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Allen D. Roses
On the discovery of the genetic association of Apolipoprotein E genotypes and common late-onset Alzheimer disease
Abstract: The association of Apolipoprotein E-4 with the age of onset of common late-onset Alzheimer’s disease (AD) was originally reported in three 1993 papers from the Duke ADRC (Alzheimer’s Disease Research Center) group. The Center was investigating two diverse experimental streams that led to this discovery. The first being a genetic linkage study performed in multiplex familial late-onset AD in which a linkage was discovered at chromosome 19q13. The 1991 multilocus analysis of linkage had been considered very controversial. The second stream came from a series of amyloid-ß binding studies in which a consistent protein “impurity” was present on gel separation analyses. After sequencing this “impurity” band, several tryptic peptide sequences were found to be identical for apoE which, at that time, had no known association with Alzheimer’s disease. The flash of recognition was the knowledge that APOE was one of the first genes localized to chromosome 19 in the mid-1980’s. Within a three week period in late 1992, a highly significant association was identified in clinical patients from multiplex families, in sporadic clinical patients, and in autopsy diagnosed series. Within the first two months of 1993, it was possible to clearly demonstrate that the APOE isoforms were associated with differing ages of onset, but the course of illness following diagnosis was related more to age than APOE genotype. The earliest submitted paper reported the familial association and amyloid-β binding. The second reported the association with common sporadic late-onset, [not-known to be familial] AD patients. The third reported that APOE4 carriers had earlier rates of onset of clinical disease than APOE2 or APOE3 carriers. Subsequently, over more than a decade, the biological expression of apoE in human neurons was confirmed as distinct from rodent brain. Proteomic experiments and positron emission tomography data have led to a series of clinical trials with agents selected to increase glucose utilization. These agents also regulate inflammatory responses of neural cells. A lead compound is currently [June 2005] in Phase IIB clinical trials.
Stephen W. Scheff, Douglas A. Price
Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus
Abstract: Alzheimer’s disease (AD) is a progressive disorder that is characterized by the accumulation of neuropathologic lesions and neurochemical alterations. Ultrastructural investigations in many association regions of the neocortex and the hippocampal dentate gyrus have demonstrated a disease-related decline in numerical synaptic density. This decline in brain connectivity occurs early in the disease process and strongly correlates with the cognitive decline observed in AD. The synapse loss does not appear to be an inevitable consequence of the aging process. This article reviews the ultrastructural studies assessing AD-related synaptic loss and the possible compensatory changes in the synaptic complex that occur as a result of the loss in brain connectivity.
Gerard D. Schellenberg
Early Alzheimer's Disease Genetics
The genetics community working on Alzheimer’s disease and related dementias has made remarkable progress in the past 20 years. The cumulative efforts by multiple groups have lead to the identification of three autosomal dominant genes for early onset AD. These are the amyloid β protein precursor gene (AβPP), and the genes encoding presenilin1 and 2. The knowledge derived from this work has firmly established Aβ as a critical disease molecule and lead to candidate drugs currently in treatment trials. Work on a related disease, frontotemporal dementia with parkinsonism – chromosome 17 type has also added to our understanding of pathogenesis by revealing that tau, the protein component of neurofibrillary tangles, is also a critical molecule in neurodegeneration. Lessons learned that still influence work on human genetics include the need to recognize and deal with genetic heterogeneity, a feature common to many genetic disorders. Genetic heterogeneity, if recognized, can be a rich source of information. Another critical lesson is that clinical, molecular, and statistical scientists need to work closely on disease projects to succeed in solving the complex problems of common genetic disorders.
Dennis J. Selkoe
Amyloid β-Peptide is Produced by Cultured Cells During Normal Metabolism: A Reprise
Abstract: In the twenty years since George Glenner identified the amyloid β-protein (Aβ), advances in understanding the biochemical pathology, genetics and cell biology of Alzheimer’s disease have led to a detailed molecular hypothesis for the genesis of AD and brought us into human trials of anti-amyloid agents. The ability to study Aβ dynamically in cultured cells and in vivo derives from the recognition in 1992 that Aβ is a normal product of cellular metabolism throughout life and circulates as a soluble peptide in biological fluids. Here, I review the background underlying this discovery and then discuss its implications for research on Alzheimer’s disease, particularly for the development of disease-modifying therapies.
Mark A. Smith
Oxidative Stress and Iron Imbalance in Alzheimer Disease: How Rust Became the Fuss!
Abstract: The role of oxidative stress in the pathogenesis of Alzheimer disease has gone from epiphenomena to phenomena. This transition, from disregarded to accepted theory, started in the early-mid 1990s and was accelerated by a number of reports in the literature showing that redox-active sources of transition metals, such as iron, were increased in the brain at early stages of disease. As such, it became apparent that not only was there damage but, more importantly, the machinery to exact such damage was ever present. In this review, the author chronicles his personal perspective on the past, present, and future of oxidative stress in Alzheimer disease.
Beka Solomon
Alzheimer’s Disease Immunotherapy: From in vitro Amyloid Immunomodulation to in vivo Vaccination
Abstract: Site-directed antibodies which modulate conformation of amyloid-β protein (Aβ) became the theoretical basis of the immunological approach for treatment of Alzheimer's disease (AD). Indeed, antibodies towards the EFRH sequence, located between amino acids 3-6 of the N-terminal region of Aβ, found to be a key position in modulation of Aβ conformation, prevent formation of fibrillar Aβ and dissolve already formed amyloid plaques. The performance of anti-Aβ antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and/or dissolving Aβ. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Development of such antibodies via active and/or passive immunization against Aβ peptide fragments has been proposed for AD immunotherapeutic strategies. Experimental active immunization with fibrillar Aβ 1-42 in humans was stopped in phase II clinical trials due to unexpected neuroinflammatory manifestations. In spite of the fact that it will take considerable effort to establish a suitable immunization procedure, these results clearly strengthen the hypothesis that Aβ plays a central role in AD, stimulating a new area for development of Alzheimer’s immunotherapeutics.
Maria Grazia Spillantini, Jill R. Murrell, Michel Goedert, Martin Farlow, Aaron Klug, Bernardino Ghetti
Mutations in the tau gene (MAPT) in FTDP-17: the family with Multiple System Tauopathy with Presenile Dementia (MSTD)
Work in the 1980s and early 1990s established that the microtubule-associated protein tau is the major component of the paired helical filament of Alzheimer’s disease. Similar filamentous deposits are also present in a number of other diseases, including progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. In 1998, the relevance of tau dysfunction for the neurodegenerative process became clear, when mutations in the tau gene were found to cause the inherited “frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).” The paper highlighted here [Spillantini M.G., Murrell J.R., Goedert M., Farlow M., Klug A. and Ghetti B. (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737-7741] reported a mutation at position +3 in the intron following alternatively spliced exon 10 of the tau gene in a family with abundant filamentous deposits made exclusively of four-repeat tau. Levels of soluble four-repeat tau were increased in individuals with this mutation. It was proposed that the +3 mutation destabilises a stem-loop structure located at the end of exon 10 and the beginning of the intron, thus resulting in an abnormal ratio of three-repeat to four-repeat tau isoforms.
Ekaterina Rogaeva, Toshitaka Kawarai, Peter St George-Hyslop
Genetic complexity of Alzheimer's disease: successes and challenges
Abstract: About 1% of Alzheimer's Disease (AD) cases have an early-onset autosomal dominant familial form of the disease, genetic analyses of which have found three causal genes: amyloid β-protein precursor (AβPP), presenilin 1 (PS1) and presenilin 2 (PS2). The APOE gene is the only robustly replicated risk factor for the common form of AD with onset after 65 years of age. In at least half of the AD cases, there is no known cause of the disease. Here we provide an overview on known AD-linked genes and discuss the strategies of searching for novel AD genetic risk factors.
William Summers
Tacrine and Alzheimer’s Treatments
Abstract: The story of the development of tacrine began from its synthesis as an intravenous antiseptic in 1940 by Adrian Albert in Australia. In the 1970’s William Summers began using tacrine in treating drug overdose coma and delirium. He felt it might have application in Alzheimer’s based on work done in England by Peter Davies. In 1981, Summers et al. gave intravenous tacrine to Alzheimer’s patients showed measurable improvement. Between 1981 and 1986, Summers worked with Art Kling and his group at UCLA to demonstrate usefulness of oral tacrine in treatment of Alzheimer’s patients. The average length of tacrine use in 14 completing patients was 12.6 months and improvement was robust. This sparked controversy in the field. In 1993, after larger studies replicated the positive effect of tacrine, it was approved by the US Food and Drug Administration for treatment of Alzheimer’s disease.
