Neurodegenerative Disease Alzheimer’s Disease


and IL-1, may contribute to this neuronal dysfunction and loss, as demonstrated by Mori et al.34


and Sheng et al.70


Growing evidence has suggested beneficial roles for microglial activation in transgenic mouse models of Aβ deposition. For instance, plaque burdens are increased by deficiencies in the chemokine receptor CCR299


or in the complement system.99 Indeed,


Aβ deposition occurs efficiently in the near absence of microglia.100 Nevertheless, considerable evidence indicates that activated microglia and their products are detrimental in many experimental models and natural disease states. It is likely that microglia could contribute to Aβ removal while simultaneously producing agents that are detrimental to neurological structure/function and conducive to progression of pathology. As evidence, genetic ablation of the


microglial fractalkine receptor CX3CR1 prevents neuronal loss in an APP-transgenic line: 20305648.37


Gene Polymorphisms as Risk Factors for Development of Alzheimer’s Disease Genetic anomalies, such as the gene mutations and duplication discussed above, account for very few of the many sporadic AD cases. Inheritance of variants in specific sequences, i.e. polymorphisms, of a relatively small number of genes may contribute to these sporadic cases. Several such polymorphisms have been implicated in modifying the risk for development of AD.


that doubtless contribute to such pathogenesis and are deserving of a more sharply focused discussion.


Apolipoprotein E Gene


The gene polymorphism that is most important in AD risk is a single nucleotide substitution in the coding region of the APOE for apolipoprotein E (ApoE) on Chr 19, creating what is termed the ε4 allele. The resulting gene product – ApoE4 – has an arginine–cysteine substitution at position 112 of its amino acid sequence. This alters the interaction of the protein with its receptor and increases AD risk.104,105 Individuals with two copies of the ε4 allele of APOE have a 50–90 % chance of developing AD by the age of 85 and those with one copy have about a 45 % chance.


The mechanisms underlying the genetic influence of APOE ε4 on AD risk are unknown, but hypotheses include an interaction with Aβ as plaques develop.106


increased Aβ plaque density107 In addition to this, ApoE is important for the molecular trafficking109 and


induction of neuronal expression of βAPP, perhaps in particular with regard to specific genotypes of APOE. This is because the APOE ε3 variant is more effective at βAPP induction than APOE ε4.110


A good deal of evidence indicates an impact of APOE genotype on inflammatory sequelae. APOE ε4 was found to produce a


92


In this article, the discussion includes the most important polymorphism, the ε4 variant of the apolipoprotein E (APOE) gene, which is moderately penetrant and confers high risk for development of AD. For the purpose of establishing a link between neuroinflammatory glial activation and excessive expression of proinflammatory cytokines, the genetic links to just two of these cytokines, TNFα and IL-1, are reviewed here. This exclusivity leaves further discussion of other important factors involved in AD pathogenesis to another review. These include components of the complement system and many other factors101–103


dose-dependent increase in microglial activation and this effect was independent of Aβ deposition.111


is much stronger in APOE ε4 carriers;112–116


The protective effect of NSAID use indeed, some of these


studies have restricted a significant NSAID effect to ε4 carriers alone. This may explain the failure of several prospective trials with NSAIDs.117–119


powered to detect an effect of APOE genotype.120


The only trial showing a benefit was the only one Mechanisms to


explain the interaction between APOE genotype and inflammatory events are suggested by studies showing that microglia are more robustly activated in the presence of human ApoE4.91,121–123


This may


involve differential inhibition of inflammatory agents, such as sAPP by ApoE3 and ApoE4.91


Reports from the first phase of the multicenter AD Neuroimaging Initiative (ADNI) are making major contributions to knowledge concerning correlations between neuroimaging and cerebrospinal fluid (CSF) analytes and AD progression. They are also helping discern the role of environmental, comorbid conditions and specific gene polymorphisms in increased risk or perhaps precocious development of AD neuropathological changes. For instance in a new report from ADNI, genotypes, including APOE and two other ‘promising genes’ contactin 5 (CNTN5) and bridging integrator 1 (BIN1), were associated with a number of neuroimaging parameters.124


More specifically, the


inheritance of APOE ε4 and a maternal history of the disease were linked to hippocampal atrophy.125


With regard to comorbid conditions, obesity is linked to lower brain volumes in AD and in mild cognitive impairment (MCI), a condition likely to be prodromal AD.126


Importantly, there were indications of


increased plaque burden by 3-D imaging with the ‘Pittsburgh compound’ PiB correlate with hippocampal atrophy127 progression from MCI to AD.128


as well as with Similar correlations hold with CSF


measurements of Aβ and tau. Worldwide ADNI efforts will aid in establishing the progression from early stages, i.e. MCI to AD. Such efforts will then be useful in defining the mechanisms involved in driving AD neuropathology as well as developing and analysing rational strategies for therapeutic interventions.129


Tumour Necrosis Factor Alpha In a study to identify polymorphisms in TNF, the gene encoding the proinflammatory cytokine TNFα, a polymorphism at -850 C/T in TNF was found to increase the risk for AD.130


Specific polymorphisms in


promoter regions of inflammatory cytokine genes, such as TNFα and IL-6, are associated with late-onset sporadic AD.131


For instance,


heterozygosity for a polymorphism at -1082 of the IL-10 gene increased the odds ratio of AD two-fold. When combined with a polymorphism at -308 in TNF, the odds ratio was increased 6.5 times.


Inheritance of APOE ε4 is associated with as well as neuronal pathologies.108


Interleukin-1 Both IL1A and IL1B, which encode proteins IL-1α and IL-1β, map to Chr 2. Polymorphisms in each of these genes have been associated with AD. Many, but not all, case-control studies of individuals who died with AD have shown that polymorphisms in either of these IL-1 genes are associated with increased odds for AD. The principal risk-conferring polymorphism in IL1A is located in the gene promoter region (-889 C/T), while that in IL1B is located either in the promoter region (-511 C/T) or in the coding region (+3954). In a number of studies, inheritance of a polymorphism at either -889 of IL1A or +3954 of IL1B was shown to increase the odds of AD by


EUROPEAN NEUROLOGICAL REVIEW


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