrocytes) led to clearance of the deposited amyloid. One significant method of activating the microglia, with immunotherapy, has proven very efficient at preventing and clearing amyloid deposits. This further leads to functional recovery, even in very old mice.

More recently, mouse models of tau deposition have been developed. These models do exhibit the neuronal loss and brain atrophy characteristic of later stages of dementia. Several approaches to increasing innate immune system activation have found an exacerbation of the tau pathology under these conditions. Moreover, recent work with a protein reducing innate immune system activation in the CNS, fractalkine, has been demonstrated to retard accumulation of pathological forms of tau and protect from neuron loss and brain atrophy. Our present understanding is that amyloid deposition in human brain occurs for 10-20 years prior to onset of symptoms. Furthermore, most mouse models of amyloid deposition lack the neuron loss and atrophy associated with AD and mouse models of tauopathy. It is increasingly recognized that brains of older mice are characterized by increased sensitivity to pro-inflammatory stimuli (referred to as inflammaging or priming). These details lead to a hypothesis that amyloid itself is relatively innocuous, but that conditions of aging lead to excess innate immune system reaction to the amyloid deposits and/or oligomers. This inflammation response then accelerates the development of tau pathology leading to the more severe neurodegeneration and cognitive deterioration associated with mid to late stages of the disease. This hypothesis would predict that some methods of decreasing the innate immune system reaction in the brains of individuals depositing amyloid may delay or prevent later stages of the disease.

John C. Morris, MD

Speaker – Workshop

Dr. John C. Morris, MD is a leading researcher in the fight against Alzheimer’s disease. Dr. Morris is the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology, Professor of Pathology and Immunology, Professor of Physical Therapy, and Professor of Occupational Therapy at Washington University. He also is the Director and Principal Investigator of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University School of Medicine. Dr. Morris is a member of the Alzheimer’s Association’s Medical & Scientific Advisory Committee. He chairs the Clinical Task Force for the NIA’s Alzheimer Disease Centers program.

He is author or co-author of over 400 peer-reviewed journal articles and 50 chapters and reviews. He edited the first and second editions of the Handbook of Dementing Illnesses.

He has received many honors, including the Distinguished Achievement Citation from his alma mater, Ohio Wesleyan University (2000), the Lifetime Achievement Award from the Alzheimer’s Association (2004), the 2004 MetLife Foundation Award for Medical Research, the 2005 Potamkin Prize for Research in Pick’s, Alzheimer’s, and Related Disease from the American Academy of Neurology and the Physician-Scientist Lifetime Achievement Award (2005) and the 2006 Dr. Neville Grant Award for Clinical Excellence from the Barnes-Jewish Hospital Foundation (St. Louis, MO). In 2008, he received the Washington University Academic Women’s Network Mentor Award. In 2010, he received the Carl and Gerti Cori Faculty Achievement Award from Washington University. He is ranked in the top 1% of investigators in the field of Neuroscience and Behavior by Essential Science Indicators database.

Harmonized Clinical Diagnostic Criteria for the Incipient Symptomatic Stages of Alzheimer’s Disease

John C. Morris

Washington University School of Medicine, St. Louis, USA

Two major sets of criteria for the clinical diagnosis of Alzheimer disease (AD) have been published in the last five years. Both sets of criteria recommend supporting the syndrome-based diagnosis of AD with in vivo evidence of AD pathology, as determined by neuroimaging modalities and by assays of AD-related proteins in the cerebrospinal fluid (CSF). Additionally, both sets of criteria recommend that the incipient symptomatic stages of AD, commonly referred to as mild cognitive impairment (MCI) or prodromal AD, receive an etiologic diagnosis. If the clinically determined etiology of AD is validated by in vivo biomarkers or by postmortem neuropathological assessment, then the incipient clinically-expressed disorder can be considered as part of the spectrum of symptomatic AD. Data from the National Alzheimer Coordinating Center (NACC), obtained from participants who were 50 years or older at their last assessment at a federally-funded Alzheimer Disease Center and who died within two years of that assessment and came to autopsy, suggest that the neuropathologic confirmation of AD in individuals with “MCI due to AD” is comparable to that for individuals with a diagnosis of very mild AD dementia. Some level of neuropathologic AD was demonstrated in 76% of MCI participants with an etiologic diagnosis of AD compared to 79% of participants with a diagnosis of very mild (Clinical Dementia Rating 0.5) AD dementia. Hence, an equivalent majority of cases for both clinical classifications represent early-stage symptomatic AD.

Ronald Petersen, MD, PhD

Moderator – MiniSymposium 2 Discussion

Dr. Ronald C. Petersen, MD, PhD, is the Cora Kanow Professorship in Alzheimer’s Disease Research, and a Mayo Clinic Distinguished Investigator at the Mayo Clinic. He is on the National Advisory Council on Aging, and is the chair of the Advisory Council on Research, Care and Services for the National Alzheimer’s Project Act by the Secretary of the Department of Health and Human Services.

Dr. Petersen is a recipient of the 2004 MetLife Award for Medical Research in Alzheimer’s Disease, and the 2005 Potamkin Prize for Research in Pick’s, Alzheimer’s and Related Disorders of the American Academy of Neurology.

Gil Rabinovici, MD

Speaker – Workshop

Dr. Gil Rabinovici received his BS from Stanford University and MD from Northwestern University Medical School in Chicago. He completed an internship in internal medicine at Stanford University, neurology residency at UCSF (where he was chief resident) and a behavioral neurology fellowship at the Memory and Aging Center.

As an attending physician at the Memory and Aging Center, Dr. Rabinovici participates in patient evaluations and management and coordinates medical student and resident training. His research focuses on how structural, functional and molecular brain imaging techniques can be used to improve diagnostic accuracy in dementia and to study the biology of neurodegenerative diseases.

He is the recipient of a fellowship award from the John Douglas French Alzheimer’s Foundation, the Kathryn Grupe Award for Excellence in Alzheimer’s Research from the Alzheimer’s Association of Northern California and Northern Nevada, and the Henry Newman Award for Research in Clinical Neurology from the San Francisco Neurological Society. His current work is supported by the John Douglas French Alzheimer’s Foundation, a New Investigator Award from the Alzheimer’s Association, and a Career Development Award from the National Institute on Aging.


Biomarker Patterns in Subtypes of Alzheimer’s Disease – Implications for Pathophysiology and Diagnosis

Gil Rabinovici

University of California, San Francisco, USA

While the most common presentation of Alzheimer’s disease (AD) is episodic memory loss, up to 15% of patients present with primary non-amnestic syndromes. Patients with early-onset AD (age of onset ≤ 65) show greater executive, language and visuospatial impairment and relatively preserved episodic memory compared to those with late-onset AD, and focal cortical syndromes such as posterior cortical atrophy and logopenic-variant primary progressive aphasia are strongly linked to underlying AD pathology. The remarkable heterogeneity of AD poses a clinical challenge, but also an opportunity to inform our understanding of basic principles of disease pathogenesis. In this talk I will summarize work from our lab and others describing biomarker findings across AD phenotypes, including CSF profiles, and patterns found on MRI (structural, functional connectivity and diffusion tensor imaging) and FDG, amyloid and tau PET. Common and distinct patterns will be interpreted in the context of a model in which Aβ aggregates across high-throughput cortical hubs, while tauopathy develops in distinct vulnerable brain regions and spreads through inter-connected posterior brain networks, driving the clinico-anatomic phenotype of the disease.

Marwan Sabbagh, MD

Speaker – MiniSymposium 2

SabbaghDr. Marwan Sabbagh is a board-certified neurologist and geriatric neurologist. Considered as one of the leading experts in Alzheimer’s and dementia, he has been at the Banner Sun Health Research Institute for the past 15 years.

Dr. Sabbagh has dedicated his entire career to finding a cure for Alzheimer’s and other age-related neurodegenerative diseases. Dr. Sabbagh is a leading investigator for many prominent national Alzheimer’s prevention and treatment trials, including Alzheimer immunotherapy studies. He is on the editorial for the Journal of Alzheimer’s disease, Alzheimer’s Disease and Associated Disorders, Current Alzheimer’s Research, American Journal of Alzheimer’s and Dementia and BMC Neurology.

He has authored and co-authored more than 250 medical and scientific articles on Alzheimer’s research. Dr. Sabbagh has authored, The Alzheimer’s Answer, the book’s forward was written by Justice Sandra Day O’Connor, and edited Palliative Care for Advanced Alzheimer’s and Dementia: Guidelines and Standards for Evidence Based Care. His new book The Alzheimer’s Prevention Cookbook: 100 recipes to better Brain Health is due to be released shortly. He has edited Geriatric Neurology published in 2014.

In addition to his clinical work and private practice in Sun City, Dr. Sabbagh is associate director of the Arizona Alzheimer’s Disease Core Center, a clinical instructor in the Banner/St. Joseph’s Geriatric Fellowship Program, and a Research Professor of Neurology at the University of Arizona College of Medicine – Phoenix. Dr. Sabbagh earned his undergraduate degree from the University of California – Berkeley and his medical degree from the University of Arizona in Tucson. He received his residency training in neurology at Baylor College of medicine and a completed his fellowship in geriatric neurology and dementia at the UCSD School of Medicine. Before joining the faculty of Barrow Neurological Institute, he was with the Banner Sun Health Research Institute for 15 years.

APOE e4, Subjective Memory Symptoms and Cognitive Decline

Marwan Sabbagh

Barrow Neurological Institute, Phoenix, AZ, USA

Subjective complaints have been traditional considered to be an expression of the “worried well” and were often dismissed. New data suggests that that subjective memory complaint (SMC) may predict incident cognitive decline. Recent studies indicate that SMC may predict amyloid positivity but does not correlate well with imaging markers of neurodegeneration. In turn, amyloid positivity has been shown to increase risk of future cognitive decline. In this presentation, the profile of SMC will be reviewed and how biomarkers such as ApoE, amyloid PET, CSF, structural markers of neurodegeneration can influence progression. It is clear that SMC is no longer to be dismissed and could portend future cognitive decline.

Andrew Saykin, PsyD

Speaker – MiniSymposium 2
Dr. Andrew Saykin PsyDDr. Andrew Saykin is the Raymond C. Beeler Professor of Radiology and Imaging Sciences at Indiana University School of Medicine where he serves as director of the IU Center for Neuroimaging and the Indiana Alzheimer Disease Center (IADC). He also holds appointments in Medical and Molecular Genetics, Neurology and Psychiatry. He completed his graduate degrees at Hahnemann Medical College in Philadelphia (now Drexel University School of Medicine) and is board-certified in Clinical Neuropsychology.

Before joining Indiana University in 2006 he served on the faculties of Dartmouth Medical School and the University of Pennsylvania. Currently, his transdisciplinary research program focuses on the integration of structural, functional and molecular brain imaging with genomic and biomarker methods to identify mechanisms of cognitive dysfunction, potential therapeutic targets and response to treatment in Alzheimer’s disease.

Dr. Saykin also serves as leader of the ADNI Genetics Core and collaborates on neuroimaging projects studying traumatic brain injury, cancer chemotherapy, and schizophrenia. He is the founding Editor-in-Chief of Brain Imaging and Behavior published by Springer.

Family History, Subjective Memory Complaints and Brain Amyloid Load in the ADNI Study

Andrew Saykin

Indiana University School of Medicine, Indianapolis, USA

Pathophysiological processes associated with Alzheimer’s disease (AD) have been shown to be detectable up to two decades prior to the onset of dementia. Early detection during the long preclinical and prodromal stages of disease is critical to support therapeutic and preventative interventions that likely need to be instituted prior to the neurodegenerative changes that accompany symptomatic stages of disease. The presence of self-perceived cognitive changes (variously described as subjective complaints, concerns, decline or impairment) and similar observations by knowledgeable informants may represent the earliest prodromal stage. However, there is heterogeneity in symptom expression and considerable variability in how these changes are defined and assessed. Recently, an international working group arrived at a consensus framework to describe this condition as subjective cognitive decline (SCD) and efforts are underway to develop fully operationalized research criteria for classifying SCD.

Early studies by our group and others showed that older adults with cognitive complaints had changes on MRI similar to those seen in amnestic mild cognitive impairment (MCI) and increasing data is now becoming available on changes in other AD biomarkers including PET and CSF in individuals with SCD. Given the substantial heritability of AD, estimated to be as high as 60-80%, cognitive concerns are often given more weight by clinicians where there is a positive family history of dementia and genetic risk and protective factors are being investigated.

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) has focused on multimodal longitudinal biomarker studies of early and late stage MCI and clinical AD, as well as cognitively normal controls. A new group with significant memory concerns (SMC), essentially equivalent to SCD, was added during ADNI-2. Efforts to standardize SCD/SMC within ADNI included a psychometrically-defined score on episodic memory items (n=12) from the 20 item Cognitive Change Index (CCI). Genetic factors play a significant role in SMC, particularly the strong influence of APOE ε4 carrier status on measures of amyloid burden (Risacher et al 2015). When contrasting the SMC group to controls and those with early MCI across key AD biomarkers available in ADNI it is clear that genetics plays a selective role depending on the specific biomarker modality.

Important future directions include longer-term follow-up of SMC/SCD samples, advances in assessment and operationalization of SCD, and analyses of other genes and biological pathways as larger samples become available. The epidemiology of SCD in older adults and the degree to which SCD can meaningfully enrich clinical trials warrant further investigation. Screening for SCD in primary care settings is feasible enabling individuals to be referred to memory centers for more detailed assessment and treatment or participation in intervention trials, as appropriate.

Philip Scheltens, MD, PhD

Keynote Speaker – Workshop

ScheltensDr. Philip Scheltens studied at the VU University Amsterdam, Netherlands, gaining his MD in 1984, and PhD (Magnetic Resonance Imaging in Alzheimer’s disease) in 1993. His clinical residencies in neurosurgery were at the Municipal Hospital Slotervaart, and at the VU University Medical Centre, Amsterdam.

Dr. Scheltens is Professor of Cognitive Neurology and Director of the Alzheimer Center at the VU University Medical Center in Amsterdam. His main clinical and research interests are Alzheimer’s disease, vascular dementia, frontotemporal dementia, magnetic resonance imaging, PET imaging and biomarkers. He is active in the field of biomarkers and clinical trials and has been the national PI for many studies, including phase 1-3 multicenter clinical trials.

He founded and directs the Alzheimer Center since 2000, from which over 34 PhD theses have appeared since then.

The Prevalence of Amyloid Positivity by Age, APOE Genotype and Cognitive Status – Implications for the Diagnosis of Alzheimer’s Disease

Philip Scheltens

VU University Medical Center, Amsterdam, Netherlands

Recently, we showed in two meta-analyses published in JAMA (1,2) that amyloid positivity as shown by either PET or CSF occurs in normal individuals from the age of 40 (panel A below). As such it precedes the occurrence of dementia by 20-30 years at least. There is a strong relationship with APOE4, indicating higher amyloid load in carriers of the epsilon 4 alle(s) (panel B below).

schelten graph 1

It also happens in other dementias, although a certain percentage of misdiagnosis needs to be accounted for here (panel A below). In AD it goes down with increasing age and amyloid burden (panel A) is lower in APOE4 non-carriers (panel B). There is a high concordance between amyloid PET and amyloid at pathology.

schelten graph 2

The following consequences for the diagnosis of AD will be discussed:

1. A diagnosis of AD rests on the presence of both amyloid and tau pathology

2. Interpreting biomarkers indicating the presence of amyloid only should be done with care, since amyloid may be present in normal aging and is influenced by APOE status, meaning that it denotes a risk state and not a diagnosis per se in clinically unaffected individuals.

3. biomarkers should never be used out of the clinical context and age should be taken into account when interpreting the results

References 1: Ossenkoppele R, Jansen WJ, Rabinovici GD, Knol DL, van der Flier WM, van Berckel BN, Scheltens P, Visser PJ et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. 2015 May 19;313(19):1939-49. 10.1001/jama.2015.4669. PubMed PMID: 25988463; PubMed Central PMCID: PMC4517678. 2: Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, Visser PJ, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015 May 19;313(19):1924-38. 10.1001/jama.2015.4668. PubMed PMID: 25988462; PubMed Central PMCID: PMC4486209.

Frederick Schmitt, PhD

Speaker – MiniSymposium 2

Dr. Frederick A. Schmitt, PhD is a Professor of Neurology with joint appointments in the Departments of Psychiatry, Psychology, Neurosurgery, and Behavioral Science. He also holds appointments in the Sanders-Brown Center on Aging and Spinal Cord and Brain Injury programs at the University of Kentucky (UK). He is an applied clinician with a primary focus on the evaluation of the relationship between brain pathologies and neurocognition, Down syndrome, normal aging and dementia associated with neurodegenerative diseases.

He has been an investigator on multiple multidisciplinary program project grants, the Alzheimer’s Disease Center at UK where he works in several Cores. He has coordinated multiple studies of experimental therapies for MCI and AD. He has published over 250 papers, reviews, and chapters. Dr. Schmitt has extensive experience as a reviewer for journals and for NIH. He has served on study sections and special review committees for NIA, NCI, NIAAA, NIMH, and NINDS and presently chairs the AD Clinical Trials special emphasis panel. His research, along with his colleagues, involves an antioxidant AD prevention trial (that recruited over 7,500 participants with outcomes in the analysis phase), statistical models of mixed dementia neuropathology, as well as diffusion tensor imaging, plasma proteomics, inflammation, and cerebrovascular disease as predictors of dementia evolution in Down syndrome.

Subjective Memory Complaint in Aging: Neuropathological Associations (Symposium)

Frederick Schmitt

University of Kentucky, Lexington, USA

Insight into cognitive functioning has been shown to change with advancing age.  More recently the concept of ‘subjective memory complaint’ (SMC) has gained momentum as a possible marker for dementia risk.  In this presentation, the concept of metacognition will be briefly reviewed. Findings from a prevention trial and longitudinal cohort studies that link autopsy-based brain pathologies and awareness of memory change or SMC will be highlighted.  SMC as a risk for brain pathologies will be described in terms of cognitive trajectories prior to autopsy as well as the multiple brain pathologies (AD and non-AD) that underlie SMC progression to dementia.

Why is an Early Diagnosis of Alzheimer’s Important and How Do We Achieve It? (Forum)

Frederick Schmitt

University of Kentucky, Lexington, USA

This presentation will review: (1) the potential risks of early dementia screening and (2) how screening for dementia may benefit individuals and their families.  In addition, guidelines for effective dementia diagnosis in primary care and the Medicare Annual Wellness Visit are highlighted.  Finally, new findings regarding awareness of memory change and their eventual associated brain pathologies will be discussed.

Julie Schneider, MD

Speaker – Workshop

Dr. Julie Schneider, MD, is a professor of neurology and neuropathology and is associate director of the Rush Alzheimer’s Disease Center. She received her training at University of Chicago and Emory University in Atlanta, Ga.

Her research is focused on the brain changes underlying the cognitive and motor changes associated with aging. She is also active in longitudinal epidemiological studies including the Rush Religious Orders Study and the Memory and Aging Project. Schneider’s clinical interests include the diagnosis and treatment of age-related cognitive impairments and the post-mortem neuropathological diagnosis of dementias.

Diagnostic Complexities in Current Clinical and Morphological Criteria for Alzheimer’s Disease

Julie Schneider

Rush University Medical Center, Chicago, USA

Alzheimer’s disease (AD) is the most common clinical and pathologic diagnosis in persons with age-related dementia; however, both diagnoses are fraught with complexities. These complexities are demonstrated using data from 2 large longitudinal community-based clinical-pathologic studies of aging and dementia. While community-dwelling older persons with the clinical diagnosis of probable AD at death are confirmed to have a pathologic diagnosis AD, almost 90% of the time; over half are shown to have additional common pathologies. These pathologies include vascular pathologies: specifically – macroscopic infarcts, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy; and other neurodegenerative pathologies including Lewy body disease, hippocampal sclerosis and TDP-43 pathology.

Often older persons harbor multiple additional pathologies, including both vascular and neurodegenerative pathologies. These pathologies lower threshold for dementia, add to cognitive impairment, and most affect episodic memory the clinical hallmark of AD, making clinical distinction of AD vs. mixed AD pathologies difficult. Patterns of mixed pathology may differ in special populations, especially racially diverse cohorts, clinic cohorts, and the oldest old. Another complexity is the common presence of AD pathology in normal older persons.

Indeed, both pathologic and radiographic studies have also shown that about 1/3 of older persons without cognitive impairment have sufficient AD pathology to render a pathologic diagnosis of AD. This has led to the concept of preclinical Alzheimer’s disease, where the pathologic hallmarks of AD are present but clinical symptoms are minimal or absent. While non-AD neurodegenerative pathologies and vascular pathologies lower brain reserve, other factors may increase cognitive or neural reserve. These factors include genetics, lifestyle, diet, and personality factors. Further study of these factors that increase and lower neural reserve may provide clues to prevention and treatment.

Sudha Seshadri, MD

Speaker – MiniSymposium 1

SeshadriDr. Sudha Seshadri completed her MBBS from the Christian Medical College, Madras University, and her MD in Internal Medicine and DM in Neurology from the All India Institute of Medical Sciences, New Delhi, India. Additionally, she has completed a Residency in Neurology at the Boston University School of Medicine and a Fellowship in the Neurobiology of Aging and Alzheimer Disease at the University of Massachusetts Medical Center.

She has previously worked as Assistant Professor of Neurology at the All India Institute of Medical Sciences, New Delhi, and joined the Boston University School of Medicine’s Department of Neurology in May 2001 as Assistant Professor in the Department of Neurology. She also serves as Co-Director of Medical Education for the Neurology Residency and Clerkship programs.

Genetic Pathways linking Neuroinflammation, Vascular Disease and Neurodegeneration

Sudha Seshadri

Boston University, Boston, USA

Over the past two decades evidence has accrued linking circulating biomarkers of inflammation, and clinical and imaging markers of brain vascular injury to risk of dementia, including dementia of the Alzheimer’s type. On the  other hand, this evidence is not consistent across studies and intervention trials targeting inflammation and vascular risk factors have been largely disappointing. It remains unclear if these mechanisms are independent and incidental or play a causal role in neurodegeneration. Since genetic changes are present from conception, studying genetic links between these 3 processes may help us better understand temporality (which comes first), and may identify novel causal pathways underlying Alzheimer and other neurodegenerative disorders.

Recently genome-wide association studies have identified novel loci and genes determining the risk of stroke, subclinical vascular brain injury and many of these genes appear to impact immune/inflammatory pathways; some additionally affect cognition and risk of dementia. As an example, the stroke associated gene HDAC9 alters PPAR-gamma and RANKL expression, brain inflammation and beta-amyloid removal. Other recently identified stroke genes alter pericyte function and blood-brain barrier integrity. Conversely, many of the recently identified AD genes, such as TREM2 are expressed in the blood vessels of the brain and/or alter microglial activation, a measure of local inflammation, in the brain. Pathway analyses of sub threshold genetic associations with AD identify greatest enrichment of genes in the immune response pathway. Further there is a 50-fold enrichment of genetic variants determining C-reactive protein levels among genes determining AD risk. Whereas all these data are intriguing, they are, as yet, insufficient data to clearly craft a single robust, verifiable hypothesis causally linking inflammation and vascular brain injury to neurodegeneration. However, since inflammation and vascular injury are complex, inter-related and above all, modifiable, this is an area of growing interest.

Ingmar Skoog, MD, PhD

Speaker – MiniSymposium 2 & Forum

Dr. Ingmar Skoog became MD in 1985, PhD in 1993, specialist in psychiatry 1993, and professor in Psychiatry in 2001. He is currently director for the Centre for Aging and Health AGECAP at the University of Gothenburg and is leading the Neuropsychiatric Epidemiology Unit (Epinep) at the Institute of Neuroscience and Physiology at the Sahlgrenska Academy of the University of Gothenburg, Sweden.

He has been involved in epidemiological research since 1983, and is leading the H70-studies in Gothenburg. The main research interest has been regarding dementia and other mental disorders in the elderly, with special emphasize on the relation between cardiovascular disorders and Alzheimer’s disease and depression.

Ingmar Skoog has published more than 230 original research articles and more than 90 reviews and book chapters. He has been invited to more than 200 international meetings. He received the Zenith Fellows Award from the American Alzheimer’s Association in 2001, the Danish Strömgren Award in Psychiatry in 2002, Inga Sandeborgs prize from Swedish Medical Society in 2006, and the Senior Award by the International College of Geriatric Psychoneuropharmacology in 2013. He was Secretary General of Vas-Cog 2002-2012. He was invited as an advisor to the National Institute of Health (NIH)-National Institute of Neurological Disorders and Stroke (NINDS)’s workshops Stroke Progress Review Group in Denver 2001 and Vascular Cognitive Impairment in Washington 2005. He was advisor and reviewer for DSM-5.

What are Subjective Memory Complaints and What is their Significance (Forum)

Ingmar Skoog, Silke Kern, Boo Johansson, Johan Skoog and Simona Sacuiu

University of Gothenburg, Gothenburg, Sweden

Subjective complaints of memory and other cognitive problems brings the patient to the doctor, and is a main component in criteria for mild cognitive impairment. However, the relevance of subjective complaints is debated, especially at the population level, and methods for measurement vary widely between studies. There is currently no consensus regarding criteria for subjective memory complaints. Nevertheless, it has been related to preclinical Alzheimer’s disease, depression, anxiety, somatic disorders, personality, and also to biological markers of Alzheimer’s disease in individuals without dementia.

Longitudinal studies on representative populations of older persons from different birth cohorts have been conducted in Gothenburg since the 1970s with comprehensive examinations, including psychiatric, cognitive, and somatic examinations, as well as brain imaging and laboratory tests. In these studies, objective cognitive function increased continuously between subsequent birth cohorts, while the prevalence of subjective memory complaints did not change. It further did not change with age. Subjective memory complaints were related to an increased risk for dementia at follow-up, but the associations were weak, and positive predictive value and sensitivity was low. Cross-sectionally, associations were stronger with depressive symptoms than with cognitive function. Self-reported executive function was related to frontal and occipital atrophy on CT, while self-reported memory complaints were related to white matter lesions. The presence of subjective memory complaints increased the risk for dementia substantially in individuals with white matter lesions. In conclusion, subjective memory complaints alone are only weakly associated with the development of dementia, and seems more related to depressive symptoms. However, it is still an important clinical observation in the context of other more objective tests of cognitive function, and in the context of other brain pathology.

The Epidemiological Relevance of Subjective Cognitive Decline (Symposium)

Ingmar Skoog, Silke Kern, Boo Johansson, Johan Skoog and Simona Sacuiu

University of Gothenburg, Gothenburg, Sweden

Background: Subjective complaints of memory and other cognitive problems is what brings the patient to the doctor, and is a main component in criteria for mild cognitive impairment. However, the relevance of subjective complaints is debated, especially at the population level.

Methods: Longitudinal studies on representative populations of elderly persons from different birth cohorts have been conducted in Gothenburg since the 1970s with comprehensive examinations, including psychiatric, cognitive, and somatic examinations, as well as brain imaging and laboratory tests.

Results: Objective cognitive function increased continuously between subsequent birth cohorts, while the prevalence of subjective memory complaints did not change. Subjective memory complaints were related to an increased risk for dementia at follow-up, but the associations were weak, and positive predictive value, sensitivity and specificity was low. Cross-sectionally, associations were stronger with depressive symptoms than with cognitive function. Self-reported executive function was related to frontal and occipital atrophy on CT, while self-reported memory complaints were not.

Conclusion: Subjective memory complaints alone were only weakly associated with the development of dementia in our Swedish populations, and was more related to depressive symptoms. However, it is still an important clinical observation in the context of other more objective tests of cognitive function.

Amanda Smith, MD

Speaker – Forum

Dr. Amanda G. Smith is the Medical Director of the USF Byrd Alzheimer’s Institute and an Associate Professor in Psychiatry and Behavioral Neuroscience at the University of South Florida Morsani College of Medicine.

She received her Bachelor’s degree from Emory University in Atlanta, and her medical degree from Jefferson Medical College in Philadelphia. She completed her residency in Psychiatry and fellowship in Geriatric Psychiatry at the University of South Florida.

Dr. Smith is a Diplomate of the American Board of Psychiatry and Neurology, with subspecialty certification in geriatric psychiatry. Her work focuses on the diagnosis and treatment of memory disorders, clinical research in Alzheimer’s disease, and education of both caregivers and health professionals. She is the Principal Investigator of several multi-center clinical trials in Mild Cognitive Impairment and Alzheimer’s disease, and collaborates regularly with basic scientists on pilot projects at the Institute. She served for eight years on the USF Institutional Review Board.

She currently sits on the steering committees of the national, federally-funded Alzheimer’s Disease Cooperative Study and the Alzheimer’s Disease Neuroimaging Initiative and was appointed by the Florida state Surgeon General to the grant review board of the Ed and Ethel Moore Alzheimer’s Disease research program.

The Importance of Participation in Clinical Trials in Alzheimer’s Disease

Amanda Smith

University of South Florida, Tampa, USA

Participating in a clinical trial or study helps medical researchers find new ways to treat and prevent Alzheimer’s and other diseases, and could help future generations lead healthier lives. Today, at least 70,000 volunteers are urgently needed to participate in more than 150 active clinical trials and studies in the United States that are testing ways to understand, treat, prevent, or cure Alzheimer’s disease. All kinds of people, including healthy volunteers, are needed. Women and minorities are especially needed. You or a loved one may have heard of clinical trials and research studies but are not sure what they are or if you want to join one. Or, you may be a health professional who isn’t sure what to say when patients and families ask about clinical trials. This public educational forum session provides information on types of clinical research in Alzheimer’s disease, answers frequently asked questions about research, and highlights the ways that clinical trial participation can bring us closer to a cure.

Beth Snitz, PhD

Speaker – Forum

Dr. Beth SnitBeth Snitz Headshotz, PhD, is an assistant professor of Neurology at the University of Pittsburgh School of Medicine. She received her doctoral degree in clinical psychology from the University of Minnesota.

She is a co-investigator with the University of Pittsburgh Alzheimer’s Disease Research Center, Clinical Core Leader for the ADRC-affiliated PiB-PET Program Project Grant, and co-investigator on the Monongahela-Youghiogheny Healthy Aging Team (MYHAT) Study, a population study of MCI in southwest Pennsylvania.

Dr. Snitz’s current research focuses on boundaries between normal and pathologic cognitive aging, including mild cognitive impairment, cognitive correlates of amyloid imaging in normal aging, and subjective cognitive complaints in clinic and community.

Subjective Cognitive Impairment, Neuroticism and Brain Amyloid Load

Beth Snitz

University of Pittsburgh, Pittsburgh, USA

Subjective cognitive complaints in otherwise normal aging are very common. It is well established that memory complaints are associated with psychosocial variables, such as personality, mood symptoms, gender, and beliefs about aging. Subjective memory complaints may also be associated with preclinical Alzheimer Disease and clinical progression/cognitive decline. Little is known, however, about when complaints may be valid indicators of underlying brain pathology, when they are not, and whether psychological variables may be useful making the distinction.

In a recent study, we explored personality factors as potential moderators of associations between subjective complaints and brain amyloid-β in cognitively normal older adults. N=92 healthy research volunteers were screened for normal cognition with comprehensive neuropsychological evaluation. Amyloid-β deposition was assessed with Pittsburgh compound B (PiB)-PET imaging.

Results indicated one of three cognitive complaint measures, the Memory Functioning Questionnaire, was associated with global PiB retention. Neuroticism modified this association such that only high neuroticism individuals showed the predicted pattern of poorer self-perceived cognition associated with higher PiB retention. Cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer Disease.

Expression and endorsement of subjective cognitive complaints, and their correlates, are also highly dependent on study setting. Subjective memory findings will be briefly compared among three ongoing studies: 1) a large, representative population study in small-town southwest Pennsylvania (MYHAT Project); 2) an ADRC / specialty memory clinic; and 3) a community research volunteer sample.

Reisa Sperling, MD, MMSc

Speaker – Workshop

Dr. Reisa Sperling is a neurologist, specializing in Alzheimer’s disease and imaging research. She is a Professor in Neurology at Harvard Medical School and the Director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital. She is also the Director of Neuroimaging for the Massachusetts ADRC at Massachusetts General Hospital.

Dr. Sperling’s research is focused on the early diagnosis and treatment of early Alzheimer’s disease (AD). She is the Principal Investigator of the Harvard Aging Brain Study, funded by a NIA Program Project grant. Dr. Sperling led the NIA-Alzheimer’s Association workgroup to develop guidelines for “Preclinical Alzheimer’s disease,” and currently serves on the NIA Council. She is the Project Leader for the ADCS Anti- Amyloid Treatment in Asymptomatic AD (A4) study – a three-year secondary prevention trial in 1000 clinically normal older individuals with PET amyloid imaging evidence of early Alzheimer’s disease pathology.

Detection of Preclinical Alzheimer’s Disease: Implications for Prevention Trials

Reisa Sperling

Massachusetts General Hospital/Harvard Medical School, Boston, USA

Converging data from PET amyloid imaging, cerebrospinal fluid studies and large autopsy series suggest that one-third of clinically normal older individuals harbor a substantial burden of cerebral amyloid-beta (Aß). It remains unknown whether these individuals are indeed in the preclinical stages of Alzheimer’s disease (AD) and what proportion will progress to dementia over time. Accumulating evidence from these “Aß-positive normals” show aberrant network, cortical thinning, increased neocortical tau on Tau PET imaging, and other “AD-like” abnormalities on multi-modality imaging. Clinical studies have reported an association between Aß burden and memory performance, increased subjective cognitive concerns, and a significantly increased risk of cognitive decline, particularly among older individuals with markers of both accumulation Aß and neurodegeneration.

One of the continued dilemmas in the field is how best to identify individuals who are clearly on the AD trajectory but at an earlier enough stage of pathology to be maximally responsive to therapeutic intervention. Several secondary prevention trials in both genetic at-risk (Dominantly Inherited Alzheimer Network and the Alzheimer Prevention Initiative) and age at-risk individuals are now ongoing, testing anti-amyloid mechanisms. The Anti-Amyloid Treatment in Asymptomatic AD (A4) Study will enroll over 1000 older individuals with evidence of amyloid accumulation on screening PET scans to determine if treatment with an anti-amyloid antibody, initiated prior to cognitive impairment, will slow neurodegeneration and the progression of memory decline towards AD dementia. The A4 Study is a 3-year Phase 3 registration trial with a primary cognitive endpoint as well as multiple biomarker outcomes, including Tau PET imaging. The A4 Study currently being conducted at 65 sites in US, Canada, and Australia. The EARLY (A5) Study will utilize a similar trial design with a BACE inhibitor in an asymptomatic population at risk for developing cognitive decline due to AD has already begun in Europe and will begin in the US in mid-2016.

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