Neuroinflammatory Cytokines—The Common Thread in Alzheimer Pathogenesis 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.
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 two- to four-fold.132–137
Importantly, in another of study of living AD
patients, a -889 polymorphism in IL1A was associated not only with increased an risk for AD (4.5 times) but also with earlier disease onset (seven to nine years earlier).134
for AD but the IL1A -889 polymorphism did not.140
In one study, IL1B at -511 increased the odds A strong association
Although the numbers of studies
supporting such an association is increasing, a few studies have failed to substantiate this.138,139
was shown between AD and IL1B +3954, but not -511 in another study.141 AD.142,143
-889 polymorphism in the IL1A gene.144–146
Other studies have found no relation between IL1B-511 and Meta-analyses have supported an association for at least the In the large Honolulu-Asia
Aging Study, the authors concluded that certain loci within the IL-1 gene cluster were associated with AD.147
There are likely multiple reasons for these conflicting reports of the link between IL-1 gene polymorphisms and AD risk. These might include the disparate population groups studied, sample size, and contributions by other risk-modifying genes. Importantly toward this point, in an extremely rigorous analysis of AD-related polymorphisms,148
a
polymorphism at -889 in IL1A was suggested as one that approached significance. It may have failed to show linkage only due to deficiencies in replication and the spectrum of populations studied. In a recent study of the importance of polymorphisms in cytokine genes, specific polymorphisms in both IL1A and IL1B were positively associated with AD. Polymorphisms in the genes for anti-inflammatory factors, such as IL-4 and IL-10, were strongly associated with a reduced risk for AD.149
As with all risk-conferring factors—whether related to inheritance or environmental events—downstream outcomes may at least be additive, or at worst multiplied. The multigene and additive nature of quantitative-trait loci is in contrast to high-penetrance single-gene mutations, which cause rather than alter risk for disease. A case in point with regard to the inheritance of specific gene combinations, or haplotypes, and the additive nature of risks on outcomes is the dramatic increase in risk with inheritance of both IL1A and IL1B polymorphisms. Inheritance of the polymorphisms in both IL1A and IL1B is associated with a much greater risk (~10 times) of developing AD.132,133,150,151
US NEUROLOGY
Until recently, little could be discerned regarding the relevance of age-related accumulations of Aβ plaques and neurofibrillary tangles, especially as to whether they were portents of later development of AD. One study used in vivo Aβ labeling together with functional magnetic resonance imaging to test cognitively intact elderly individuals. Sperling and her colleagues found a relationship between Aβ deposit density and changes in a specific memory mode previously noted in AD patients.154 These findings suggest that events during supposedly normal aging may presage memory loss and neural dysfunctions related to learning and memory. In this way, they may contribute to later development of AD, with greater memory dysfunction and neuropathological change. The changes highlight the importance of defining seminal events and triggers of the progressive acquisition of such Aβ deposits. This will help toward the development of rational strategies to halt or impede such acquisition. In this way it may be possible to prevent or delay consequent neural dysfunction and dementia.
Some cognitively intact individuals have large numbers of non-neuritic Aβ deposits, but interestingly these deposits are not associated with activated microglia. This suggests that microglial activation contributes to the progression of Aβ deposits into the more mature neuritic Aβ plaques diagnostic of AD.155
Even in individuals who are cognitively
normal and who have few Aβ deposits or plaques, the density and activation state of astrocytes and microglia increase with advancing age. The levels of S100B expressoin gradually increase,57,156 levels of IL-1 remain stable until the sixth decade.157
while the The latter finding
suggests that in normal aging, IL-1 levels are maintained at lower levels in order to delay neurodegenerative consequences.
Environmental Events that Contribute to Precocious (Age-inappropriate) Development of Alzheimer’s Disease Neuropathological Changes In addition to genetic mutation, gene duplication, gene polymorphisms, and the wear and tear of time with aging, a number of lifestyle or
23
Age-related Alzheimer’s Disease Neuropathological Changes Advancing Age
Aging provides the backdrop for the progression of degenerative events in general, including the development of the clinical symptoms and neuropathological changes characteristic of AD. Only with aging do the cognitive and functional declines, as well as the elevated densities of neuritic Aβ plaques in neuronal layers and neurofibrillary tangles within neurons, manifest themselves. The importance of aging in neuropathogenesis is readily apparent. Even individuals who have causative factors—specific genetic mutations or DS, both of which provide virtual assurance of development of AD—reach adulthood or even middle-to-late age before overt signs appear. In addition to this, with advancing age cognitively-normal individuals often have an abundance of neurofibrillary tangles and neuritic Aβ plaques that may approach densities consistent with a neuropathological diagnosis of AD (for a review, see Mrak and Griffin152
). As it is uncommon for the
densities of these anomalies to reach those necessary for a definitive diagnosis of AD, Mackenzie and colleagues153
suggest that cognitive
function is related to plaque density and that aging per se is not synonymous with Aβ deposition and cognitive failure.
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