Research Article: CLU, CR1 and PICALM genes associate with Alzheimer’s-related senile plaques

Date Published: April 5, 2011

Publisher: BioMed Central

Author(s): Eloise H Kok, Teemu Luoto, Satu Haikonen, Sirkka Goebeler, Hannu Haapasalo, Pekka J Karhunen.


APOE is the strongest risk gene for sporadic Alzheimer’s disease (AD) so far. Recent genome wide association studies found links for sporadic AD with CLU and CR1 involved in Aβ clearance, and PICALM affecting intracellular trafficking.

We investigated the associations of senile plaques (SP) and neurofibrillary tangles (NFT) with the proposed risk genes and APOE, in the Tampere Autopsy Study (TASTY) series (603 cases), a sample of the general population (0 to 97 yrs), who died out-of-hospital.

Age and the APOEε4 allele associated strongly with all phenotypes of SP, as expected. In age and APOEε4 adjusted analyses, compared to the most common homozygous genotype, burnt out SP were more common among carriers of the C-allele of CLU, whereas the T-allele of PICALM and C-allele of CR1 were linked with lower SP coverage. We found no significant associations between any of the genetic variants and NFT.

Marginal effects from CLU, CR1 and PICALM suggest that these genes have minimal effects on the development of AD lesions.

Partial Text

Alzheimer’s disease (AD) is the most common form of dementia in Western society and is, and will continue to be, a burden on health systems in the future as the population ages. Age is the largest risk factor for the disease, with higher incidences in older populations [1,2].

AD is the most common form of dementia, but to date its aetiology has remained elusive, despite intensive research. The proposed causes of AD relate to neuropathological findings post-mortem, which is the only way to definitively confirm a patient’s diagnosis [11-14]. Diagnosis of the first AD patient, back in 1906, revealed large numbers of SP and NFT; however, although new treatments aimed at reversing the disease by reducing SP have proven successful, they have been without improvements in cognitive abilities of patients [35]. Furthermore, studies have shown cognitively normal elderly can also have large numbers of these brain lesions [16-19] and not all AD cases have the required amounts to corroborate cognitive dysfunction [15].

We have an interesting window into the development of neuropathological lesions and their associations with AD-risk genes in the general population, and as far as we know, this is the first study of its kind. SP were found to associate with age, gender, and APOEε4, but not consistently with CLU, CR1 or PICALM, suggesting that these SNPs most likely do not affect the development of the studied neuropathological lesions. Further studies should replicate these findings in a larger autopsy series of the same kind, both with and without AD cases, to define the occurrence of these neuropathological lesions within the context of normal aging.

AD: Alzheimer’s disease; APOE: apolipoprotein E; CI: confidence interval; CLU: clusterin; CR1: complement component (3b/4b) receptor 1; GWAS: genome wide association studies; NFT: neurofibrillary tangles; OR: odds ratio; PICALM: phosphatidylinositol binding clathrin assembly protein; SNPs: single nucleotide polymorphisms; SP: senile plaques; TASTY: Tampere autopsy study.

The authors declare that they have no competing interests.

All authors contributed to this manuscript. EHK performed experiments and analyses and wrote the manuscript. HH, TL and SH measured the neuropathological lesions. SG and PJK collected the autopsy series. SG, HH and PJK provided comments and discussions on the progress of the manuscript.




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