| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 02.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 15.02.00 |
| PATENT TITLE |
Method of preventing or delaying the onset and progression of Alzheimer's disease and related disorders |
| PATENT ABSTRACT |
The present invention relates, in general, to a method of preventing or delaying the onset of Alzheimer's disease and related neurodegenerative disorders. The invention also relates to a method of treating Alzheimer's disease and related neurodegenerative disorders so as to ameliorate the further progress of symptoms. The methods involve the administration of a non-steroidal anti-inflammatory agent and/or a histamine H2 receptor blocking agent. According to indication, the present method can be applied to individuals who are currently asymptomatic but at risk of developing Alzheimer's disease, to individuals who have mild cognitive symptoms that may either denote an incipient prodrome of Alzheimer's disease or represent early symptoms (prodromal stage), or to individuals who have a clinical diagnosis of Alzheimer's disease. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 14.04.97 |
| PATENT REFERENCES CITED |
CA 113:17731, Yanagawa et al, 1990. Breitner et al, "Delayed Onset of Alzheimer's Disease With Nonsteroidal Anti-Inflammatory and Histamine H2 Blocking Drugs", Neurobiology of Aging 16(4):523-530 (1995). McGeer et al, Anti-inflammatory drugs and Alzheimer's disease, The Lancet 335:1037 (1990). Schnabel, J., "New Alzheimer's Therapy Suggested", Science 260:1719 (1993). Vane, "Towards a better aspirin", Nature 367:215 (1994). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method of retarding a pathogenetic process that, if not retarded, results in the development of clinical symptoms of Alzheimer's disease comprising: i) identifying an individual at risk of developing clinically diagnosable Alzheimer's disease; ii) administering to said individual an amount of a nonsteroidal anti-inflammatory agent sufficient to effect said retardation; and iii) monitoring said individual for the development of clinical symptoms of Alzheimer's disease. 2. The method according to claim 1 wherein said individual is genetically predisposed to said disease. 3. The method according to claim 1 wherein said individual has a family history of Alzheimer's disease. 4. The method according to claim 1 wherein said individual has at least one .epsilon.4 allele at the genetic locus for apolipoprotein E or lacks an .epsilon.2 allele at the genetic locus for apolipoprotein E. 5. The method according to claim 1 wherein said individual bears a biological marker type that denotes increased risk of Alzheimer's disease. 6. The method according to claim 1 wherein said individual is over about 60 years old and free of clinical symptoms of Alzheimer's disease. 7. The method according to claim 1 wherein anti-inflammatory agent is administered to said individual from an age of 20 or older and prior to onset of clinical symptoms of. 8. The method according to claim 7 wherein said anti-inflammatory agent is administered to said individual from an age of 40 or older and prior to onset of clinical symptoms of Alzheimer's disease. 9. The method according to claim 1 wherein said anti-inflammatory agent is specific for inhibition of inducible cyclooxygenase (COX2). 10. A method of retarding a pathogenetic process that, if not retarded, results in the development of clinical symptoms of Alzheimer's disease comprising: i) identifying an individual at risk of developing clinically diagnosable Alzheimer's disease; ii) administering to said individual an amount of a histamine H2 receptor blocking agent sufficient to effect said retardation; and iii) monitoring said individual for the development of clinical symptoms of Alzheimer's disease. 11. The method according to claim 10 wherein said individual is genetically predisposed to Alzheimer's disease. 12. The method according to claim 10 wherein said individual has a family history of Alzheimer's disease. 13. The method according to claim 10 wherein said individual has at least one .epsilon.4 allele at the genetic locus for apolipoprotein E or lacks an .epsilon.2 allele at the genetic locus for apolipoprotein E. 14. The method according to claim 10 wherein said individual bears a biological marker type that denotes increased risk of Alzheimer's disease. 15. The method according to claim 10 wherein said individual is about 60 years old or older and free of clinical symptoms of Alzheimer's disease. 16. The method according to claim 10 wherein H2 blocking agent is administered to said individual from an age of 20 or older and prior to onset of clinical symptoms of Alzheimer's disease. 17. The method according to claim 16 wherein said H2 blocking agent is administered to said individual from an age of 40 or older and prior to onset of clinical symptoms of Alzheimer's disease. 18. A method of retarding a pathogenetic process that, if not retarded, results in the development of clinical symptoms of Alzheimer's disease comprising: i) identifying an individual at risk of developing clinically diagnosable Alzheimer's disease; ii) administering to said individual an amount of a nonsteriodal anti-inflammatory agent and a histamine H2 receptor blocking agent sufficient to effect said retardation; and iii) monitoring said individual for the development of clinical symptoms of Alzheimer's disease. 19. The method according to claim 18 wherein said anti-inflammatory agent and said H2 blocking agent are administered concurrently. 20. The method according to claim 18 wherein said anti-inflammatory agent is specific for inhibition of COX2. 21. A method of treating the clinical symptoms of Alzheimer's disease or related neurodegenerative disorder comprising administering to an individual showing said clinical symptoms an amount of a histamine H2 receptor blocking agent sufficient to effect said treatment. 22. The method according to claim 21 wherein said clinical symptoms are clinical symptoms of Alzheimer's disease. 23. A method of treating the clinical symptoms of Alzheimer's disease or related neurodegenerative disorder comprising administering to an individual showing said clinical symptoms an amount of a histamine H2 receptor blocking agent and a nonsteroidal anti-inflammatory agent sufficient to effect said treatment. 24. The method according to claim 23 wherein said H2 blocking agent and anti-inflammatory agent are administered concurrently. 25. The method according to claim 23 wherein said clinical symptoms are clinical symptoms of Alzheimer's disease. 26. A method of inhibiting age-related cognitive decline in an individual at risk of developing clinically diagnosable Alzheimer's disease comprising: i) identifying an individual at risk of developing clinically diagnosable Alzheimer's disease; ii) administering to said individual an amount of a nonsteroidal anti-inflammatory agent sufficient to effect said inhibition; and iii) monitoring said individual for progression of said cognitive decline. 27. The method according to claim 26 wherein said individual is genetically predisposed to Alzheimer's disease. 28. The method according to claim 26 wherein said individual has a family history of Alzheimer's disease. 29. The method according to claim 26 wherein said individual has at least one .epsilon.4 allele at the genetic locus for apolipoprotein E or lacks an .epsilon.2 allele at the genetic locus for apolipoprotein E. 30. The method according to claim 26 wherein said individual is over about 60 years old. 31. The method according to claim 26 wherein said anti-inflammatory agent is specific for inhibition of inducible cyclooxygenase (COX2). 32. A method of inhibiting age-related cognitive decline in an individual at risk of developing clinically diagnosable Alzheimer's disease comprising: i) identifying an individual at risk of developing clinically diagnosable Alzheimer's disease; ii) administering to said individual an amount of a histamine H2 receptor blocking agent sufficient to effect said inhibition; and iii) monitoring said individual for progression of said cognitive decline. 33. The method according to claim 32 wherein said individual is genetically predisposed to Alzheimer's disease. 34. The method according to claim 32 wherein said individual has a family history of Alzheimer's disease. 35. The method according to claim 32 wherein said individual has at least one .epsilon.4 allele at the genetic locus for apolipoprotein E or lacks an .epsilon.2 allele at the genetic locus for apolipoprotein E. 36. The method according to claim 32 wherein said individual is over about 60 years old. 37. A method of inhibiting age-related cognitive decline in an individual at risk of developing clinically diagnosable Alzheimer's disease comprising: i) identifying an individual at risk of developing clinically diagnosable Alzheimer's disease; ii) administering to said individual an amount of a nonsteriodal anti-inflammatory agent and a histamine H2 receptor blocking agent sufficient to effect said inhibition; and iii) monitoring said individual for progression of said cognitive decline. 38. The method according to claim 37 wherein said individual is genetically predisposed to Alzheimer's disease. 39. The method according to claim 37 wherein said individual has a family history of Alzheimer's disease. 40. The method according to claim 37 wherein said individual has at least one .epsilon.4 allele at the genetic locus for apolipoprotein E or lacks an .epsilon.2 allele at the genetic locus for apolipoprotein E. 41. The method according to claim 37 wherein said individual is over about 60 years old. 42. The method according to claim 37 wherein said anti-inflammatory agent is specific for inhibition of inducible cyclooxygenase (COX2). 43. The method according to claim 37 wherein said anti-inflammatory agent and said H2 blocking agent are administered in combination. |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates, in general, to a method of preventing or delaying the onset and progression of Alzheimer's disease and related neurodegenerative disorders. The method involves the administration to individuals at risk of developing the disease a non-steroidal anti-inflammatory agent and/or a histamine H2 receptor blocking agent. The invention also relates to a method of treating Alzheimer's disease that involves the use of such agents. BACKGROUND Alzheimer's disease is a progressive neurocognitive disorder which, without preventive intervention, will affect 10% of the developed world's population (Hagnell et al, Neuropsychobiology 7:201 (1981); Katzman et al, Ann. Neurol. 25:317 (1989)). Susceptibility to the disease is strongly influenced by genes. Two forms of this disease have been attributed to mutations on chromosomes 14 and 21 that act as dominant genetic traits (Hardy, Nature Genet. 4:233 (1992), (Schellenberg et al, Science 258:668 (1992), St. George-Hyslop et al, Nature Genet. 2:330 (1992), Van Broeckhoven et al, Nature Genet. 2:335 (1992)). At least two additional forms of Alzheimer's disease are presumed to be provoked by mutations or polymorphisms located elsewhere in the genome (Pericak-Vance et al, Am. J. Hum. Genet. 48:1034 (1991); Schellenberg et al, Science 241:1507 (1988); Roses et al, Current Neurology 14, C. V. Mosby, Chicago (1994)). One such polymorphic locus on chromosome 19, APOE which encodes the lipid transport protein apolipoprotein E, strongly influences the risk of Alzheimer's disease (Corder et al, Science 261:921 (1993)) and its timing of expression (Corder et al, Nature Genet. (1994)). New genetic marker loci on chromosome 12 or elsewhere are believed to bear similar influence (Pericak-Vance et al, Neurobiology of Aging, Keystone Symposium (1997)). Although genetic influences predominate in determining which individuals are at risk of developing Alzheimer's disease, it is clear from twin studies that environmental factors are also important (Nee et al, Neurology 37:359 (1987)); Gatz et al, J. Geront. Medical Sciences 52AM117-M125 (1997)). It is believed that such environmental factors, possibly including pharmacologic exposures, may influence the risk of Alzheimer's disease at a given age by accelerating or retarding the unfolding of the disease process (Breitner et al, Epidemiologic Reviews 17:39 (1995)). This explanation is supported by recent evidence which shows that anatomic and metabolic markers of incipient Alzheimer's disease are apparent at least a decade prior to the appearance of clinical symptoms (Ohm et al, Neuroscience 69:209 (1995); Ohm et al, Neuroscience 66:583 (1995); Reiman et al, N. Eng. J. Med. 334:752 (1996)). Non-demented fraternal twin research subjects who have the pathogenic .epsilon.4 allele at APOE also show mild cognitive deficit when compared with their co-twins who lack the .epsilon.4 allele, and pooled subjects with .epsilon.4 show mild cognitive deficits when compared with age-matched subjects from the same cohort (Reed et al, Arch. Neurol. 51:1189 (1994)). Thus, there is increasing agreement that, whatever its causes, the pathogenetic process of Alzheimer's disease includes an extended latent phase, a briefer prodromal phase (mild symptoms not sufficient for clinical diagnosis), and the clinically recognizable symptomatic phase of Alzheimer's disease proper (Plassman et al, Neurology 47:317 (1996)). The symptoms of Alzheimer's disease appear typically between ages 65 and 90 (Breteler et al, Epidemiol. Rev. 14:59 (1992)). Symptoms include deterioration of cognition, memory and language. An agent which retards the progression of the latent or prodromal phase of Alzheimer's disease should therefore delay the appearance of symptoms (onset). Since later onset implies briefer and less severe symptoms, if any, before death (Breitner, Ann. Intern. Med. 115:601 (1991)), the identification of factors that retard the pathogenetic process and thus delay onset is important. In like manner, an agent that retards the progression of symptoms in clinically diagnosed Alzheimer's disease will also result in reduced disability and, possibly, extended life span. Prior to the present invention, no such agents were securely known, but prior use of glucocorticoids was shown in an exploratory study of twins to be associated with a delay in expression of the disease (Breitner et al, Neurology 44:227 (1994)). A particular method of case-control comparisons in affected twin pairs and other populations at high risk of Alzheimer's disease (Breitner et al, Am. J. Epidemiol. 131:246 (1991))has resulted in the present invention which provides a novel and highly effective method of preventing Alzheimer's disease or delaying the onset or progression of its symptoms. SUMMARY OF THE INVENTION The present invention relates, in one embodiment, to a method of preventing or delaying onset of the symptoms of Alzheimer's disease and related neurodegenerative disorders. These symptoms may be either mild (prodromal) or moderate to severe (clinically diagnosable Alzheimer's disease) in degree. The method comprises administering to an individual at risk of developing the disease a nonsteroidal anti-inflammatory agent and/or a histamine H2 receptor blocking agent in an amount sufficient to effect the prevention or delay. The present invention relates, in a further embodiment, to a method of treating the symptoms of (or preventing the progression of) Alzheimer's disease, or related neurodegenerative disorder. The symptoms may be either mild in degree (at the cusp between the prodromal and obviously symptomatic stages of the disease) or moderate to severe (clinically diagnosable Alzheimer's disease). The method comprises administering to an individual displaying such symptoms an amount of a histamine H2 receptor blocking agent, alone or in combination with a non-steroidal anti-inflammatory agent, sufficient to effect that treatment (eg prevent or retard symptom progression). The invention relates, in yet another embodiment, to a composition comprising a histamine H2 receptor blocking agent and a nonsteroidal anti-inflammatory agent. Advantages of the invention will be clear from the description that follows. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. Disease-free survival in subjects categorized by exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) or histamine H2 blocking drugs: FIG. 1A. Effect with NSAIDS. Twenty-one members of sibships with high prevalence of Alzheimer's disease were exposed to NSAIDs for .gtoreq.1 month; 110 were not. The dosage of NSAIDs taken by those who used these drugs was typically moderate (eg, between 400 and 1200 mg of ibuprofen daily). The survival curves plot the estimated probability of remaining free of disease as a function of age. The squares and triangles at the bottom of each riser in the step-plot indicate the appearance of one or more new cases among the unexposed and exposed groups, respectively. The method intrinsically adjusts for attrition in the sample as older ages are considered. This attrition results from death, prior onset of Alzheimer's disease, or the fact that living subjects have not yet reached the age in question. Cumulative survival estimates are obtained by chain multiplying the individual survival fractions (number surviving free of disease divided by number at risk) at the appearance of each new case through the age in question (Kaplan et al, J. Am. Stat. Assoc. 53:457 (1958)). The cumulative incidence before age 90 in the exposed group is 1 minus the survival at age 90 fraction of 0.77, or 0.23. The comparable figure for unexposed subjects is 0.98. The difference in lifetime risk in the two groups is highly significant (log rank .chi..sup.2 =14.97, d.f.=1, p=0.0001). There is a difference of 11 years between the two groups in the age at which a cummulative incidence of 20% is realized. FIG. 1B. Effect with histamine H2 blocking drugs. Twenty-one members of sibships with high prevalence of Alzheimer's disease were exposed to histamine H2 receptor blockers for .gtoreq.1 month (circles); 135 were not (squares). The step-plot is generated as in FIG. 1A. There is a 10 year difference between the exposed and unexposed groups' ages at which cumulative incidence of 20% is realized. The difference in the two curves is highly significant (log rank .chi..sup.2 =9.413, d.f.=1, p=0.0022). FIG. 2. Alteration in proportion affected by Alzheimer's disease with exposure to NSAIDs, H2 blockers, or both. Crude proportions of subjects who developed Alzheimer's disease (with standard errors) are shown. Subjects exposed to NSAIDs were evaluated without consideration of exposure to H2 blockers, and vice versa. Reduced proportions of subjects with 1-12 months exposure to NSAIDs or H2 blockers were affected by Alzheimer's disease. With >1 yr. of exposure, the proportions affected were reduced further. Despite the use of relaxed criteria for exposure (.gtoreq.1 month duration of treatment), no subject exposed to both types of drugs (not necessarily concurrently) was affected. DETAILED DESCRIPTION OF THE INVENTION The present invention relates, in one embodiment, to a method of retarding the earlier stages of the pathogenetic process, and thus preventing or delaying the onset of the prodromal or symptomatic phase, of Alzheimer's disease or related neurodegenerative disorders associated with excitotoxic neuronal cell death (for example, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, and Pick's disease). The method comprises administering to an individual at risk of developing the disease (or disorder) an amount of a nonsteroidal anti-inflammatory agent and/or a histamine H2 receptor blocking agent sufficient to effect the prevention or delay. The agents used in the present method are sufficiently well tolerated that the method can be used in connection with individuals of low or unknown risk of developing Alzheimer's disease or related disorder. However, the method is preferred for use in connection with individuals at substantial or increased risk, relative to the general population. Individuals at substantial or increased risk include those having a family history of dementia, senility, or Alzheimer's, Parkinson's or Pick's disease. High risk individuals also include those having one or more .epsilon.4 alleles at the apolipoprotein E (APOE) locus and those lacking an .epsilon.2 allele at the APOE locus. (See also Hardy, Nature Genet. 4:233 (1992); Schellenberg et al, Science 24:1507 (1988) and Science 258:668 (1992); St. George-Hyslop et al, Nature Genet. 2:330 (1992); Van Broeckhoven et al, Nature Genet. 2:335 (1992); Pericak-Vance et al, Am. J. Hum. Genet. 48:1034 (1991); and Corder et al, Nature Genet. (1994)). It is believed that there are other genetic loci or biologic markers (eg the skin fibroblast assay) for increased risk of Alzheimer's disease. Individuals bearing these genetic variants or biological marker types that denote increased risk of Alzheimer's disease should be similarly suitable for intervention. Also at increased risk and suitable for intervention are individuals who suffer from mild memory loss and/or other cognitive symptoms. Depending on age and criteria for this category, it is believed that (without effective intervention) one third of this group will develop clinical Alzheimer's disease within three years, and at least half will develop Alzheimer's disease within seven years (Rubin et al, Arch. Neurol. 46:379 (1989)). Finally, even in the absence of other identified risk-markers, the elderly (for example, those over 75 years old) are at increased risk. Nonsteroidal anti-inflammatory agents suitable for use in the present invention include the arylcarboxylic acids (salicylic acid, acetylsalicylic acid, diflunisal, choline magnesium trisalicylate, salicylate, benorylate, flufenamic acid, mefenamic acid, meclofenamic acid and triflumic acid), arylalkanoic acids (diclofenac, fenclofenac, alclofenac, fentiazac, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen, suprofen, indoprofen, tiaprofenic acid, benoxaprofen, pirprofen, tolmetin, zomepirac, clopinac, indomethacin and sulindac) and enolic acids (phenylbutazone, oxyphenbutazone, azapropazone, feprazone, piroxicam, isoxicam and sudoxicam) described by McGeer (see U.S. Pat. No. 5,192,753); in addition to the arylalkanoic acids recited by McGeer, nabumetone, ketorolac and etodolac can also be used. These agents are potent inhibitors of cyclooxygenase (COX). Compounds preferred for use in the present invention include those demonstrating a specificity for inducible cyclooxygenase (COX-2) (Mitchell et al, Proc. Natl. Acad. Sci. USA 90:11693 (1994); Vane, Nature 367:215 (1994); Akarasereenont et al, Br. J. Pharmacol. (1994)), including naproxen and diclofenac (note also BF389 and BW755C; other compounds in development as inhibitors of COX-2 should also be suitable for use), and/or those having a long duration of action, including naproxen, sulindac, nabumetone, phenylbutazone, and piroxicam. Lipid soluble agents are also preferred. Histamine H2 receptor blocking agents that are currently marketed and suitable for use in the present invention include cimetidine, ranitidine, famotidine and nizatidine, the more lipid soluble and/or longer acting compounds being preferred. Other compounds in development by the pharmaceutical industry as blockers of histamine H2 receptors should also be suitable. The amount of nonsteroidal anti-inflammatory agent or histamine H2 receptor blocking agent to be administered and the regimen to be used will vary depending on the agent, or combination of agents, and the individual involved. By way of example, a nonsteroidal anti-inflammatory agent can be administered in a range of 10 mg to 3 g per 100 kg body weight daily or at least 4 times per week. Similarly, and by way of example, currently marketed histamine H2 receptor blocking agents can be administered in a range of 5 mg to 2 g per 100 kg body weight daily or at least 4 times per week. These agents are, advantageously, administered virtually continuously starting at an age of about 20 for individuals at high risk (e.g., genetically predisposed individuals) but starting at an age of about 30, 40 or 50, regardless of risk. Although the administration of a nonsteroidal anti-inflammatory agent alone or a histamine H2 receptor blocker alone is effective, it is preferred that both agents be administered, preferably, concurrently. Histamine H2 receptor blocking agents can also be used to treat the symptoms (either mild, ie, prodromal, or fully apparent) of Alzheimer's disease, and related disorders, as well to delay the onset of the disease (or disorder). The administration of such agents to those with prodromal or fully apparent symptoms of Alzheimer's disease can prevent or ameliorate the further progression of the symptoms. When used for treating individuals showing prodromal or clinical symptoms, the H2 blocking agent is administered, for example, in a dose of 5 mg to 2 g per 100 kg body weight per day. The H2 blocking agents can be used alone or in combination with other agents suitable for use in preventing or treating Alzheimer's disease, for example, nonsteroidal anti-inflammatory agents. Active agents suitable for use in the present method can be formulated as compositions. In addition to the agent, or, as appropriate, pharmaceutically acceptable salt thereof, the composition can comprise a pharmaceutically acceptable carrier. The composition can, depending on the agent, be in a form suitable for, for example, oral, intravenous or intramuscular administration. While not limiting the invention to any particular mechanism of action, it is noted that both nonsteroidal anti-inflammatory agents and histamine H2 receptor blocking agents may inhibit the pathogenesitic process of Alzheimer's disease (or its latent or prodromal phases) via processes mediated by COX, including excitatory events in the n-methyl-d-aspartate (NMDA) pathway. The principal therapeutic action of nonsteroidal anti-inflammatory agents is suppression of COX (Vane, Nature 367:215 (1994)), and, in particular, the inducible isoform, COX-2, that is responsible for promoting inflammation. COX-dependent events are also part of the calcium-dependent postsynaptic cascade that follows stimulation of glutamate receptors specific for NMDA (Lerea et al, Neuron 10:31 (1993)). COX-2 synthesis has been demonstrated in neurons (O'Banion et al, Annual Meeting Syllabus, Amer. Coll. of Neuropsychopharmacol., p. 58 1996). Under aberrant conditions (eg, excessive stimulation), the NMDA pathway can induce excitotoxic cell death (Choi, Neuron 1:623 (1988)). Both the oxidation of arachidonic acid to prostaglandins (which requires COX) (Lerea et al, Neuron 10:31 (1993)) and the concomitant generation of superoxide anions appear to be involved in this excitotoxic process (Shearman et al, Proc. Natl. Acad. Sci. USA 11:1470 (1994)). In keeping with these findings, there is depletion of COX-2 in the brains of individuals who have died with Alzheimer's disease, and this depletion is specific to areas of the brain that are rich in NMDA receptor cells that are vulnerable to excitotoxic death. (O'Banion, ibid 1996). The NMDA response is potentiated by histaminergic activation of H2 receptors (Sunami et al, Methods Find. Exp. Clin. Pharmacol. 13:85 (1991)), and possibly H3 (Bekkers, Science 261:104 (1993)) receptors (the effect of H2 blockers on the latter in the central nervous system being presently unknown). The fact that both nonsteroidal anti-inflammatory agents and H2 blockers prevent or delay the onset of Alzheimer's disease may result from the involvement of COX and the NMDA pathway in development of the disease. That being the case, inhibition of Alzheimer's disease pathogenesis can be expected to be effected using compounds, other than those described above, that similarly impact on the NMDA pathway and thereby protect against neuronal cell death that may underlie the neurodegeneration of Alzheimer's disease and related disorders. Non-limiting Examples I-III that follow describe, in some detail, the studies that resulted in the present invention. Briefly, doubly affected sib pairs with Alzheimer's disease onset ages that differed by at least 3 years were studied, as were disease-discordant siblings whose unaffected sib(s) had survived at least 3 years beyond the onset age of the affected sib. Premorbid exposures to steroids, NSAIDs and other treatments were assessed for 186 subjects (91% response rate) by focused retrospective interviews using appropriate blinding and multiple informants when possible. Survival analysis methods were used to compare age-adjusted risk of Alzheimer's disease among sibs who had been exposed or unexposed, before onset, to glucocorticoids, aspirin, non-aspirin NSAIDs, and histamine H2 receptor blockers. The estimated odds ratios (o.r.) with these exposures were 0.54, 0.35 (p=0.04), 0.23 (p=0.02), and 0.15 (p=0.002), respectively, indicating that each type of drug was more commonly used in unaffected or late-affected sibs. The odds ratios for steroids, aspirin and non-aspirin NSAIDs fell within the related confidence interval from the prior twin study (Breitner, Neurology 44:227 (1994)). In this high risk sample, subjects not exposed to NSAIDs experienced a 98% cumulative incidence of Alzheimer's disease (s.e. 2%) by age 90, compared with 23% (s.e. 11%) for those who had taken NSAIDs (p=0.0001). Unexposed subjects realized a 20% cumulative incidence by age 64, 11 years before exposed individuals. An inverse association between the prior use of histamine H2 blocking drugs and Alzheimer's disease was also found. The age-adjusted lifetime risk of disease among those exposed to histamine H2 blocking drugs was also significantly reduced (p=0.002). The effects with both NSAIDs or aspirin and H2 blockers increased with duration of exposure. The two effects appeared to be additive or complementary, such that no subject who had taken both NSAIDs and H2 blockers developed Alzheimer's disease. The inverse association of Alzheimer's disease with exposure to NSAIDs appeared to be stronger after age 70, and in subjects without an .epsilon.4 allele at the polymorphic genetic locus for APOE. The inverse association with H2 blockers showed no strong interaction with age but was stronger in subjects whose genotype included at least one .epsilon.4 allele at APOE. |
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