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

Authors: Perry, George | Zhu, Xiongwei | Smith, Mark A. | Sorensen, Aaron | Avila, Jesús

Article Type: Editorial

DOI: 10.3233/JAD-2012-129045

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S1-S1, 2013

Authors: Tanzi, Rudolph E.

Article Type: Review Article

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 APP, 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. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, APOE, CD33, chromosome 21, down syndrome, genome-wide association study, presenilin

DOI: 10.3233/JAD-2012-129044

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S5-S13, 2013

Authors: Myers, Amanda J.

Article Type: Review Article

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.

Keywords: Alzheimer's disease, eQTL, expression quantitative trait locus, gene expression, gene expression regulation, genetic, genetic predisposition to disease, human brain, transcription

DOI: 10.3233/JAD-2012-129013

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S15-S22, 2013

Authors: Lovestone, Simon

Article Type: Review Article

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. Show more

Keywords: Biomarkers, clusterin, disease modification, GSK3, signaling, tau

DOI: 10.3233/JAD-2012-129014

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S23-S33, 2013

Authors: Gendron, Tania F. | Rademakers, Rosa | Petrucelli, Leonard

Article Type: Review Article

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) in familial ALS patients, two of which were novel. With over 40 TARDBP mutations 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. Show more

Keywords: Amyotrophic lateral sclerosis, frontotemporal lobar degeneration, mutation, neurodegeneration, TARDBP, TDP-43

DOI: 10.3233/JAD-2012-129036

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S35-S45, 2013

Authors: Klein, William L.

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease pathogenesis, amyloid-β oligomers, animal models, biomarkers, cellular mechanisms, vaccines

DOI: 10.3233/JAD-2012-129039

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S49-S65, 2013

Authors: Kayed, Rakez | Lasagna-Reeves, Cristian A.

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, amyloid, amyloid oligomers, amyloid toxicity

DOI: 10.3233/JAD-2012-129001

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S67-S78, 2013

Authors: Hampel, Harald

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid cascade hypothesis, asymptomatic, biomarkers, connectivity, CSF, default mode network, dementia, detection, diagnosis, dimers, DMN, fMRI, mild cognitive impairment, molecular mechanisms, neurophysiology, network paradigm, neural networks, oligomers, pathophysiology, preclinical, prodromal

DOI: 10.3233/JAD-2012-129003

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S79-S86, 2013

Authors: Sagare, Abhay P. | Bell, Robert D. | Zlokovic, Berislav V.

Article Type: Review Article

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. Show more

Keywords: Amyloid-β clearance, blood-brain barrier, low-density lipoprotein receptor-related protein 1, pericytes, receptor for advanced glycation end products

DOI: 10.3233/JAD-2012-129037

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S87-S100, 2013

Authors: Pacheco-Quinto, Javier | Herdt, Aimee | Eckman, Christopher B. | Eckman, Elizabeth A.

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, angiotensin-coverting enzyme, degradation, endothelin-converting enzyme, neprilysin, phosphoramidon, vasopeptidase

DOI: 10.3233/JAD-2012-129043

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S101-S110, 2013