CRP Gene Variation Affects Early Development of Alzheimer's Disease-related Plaques

Eloise Helena Kok; Mervi Alanne-Kinnunen; Karita Isotalo; Teemu Luoto; Satu Haikonen; Sirkka Goebeler; Markus Perola; Mikko A Hurme; Hannu Haapasalo; Pekka J Karhunen


J Neuroinflammation. 2011;8(96) 

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The only method for definitive diagnosis of Alzheimer's disease (AD) to date is postmortem examination of the brain. Current understanding indicates that the neuropathological hallmarks, senile plaques (SP) and neurofibrillary tangles (NFT) develop within the brain, interrupting neuronal signalling and causing the irreversible symptoms of memory impairment and gradual cognitive decline.[1,2] Efforts to prevent or slow the disease are hampered by a lack of understanding as to how these neuropathological hallmarks develop and actually cause the disease - if they do.

There are two forms of AD - familial and sporadic - of which the sporadic is much more common, comprising 96% of all cases. Familial AD (FAD) is mostly caused by mutations in 3 particular genes (amyloid precursor protein, presenilin 1 and presenilin 2),[3] which are directly related to the formation of SP. This has lead researchers to believe that SP are the main culprit in all forms of AD. Many studies have revealed environmental and genetic factors that affect the risk of sporadic AD, such as exercise, education level and the ε4 allele of APOE.[4]

At present, the apolipoprotein E (APOE) ε4 allele is the only commonly accepted gene known to confer increased risk for sporadic AD, whilst the rare ε2 allele is believed to convey protection. Various studies have found ORs of between 2 and 8, as well as lowering the age of onset, with ε4 allele dosage.[5,6] Recently, genome wide association studies[7–9] have revealed some lower impact genes that may increase AD risk, possibly accounting for a part of the remaining unexplained ~50% of genetic risk effects. Many other genes have also been suggested to increase the risk of AD, but the evidence has been conflicting, with APOE being the only consistent association.

The possible connection between AD and inflammation was ignited by a study[10] showing a reduced incidence of AD in a cohort of rheumatoid arthritic patients taking non-steroidal anti-inflammatory drugs (NSAIDs), however other studies have disputed this connection.[11] New research[12–14] supports this, as many inflammatory markers have been found localised with the neuropathological characteristics of AD; these include neuroinflammatory cells, astrocytes, and microglia. Recent genome wide association studies have also shed light on this, with inflammatory genes being put in the spotlight.[9] It has also been suggested that chronic inflammation in the brain from various bacterial/viral diseases could contribute to the disease.[15,16] Interactions between inflammatory gene polymorphisms and invading pathogens have also been proposed to participate in disease manifestation.[17] The question remains, however, whether the inflammatory processes are a cause or consequence of the disease, as a majority of previous studies have been conducted in advanced stage AD cases.

C-reactive protein (CRP) is an acute phase inflammatory marker found in plasma, primarily produced by the liver to combat pathogens through activation of immune responses.[18] Additionally, CRP activates the cleanup of cellular debris through its action as a pattern recognition receptor involving calcium-dependent ligand binding.[19] Its role in AD has already been suggested by work by Yasojima et al., which showed that CRP production is upregulated in affected areas of AD brains.[20]

Some single nucleotide polymorphisms (SNPs) of the CRP gene have been shown to associate with higher CRP levels. One of the most influential of these polymorphisms, identified in a genome-wide association study, was rs3091244 (T and A alleles), as well as others; rs1130864 (T allele), rs1205 (G allele) and rs3093075 (C allele).[21–23] The SNP rs2794521 (T allele) has been reported to increase transcription of the CRP allele.[24,25] Haplotypes associated with 2–3-fold increases in CRP levels correlate with poorer survival in general of elderly subjects.[22] Lower CRP levels have been associated with the C allele of SNP rs1800947[21,26,24,27] and common haplotypes of the gene are also associated with serum CRP concentration.[24]

We have shown previously that accumulation of AD neuropathological lesions is unexpectedly common, with 31.1% of individuals living outside institutions having SP and 42.1% having NFT.[28] This accumulation starts already around 30 years of age, especially among the carriers of the APOE ε4 allele, reaching an occurrence of almost 100% in the oldest. Other studies have also shown associations with the APOE ε4 allele and both SP and NFT.[29,30]

We hypothesised that individuals with CRP genotypes associated with higher CRP production would be more likely to show development of SP already in the prodromal phase before the development of clinical AD. At the least, these phenomena might participate in the early stages in the development of the lesions. We explored potential associations between the CRP gene and the brain changes commonly linked to AD in a large autopsy cohort representing a population living outside institutions, of which the majority were non-AD patients who died mainly out-of-hospital. As far as we are aware, this is the first study that has looked at the association between AD pathology and CRP, both at a genetic and cellular level.


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