Journal of Alzheimer's Disease - Volume 9, issue s3

Authors: Nixon, Ralph A. | Cataldo, Anne M.

Article Type: Research Article

Abstract: The identification of cathepsins in amyloid-β plaques revealed broad dysfunction of the lysosomal system in Alzheimer's disease (AD). Coinciding with the discovery that proteolysis is required to generate the Aβ-peptide, these findings heralded an era of intense investigation on proteases in neurodegeneration. This review traces lysosomal system pathology from its early characterization to its origins within two pathways leading to the lysosome, the endocytic and autophagic pathways. An understanding has grown about how these two pathways are adversely influenced by normal brain aging and by genetic and environmental risk factors for AD, resulting in increased susceptibility of neurons to injury, …amyloidogenesis, and neurodegeneration. Show more

Keywords: Amyloid-β, cathepsin, apoptosis, endosome, autophagy, necrosis, Alzheimer's disease, protease, endocytosis

DOI: 10.3233/JAD-2006-9S331

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 277-289, 2006

Authors: Perl, Daniel P. | Moalem, Sharon

Article Type: Research Article

Abstract: It is now 25 years since the publication of our original paper investigating the association aluminum with Alzheimer's disease. This publication reported on the results of scanning electron microscopy coupled with x-ray spectrometry microprobe elemental studies of both neurofibrillary tangle-bearing and tangle-free neurons in the hippocampus of cases of Alzheimer's disease and controls. Peaks related to the presence of aluminum were consistently detected within the tangle-bearing neurons. This paper supported the association of aluminum and Alzheimer's disease on the cellular level of resolution and caused considerable interest and discussion. Subsequent work demonstrated prominent evidence of aluminum accumulation in the tangle-bearing …neurons of cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. This latter observation has now been replicated using five different forms of microanalysis. Finally, using laser microprobe mass analysis, we demonstrated that the abnormally high aluminum-related signal which we originally detected was actually located within the neurofibrillary tangle, itself, and was accompanied by excess concentrations of iron. Although it is unlikely that aluminum represents an etiologic cause of Alzheimer's disease, we believe that this highly reactive element, known to cross-link hyperphosphorylated proteins, may play an active role in the pathogenesis of critical neuropathologic lesions in Alzheimer's disease and other related disorders. Show more

DOI: 10.3233/JAD-2006-9S332

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 291-300, 2006

Authors: Perry, George

Article Type: Research Article

Abstract: Dissection of neurofibrillary tangles has been confounded by the insolubility of their fibers. While the majority of biochemical studies have considered τ filaments equivalent to neurofibrillary tangles, they forget that the former are soluble and the latter completely resistant to solvents. What, then, accounts for the insolubility of neurofibrillary tangles while τ filaments are soluble? Investigation of these distinctions played a critical role in our findings on proteolytic abnormalities and oxidative stress.

DOI: 10.3233/JAD-2006-9S333

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 301-304, 2006

Authors: Smith, Mark A.

Article Type: Research Article

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. Show more

DOI: 10.3233/JAD-2006-9S334

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 305-308, 2006

Authors: Takashima, Akihiko

Article Type: Research Article

Abstract: Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3β is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. GSK-3β has exactly the same oligonucleotide sequence as tau-protein kinase I (TPKI), which was first purified from the microtubule fraction of bovine brain. Initially, we discovered that GSK-3β was involved in amyloid-β (Aβ)-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional …investigations showing that Aβ activates GSK-3β through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Aβ-activated GSK-3β induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3β can induce memory deficits in vivo; and that inhibition of GSK-3α (an isoform of GSK-3β) reduces Aβ production. These combined results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD, preceding both the NFT and neuronal death pathways. Therefore, therapeutics targeted to inhibiting GSK-3 may be beneficial in the treatment of this devastating disease. Show more

Keywords: GSK-3β, NFT, Aβ, AD, tauopathy

DOI: 10.3233/JAD-2006-9S335

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 309-317, 2006

Authors: van Leeuwen, F.W. | Hol, E.M. | Fischer, D.F.

Article Type: Research Article

Abstract: Neuronal homeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the ubiquitin-proteasome system (UPS) and discovered a frameshift protein for ubiquitin (UBB+1 ), that accumulates in the neuritic plaques and tangles in patients with Alzheimer's disease (AD). UBB+1 , unable to tag proteins to be degraded, has been shown to be a substrate for ubiquitination and subsequent proteasomal degradation. If UBB+1 is accumulated, it inhibits the proteasome, which may result in neuronal death. We showed that UBB+1 …is also present in other tauopathies (e.g. Pick's disease) and in several polyglutamine diseases, but remarkably not in synucleinopathies (e.g. Parkinson's disease). Accumulation of UBB+1 -being a reporter for proteasomal dysfunctioning- thus differentiates between these conformational diseases. The accumulation of UBB+1 causes a dysfunctional UPS in these multifactorial neurodegenerative diseases. Novel transgenic mouse models and large-scale expression profiling and functional analyses of enzymes of the UPS compounds – enabling us to identify the targets of the UPS in these conformational diseases – may now pave the way for intervention and treatment of AD. Show more

Keywords: Conformational diseases, molecular misreading, polyglutamine diseases, synucleinopathies, tauopathies, vasopressin

DOI: 10.3233/JAD-2006-9S336

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 319-325, 2006

Authors: Levy, Efrat | Prelli, Frances | Frangione, Blas

Article Type: Research Article

Abstract: Amyloid protein deposited in cerebral vessel walls and diffuse plaques of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is similar to the 40–42 residues amyloid β (Aβ) in vessel walls and senile plaques in brains of patients with Alzheimer's disease (AD), Down's syndrome, and familial and sporadic cerebral amyloid angiopathy (CAA). In 1990 we sequenced the amyloid β-protein precursor (AβPP) gene from HCHWA-D patients revealing a single mutation that results in an amino acid substitution, Aβ E22Q. Subsequent identification of additional mutations in the AβPP gene in familial AD (FAD) pedigrees revealed that whereas substitutions in the …middle of Aβ, residues Aβ21-23, are predominantly vasculotropic, those found amino- or carboxyl-terminal to the Aβ sequence within AβPP enhance amyloid parenchymal plaque deposition. Studies of transfected cells showed that substitutions amino- or carboxyl-terminal to Aβ lead to either greater Aβ production or to enhanced secretion of the more hydrophobic thus more fibrillogenic Aβ1-42. Substitutions in the center of Aβ facilitate rapid aggregation and fibrillization, slower clearance across the blood-brain barrier and perivascular drainage to the systemic circulation, possibly higher resistance to proteolysis, and enhanced toxicity towards endothelial and smooth muscle cells. However, most AD patients have no genetic defects in AβPP, indicating that other factors may alter Aβ production, conformation, and/or clearance initiating the disease process. Show more

Keywords: Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), cerebral amyloid angiopathy (CAA), amyloid β-protein precursor (AβPP), amyloid β (Aβ)

DOI: 10.3233/JAD-2006-9S337

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 329-339, 2006

Authors: Goate, Alison

Article Type: Research Article

Abstract: In 1991 we described a missense mutation in the amyloid β-protein precursor (AβPP) gene in two familial Alzheimer's disease (FAD) kindreds. This gene encodes the amyloid β peptide deposited in senile plaques in AD. We made four predictions based upon these results: 1. Other FAD kindreds would be identified wth AβPP mutations; 2. FAD is genetically heterogeneous; 3. Aβ deposition is central to the pathogenesis of AD and 4, Regulatory variants in the AβPP gene lead to late onset AD. In the ensuing years substantial evidence has accrued in support of these predictions. Nineteen mutations in the AβPP gene have …been reported. These mutations have all been shown to alter AβPP processing or Aβ fibrillogenesis, leading to early Aβ deposition. Furthermore, mutations in the genes encoding presenilin 1 and presenilin 2, that cause FAD, also lead to changes in AβPP processing and Aβ deposition. Together these observations strongly support the hypothesis that Aβ deposition is central to AD pathogenesis. Suprisingly, the fourth prediction, that variation in AβPP expression may predispose to late onset AD, has not been rigorously tested, despite the fact that overexpression of AβPP is sufficient to cause dementia and AD neuropathology in Down Syndrome. Show more

Keywords: Familial Alzheimer's disease, Amyloid β-protein precursor, Amyloid β, gene, mutation, pathogenesis

DOI: 10.3233/JAD-2006-9S338

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 341-347, 2006

Authors: Goldgaber, Dmitry

Article Type: Research Article

Abstract: When I decided to clone the amyloid gene I did not know that there were some twenty groups around the research world that desperately tried to do the same. If I knew that I would have never started the project. I was so ignorant about the disease that I did not know how to spell the name Alzheimer. I had to look at the papers of other researchers to make sure that my spelling was correct. After the cloning, I was invited to numerous national and international meetings on AD. These meetings became my University where I majored in AD.

DOI: 10.3233/JAD-2006-9S339

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 349-360, 2006

Authors: Roses, Allen D.

Article Type: Research Article

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 [1--3]. 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 [4,5]. The 1991 multilocus analysis of linkage had been considered very controversial [6]. The second stream came from a series of amyloid-β binding studies in which a consistent protein “impurity” was present …on gel separation analyses [1]. 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 [1,2]. 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 [3]. The earliest submitted paper reported the familial association and amyloid-β binding [1]. The second reported the association with common sporadic late-onset, [not-known to be familial] AD patients [2]. The third reported that APOE4 carriers had earlier rates of onset of clinical disease than APOE2 or APOE3 carriers [3]. Subsequently, over more than a decade, the biological expression of apoE in human neurons was confirmed as distinct from rodent brain [7,8] 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. Rosiglitazone, a PPARγ agonist which also leads to mitochondrial proliferation shown efficacy as a monotherapy in a Phase IIB clinical trial of 511 patients in an APOE allele-specific analysis. Show more

DOI: 10.3233/JAD-2006-9S340

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 361-366, 2006

Authors: Schellenberg, Gerard D.

Article Type: Research Article

Abstract: 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 (APP), 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 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. Show more

Keywords: Alzheimer disease, AβPP, genetics, mutation, tau

DOI: 10.3233/JAD-2006-9S341

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 367-372, 2006

Authors: Spillantini, Maria Grazia | Murrell, Jill R. | Goedert, Michel | Farlow, Martin | Klug, Aaron | Ghetti, Bernardino

Article Type: Research Article

Abstract: Work in 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. Show more

Keywords: Mutation, tau, tauopathy

DOI: 10.3233/JAD-2006-9S342

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 373-380, 2006

Authors: Rogaeva, Ekaterina | Kawarai, Toshitaka | George-Hyslop, Peter St

Article Type: Research Article

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.

Keywords: Alzheimer's disease, presenilin, gene, AβPP, APOE

DOI: 10.3233/JAD-2006-9S343

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 381-387, 2006

Authors: Van Broeckhoven, Christine | Kumar-Singh, Samir

Article Type: Research Article

Abstract: Development of therapeutics begins with delineating the precise disease pathology along with a reasonable understanding of the sequence of events responsible for the development of disease, or disease pathogenesis. For Alzheimer's disease (AD), the classical pathology is now known for quite some time; however, the disease pathogenesis has eluded our understanding for a complete century. This review, in addition to providing a brief overview of all primary events, will highlight those aspects of AD genetics and novel pathological descriptions linked to unique mutations within AβPP that have led to our better understanding of the pathogenesis of AD. Specifically, we will …discuss how pathologies linked to the Dutch (E693Q) and Flemish AβPP (A692G) mutations have helped in understanding the role of CAA in dementia and in the development of dense-core plaques. In addition, this review will also point directions that warrant additional studies. Show more

Keywords: Dementia, Alzheimer's disease, Cerebral Amyloid Angiopathy (CAA), cerebral hemorrhages, AβPP mutations, Flemish APP692 disease, HCHWAD

DOI: 10.3233/JAD-2006-9S344

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 389-398, 2006

Authors: Skoch, Jesse | Hyman, Bradley T. | Bacskai, Brian J.

Article Type: Research Article

Abstract: Multiphoton microscopy is an optical imaging technique that allows high resolution detection of fluorescence in thick, scattering tissues. The technique has been used for trans-cranial imaging of the brains of living transgenic mouse models of Alzheimer's disease. Direct detection of senile plaques in these mice has allowed the characterization of the natural history of individual senile plaques, the evaluation of plaque clearance during immunotherapy, and the characterization of the kinetics and biodistribution of the PET ligand, PIB. With the expanding repertoire of structural and functional fluorescent probes, and the preclinical characterization of new contrast agents for complementary imaging modalities like …MRI, PET, SPECT, and NIRS, multiphoton microscopy will continue to be a powerful tool in understanding and combating Alzheimer's disease. Show more

DOI: 10.3233/JAD-2006-9S345

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 401-407, 2006

Authors: Khachaturian, Zaven S.

Article Type: Research Article

Abstract: A retrospective view of the critical events and advances in the development of criteria, instruments and algorithms in the diagnosis of Alzheimer's disease. The review is from the vantage point of the National Institute on Aging and its role in the development of the national infrastructure, in the US, for clinical research on dementia. The paper discusses future research needs and challenges for developing new diagnostic armamentarium for early and accurate detection of neurodegenerative processes of dementia in the early prodromal stages or during early mild cognitive impairments.

Keywords: Diagnosis, dementia, Alzheimer's disease, mild cognitive impairments, MCI, diagnostic criteria, biomarkers, diagnostic instruments, neuroimaging, National Institute on Aging, NIA, NIH

DOI: 10.3233/JAD-2006-9S346

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 409-415, 2006

Authors: McKeith, Ian G.

Article Type: Research Article

Abstract: Dementia with Lewy bodies (DLB) was considered to be an uncommon cause of dementia until improved neuropathological staining methods for ubiquitin were developed in the late 1980's. Subsequent recognition that 10–15% of dementia cases in older people were associated with Lewy body pathology led to the publication in 1996 of Consensus clinical and pathological diagnostic criteria for the disorder. These have greatly raised global awareness of DLB and helped to generate a body of knowledge which informs modern clinical management of this pharmacologically sensitive group of patients. They have also enabled important issues surrounding the relationships of DLB with Alzheimer's …disease and Parkinson's disease to be addressed and partially resolved. A recent re-evaluation of the Consensus criteria has confirmed many aspects of the original recommendations, supplementing these with suggestions for improved pathological characterisation, clinical detection and management. Virtu-ally unrecognised 20 years ago, DLB could within this decade be one of the best characterised and potentially treatable neurodegenerative disorders of late life. Show more

Keywords: Dementia with Lewy bodies, diagnosis

DOI: 10.3233/JAD-2006-9S347

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 417-423, 2006

Authors: Morgan, Dave

Article Type: Research Article

Abstract: A primary goal of research on Alzheimer's disease is to develop disease modifying therapeutics. The amyloid cascade hypothesis has focused the initial efforts on methods to reduce amyloid. One surprising approach that has shown considerable success in mouse models and has hinted at benefits in human trials is anti-Aβ immunotherapy. Schenk first showed the amyloid reducing potential of active immunization in 1999. This prompted our group and that of St. George-Hyslop to investigate whether active immunization would similarly retard the memory deficits that develop in amyloid depositing transgenic mice. Contrary to our initial predictions of premature memory dysfunction due to …inflammation, vaccination protected amyloid depositing mice from developing memory deficits. Subsequent studies found that passive immunization could reverse memory deficits, even when administered for short periods. These encouraging findings led to a trial of an Aβ vaccination in Alzheimer patients. The trial was cut short due to meningoencephalitic symptoms in 6% of patients, yet, in a subset of patients, those developing brain reactive antibodies benefited from slower rates of cognitive decline. These observations have accelerated the development of passive immunization protocols and safer vaccines. At this time, anti-amyloid immunotherapy stands poised to be the first test of the amyloid hypothesis in the treatment of Alzheimer disease. Show more

Keywords: Alzheimer disease, amyloid-β, therapeutics, transgenic, vaccine

DOI: 10.3233/JAD-2006-9S348

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 425-432, 2006

Authors: Solomon, Beka

Article Type: Research Article

Abstract: Site-directed antibodies which modulate conformation of amyloid-β peptide (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 hu-mans 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. Show more

Keywords: Amyloid-β, site-directed antibodies, therapeutic chaperones, single-chain antibodies, EFRH sequence, immunomodulation

DOI: 10.3233/JAD-2006-9S349

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 433-438, 2006

Authors: Summers, William K.

Article Type: Research Article

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. Show more

DOI: 10.3233/JAD-2006-9S350

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 439-445, 2006

Authors: Whitehouse, Peter J.

Article Type: Research Article

Abstract: Our paper on loss of neurons in the Nucleus Basalis of Meynert (now considered part of the cholinergic basal forebrain) in Alzheimer disease (AD) stimulated scientific interest in this little studied brain region. Our subsequent studies associated pathology in the basal forebrain with other dementias, such as Parkinson's disease, and with neurotransmitter receptor changes, such as in nicotinic receptors. We and many others worked to develop medications to treat AD through cholinergic mechanisms and eventually four cholinesterase inhibitors were approved. However the effect sizes of currently available drugs are modest and ethical issues in conducting research in dementia are challenging. …In Cleveland we came to focus on the goals of improving quality of life and the importance on non-pharmacological approaches to treatment. International efforts were organized to improve the efficiency of drug development and to focus on important cultural and pharmacoeconomic issues. Eventually I became concerned about the very way we conceive AD and related concepts like MCI (mild cognitive impairment). As the hundredth anniversary of the first case approaches I am helping to organize meetings to reflect deeply on what we have learned and how to imagine creating a more positive future for persons affected by what I used to call AD. Show more

Keywords: Cholinergic basal forebrain, Alzheimer disease, neuropathology, drug development, quality of life, bioethics, cognitive science

DOI: 10.3233/JAD-2006-9S351

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 447-453, 2006