By P.L. McGeer and E.G. McGeer, Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada

Posted 11 February 2002

The concept of inflammation as a major factor in Alzheimer disease (AD) has heretofore been based on postmortem findings of autodestructive changes associated with the lesions, coupled with epidemiological evidence of a protective effect of antiinflammatory agents. (1). Now there is evidence that the risk of AD is substantially influenced by a total of 8 polymorphisms in the inflammatory agents interleukin-1 (IL-1)a, IL-1b, IL-6, tumor necrosis factor-a (TNFa) and antichymotrypsin (ACT), with AD apparently being associated with alleles that promote increased transcription. All of the protein products are upregulated in AD tissue and are prominently associated with AD lesions.

The polymorphisms are all common ones in the general population, so there is a strong likelihood that any given individual will inherit one or more of the high-risk alleles. The overall chances of an individual developing AD might be profoundly affected by a "susceptibility profile" reflecting the combined influence of inheriting multiple high-risk alleles.

The strongest evidence of polymorphisms in inflammatory agents increasing the risk of AD involves the IL-1 complex. The IL-1a -889 regulatory region exists in C (allele 1) and T (allele 2) forms. Four groups (2, 3, 4, 5.) have now reported that carriers of the T form have an increased risk of AD. All found an association between the T/T genotype and AD, with odds ratios of 1.95, 3.1, 4.86 and 7.2. There are two caveats to these results and the other polymorphisms that are described. The first is that a distinction cannot be made between the polymorphism itself and a nearby genetic variation that is in equilibrium. The second is that studies of this kind are prone to type I and type II statistical errors. It will be important in the future to determine the influence of ethnicity on allele frequency, as well as to rule out, to the extent that it is possible, the existence of latent disease in control populations. In these studies, allowance was made for ApoE4 as a confounding factor, but numerous other polymorphisms may have influenced the outcome.

Two common polymorphisms in the IL-1b gene have been reported to increase the risk of AD. These are located at the -511 position of the regulatory region where T and C alleles exist, and in the +3953 position in exon 5 where again T and C alleles exist. Grimaldi et al. found that the T/T genotype for the -511 polymorphism was associated with a slightly increased risk for late onset AD (odds ratio 1.95). Nicoll et al found the +3953 T/T genotype to occur in 7.3% of AD patients and 4.8% of controls. When they analyzed for simultaneous inheritance of the T/T alleles for IL-1a -889 and IL-1b +3953, the odds ratio for developing AD rose to 10.8.

Polymorphisms in the IL-6 gene exist in the -174 promoter region and in the region of a variable number of tandom repeat (VNTR). Papassotiropoulos et al. found the C allele of the VNTR region to be protective against AD (odds ratio 0.60), delaying the initial disease onset. Licastro et al. found the D allele to have an opposite effect, i.e. increasing the risk of late onset AD (odds ratio 1.42). They confirmed the finding of Papassotiropoulos et al. of a reduced risk of the C allele (odds ratio 0.53). They also found that the C allele of the C/G -174 promoter region was associated with a risk for late onset AD (odds ratio 1.56). Plasma levels of IL-6 were higher in the AD patients than controls, with the highest levels occurring in patients carrying the VNTR D allele.

The TNFa -308 promoter A allele was known to be associated with autoimmune and inflammatory diseases and to have stronger transcriptional activity than the G allele. Similarly, the TNF microsatellite 2 allele had previously been associated with higher TNF secretion and a susceptibility to rheumatoid arthritis. No associations had previously been found for polymorphisms of the -238 TNF promoter region. Collins et al. found that the TNFa 2 microsatellite allele was by itself significantly associated with AD (p = 0.04) but that the 2-1-2 haplotype for -308, -238 and the microsatellite polymorphism was even more strongly associated with AD (p = 0.0005). These data provide further suggestive evidence of a correlation between AD and polymorphisms known to enhance production of an inflammatory cytokine.

Alpha-1-antichymotrypsin (ACT) is an acute phase reactant which is produced by activated astrocytes and is elevated in AD brain. Licastro et al. investigated the combined effects of ACT and IL-1b polymorphisms on the risk of AD as well as on levels of expression of the protein in plasma. The ACT T/T and IL-1b T/T genotypes were slightly and independently increased in AD patients. The concomitant presence of the ACT T/T and IL-1b T/T genotypes increased the odds ratio for AD to 5.6. A study of plasma levels in a subset of patients showed that the plasma levels of ACT and IL-1b were increased in AD patients with T/T genotypes. This study is a further illustration of a robust increase in odds ratio when multiple risk alleles are simultaneously carried.

In summary, at least 8 polymorphisms, involving four inflammatory cytokines and two acute phase reactants have been shown to enhance the risk of developing AD. When 2 or more polymorphisms in linkage disequilibrium have been simultaneously evaluated, the risk is substantially increased over each one assessed separately. In some cases, the polymorphisms have also been linked to peripheral inflammatory disorders. In general, they correlate with increased production of the protein product. The overall implication is that individuals carrying one or more of these high risk alleles are hypersensitive to pathologies which provoke a chronic inflammatory response, with consequent vulnerability to autodestructive processes.

1. McGeer PL, McGeer EG. Autotoxicity and Alzheimer disease. Arch Neurol. 2000;57:789-790. Abstract.

2. Grimaldi LME, Casadei CM, Ferri C et al. Association of early-onset Alzheimer's disease with an interleukin-1a gene polymorphism. Ann Neurol. 2000;47:361-365. Abstract.

3. Nicoll JAR, Mrak RE, Graham DI et al. Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Ann Neurol. 2000;47:365-368. Abstract.

4. Du Y, Dodel RC, Eastwood BJ et al. Association of an interleukin 1 alpha polymorphism with Alzheimer's disease. Neurology. 2000;55:480-483. Abstract.

7. Licastro F, Pedrini S, Bonafe M et al. Polymorphisms of the IL-6 gene increase the risk for late onset Alzheimer's disease and affect IL-6 plasma levels. Neurobiol Aging. 2000;21(1S):S38. No abstract available.