Alzheimer’s disease (AD) remains the most common form of dementia, particularly the late-onset version which typically develops in patients aged over 65. Although there is believed to be a strong genetic basis to the disease, the only gene previously identified as a susceptibility factor in all version of the disease was APOE, coding for Apolipoprotein E. In addition, genes for Amyloid precursor protein (APP), Presenilin 1 (PSEN1) and Presenilin 2 (PSEN2) have been noted as factors in the less common early-onset form of AD, which has a strong pattern of familial inheritance. Other attempts to find genes influencing the more common late onset form of AD have been ‘under-powered’, i.e. have involved insufficient individuals (≤1,100) to reveal any further statistically-significant correlations.
In October 2009, however, two independent studies published “back-to-back” in the journal Nature Genetics identified a number of other genes in which Single Nucleotide Polymorphisms (SNPs) seem to be associated with development of late-onset AD.
Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease
Harold et al (2009) Nature Genetics 41:1088-1093
The authors of the first study (n = 86, headed by Julie Williams from Cardiff University) began by examining SNPs in about 19,000 research subjects (reduced to about 16,000 after quality control). These genotypes were drawn from seven different primary studies, hence the fairly stringent application of quality control leading to the exclusion of a significant number of genomes.
The investigation was conducted in two stages. In the first part, over 500,000 SNPs from nearly 12,000 individuals (4000 known AD cases, 7850 controls) were investigated. Analysis was limited to autosomal chromosomes (except for one SNP on the X-chromosome already known to be associated with AD). In addition to the established link to APOE, the study suggested involvement of two further genes CLU and PICALM. CLU (on chromosome 8) encodes clusterin, another significant brain apolipoprotein . The specific SNP identified lies within an intron. PICALM (chromosome 11) encodes phosphatidylinositol-binding clathrin assembly protein (aka clathrin assembly lymphoid-myeloid leukaemia gene). The specific SNP identified is 88.5 kb 5’ to the gene. The authors of this study had prior notice of the study of Lambert et al (see below) and note that CLU is also the novel gene demonstrating the strongest association with AD in their work.
During the second stage, the researchers looked at the two newly identified SNPs in five additional European cohorts, drawn from Belgium, Greece, Bonn, the Medical Research Council, UK and the Alzheimer’s Research Trust. These included just over 2,000 AD cases and about 2,300 age-matched, cognitively screened controls.
Armed with the data of Amouyel et al, these authors also re-examined their own results looking for evidence of associations identified in the other paper. They confirm “suggestive evidence” for association with CR1, the gene encoding complement receptor 1. They also report the genes for bridging integrator 1 (BIN1) and disabled homolog 1 (DAB1) as being “noteworthy”.
Finally, the authors consider the physiological implications of the various mutations.
- APOE acts as a chaperone for Ab, influencing the latter’s conformation, conversion to an insoluble form, aggregation and toxicity.
- Clusterin is a molecule that occurs in a fairly wide number of tissue types and with several likely functions. The gene product is a 449 AA protein which is later glycosylated. It binds soluble Ab in a specific and reversible manner; the resulting complex has been demonstrated to cross the blood-brain barrier.
- PICALM is ubiquitously in all tissues, but particularly so in neurons. It is involved in clatharin-mediated endocytosis (as too is BIN1). The role of PICALM in trafficking of VAMP2, a protein involved in synaptic vesicle fusion to presynaptic membranes, may underlie its role in AD.
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease
Lambert et al (2009) Nature Genetics 41:1094-1099
In the second paper, the authors (n = 50, plus unnamed members of the European AD Initiative Investigators, and headed by Philippe Amouyel in Lille) conducted an initial study of about 2000 French cases of AD and about 5,300 controls, also from France. As was also seen in the separate study by Harold et al, this analysis identified the CLU gene as having genome-wide significance in AD.
A number of further markers across several chromosomes had “suggestive evidence of association”. Therefore in a second stage, analogous to the methodology used by Harold et al, the researchers looked to confirm the observed association with CLU and probe more deeply the correlation with other markers in the major loci identified. The individuals in this stage (approx 4000 AD cases and 3,300 controls) came from Belgium, Finland, Italy and Spain. This second stage confirmed the significant association with CLU, and also identified a second gene CR1 (for complement receptor 1, the main protein interacting with complement protein C3b).
These authors review several previous experiments that support a suggestion that CR1 is involved in clearance of Ab. It is therefore their contention that whereas the gene errors implicated in early-onset (familial) AD result in Ab overproduction, those involved in standard late-onset AD may lead to inadequate Ab clearance.
None of the genes identified in the recent studies guarantee the development of AD – in this paper it is estimated the risk factors are 25.5% for APOE, 8.9% for CLU and 3.8% for CR1.
Two further points of note. One is the care taken to ensure results are genuine – when aware that a Belgian dataset had been examined in both this study and in the work by Harold et al the present authors recalculated their results excluding the shared data lest it introduced any unwarranted significance by being counted twice. Secondly, this paper labels the gene for phosphatidylinositol-binding clathrin assembly protein as PILCAM. Looking at the literature it seems that this is a typo, not an alternative name.