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4. OTHER ASPECTS OF ETIOLOGY OF ALZHEIMER'S DISEASE

AMYLOID-BETA PEPTIDE LEVELS IN BRAIN ARE INVERSELY CORRELATED WITH INSULYSIN ACTIVITY LEVELS IN VIVO

The following points are made by B.C. Miller et al (Proc. Nat. Acad. Sci. 2003 100:6221):

1) Amyloid-beta (A-beta) peptide-containing senile plaques are a prominent feature of the pathology of Alzheimer's disease (AD) and occur consistently in AD of all etiologies, from early-onset, familial-linked AD to late-onset AD of indeterminate origin (1). A-beta is formed from the amyloid precursor protein (APP) by sequential enzymatic processing. A beta-secretase cleavage first yields the 99-aa C-terminal fragment (CTF) of APP, CTF, which then is cleaved by gamma-secretase to release A-beta peptides, predominately A40 and A42, and the CTF peptides of 49-51 residues (2).

2) The proteolysis of APP to yield A-beta peptides is a normal physiologic process observed in multiple cell types, although the endogenous function of APP processing and its products is still not well defined (3). To date, all of the genetic mutations linked to AD result in increased A-beta accumulation, albeit by distinct mechanisms.

3) Although considerable effort has been directed toward generating specific inhibitors of the beta- and gamma-secretases as a means of preventing A-beta formation (4), the mechanism of A-beta clearance also is of considerable interest because the steady-state concentrations of A-beta peptides are dependent on both their rates of synthesis and their rates of clearance. Recent studies suggest that an important route of A-beta clearance is through hydrolytic cleavage by proteases and peptidases. The peptidase insulysin is one of the enzymes that has been suggested as a candidate A-beta-degrading enzyme primarily based on its ability to degrade A-beta peptides in vitro (5).

4) Insulysin is a zinc metalloprotease, originally identified as an insulin-degrading enzyme, that migrates with reported molecular masses of 110-115 kDa on SDS/polyacrylamide gels and has no demonstrated posttranslational modifications. The observed molecular mass of insulysin is consistent with the use of the second of its two potential translation initiation sites, although N-terminal sequencing of authentic insulysin has not been reported.

5) In summary: Factors that elevate amyloid-beta (A-beta) peptide levels are associated with an increased risk for Alzheimer's disease. Insulysin has been identified as one of several proteases potentially involved in A-beta degradation based on its hydrolysis of A-beta peptides in vitro. The authors report that in vivo levels of brain A40 and A42 peptides were found to be increased significantly (1.6- and 1.4-fold, respectively) in an insulysin-deficient gene-trap mouse model. In mice heterozygous for the insulysin gene trap, in which insulysin activity levels were decreased 50%, brain A-beta peptides were increased to levels intermediate between those in wild-type mice and homozygous insulysin gene-trap mice that had no detectable insulysin activity. The authors suggest these findings indicate that there is an inverse correlation between in vivo insulysin activity levels and brain A-beta peptide levels, so that modulation of insulysin activity may alter the risk for Alzheimer's disease.

References (abridged):

1. Hardy, J. & Selkoe, D. J. (2002) Science 297, 353-356

2. Sambamurti, K., Greig, N. H. & Lahiri, D. K. (2002) Neuromol. Med. 1, 1-31

3. Kamal, A., Almenar-Queralt, A., LeBlanc, J. F., Roberts, E. A. & Goldstein, L. S. (2001) Nature 414, 643-648

4. Nunan, J. & Small, D. H. (2000) FEBS Lett. 483, 6-10

5. Kurochkin, I. V. & Goto, S. (1994) FEBS Lett. 345, 33-37

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INSULIN-DEGRADING ENZYME REGULATES THE LEVELS OF INSULIN, AMYLOID BETA-PROTEIN, AND THE BETA-AMYLOID PRECURSOR PROTEIN INTRACELLULAR DOMAIN IN VIVO

The following points are made by W. Farris et al (Proc. Nat. Acad. Sci. 2003 100:4162):

1) Insulin-degrading enzyme (IDE, insulysin) is an 110-kDa thiol zinc-metalloendopeptidase located in cytosol, peroxisomes, endosomes, and on the cell surface (1-4) that cleaves small proteins of diverse sequence, many of which share a propensity to form beta-pleated sheet-rich amyloid fibrils under certain conditions [e.g., amyloid beta-protein (A-beta), insulin, glucagon, amylin, atrial natriuretic factor, and calcitonin] (5). IDE is the major enzyme responsible for insulin degradation in vitro (1), but the extent to which it mediates insulin catabolism in vivo has been controversial, with doubts expressed that IDE has any physiological role in insulin catabolism. Insulin, which is critical for glucose, lipid, and protein metabolism, as well as for cell growth and differentiation, is cleared mainly by the liver and kidney, but most other tissues also degrade the hormone.

2) It was recently shown that transferring an 3.7-cM chromosomal region containing the IDE gene from an inbred rat model of type 2 diabetes mellitus (DM2) (the GK rat) to a normoglycemic rat recapitulated several features of the diabetic phenotype, including hyperinsulinemia and postprandial hyperglycemia. The GK allele of IDE in this chromosomal region was found to bear two missense mutations that, when transfected into COS-1 cells, resulted in 31% less insulin degradation compared with cells transfected with the WT allele. Furthermore, the IDE region of chromosome 10q has been genetically linked to DM2 (9, 10) and to elevated fasting glucose levels [20-year means (11)].

3) In addition to its putative role in insulin catabolism, IDE has been found to degrade A-beta in neuronal and microglial cell cultures (4), and to eliminate A-beta's neurotoxic effects. Although cerebral accumulation of A-beta is believed to play a central role in Alzheimer's disease (AD) pathogenesis, in the vast majority of cases the underlying causes for this elevation are unknown. Several lines of evidence demonstrate that newly generated A-beta is rapidly cleared from the brain, suggesting that A-degrading proteases could play a role in regulating cerebral levels of the peptide.

4) In summary: Two substrates of insulin-degrading enzyme (IDE), amyloid-beta-protein (A-beta) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. The authors previously identified IDE as a principal regulator of A-beta levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases A-beta and insulin degradation in vivo and chronically increases their levels, the authors characterized mice with homozygous deletions of the IDE gene. IDE deficiency resulted in a >50% decrease in A-beta degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE deletion mice showed increased cerebral accumulation of endogenous A-beta, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, the in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.

References (abridged):

1. Duckworth, W. C., Bennett, R. G. & Hamel, F. G. (1998) Endocr. Rev. 19, 608-624

2. Goldfine, I. D., Williams, J. A., Bailey, A. C., Wong, K. Y., Iwamoto, Y., Yokono, K., Baba, S. & Roth, R. A. (1984) Diabetes 33, 64-72

3. Seta, K. A. & Roth, R. A. (1997) Biochem. Biophys. Res. Commun. 231, 167-171

4. Vekrellis, K., Ye, Z., Qiu, W. Q., Walsh, D., Hartley, D., Chesneau, V., Rosner, M. R. & Selkoe, D. J. (2000) J. Neurosci. 20, 1657-1665

5. Bennett, R. G., Duckworth, W. C. & Hamel, F. G. (2000) J. Biol. Chem. 275, 36621-36625

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EVIDENCE FOR DEFECTIVE RETINOID TRANSPORT AND FUNCTION IN LATE ONSET ALZHEIMER'S DISEASE

The following points are made by A.B. Goodman and A.B. Pardee (Proc. Nat. Acad. Sci. 2003 100:2901):

1) Alzheimer's disease (AD), the most common cause of dementia in later life, is a worldwide problem for affected individuals, for their families, and for society at large. Although it involves both genetic risk factors (1) and environmental influences (2), the underlying molecular mechanisms are incompletely understood (3). Effective treatments for preventing the disease, slowing its progression, or alleviating its symptoms are sorely needed.

2) Of the several chromosomal loci identified by genome scans, chromosomes 10q23 and 12q13 are the most frequently associated with AD. However, no genes have been unequivocally identified by genome screens at any of the AD loci. Remarkably, at each of these loci are found important gene(s) related to retinoids.

3) The authors propose that vitamin A (retinoid) available from the diet and carried through the body by means of a complex genetic cascade (4) is related to AD. In mice, retinoid modulates early development of brain structure and function (5), and these processes continue into adulthood affecting differentiation, apoptosis, and neuronal signaling. Dietary retinoid status has marked effects on adult neuronal functioning, on memory, and on neuronal plasticity. Up-regulation of retinoid receptor expression alleviates performance deficits in aged mice, supporting the role of retinoids in the cognitive decline associated with aging.

4) In summary: The hypothesis of the authors is that late onset Alzheimer's disease (AD) is influenced by the availability in brain of retinoic acid (RA), the final product of the vitamin A (retinoid) metabolic cascade. Genetic, metabolic, and environmental/dietary evidence is cited by the authors supporting this hypothesis. Significant genetic linkages to AD are demonstrated for markers close to four of the six RA receptors, RA receptor G at 12q13, retinoid X receptor B at 6p21.3, retinoid X receptor G at 1q21, and RA receptor A at 17q21. Three of the four retinol-binding proteins at 3q23 and 10q23 and the RA-degrading cytochrome P450 enzymes at 10q23 and 2p13 map to AD linkages. The authors suggest that synthesis of the evidence supports retinoid hypofunction and impaired transport as contributing factors. The authors propose these findings suggest testable experiments to determine whether increasing the availability of retinoid in brain, possibly through pharmacologic targeting of the RA receptors and the cytochrome P450 RA-inactivating enzymes, can prevent or decrease amyloid plaque formation.

References (abridged):

1. Cacabelos, R. (2002) Mini. Rev. Med. Chem. 2, 59-84

2. Hendrie, H. C., Ogunniyi, A., Hall, K. S., Baiyewu, O., Unverzagt, F. W., Gureje, O., Gao, S., Evans, R. M., Ogunseyinde, A. O., Adeyinka, A. O., et al. (2001) J. Am. Med. Assoc. 285, 739-747

3. Hardy, J. & Selkoe, D. J. (2002) Science 297, 353-356

4. Goodman, D. S. (1987) Harvey Lect. 81, 111-132

5. Wagner, E., Luo, T. & Drager, U. C. (2002) Cereb. Cortex 12, 1244-1253

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SPHERICAL AGGREGATES OF BETA-AMYLOID (AMYLOSPHEROID) SHOW HIGH NEUROTOXICITY AND ACTIVATE TAU PROTEIN KINASE I/GLYCOGEN SYNTHASE KINASE-3

The following points are made by M. Hoshi et al (Proc. Nat. Acad. Sci. 2003 100:6370):

1) A 40- to 42-residue peptide named beta-amyloid (A-beta) is a major constituent of senile plaques in Alzheimer's disease (AD) (1). Although multiple pathways have been suggested to lead to AD, recent advances indicate a causal link between A-beta and AD (2), and this idea is supported further by findings that vaccination against A-beta ameliorates behavioral deficits in transgenic mice (3-5). Among various in vivo A-beta species, A1–42 generally is considered as the primary vehicle of toxicity, whereas A1–40, a major species under physiological conditions, is considered less harmful and more resistant to the formation of oligomers than A1–42. However, it remains controversial which A-beta species contributes predominantly to AD pathogenesis, because both in vitro and in vivo studies have confirmed toxicity of A1–40 aggregates.

2) It has been widely accepted that toxicity of A-beta requires aggregation of native A-beta monomers. Besides fibrils, several types of nonfibrillar aggregates have been reported: A1–40 oligomers from dimers–hexamers; a mixture of A1–42 oligomers named A-derived diffusible ligands (ADDLs), ranging from trimers–hexamers up to 24-mers; and fibril intermediates named protofibrils (PFs). All of these aggregates are mixtures of A-beta oligomers with a variety in oligomer size, and precise morphological analysis of each A-beta aggregate is difficult. In other words, the heterogeneity of A-beta aggregates in terms of A-beta species and oligomer size makes it difficult to reach a consensus about the oligomerization state of A-beta causing the pathogenicity. It is yet to be determined whether all of these in vitro oligomers actually exist in vivo and induce neuronal damage, or whether a particular oligomer is primarily responsible for AD.

3) In summary: Beta-Amyloid (A-beta) acquires toxicity by self-aggregation. To identify and characterize the toxic form(s) of A-beta aggregates, the authors examined in vitro aggregation conditions by using large quantities of homogenous, chemically synthesized A1–40 peptide. The authors found that slow rotation of A1–40 solution reproducibly gave self-aggregated A1–40 containing a stable and highly toxic moiety. Examination of the aggregates purified by glycerol-gradient centrifugation by atomic force microscopy and transmission electron microscopy revealed that the toxic moiety is a perfect sphere, which the authors call amylospheroid (ASPD). Other A1–40 aggregates, including fibrils, were nontoxic. Correlation studies between toxicity and sphere size indicate that 10- to 15-nm ASPD was highly toxic, whereas ASPD less than 10 nm was nontoxic. A positive correlation between the toxicity and ASPD >10 nm also appeared to exist when A1–42 formed ASPD by slow rotation. However, A1–42-ASPD formed more rapidly, killed neurons at lower concentrations, and showed 100-fold-higher toxicity than A1–40-ASPD. The toxic ASPD was associated with SDS-resistant oligomeric bands in immunoblotting, which were absent in nontoxic ASPD. Because the formation of ASPD was not disturbed by pentapeptides that break beta-sheet interactions, A may form ASPD through a pathway that is at least partly distinct from that of fibril formation. Inhibition experiments with lithium suggest the involvement of tau protein kinase I/glycogen synthase kinase-3 in the early stages of ASPD-induced neurodegeneration.

References (abridged):

1. Glenner, G. G. & Wong, C. W. (1984) Biochem. Biophys. Res. Commun. 120, 885–890

2. Selkoe, D. J. (2001) Physiol. Rev. 81, 741–766

3. Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., et al. (1999) Nature 400, 173–177

4. Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., et al. (2000) Nature 408, 979–982

5. Morgan, D., Diamond, D. M., Gottschall, P. E., Ugen, K. E., Dickey, C., Hardy, J., Duff, K., Jantzen, P., DiCarlo, G., Wilcock, D., et al. (2000) Nature 408, 982–985

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ON BETA-AMYLOID AND ZINC IN ALZHEIMER'S DISEASE

The following points are made by A.I. Bush and R.E. Tanzi (Proc. Nat. Acad. Sci. 2002 99:7317):

1) Whereas a decade ago thoughts of metals and Alzheimer's disease (AD) conjured up thoughts of tossing out your aluminum cookware, more recently, zinc, copper, and iron have been implicated in AD pathology. These metals are not derived from your saucepan or deodorant, but are already resident in the brain. Zinc is not a trace metal in the brain. In fact, zinc, copper, and iron concentrations in gray matter are in the same order of magnitude as magnesium (0.1-0.5 mM)(1,2) and their participation in major neurological diseases is being increasingly appreciated (3).

2) The argument for exploiting the interaction between beta-amyloid (A-beta), and cortical zinc and copper, in designing novel therapies for AD has gathered considerable momentum over the last 5 years. This notion was originally prompted by the finding that the precipitation and redox activity of A-beta are modulated by copper, iron, and zinc (4,5). Lee et al. (2002) reported marked decrease in A deposition in the brains of Tg2576 mice lacking the synaptic ZnT3 zinc transporter. These findings provide in vivo evidence that the characteristic amyloid neuropathology of AD is principally caused by zinc released during neurotransmission.

3) These data will likely have a significant impact on the development of drugs aimed at attenuating beta-amyloid pathology underlying AD neurodegeneration. The zinc model for AD that emerges from these and other findings is more complex than the widely held A-beta autoaggregation model. However, it is also more satisfying because it can explain mysteries such as why A-beta deposits exclusively in the brain, why women more frequently develop Alzheimer's disease, and why rats and mice do not.

4) AD is the most prevalent of age-dependent neurodegenerative disorders, and the most common cause of dementia, affecting about 10% of people over the age of 60, or over 4 million Americans. With the graying of society, it is becoming increasingly more urgent to find a cure. Current therapeutics aim at enhancing neurotransmitter systems, and do not address the underlying etiology, which remains uncertain. Because A-beta is implicated in the pathogenesis of AD, emerging therapeutic approaches have targeted the inhibition of A-beta production [e.g., protease (secretase) inhibitors that inhibit the generation of A-beta from the amyloid precursor protein, APP], or the enhancement of A-beta clearance (e.g., the A-beta "vaccine"). These approaches simplistically assume that A-beta precipitation in the brain only requires elevated levels of A-beta. However, neurochemical reactions apart from A-beta production also contribute to amyloid deposition in AD. The zinc model can explain why beta-amyloid deposits are limited to the neocortex even though A-beta is ubiquitously produced in the brain. At the histological level, the deposits are focal (related to synapses, and the cerebrovascular lamina media), implicating a unique chemical interaction in these microregions that causes A-beta to precipitate. The extracellular concentration of zinc, driven up to 300 microM during synaptic transmission, is likely to be far higher in this space than in any other extracellular compartment in the body.

References (abridged):

1. Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L. & Markesbery, W. R. (1998) J. Neurol. Sci. 158, 47-52

2. Atwood, C. S., Huang, X., Moir, R. D., Tanzi, R. E. & Bush, A. I. (1999) Metal Ions Biol. Syst. 36, 309-364

3. Bush, A. I. (2000) Curr. Opin. Chem. Biol. 4, 184-191

4. Bush, A. I., Pettingell, W. H, Jr., Paradis, M. D. & Tanzi, R. E. (1994) J. Biol. Chem. 269, 12152-12158

5. Bush, A. I., Pettingell, W. H., Multhaup, G., Paradis, M. D., Vonsattel, J. P., Gusella, J. F., Beyreuther, K., Masters, C. L. & Tanzi, R. E. (1994) Science 265, 1464-1467

Related Brief:

PROJECTIONS OF ALZHEIMER'S DISEASE IN THE UNITED STATES AND THE PUBLIC HEALTH IMPACT OF DELAYING DISEASE ONSET. The authors report a study to project the future prevalence and incidence of Alzheimer's disease in the US and the potential impact of interventions to delay disease onset. The numbers of individuals in the US with Alzheimer's disease and the numbers of newly diagnosed cases that can be expected over the next 50 years were estimated from a model that used age-specific incidence rates summarized from several epidemiological studies, US mortality rates, and US Bureau of the Census projections. RESULTS: in 1997, the prevalence of Alzheimer's disease in the US was 2.32 million (range: 1.09 to 4.58 million); of these individuals, 68% were female. It is projected that the prevalence will nearly quadruple in the next 50 years, by which time approximately 1 in 45 Americans will be afflicted with the disease. Currently, the annual number of new incident cases in 360,000. If interventions could delay onset of the disease by 2 years, after 50 years there would be nearly 2 million fewer cases than projected; if onset could be delayed by 1 year, there would be nearly 800,000 fewer prevalent cases. The authors conclude: As the US population ages, Alzheimer's disease will become an enormous public health problem. interventions that could delay disease onset even modestly would have a major public health impact. R. Brookmeyer et al: Am J Public Health 1998 88:1337.

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PRACTICE PARAMETER: EARLY DETECTION OF DEMENTIA: MILD COGNITIVE IMPAIRMENT (AN EVIDENCE-BASED REVIEW). REPORT OF THE QUALITY STANDARDS SUBCOMMITTEE OF THE AMERICAN ACADEMY OF NEUROLOGY. The authors report a study to determine whether screening different groups of elderly individuals in a general or specialty practice would be beneficial in detecting dementia. Epidemiologic studies of aging and dementia have demonstrated that the use of research criteria for the classification of dementia has yielded three groups of subjects: those who are demented, those who are not demented, and a third group of individuals who cannot be classified as normal or demented but who are cognitively (usually memory) impaired. The authors conducted computerized literature searches and generated a set of abstracts based on text and index words selected to reflect the key issues to be addressed. Articles were abstracted to determine whether there were sufficient data to recommend the screening of asymptomatic individuals. Other research studies were evaluated to determine whether there was value in identifying individuals who were memory-impaired beyond what one would expect for age but who were not demented. Finally, screening instruments and evaluation techniques for the identification of cognitive impairment were reviewed. The authors report there were insufficient data to make any recommendations regarding cognitive screening of asymptomatic individuals. Persons with memory impairment who were not demented were characterized in the literature as having mild cognitive impairment. These subjects were at increased risk for developing dementia or Alzheimer's disease (AD) when compared with similarly aged individuals in the general population. There were sufficient data to recommend the evaluation and clinical monitoring of persons with mild cognitive impairment due to their increased risk for developing dementia. Screening instruments, e.g., Mini-Mental State Examination, were found to be useful to the clinician for assessing the degree of cognitive impairment, as were neuropsychologic batteries, brief focused cognitive instruments, and certain structured informant interviews. Increasing attention is being paid to persons with mild cognitive impairment for whom treatment options are being evaluated that may alter the rate of progression to dementia. R.C. Petersen et al: Neurology. 2001 56:1131.

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COGNITIVE ACTIVITY AND THE RISK OF ALZHEIMER DISEASE

The following points are made by R.S. Wilson et al (J. Am. Med. Assoc. 2002 287:742):

1) Alzheimer disease is the leading cause of dementia in older persons, but few risk factors for the disease have been identified. Frequent participation in cognitively stimulating activities has been hypothesized to reduce the risk of Alzheimer's disease, but this hypothesis has not been tested prospectively in longitudinal studies of incident disease. Support for the hypothesis currently comes mainly from retrospective case-control studies suggesting that mid-life cognitive activity is associated with disease risk, and from cross-sectional research showing an association between frequency of cognitive activity and level of cognitive function in old age.

2) The authors report they used a previously established measure of frequency of participation in common cognitive activities and tested its association with incident Alzheimer disease and decline in cognitive function in a large cohort of older Catholic clergy members examined annually for up to 7 years.

3) The authors report their results suggest that frequent participation in cognitively stimulating activities is associated with reduced risk of Alzheimer disease.

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MEDICAL BIOLOGY: MIDLIFE REDUCED ACTIVITY IN ALZHEIMER'S DISEASE

The following points are made by R.P. Friedland et al (Proc. Nat. Acad. Sci. 2001 98:3440):

1) The authors point out that research in North America, Europe, Asia, and the Middle East has demonstrated that the *incidence and prevalence of Alzheimer's disease is lower in subjects with relatively higher levels of education. According to one study (the East Boston study), each year of education reduces the risk of Alzheimer's disease by 17 percent. Although the protection against the development of Alzheimer's disease provided by education could be an artifact produced by the ability of more highly educated persons to perform better on cognitive tests, many studies have used functional rather than psychometric measures for diagnosis and have documented the protective effect of education. Although the mechanisms of education protection remain unknown, it has been proposed that the protective effects of education are related to neuronal reserve, with individuals with higher levels of education more resistant to the effects of the disease on cognition because of enhanced synaptic complexity. Occupational attainment also has been demonstrated to be protective against the disease.

2) The authors point out that education protection also may be induced by lifelong patterns of neuronal activation associated with exposure to education. But education and occupation are not the only reflection of these lifelong patterns: recreational activities are also indications of the ways in which cognitive and other skills are used in daily life. The authors have hypothesized that recreational tasks, in addition to education and occupation, are protective against the development of Alzheimer's disease. Leisure endeavors are reflective of the intrinsic value of an activity for an individual -- they may be more reflective of neurological factors than education or occupation, which are strongly influenced by socioeconomic determinants, especially in the earlier years of this century, when economic, social, and military factors often determined who went to school and for how long. Recreational activities thus may provide a reflection of neuronal reserve and activation that may be relatively independent of these economic, social, and military factors.

3) The authors report their results indicate that patients with Alzheimer's disease are less active in midlife (early and middle adulthood) in terms of intellectual, passive, and physical activities than members of the control group used in this study. The lower activity levels prior to onset of disease (premorbid levels) in patients with Alzheimer's disease persisted in measures of intellectual, passive, and physical activities, calculated by using an independently developed scale following statistical correction for year of birth, sex, education, and income adequacy. These differences were not explained by differing educational levels in the two groups. The study minimized the influence of early disease on participation in activities by the collection of data only concerning the period of midlife ending at age 60 or ending 5 years before disease onset (whichever was earlier). The authors suggest their results indicate that low participation in activities in midlife (in addition to low levels of educational and occupational achievement) is a risk factor for the disease.

Notes:

incidence and prevalence: In this context, the term "incidence" refers to the number of new cases during a specified time period; the term "prevalence" refers to the total number of existing cases at a specified time or during a specified time period.

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ON THE BETA-AMYLOIDS OF ALZHEIMER'S DISEASE

The following points are made by C. Nicolau et al (Proc. Nat. Acad. Sci. 2002 99:2332):

1) Alzheimer's disease is a progressive degenerative disorder of insidious onset characterized by memory loss, confusion, and a variety of cognitive disabilities. The major neuropathological change in the brain of Alzheimer's disease patients is neuronal death, particularly in regions related to memory and cognition. One of the major pathological features of the disease is the abundant presence of amyloid plaques in the brain of the affected individuals. Intracellular bundles of paired helical filaments, composed largely of phosphorylated tau protein, accumulate in large amounts in dying neurons. On the neuron surfaces, insoluble aggregates of proteinaceous debris, termed "amyloid", appear in the form of neuritic plaques and vascular amyloid deposits. The frequency and distribution of the neurofibrillar tangles and of the neuritic plaques appear to correlate well with the extent of the cognitive impairment and other characteristic symptoms of the disease.

2) Amyloid plaques are formed by the beta-amyloid peptide, a 39-to 43-amino acid-long polypeptide that is mostly coiled and slightly alpha-helical in its benign soluble form and, on conformational transition into a mainly beta-sheet secondary structure, spontaneously aggregates into insoluble deposits. This peptide is a physiological metabolite of the much larger "amyloid precursor protein", 695- 770 amino acids long, which undergoes sequential proteolysis. The peptide may remain in solution as a random coil or an alpha-helix.

3) The authors report a study in mice whose results indicate that palmitoylated beta-amyloid peptides, reconstituted in liposomes-lipid A, are highly immunogenic, eliciting "therapeutic" antibody titers within 3 months of the first inoculation and preventing amyloid plaque formation in young animals or significantly reducing existing plaques in older transgenic mice. The authors conclude their results suggest a possible therapeutic and prophylactic role for vaccination with a chemically modified beta-amyloid peptide fragment reconstituted in liposomes.

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