Journal of Alzheimer's Disease - Volume 33, issue s1

Authors: Hodges, John R.

Article Type: Review Article

Abstract: This review focuses on six key papers published in the mid 2000 s based on work conducted in Cambridge. The first two relate to clinico-pathological studies which established that Alzheimer's disease (AD) is a relatively common cause of focal cortical syndromes, notably progressive aphasia (largely nonfluent), progressive apraxia, and posterior cortical atrophy with complex visual symptoms. Building on these findings, criteria for the progressive aphasias have been developed which define the variant associated with AD (progressive logopenic aphasia). Memory in the dementias has been a major area of interest and one paper discussed here explored the neural basis for episodic …and semantic memory failure in AD and semantic dementia. Despite very different memory profiles, the two disorders both cause severe hippocampal hypometabolism and atrophy but differ in the degree of involvement of other memory related structures. This work drew attention to the role of pathology in non-hippocampal structures early in AD. The next two articles deal with the behavioral variant frontotemporal dementia (bvFTD) which we have shown is associated with breakdown in theory of mind, social reasoning, empathy, and emotion processing and contributed to work on the neural basis of social cognition. We also identified a subgroup of bvFTD who fail to progress over many years, termed phenocopy cases, who are differentiated by their lack of atrophy on MRI. The final paper described the application of the Addenbrooke's Cognitive Examination-Revised, which has proven a useful brief assessment tool for the early detection of a range of neurodegenerative disorders including AD and FTD. It also appears to be helpful in predicting those with mild cognitive impairment who will progress to frank dementia. Show more

Keywords: Addenbrooke's cognitive examination, Alzheimer's disease, episodic memory, frontotemporal dementia, Papez circuit, progressive aphasia, semantic dementia

DOI: 10.3233/JAD-2012-129038

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S211-S217, 2013

Authors: Beach, Thomas G.

Article Type: Review Article

Abstract: Medical science is currently perceived as underperforming. This is because of the relatively slow recent rate of development of new disease treatments. This has been blamed on cultural, regulatory, and economic factors that generate a so-called “Valley of Death”, hindering new drug candidates from being moved into clinical trials and eventually approved for use. We propose, however, that for neurodegenerative diseases, a relative decline of human brain tissue research is also a contributor. The present pharmacological agents for treating Alzheimer's disease (AD) were identified through direct examination of postmortem human brain tissue more than 30 years ago. Since that time …the percentage of research grants awarded to human brain tissue-using projects has dropped precipitously and publication rates have stagnated. As human brain tissue research has played a central and often initiating role in identifying most of the targets that have gone to AD clinical trials, it is proposed that the rate of discovery of new targets has been curtailed. Additionally, the continued rejection of cortical biopsy as a diagnostic method for AD has most probably depressed the perceived effect sizes of new medications and contributed to the high Phase II clinical trial failure rates. Despite the relative lack of funding, human brain discovery research has continued to make important contributions to our understanding of neurodegenerative disease, and brain banks have played an essential role. It is likely that the pace of discovery will dramatically accelerate over the coming decades as increasingly powerful tools including genomics, epigenetics, transcriptomics, regulatory RNA, gene expression profiling, proteomics, and metabolomics are applied. To optimize the promise of these new technologies, however, it is critical that brain banks are rejuvenated by enhanced governmental and/or private support. Show more

Keywords: Alzheimer's disease, autopsy, brain, clinical trials, human, neuropathology, postmortem

DOI: 10.3233/JAD-2012-129020

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S219-S233, 2013

Authors: Praticò, Domenico

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia in the elderly. Although the initiating events are still unknown, it is clear that AD results from a combination of genetic and environmental risk factors. Recently proposed diagnostic criteria, in addition to the clinical neuropsychological examination aimed at identifying the typical AD symptoms, include staging criteria based on AD biological measures related to its pathology. Despite the obvious benefits of these new criteria, an accurate diagnosis is not always easily reached because, particularly in its earliest stages, the symptoms of the disease are very variable. Biological measures, or …biomarkers, of the disease should first facilitate an early and accurate diagnosis, have a prognostic and predictive value, and have the capacity to monitor therapeutic efficacy. While amyloid-β and tau represent the two key pathological features of the disease, other aspects of this complex disease are emerging as important mediators in its pathogenesis. Among them, oxidative stress is probably one of the most investigated, and so are biomarkers reflecting it. Intrinsic limitation of biomarkers is the fact that they do not define mechanism of disease, but by nature are associative and/or correlative and unable to prove causality. Longitudinal studies are helping us in this difficult task by providing a clearer picture of the dynamic relationship between biomarkers, AD neuropathology, and cognitive phenotype. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, oxidative stress, tau

DOI: 10.3233/JAD-2012-129023

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S237-S241, 2013

Authors: Sultana, Rukhsana | Butterfield, D. Allan

Article Type: Review Article

Abstract: Aging is the major risk factor associated with neurodegenerative diseases, including Alzheimer's disease (AD). Until now no clear understanding of the mechanisms of initiation and progression of this dementing disorder exists. Based on the studies that have been conducted so far amyloid β-peptide (Aβ), a protein found in senile plaques, one of the key pathological hallmarks of AD, has been reported to be critical in the pathogenesis of AD. Studies from our laboratory and others showed that Aβ can induce oxidative stress, which leads to oxidative modification of biomolecules, thereby diminishing the normal functions of neuronal cells and eventually leading …to loss of neurons and AD. In this review paper, we summarize evidence of oxidative stress in brains of AD and mild cognitive impairment patients, as well as the results from redox proteomics studies. The investigations have provided insights into the downstream effects of oxidative modification of key brain proteins in the pathogenesis of AD. Based on these redox proteomics results, we suggest future areas of research that could be considered to better understand this devastating dementing disorder. Show more

Keywords: Alzheimer's disease, lipid peroxidation, mild cognitive impairment, oxidative stress, protein carbonylation, protein nitration, redox proteomics

DOI: 10.3233/JAD-2012-129018

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S243-S251, 2013

Authors: Zhu, Xiongwei | Perry, George | Smith, Mark A. | Wang, Xinglong

Article Type: Review Article

Abstract: Mitochondrial dysfunction is one of the most early and prominent features in vulnerable neurons in the brain of Alzheimer's disease (AD) patients. Recent studies suggest that mitochondria are highly dynamic organelles characterized by a delicate balance of fission and fusion, a concept that has revolutionized our basic understanding of the regulation of mitochondrial structure and function which has far-reaching significance in studies of health and disease. Tremendous progress has been made in studying changes in mitochondrial dynamics in AD brain and models and the potential underlying mechanisms. This review highlights the recent work demonstrating abnormal mitochondrial dynamics and distribution in …AD models and discusses how these abnormalities may contribute to various aspects of mitochondrial dysfunction and the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, mitochondrial distribution, mitochondrial dynamics, mitochondrial dysfunction, mitochondrial fission, mitochondrial fusion

DOI: 10.3233/JAD-2012-129005

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S253-S262, 2013

Authors: Craft, Suzanne | Cholerton, Brenna | Baker, Laura D.

Article Type: Review Article

Abstract: The recognition of Alzheimer's disease (AD) as a heterogeneous disorder that results from incremental pathological changes in dynamic organismic systems is essential to move beyond the unidimensional approaches to prevention and therapy that have proven largely ineffective to date. Biological systems related to insulin metabolism are arguably the most critical regulators of longevity and corporeal aging. Our work has focused on identifying the relationship of the insulin network to brain aging, and determining the mechanisms through which insulin dysregulation promotes AD pathological processes. Candidate mechanisms include the effects of insulin on amyloid-β, cerebral glucose metabolism, vascular function, lipid metabolism, and …inflammation/oxidative stress. It is likely that different nodes of the insulin network are perturbed for subgroups of AD patients, or that for some subgroups, pathways independent of insulin are critical pathogenetic factors. New methods from systems network analyses may help to identify these subgroups, which will be critical for devising tailored prevention and treatment strategies. In the following review, we will provide a brief description of the role of insulin in normal brain function, and then focus more closely on recent evidence regarding the mechanisms through which disruption of that role may promote AD pathological processes. Finally, we will discuss the implications of this area for AD therapeutics and prevention. Show more

Keywords: Alzheimer's disease, diabetes, insulin, network analysis

DOI: 10.3233/JAD-2012-129042

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S263-S275, 2013

Authors: Bush, Ashley I.

Article Type: Review Article

Abstract: Brain homeostasis of transition metals is severely perturbed in Alzheimer's disease (AD), with extracellular pooling of zinc and copper in amyloid, and intraneuronal accumulation of iron. Rapidly accumulating evidence indicates that these perturbances themselves may contribute significantly to the cognitive loss and neurodegeneration, even in the absence of AD proteopathy. There is now strong evidence that each of the major protein participants in AD pathology has physiologically important interactions with transition metals: AβPP is the neuronal iron export ferroxidase with a major interaction with ferroportin, presenilins are needed for the import of ≈50% of cellular copper and zinc, and tau …promotes the export of neuronal iron by facilitating the trafficking of AβPP to the surface. Therefore, amyloid and tau pathology arise in a milieu of constitutively high metal flux, and the major components of AD pathology may contribute to the disease by failing in their metal transport roles. Show more

Keywords: Alzheimer's disease, amyloid, copper, iron, presenilin, tau, zinc

DOI: 10.3233/JAD-2012-129011

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S277-S281, 2013

Authors: Watt, Andrew D. | Villemagne, Victor L. | Barnham, Kevin J.

Article Type: Review Article

Abstract: Over the past 100 years, there has been an exponential increase in our understanding of the underlying pathology of Alzheimer's disease (AD). This growth in knowledge has largely stemmed from the intensification of research into AD which has occurred over the past three decades and the incorporation of the amyloid cascade hypothesis as the generally accepted dogma of AD pathogenesis. While at times contentious, the notion that AD arises from aberrations in amyloid-β (Aβ) production and degradation has led to a number of significant breakthroughs in the way in which AD is currently diagnosed and in the attempts at disease …modifying therapies, from investigations into the underlying factors mediating the aggregation of Aβ to the development of therapeutic strategies and measures of neuroimaging allowing Aβ burden to be monitored within the AD-affected brain. This review focuses on some of the recent work we have conducted toward elucidating the role of Aβ in AD. Show more

Keywords: Biomarker, blood, copper, mass spectrometry, metal chaperone, NMDA, toxicity, zinc

DOI: 10.3233/JAD-2012-129017

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S283-S293, 2013

Authors: Hickman, Suzanne E. | El Khoury, Joseph

Article Type: Review Article

Abstract: It is well established that microglia, the neuroimmune cells of the brain, are associated with amyloid-β (Aβ) deposits in Alzheimer's disease (AD). However, the roles of these cells and other mononuclear phagocytes such as monocytes and macrophages in AD pathogenesis and progression have been elusive. Clues to mononuclear phagocyte involvement came with the demonstration that Aβ directly activates microglia and monocytes to produce neurotoxins, signifying that a receptor mediated interaction of Aβ with these cells may be critical for neurodegeneration seen in AD. Also, in AD brain, mononuclear phagocyte distribution changes from a uniform pattern that covers the brain parenchyma …to distinct clusters intimately associated with areas of Aβ deposition, but the driving force behind this choreography was unclear. Here, we review our recent work identifying mononuclear phagocyte receptors for Aβ and unraveling mechanisms of recruitment of these cells to areas of Aβ deposition. While our findings and those of others have added significantly to our understanding of the role of the neuroimmune system in AD, the glass remains half full (or half empty) and a lot remains to be uncovered. Show more

Keywords: Alzheimer's disease, amyloid-β, chemokines, microglia, mononuclear phagocytes, scavenger receptors

DOI: 10.3233/JAD-2012-129027

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S295-S302, 2013

Authors: Liang, Yuying | Ryan, Natalie S. | Schott, Jonathan M. | Fox, Nick C.

Article Type: Review Article

Abstract: Excess neuronal loss—atrophy—is an inevitable feature of Alzheimer's disease (AD). Following studies in the early 1990 s demonstrating that non-invasive imaging can be used to visualize excess volume loss, i.e., the consequences of atrophy in AD, a major interest has been improving and validating methods to quantify measures of atrophy from serially acquired magnetic resonance imaging. Here we summarize our experience of measuring the extent and pattern of atrophy to understand disease pathogenesis, particularly through studies of individuals with or destined to develop familial AD; to aid diagnosis; and as an outcome measure for treatment trials. As the field moves …toward earlier diagnosis and prevention, we outline the important roles that we believe structural imaging will play alongside other biomarkers both in identifying individuals in the earliest stages of neurodegeneration and assessing the effects of novel therapies. Show more

Keywords: Biomarkers, clinical trials, familial Alzheimer's disease, magnetic resonance imaging, presymptomatic

DOI: 10.3233/JAD-2012-129010

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S305-S312, 2013

Authors: Braskie, Meredith N. | Toga, Arthur W. | Thompson, Paul M.

Article Type: Review Article

Abstract: Advances in brain imaging technology in the past five years have contributed greatly to the understanding of Alzheimer's disease (AD). Here, we review recent research related to amyloid imaging, new methods for magnetic resonance imaging analyses, and statistical methods. We also review research that evaluates AD risk factors and brain imaging, in the context of AD prediction and progression. We selected a variety of illustrative studies, describing how they advanced the field and are leading AD research in promising new directions.

Keywords: Alzheimer's disease, amyloid, imaging, magnetic resonance imaging, methods, positron emission tomography, prediction, progression, risk factors

DOI: 10.3233/JAD-2012-129016

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S313-S327, 2013

Authors: Teipel, Stefan J. | Sabri, Osama | Grothe, Michel | Barthel, Henryk | Prvulovic, David | Buerger, Katharina | Bokde, Arun L.W. | Ewers, Michael | Hoffmann, Wolfgang | Hampel, Harald

Article Type: Review Article

Abstract: The diagnosis of Alzheimer's disease (AD) is presently going through a paradigm shift from disease categories to dimensions and toward the implementation of biomarkers to support identification of predementia and even preclinical asymptomatic stages of the disease. We outline the methodological basis of presently available biomarkers and technological methodologies in AD, including exploratory and hypothesis-based plasma and blood candidates, cerebrospinal fluid markers of amyloid load and axonal destruction, and imaging markers of amyloid deposition, synaptic dysfunction, cortical functional and structural disconnection, and regional atrophy. We integrate biomarker findings into a comprehensive model of AD pathogenesis from healthy aging to cognitive …decline, the resilience to cerebral amyloid load (RECAL) matrix. The RECAL framework integrates factors of risk and resilience to cerebral amyloid load for individual risk prediction. We show the clinical consequences when the RECAL matrix is operationalized into a diagnostic algorithm both for individual counseling of subjects and for the identification of at risk samples for primary and secondary preventive trials. We discuss the implication of biomarkers for the identification of prodromal AD for the primary care system that seems presently not even prepared to cope with the increasing number of subjects afflicted with late stage AD dementia, let alone future cohorts of subjects searching counseling or treatment of predementia and asymptomatic stages of AD. The paradigm shift in AD diagnosis and its operationalization into a diagnostic framework will have major implications for our understanding of disease pathogenesis. Now, for the first time, we have access to in vivo markers of key events in AD pathogenesis integrated into a heuristic framework that makes strong predictions on pattern of multimodal biomarkers in different stages of AD. Critical testing of these predictions will help us to modify or even falsify the currently hold assumptions on the pathogenesis of AD based on in vivo evidence in humans. Show more

Keywords: Alzheimer's disease, amyloid, atrophy, biomarker, blood, cerebrospinal fluid, diagnosis, diffusion tensor imaging, hippocampus, mild cognitive impairment, neurodegeneration, neuroimaging, pathophysiology, positron emission tomography, prognosis, resting state functional magnetic resonance imaging, tau, therapy

DOI: 10.3233/JAD-2012-129030

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S329-S347, 2013

Authors: Villemagne, Victor L. | Rowe, Christopher C.

Article Type: Review Article

Abstract: The introduction of radiotracers for the non-invasive in vivo quantification of amyloid-β (Aβ) burden in the brain has revolutionized the approach to the evaluation of Alzheimer's disease (AD). Aβ burden as measured by positron emission tomography (PET) matches histopathological reports of Aβ distribution in aging and dementia. It appears more accurate than FDG for the diagnosis of AD, and is an excellent aid in the differential diagnosis of AD from frontotemporal lobar degeneration. Apolipoprotein E ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non-ε4 carriers. As new therapies enter clinical trials, the role of …Aβ imaging in vivo is becoming increasingly crucial. Aβ imaging allows the in vivo assessment of brain Aβ pathology and its changes over time, providing highly accurate, reliable, and reproducible quantitative statements of regional or global Aβ burden in the brain, essential for therapeutic trial recruitment and for the evaluation of anti-Aβ treatments. Although Aβ burden as assessed by PET does not strongly correlate with cognitive impairment in AD, it does correlate with memory impairment and a higher risk for cognitive decline in the aging population and mild cognitive impairment (MCI) subjects. This correlation with memory impairment, one of the earliest symptoms of AD, suggests that Aβ deposition is not part of normal aging, supporting the hypothesis that Aβ deposition occurs well before the onset of symptoms and likely represents preclinical AD in asymptomatic individuals and prodromal AD in MCI. Further longitudinal observations, coupled with different disease-specific biomarkers to assess potential downstream effects of Aβ, are required to confirm this hypothesis and further elucidate the role of Aβ deposition in the course of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, brain imaging, dementia, positron emission tomography

DOI: 10.3233/JAD-2012-129034

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S349-S359, 2013

Authors: Zetterberg, Henrik | Blennow, Kaj

Article Type: Review Article

Abstract: The past decades have witnessed an enormous expansion of the literature on cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD). It is now clear that a triplet of CSF biomarkers (total-tau, phospho-tau, and the 42 amino acid fragment of amyloid-β) reflects core neuropathological features of AD and contributes diagnostically relevant information if measured in a proper manner. Here, we discuss what is needed for these biomarkers to become generally implemented in the clinical routine. We also discuss novel CSF biomarkers, the challenge of differential diagnosis-making in diseases with shared pathologies, and if CSF biomarkers will survive in the long run, …given the advancements in molecular neuroimaging and ultra-sensitive blood tests. Show more

Keywords: Alzheimer's disease, amyloid, biomarkers, cerebrospinal fluid, tau

DOI: 10.3233/JAD-2012-129035

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S361-S369, 2013

Authors: Quinn, Joseph F.

Article Type: Review Article

Abstract: The indolent nature of Alzheimer's disease, coupled with burgeoning interest in a “presymptomatic” stage of disease, has motivated efforts to identify, validate, and exploit surrogate disease markers for trials of disease-modifying or preventive strategies. Many of these efforts have been productive, and biomarkers are now routinely applied in selection of study subjects and evaluation of outcomes in clinical trials. On the other hand, biomarkers also have the capacity to lead to bad therapeutic outcomes when they determine “go- no go” decisions in early drug development. This paper reviews several reports of biomarker studies which illustrate the great potential, for both …good and ill, of biomarkers of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, biomarkers, clinical trials

DOI: 10.3233/JAD-2012-129022

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S371-S376, 2013

Authors: Grossman, Murray

Article Type: Review Article

Abstract: Here we provide a brief description of our program to improve diagnostic accuracy in cases with phenotypically similar presentations that are due to distinct histopathologic abnormalities. We propose a staged approach to diagnosis, beginning with a screening assessment of specific, quantitative neuropsychological measures, and followed by assessments of imaging and biofluid biomarkers. Our goal is to determine the specific histopathologic abnormalities contributing to an individual's neurodegenerative condition.

Keywords: Amyotrophic lateral sclerosis, biomarker, corticobasal degeneration, frontotemporal degeneration

DOI: 10.3233/JAD-2012-129002

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S379-S383, 2013

Authors: Brayne, Carol | Barker, Roger A. | Harold, Denise | Ince, Paul G. | Savva, George M. | Williams, Julie | Williams-Gray, Caroline H. | Wharton, Stephen B.

Article Type: Review Article

Abstract: Six papers based on studies with particular epidemiological designs are presented here which have been selected on the basis of their visibility in the literature. The designs are intended to provide robust evidence on risk, natural history, and underpinning neurobiology and outcomes relevant to aging populations. There is a large case control study (the Late Onset Alzheimer's Disease study), a case cohort study of Parkinson's Disease (the CamPaIGN study), and the Medical Research Council Cognitive Function and Ageing Study. Each study has included genetic investigation and risk, and the latter two include investigation of the clinical syndromes and their natural …histories in relation to underlying pathology. Each aimed to provide results which were as generalizable to usual older populations as possible and each has produced findings which have contributed to current understanding of genetic risk, the heterogeneity of the syndrome of Parkinson's disease, and the underlying neuropathology of dementia in older population. They have influenced thinking about future directions, and the cohorts on which the findings are based will continue to provide an important resource for novel areas of research and future health care planning. Show more

Keywords: Alzheimer's disease, dementia, epidemiology, genetics, pathology

DOI: 10.3233/JAD-2012-129006

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S385-S396, 2013

Authors: Bennett, David A. | Wilson, Robert S. | Arvanitakis, Zoe | Boyle, Patricia A. | de Toledo-Morrell, Leyla | Schneider, Julie A.

Article Type: Review Article

Abstract: The Religious Orders Study and the Rush Memory and Aging Project are both cohort studies of aging and dementia that include organ donation at death. Together, more than 2,700 persons have agreed to annual clinical evaluation and brain donation at death. A subset of participants also participated in a substudy that included ante-mortem imaging. We highlight recent findings that have been highly cited over the past five years. The findings fall into three general categories. The first relates to the neuropathology of probable Alzheimer's disease, mild cognitive impairment, and those without dementia or mild cognitive impairment. The second relates to …risk factors for Alzheimer's disease and neuropathology. The third are clinical and imaging studies of mild cognitive impairment. The findings illustrate the range of insights that can be gained into cognitive aging by incorporating neuropathologic indices into well designed, prospective cohort studies. Show more

Keywords: Clinical-pathology, mild cognitive impairment, risk factors

DOI: 10.3233/JAD-2012-129007

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S397-S403, 2013

Authors: Caselli, Richard J. | Reiman, Eric M.

Article Type: Review Article

Abstract: Studies of asymptomatic carriers of genes that are known to predispose to Alzheimer's disease (AD) have facilitated the characterization of preclinical AD. The most prevalent genetic risk factor is the ε4 allele of apolipoprotein E (APOE). Neuropathological studies of young deceased ε4 carriers have shown modest but abnormal amounts of neocortical amyloid and medial temporal neurofibrillary tangles that is also reflected in cerebrospinal fluid (CSF) biomarkers, amyloid-β, and phospho-tau in particular. MRI studies have shown progressive hippocampal and gray matter atrophy with the advent of mild cognitive impairment (MCI), and fluorodeoxyglucose PET scans show reduced cerebral metabolism in posterior cingulate …and related AD regions evident even in 30 year olds. Cerebral amyloidosis disclosed by more recent amyloid ligand PET studies in asymptomatic 60 year olds increases in parallel with ε4 gene dose. Longitudinal neuropsychological studies have revealed accelerated memory decline in ε4 carriers beginning around age 55–60 years whose severity again parallels ε4 gene dose. The clinico-pathological correlation of declining memory and AD-like neuropathological change defines preclinical AD and has set the stage for the accelerated evaluation of presymptomatic AD treatments. In this article, we briefly consider some of the earliest detectable changes associated with the predisposition to AD, and some of the prevention trial strategies that have been proposed to help find treatments to reduce the risk, postpone the onset of, or completely prevent AD symptoms as soon as possible. Show more

Keywords: APOE, normal aging, preclinical, prevention

DOI: 10.3233/JAD-2012-129026

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S405-S416, 2013

Authors: DeCarli, Charles

Article Type: Review Article

Abstract: Cerebrovascular risk factors and stroke are highly prevalent with advancing age, and stroke may be more common than Alzheimer's disease, particularly among older men. While stroke mortality continues to decline, the prevalence of individuals with various vascular risk factors continues to rise and many are undiagnosed or undertreated. Asymptomatic cerebrovascular brain injury that includes asymptomatic brain infarction and white matter hyperintensities as well as accelerated brain atrophy is even more frequent than clinical stroke. Moreover, the impact of cerebrovascular risk factors on brain injury appears to begin in middle life and additively increases the likelihood of later life dementia. This …review focuses on the use of neuroimaging and genetics to understand the impact of asymptomatic vascular risk factors on the trajectories of cognitive aging as well as incident cognitive impairment, stroke, and mortality. Results of this review emphasize the need for early detection and treatment of vascular risk factors to improve the cognitive health of our rapidly aging population. Show more

Keywords: Cerebrovascular disease, magnetic resonance imaging, pathophysiology, white matter hyperintensities

DOI: 10.3233/JAD-2012-129004

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S417-S426, 2013

Authors: Lopez, Oscar L. | Becker, James T. | Kuller, Lewis H.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most frequent form of dementia in elderly individuals and its incidence and prevalence increases with age. This risk of AD is increased in the presence of genetic and demographic factors including apolipoprotein E 4 allele, lower education, and family history of AD. There are medical risk modifiers including systemic hypertension, diabetes mellitus, cardiovascular disease, and cerebrovascular disease that increase the vulnerability for AD. By contrast, there are lifestyle risk modifiers that reduce the effects of AD risk factors include diet and physical and cognitive activity. Our research has consistently shown that it is the interactions …among these risk factors with the pathobiological cascade of AD that determine the likelihood of a clinical expression of AD—either as dementia or mild cognitive impairment. However, the association between “vulnerability” and “protective” factors varies with age, since the effects of these factors on the risk for AD may differ in younger (age < 80) versus older (age > 80) individuals. The understanding of the dynamic of these factors at different age periods will be essential for the implementation of primary prevention treatments for AD. Show more

Keywords: Alzheimer's disease, cardiovascular disease, cerebrovascular disease, mild cognitive impairment

DOI: 10.3233/JAD-2012-129015

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S427-S438, 2013

Authors: Weinstein, Galit | Wolf, Philip A. | Beiser, Alexa S. | Au, Rhoda | Seshadri, Sudha

Article Type: Review Article

Abstract: The study of Alzheimer's disease (AD) in the Framingham Heart Study (FHS), a multi-generational, community-based population study, began nearly four decades ago. In this overview, we highlight findings from seven prior publications that examined lifetime risk estimates for AD, environmental risk factors for AD, circulating and imaging markers of aging-related brain injury, and explorations on the genetics underlying AD. First, we describe estimations of the lifetime risk of AD. These estimates are distinguished from other measures of disease burden and have substantial public health implications. We then describe prospective studies of environmental AD risk factors: one examined the association between …plasma levels of omega-3 fatty-acid and risk of incident AD, the other explored the association of diabetes to this risk in subsamples with specific characteristics. With evidence of inflammation as an underlying mechanism, we also describe findings from a study that compared the effects of serum cytokines and spontaneous production of peripheral blood mononuclear cell cytokines on AD risk. Investigating AD related endophenotypes increases sensitivity in identifying risk factors and can be used to explore pathophysiologic pathways between a risk factor and the disease. We describe findings of an association between large volume of white matter hyperintensities and a specific pattern of cognitive deficits in non-demented participants. Finally, we summarize our findings from two genetic studies: The first used genome-wide association (GWA) and family-based association methods to explore the genetic basis of cognitive and structural brain traits. The second is a large meta-analysis GWA study of AD, in which novel loci of AD susceptibility were found. Together, these findings demonstrate the FHS multi-directional efforts in investigating dementia and AD. Show more

Keywords: Alzheimer's disease, cerebrovascular disorders, cohort studies, genetic variation, risk factors

DOI: 10.3233/JAD-2012-129040

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S439-S445, 2013

Authors: Devanand, Devangere | Lee, Joseph | Luchsinger, Jose | Manly, Jennifer | Marder, Karen | Mayeux, Richard | Scarmeas, Nikolaos | Schupf, Nicole | Stern, Yaakov

Article Type: Review Article

Abstract: This review summarizes the findings and importance of 12 articles from research at Columbia University in New York City that were among the most cited in the literature between 2006 and 2011. The 12 articles summarized in this review made important contributions to the field of Alzheimer's disease in the last 5 years. Four of the articles established the Mediterranean diet as a food consumption pattern that may prevent Alzheimer's disease in addition to physical activity. Two of the articles advanced our knowledge of predictors of conversion from mild cognitive impairment to dementia. Four of the articles provided important knowledge …of risk factors for the progression of Alzheimer's disease and its complications. Lastly, one of the articles laid the theoretical framework for the study of cognitive reserve, an important modifier of the manifestation of Alzheimer's disease. These studies have advanced our knowledge about risk factors, modifiers, and progression of late onset Alzheimer's disease. Show more

Keywords: Alzheimer's disease, conversion, diet, cognitive reserve, epidemiology, genes, mild cognitive impairment, predictors, progression, risk factors

DOI: 10.3233/JAD-2012-129041

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S447-S455, 2013

Authors: Barberger-Gateau, Pascale | Lambert, Jean-Charles | Féart, Catherine | Pérès, Karine | Ritchie, Karen | Dartigues, Jean-François | Alpérovitch, Annick

Article Type: Review Article

Abstract: Late-life dementia results from non-modifiable risk factors such as age and genetics, modulated by deleterious and protective environmental factors among which nutrition may play a major role. This paper highlights five major recent contributions of the French Three-City (3C) and PAQUID epidemiological studies to Alzheimer's disease (AD) knowledge, targeting genetic and dietary risk factors, and the impact of cognitive decline in daily living. The 3C study contributed to a large genome-wide association study to identify new genetic risk factors for AD. In addition to apolipoprotein E (APOE), two loci gave replicated evidence of association: one within CLU, encoding clusterin or …apolipoprotein J, and the other within CR1, encoding the complement component receptor 1. Although the attributable fraction of risk for these polymorphisms is moderate, genetic studies provide significant insights into the molecular bases of AD. Regarding dietary data, findings from 3C suggest that healthy diets associating sources of both omega 3 fatty acids (fish) and antioxidants (fruits and vegetables) such as the Mediterranean diet, and caffeine could be associated with decreased risk for AD. However, the protective effect of omega3 fatty acids might be limited to APOE4 non-carriers. Future research should focus on gene-nutrient interactions. Regarding the functional impact of prodromal AD, the PAQUID study showed that taking into account mild functional limitations considerably increases the predictive value of neuropsychological tests for conversion to dementia. Research should focus on sensitive instruments to capture early functional decline to improve the identification of elderly patients at high risk of conversion to dementia. Show more

Keywords: Activities of daily living, Alzheimer's disease, caffeine, cohort studies, dementia, epidemiology, genome-wide association study, Mediterranean diet

DOI: 10.3233/JAD-2012-129019

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S457-S463, 2013

Authors: Solomon, Alina | Kivipelto, Miia | Soininen, Hilkka

Article Type: Review Article

Abstract: This is a brief summary of experiences from Finland related to Alzheimer's disease (AD) prevention research. The first signals that AD may have vascular modifiable risk factors came from studies on cardiovascular conditions and diabetes. Cardiovascular prevention projects such as North Karelia Project and WHO-MONICA in the 1970–1980 s were focused on younger populations, which led to the idea of looking for risk factors as far back as middle age. Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) is one of the few studies in the world focusing on late-life cognition with a large and representative population-based cohort, baseline …examination at midlife, and follow-up time up to three decades. Since 1998, it has identified several modifiable risk factors for cognitive impairment/dementia, and produced the first risk score for estimating dementia risk based on midlife profiles. The CAIDE Dementia Risk Score has been used to select participants in the Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER). FINGER is an ongoing multicenter RCT involving 1,200 participants aged 60–77 years, and testing the effects of a two-year multi-domain intervention targeting several risk factors simultaneously. It started in September 2009 and will be completed at the end of 2013. The FINGER study is at the forefront of international collaborative efforts to solve the clinical and public health problems of early identification of individuals at increased risk of late-life cognitive impairment, and of developing intervention strategies to prevent or delay the onset of cognitive impairment and dementia. Show more

Keywords: Alzheimer's disease cognitive impairment, epidemiology, prevention, randomized controlled trials

DOI: 10.3233/JAD-2012-129021

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S465-S469, 2013