Volume 33, Supplement 1, January 2013 - "Alzheimer’s Disease: Advances for a New Century" (Editors: George Perry, Xiongwei Zhu, Mark A. Smith†, Aaron Sorensen, Jesus Avila)

Page S1
Preface
George Perry, Xiongwei Zhu, Mark A. Smith, Aaron Sorensen, Jesus Avila
Alzheimer's Disease: Advances for a New Century

Genetics

Pages S5-S13
Rudolph E. Tanzi
A Brief History of Alzheimer's Disease Gene Discovery
Abstract: The rich and colorful history of gene discovery in Alzheimer’s disease (AD) over the past three decades is as complex and heterogeneous as the disease, itself. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in AβPP, PSEN1, and PSEN2 are fully penetrant for early-onset (<60 years) familial AD, which represents <5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, influence susceptibility for common (>95%) late-onset AD. These four genes account for 30-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of additional highly confirmed AD candidate genes. Here, I review the past, present, and future of attempts to elucidate the complex and heterogeneous genetic underpinnings of AD along with some of the unique events that made these discoveries possible.

Pages S15-S22
Amanda J. Myers
AD Gene 3-D: Moving Past Single Layer Genetic Information to Map Novel Loci Involved in Alzheimer's Disease
Abstract: Over the past 5 years, there has been considerable advancement in the genetics of Alzheimer’s disease. This review will provide an overview of the current state of the field for analysis of genetic variation and Alzheimer’s disease. Highlighted in this review will be the results from some of the more conventional approaches, including linkage and association studies, as well as an overview of an alternate approach: eQTL analysis. The emphasis will be on taking genomics to the next level by applying additional datasets to truly create maps of a 3-dimensional Alzheimer’s genome by including the downstream effects of risk variation.

Pages S23-S33
Simon Lovestone
Trait, State, and Mechanism: Looking Back, Looking Forward, and Understanding Why
Abstract: The papers selected by the Journal of Alzheimer's Disease for commentary cover three interlinked areas of research: the search for genetic susceptibility of trait markers, the search for biomarkers or state markers, and the search for novel therapeutic targets through an understanding of the mechanisms of disease. This work is reviewed and some directions of travel for the next phase of research suggested. Specifically both state and trait marker research will benefit from advances in technology but will require, on the one hand, larger sample sets and, on the other, the use of study designs other than case-control. Routine collection of data through the electronic medical record coupled with samples collected in clinical care represents a major opportunity to scale these studies. Success in identifying trait markers for stratification and state markers for experimental medicine may be necessary to exploit the increased understanding of mechanisms and the new therapeutic opportunities this is allowing.

Pages S35-S45
Tania F. Gendron, Rosa Rademakers, Leonard Petrucelli
TARDBP Mutation Analysis in TDP-43 Proteinopathies and Deciphering the Toxicity of Mutant TDP-43
Abstract: The identification of TAR DNA-binding protein 43 (TDP-43) as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions has defined a new class of neurodegenerative conditions: the TDP-43 proteinopathies. This breakthrough was quickly followed by mutation analysis of TARDBP, the gene encoding TDP-43. Herein, we provide a review of our previously published efforts that led to the identification of 3 TARDBP mutations (p.M337V, p.N345K, and p.I383V) infamilial ALS patients, two of which were novel. With over 40 TARDBP mutation now discovered, there exists conclusive evidence that TDP-43 plays a direct role in neurodegeneration. The onus is now on researchers to elucidate the mechanisms by which mutant TDP-43 confers toxicity, and to exploit these findings to gain a better understanding of how TDP-43 contributes to the pathogenesis of disease. Our biochemical analysis of TDP-43 in ALS patient lymphoblastoid cell lines revealed a substantial increase in TDP-43 truncation products, including a ~25 kDa fragment, compared to control lymphoblastoid cell lines. We discuss the putative harmful consequence of abnormal TDP-43 fragmentation, as well as highlight additional mechanisms of toxicity associated with mutant TDP-43.

Amyloid-β

Pages S49-S65
William L. Klein
Synaptotoxic Amyloid-β Oligomers: A Molecular Basis for the Cause, Diagnosis, and Treatment of Alzheimer’s Disease?
Abstract: The oligomer hypothesis for Alzheimer’s disease (AD) was introduced in 1998. It was based on evidence that oligomers could exist free of amyloid fibrils, that fibril-free oligomer solutions rapidly inhibited long term potentiation, and that oligomers ultimately caused a highly selective nerve cell death. Fibrils no longer were the only toxins made by amyloid-β (Aβ), and likely not the most important ones. Oligomers provided a new basis for instigating AD. Since introduction of the hypothesis, more than 1,500 articles on oligomers have been published. Articles for this review were selected for contributions to oligomer theory at three different levels. The first set demonstrated new aspects of oligomer pathobiology in cell models, showing that exposure of neurons to oligomers is sufficient to cause key features of AD neuropathology. The second set confirmed the relationship between oligomers and salient AD neuropathology in animal models, consistent with other in vivo studies that overall have substantiated cell-based discoveries. The third set developed strategies for therapeutic targeting of oligomers, introducing both small molecule and antibody-based approaches. These and related findings from many groups have helped establish oligomers as central to the mechanism of AD pathogenesis. Comprising a ligand-based attack on specific synapses, the action of toxic oligomers gives a molecular basis to account for key features of AD neuropathology and to explain why early disease targets memory. Although there still is no effective treatment for AD, insights over the past five years raise hopes that new approaches targeting Aβ oligomers could finally bring disease-modifying therapeutics.

Pages S67-S78
Rakez Kayed, Cristian Lasagna-Reeves
Molecular Mechanisms of Amyloid Oligomers Toxicity
Abstract: Amyloid oligomers have emerged as the most toxic species of amyloid-β (Aβ). This hypothesis might explain the lack of correlation between amyloid plaques and memory impairment or cellular dysfunction. However, despite the numerous published research articles supporting the critical role Aβ oligomers in synaptic dysfunction and cell death, the exact definition and mechanism of amyloid oligomers formation and toxicity still elusive. Here we review the evidence supporting the many molecular mechanisms proposed for amyloid oligomers toxicity and suggest that the complexity and dynamic nature of amyloid oligomers may be responsible for the discrepancy among these mechanisms and the proposed cellular targets for amyloid oligomers.

Pages S79-S86
Harald Hampel, David Prvulovic
Amyloid-β and Cognition in Aging and Alzheimer’s Disease: Molecular and Neurophysiological Mechanisms
Abstract: Amyloid-β (Aβ) deposition in the brain is one of the key pathological features of Alzheimer’s disease (AD). Neither traditional clinical-pathological studies nor modern in vivo biomarker investigations of brain amyloid load, however, could reveal a convincing relationship between brain Aβ load and cognitive deficits and decline in patients with AD. Evidence suggests that pathophysiological Aβ dysregulation and accumulation are very early events that precede the onset of cognitive impairment reaching a plateau at the clinical stage of the beginning dementia syndrome. Therefore, research efforts have focused on the role of Aβ in asymptomatic older adults: the results of combined amyloid-PET and neuropsychological studies show a modest but significant correlation between brain fibrillar amyloid load and various subtle cognitive deficits, most notably in challenging episodic associative memory tasks. In order to elucidate the pathophysiological link between cognition and Aβ, a number of combined functional neuroimaging studies have been performed, resulting in early and complex functional alterations in cognitively relevant neural networks such as the default mode network and the largely overlapping episodic memory networks. Multimodal studies using amyloid-tracing imaging methods and neurodegeneration biomarkers strongly suggest that neural network discoordination is specifically related to Aβ-mediated functional and potentially reversible disruption of synaptic plasticity rather than a direct consequence to neurodegenerative pathological processes. These pathophysiological processes and mechanisms may dynamically and non-linearly evolve through fully reversible adaptive compensatory stages and through reactive decompensatory stages into fully irreversible neurodegenerative stages of AD.

Pages S87-S100
Abhay P. Sagare, Robert D. Bell, Berislav V. Zlokovic
Neurovascular Defects and Faulty Amyloid-β Vascular Clearance in Alzheimer’s Disease
Abstract: The evidence that neurovascular dysfunction is an integral part of Alzheimer’s disease (AD) pathogenesis has continued to emerge in the last decade. Changes in the brain vasculature have been shown to contribute to the onset and progression of the pathological processes associated with AD, such as microvascular reductions, blood brain barrier (BBB) breakdown, and faulty clearance of amyloid β-peptide (Aβ) from the brain. Herein, we review the role of the neurovascular unit and molecular mechanisms in cerebral vascular cells behind the pathogenesis of AD. In particular, we focus on molecular pathways within cerebral vascular cells and the systemic circulation that contribute to BBB dysfunction, brain hypoperfusion, and impaired clearance of Aβ from the brain. We aim to provide a summary of recent research findings implicated in neurovascular defects and faulty Aβ vascular clearance contributing to AD pathogenesis.

Pages S101-S110
Javier Pacheco-Quinto, Aimee Herdt, Christopher B. Eckman, and Elizabeth A. Eckman
Endothelin-Converting Enzymes and Related Metalloproteases in Alzheimer’s Disease
Abstract: The efficient clearance of amyloid-β (Aβ) is essential to modulate levels of the peptide in the brain and to prevent it from accumulating in senile plaques, a hallmark of Alzheimer’s disease (AD) pathology. We and others have shown that failure in Aβ catabolism can produce elevations in Aβ concentration similar to those observed in familial forms of AD. Based on the available evidence, it remains plausible that in late-onset AD, disturbances in the activity of Aβ degrading enzymes could induce Aβ accumulation, and that this increase could result in AD pathology. The following review presents a historical perspective of the parallel discovery of three vasopeptidases (neprilysin and endothelin-converting enzymes-1 and -2) as important Aβ degrading enzymes. The recognition of the role of these vasopeptidases in Aβ degradation, beyond bringing to light a possible explanation of how cardiovascular risk factors may influence AD risk, highlights a possible risk of the use of inhibitors of these enzymes for other clinical indications such as hypertension. We will discuss in detail the experiments conducted to assess the impact of vasopeptidase deficiency (through pharmacological inhibition or genetic mutation) on Aβ accumulation, as well as the cooperative effect of multiple Aβ degrading enzymes to regulate the concentration of the peptide at multiple sites, both intracellular and extracellular, throughout the brain.

Pages S111-S120
Daniela Puzzo, Ottavio Arancio
Amyloid-β Peptide: Dr. Jekyll or Mr. Hyde?
Abstract: Amyloid-β peptide (Aβ) is considered a key protein in the pathogenesis of Alzheimer’s disease (AD) because of its neurotoxicity and capacity to form characteristic insoluble deposits known as senile plaques. Aβ derives from amyloid-β protein precursor (AβPP), whose proteolytic processing generates several fragments including Aβ peptides of various lengths. The normal function of AβPP and its fragments remains poorly understood. While some fragments has been suggested to have a function in normal physiological cellular processes, Aβ has been widely considered as a “garbage” fragment that becomes toxic when it accumulates in the brain, resulting in impaired synaptic function and memory. Aβ is produced and released physiologically in the healthy brain during neuronal activity. In the last 10 years, we have been investigating whether Aβ plays a physiological role in the brain. We first demonstrated that picomolar concentrations of a human Aβ42 preparation enhanced synaptic plasticity and memory in mice. Next, we investigated the role of endogenous Aβ in healthy murine brains and found that treatment with a specific antirodent Aβ antibody and an siRNA against murine AβPP impaired synaptic plasticity and memory. The concurrent addition of human Aβ42 rescued these deficits, suggesting that in the healthy brain, physiological Aβ concentrations are necessary for normal synaptic plasticity and memory to occur. Furthermore, the effect of both exogenous and endogenous Aβ was seen to be mediated by modulation of neurotransmitter release and α7-nicotinic receptors. These findings need to be taken into consideration when designing novel therapeutic strategies for AD.

Tau

Pages S123-S139
Jian-Zhi Wang, Yi-Yuan Xia, Inge Grundke-Iqbal, Khalid Iqbal
Abnormal Hyperphosphorylation of Tau: Sites, Regulation, and Molecular Mechanism of Neurofibrillary Degeneration
Abstract: Microtubule associated protein tau is a phosphoprotein which potentially has 80 serine/threonine and 5 tyrosine phosphorylation sites. Normal brain tau contains 2-3 moles of phosphate per mole of the protein. In Alzheimer’s disease brain, tau is abnormally hyperphosphorylated to a stoichiometry of at least three-fold greater than normal tau, and in this altered state it is aggregated into paired helical filaments forming neurofibrillary tangles, a histopathological hallmark of the disease. The abnormal hyperphosphorylation of tau is also a hallmark of several other related neurodegenerative disorders, called tauopathies. The density of neurofibrillary tangles in the neocortex correlates with dementia and, hence, is a rational therapeutic target and an area of increasing research interest. Development of rational tau-based therapeutic drugs requires understanding of the role of various phosphorylation sites, protein kinases and phosphatases, and post-translational modifications that regulate the phosphorylation of this protein at various sites, as well as the molecular mechanism by which the abnormally hyperphosphorylated tau leads to neurodegeneration and dementia. In this article we briefly review the progress made in these areas of research.

Pages S141-S144
Felix Hernandez, Jose J. Lucas, Jesus Avila
GSK3 and Tau: Two Convergence Points in Alzheimer’s Disease
Abstract: Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that plays a key role in the pathogenesis of Alzheimer’s disease (AD). GSK3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired helical filaments, and GSK3 activity contributes both to amyloid-β production and amyloid-β-mediated neuronal death. Thus, mice generated in our laboratory with conditional overexpression of GSK3 in forebrain neurons (Tet/GSK3β mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis, as well as spatial learning deficit.  In this review, we describe recent contributions of our group showing that transgene shutdown in that animal model leads to normal GSK3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK3 inhibitors for AD therapeutics. In addition, we have combined transgenic mice overexpressing the enzyme GSK3β with transgenic mice expressing tau with a triple FTDP-17 mutation that develop prefibrillar tau-aggregates. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Further, it is possible to partially reverse tau pathology in advanced stages of the disease, although the presence of already assembled neurofibrillary tangle-like structures cannot be reversed.

Pages S145-S151
Casey Cook, Leonard Petrucelli
Tau Triage Decisions Mediated by the Chaperone Network
Abstract: The pathological accumulation of the microtubule-binding protein tau is linked to an increasing number of neurodegenerative conditions associated with aging, though the mechanisms by which tau accumulates in disease are unclear. In this review, we will summarize our previous research assessing the mechanism of action, as well as the therapeutic potential of Hsp90 inhibition for the treatment of tauopathies. Specifically, we describe the development of a high-throughput screening approach to identify and rank compounds, and demonstrate the selective elimination of aberrant p-tau species in the brain following treatment with an Hsp90 inhibitor. Additionally, we identify CHIP as an essential component of the Hsp90 chaperone complex that mediates tau degradation, and present evidence to suggest that CHIP functions to identify and sequester neurotoxic tau species. Finally, we discuss recent data identifying an additional mechanism by which CHIP modulates protein triage decisions involving Hsp90. Specifically, CHIP indirectly regulates Hsp90 chaperone activity by modulating steady-state levels of the Hsp90 deacetylase, HDAC6, thus influencing both the acetylation state and function of Hsp90. Thus future research directions will focus on the manipulation of this network to promote degradation of pathogenic tau species in disease.

Neuropathology

Pages S155-S161
Heiko Braak, Kelly Del Tredici-Braak
Evolutional Aspects of Alzheimer’s Disease Pathogenesis
Abstract: Tau lesions (pretangles, neuropil threads, neurofibrillary tangles) that develop in a few types of nerve cells in the brain are essential to the pathogenesis of Alzheimer’s disease (AD). The formation of non-argyrophilic pretangles marks the beginning of the pathological process and is of increasing interest because it is temporally closer to the prevailing conditions that induce the pathological process underlying AD in contrast to late-stage disease. Not all of the pretangle material, however, converts into argyrophilic neurofibrillary lesions. The propensity to develop tau lesions may be related to the exceptionally protracted myelination of late developing portions in the human brain.

Pages S163-S172
Paul M. Matthews, Nicola Filippini, Gwenaëlle Douaud
Brain Structural and Functional Connectivity and the Progression of Neuropathology in Alzheimer’s Disease
Abstract: In our contribution to this special issue focusing on advances in Alzheimer’s disease (AD) research since the centennial, we will briefly review some of our own studies applying magnetic resonance imaging (MRI) measures of function and connectivity for characterization of genetic contributions to the neuropathology of AD and as candidate biomarkers. We review how functional MRI during both memory encoding and at rest is able to define APOE4 genotype-dependent physiological changes decades before potential development of AD and demonstrate changes distinct from those with healthy aging. More generally, imaging provides a powerful quantitative measure of phenotype for understanding associations arising from whole genome studies in AD. Structural connectivity measures derived from diffusion tensor MRI (DTI) methods offer additional markers of neuropathology arising from the secondary changes in axonal caliber and myelination that accompany decreased neuronal activity and neurodegeneration. We illustrate applications of DTI for more finely mapping neurodegenerative changes with AD in the thalamus in vivo and for defining neuropathological changes in the white matter itself. The latter efforts have highlighted how sensitivity to the neuropathology can be enhanced by using more specific DTI measures and interpreting them relative to knowledge of local white matter anatomy in the healthy brain. Together, our studies and related work are helping to establish the exciting potential of a new range of MRI methods as neuropathological measures and as biomarkers of disease progression.

Pages S173-S179
Irina Alafuzoff
Alzheimer’s Disease-Related Lesions
Abstract: The invitation to contribute to “Alzheimer’s Disease: Advances for a New Century” gave me an opportunity to briefly summarize my personal opinions about how the field of neuropathology has evolved. The goal is to briefly exemplify the changes that have influenced the way we conduct our diagnostic work as well as the way we interpret our results. From an era of histological stains, we have moved to visualization of altered proteins in predicted brain regions; we have also realized that in many aged subjects, not one but a plethora of co-pathologies are seen, and finally, we have become aware that the degenerative process is initiated much earlier than we ever suspected.

Pages S181-S184
Kathleen S. Montine and Thomas J. Montine
Anatomic and Clinical Pathology of Cognitive Impairment and Dementia
Abstract: Progressive cognitive impairment and its clinical culmination in dementia loom as a major public health problem in the coming generation of older adults, and this fact compels investigation to develop interventions that prevent, delay, or cure. The tools of anatomic pathology have provided key insights into the complex convergence of multiple diseases that commonly contribute to the dementia syndrome and its prodrome in the community setting, and they have suggested some exposures that may modulate disease burden. The tools of clinical pathology, in combination with neuroimaging, have revolutionized the approach to clinical investigation of Alzheimer’s disease and are now doing the same with Lewy body disease and vascular brain injury. The tools of anatomic and clinical pathology will continue to contribute to our understanding of these diseases as we advance toward effective interventions for the diseases that commonly cause cognitive impairment and dementia in older adults.

Pages S185-S194
Kiren Ubhi, Eliezer Masliah
Alzheimer’s Disease: Recent Advances and Future Perspectives
Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory deficits and other cognitive disturbances. Neuropathologically, AD is characterized by the progressive loss of basal forebrain cholinergic neurons that innervate the hippocampus and cortex and the abnormal extracellular accumulation of amyloid-β and intracellular tau protein. Current research on AD is focused on the mechanisms underlying the abnormal oligomerization, fibrillation, and accumulation of the amyloid-β and tau proteins, mechanisms that may alter the dynamics of this accumulation and on experimental therapeutics approaches aimed at the clearance of the abnormally folded proteins and other potentially neuroprotective interventions. This review will summarize the main areas of investigation in AD and present ways forward for future work.

Pages S195-S210
Rodrigo Medeiros, Meredith A. Chabrier, Frank M. LaFerla
Elucidating the Triggers, Progression, and Effects of Alzheimer’s Disease
Abstract: As the number of patients with Alzheimer’s disease (AD) continues to rise, the need for efficacious therapeutics is becoming more and more urgent. Understanding the molecular relationship and interactions between Aβ and tau and their contribution to cognitive decline remain one of the most fundamental and unresolved questions in the AD field. Likewise, elucidating the initial triggers of disease pathology, as well as the impact of various factors such as stress and inflammation on disease progression, are equally important to fully understand this devastating disorder. Here we discuss recent studies that have illuminated the importance of key facilitators of disease progression using the 3xTg-AD and CaM/Tet-DTA mouse models, and suggest viable targets for ameliorating both molecular pathology and cognitive decline.

Pages S211-S217
John R. Hodges
Alzheimer’s Disease and the Frontotemporal Dementias: Contributions to Clinico-Pathological Studies, Diagnosis, and Cognitive Neuroscience
Abstract: This review focuses on six key papers published in the mid 2000s 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.

Pages S219-S233
Thomas G. Beach
Alzheimer’s Disease and The Valley of Death: Not Enough Guidance from Human Brain Tissue?
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, 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.

Oxidative Stress, Metabolism, Metals, and Inflammation

Pages S237-S241
Domenico Praticò
Alzheimer’s Disease and the Quest for its Biological Measures
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.

Pages S243-S251
Rukhsana Sultana, D. Allan Butterfield
Oxidative Modification of Brain Proteins in Alzheimer’s Disease: Perspective on Future Studies Based on Results of Redox Proteomics Studies
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.

Pages S253-S262
Xiongwei Zhu, George Perry, Mark A. Smith, Xinglong Wang
Abnormal Mitochondrial Dynamics in the Pathogenesis of Alzheimer’s Disease
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.

Pages S263-S275
Suzanne Craft, Brenna Cholerton, Laura D. Baker
Insulin and Alzheimer’s Disease: Untangling the Web
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.

Pages S277-S281
Ashley I. Bush
The Metal Theory of Alzheimer's Disease
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.

Pages S283-S293
Andrew D. Watt, Victor L. Villemagne, Kevin J. Barnham
Metals, Membranes, and Amyloid-β Oligomers: Key Pieces in the Alzheimer’s Disease Puzzle?
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.

Pages S295-S302
Suzanne E. Hickman, Joseph El Khoury
The NeuroImmune System in Alzheimer’s Disease: The Glass is Half Full
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.

Imaging and Biomarkers

Pages S305-S312
Yuying Liang, Natalie S. Ryan, Jonathan M. Schott, Nick C. Fox
Imaging the Onset and Progression of Alzheimer’s Disease: Implications for Prevention Trials
Abstract: Excess neuronal loss—atrophy—is an inevitable feature of Alzheimer’s disease (AD). Following studies in the early 1990s 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.

Pages S313-S327
Meredith N. Braskie, Arthur W. Toga, Paul M. Thompson
Recent Advances in Imaging Alzheimer’s Disease
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.

Pages S329-S347
Stefan J. Teipel, Osama Sabri, Michel Grothe,, Henryk Barthel, David Prvulovic, Katharina Buerger, Arun L.W. Bokde, Michael Ewers, Wolfgang Hoffmann, Harald Hampel
Perspectives for Multimodal Neurochemical and Imaging Biomarkers in Alzheimer’s Disease
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.

Pages S349-S359
Victor L. Villemagne, Christopher C. Rowe
Long Night’s Journey into the Day: Amyloid-β Imaging in Alzheimer’s Disease
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.

Pages S361-S369
Henrik Zetterberg, Kaj Blennow
Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: More to Come?
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.

Pages S371-S376
Joseph Quinn
Biomarkers for Alzheimer’s Disease: Showing the Way or Leading Us Astray?
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.

Diagnosis and Epidemiology

Pages S379-S383
Murray Grossman
Multimodal Comparative Studies of Neurodegenerative Diseases
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.

Pages S397-S403
David A. Bennett, Robert S. Wilson, Zoe Arvanitakis, Patricia A. Boyle, Leyla de Toledo-Morrell, Julie A. Schneider
Selected Findings from the Religious Orders Study and Rush Memory and Aging Project
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.

Pages S405-S416
Richard J. Caselli, Eric M. Reiman
Characterizing the Preclinical Stages of Alzheimer’s Disease and the Prospect of Presymptomatic Intervention
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.

Pages S417-S426
Charles DeCarli
Clinically Asymptomatic Vascular Brain Injury: A Potent Cause of Cognitive Impairment Among Older Individuals
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.

Pages S427-S438
Oscar L. Lopez, James T. Becker, Lewis H Kuller
Patterns of Compensation and Vulnerability in Normal Subjects at Risk of Alzheimer’s Disease
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 ofAD 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.

Pages S439-S445
Galit Weinstein, Philip A. Wolf, Alexa S. Beiser, Rhoda Au, Sudha Seshadri
Risk Estimations, Risk Factors, and Genetic Variants Associated with Alzheimer’s Disease in Selected Publications from the Framingham Heart Study
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.

Pages S447-S455
Devangere Devanand, Joseph Lee, Jose Luchsinger, Jennifer Manly, Karen Marder, Richard Mayeux, Nikolaos Scarmeas, Nicole Schupf, Yaakov Stern
Lessons from Epidemiologic Research about Risk Factors, Modifiers, and Progression of Late Onset Alzheimer’s Disease in New York City at Columbia University Medical Center
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.

Pages S457-S463
Pascale Barberger-Gateau, Jean-Charles Lambert, Catherine Féart, Karine Pérès, Karen Ritchie, Jean-François Dartigues, Annick Alpérovitch
From Genetics to Dietetics: The Contribution of Epidemiology to Understanding Alzheimer’s Disease
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.

Pages S465-S469
Alina Solomon, Miia Kivipelto, Hilkka Soininen
Prevention of Alzheimer’s Disease: Moving Backward through the Lifespan
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 1970-1980s 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.