Additionally, our cohort may over-represent early and violent dea

Additionally, our cohort may over-represent early and violent deaths; however, all cases were included to best represent a population-based investigation. We hypothesised that the three other SNPs (CLU, CR1 during and PICALM) would also associate with SP, as they are involved in AD pathways and most likely would be associated with the development of brain lesions [24-34]. Our results indicate that we did not find as many robust correlations as for APOE. Genetic variants of CLU, PICALM and CR1 genes were associated with SP and remained so with the inclusion of APOE??4 carriers and age as covariates. The appearance of an increased risk for CLU C carriers versus TT is unusual in that it only applies for Burnt Out SP – a group in the cohort that is relatively small and are majority females.

This suggests that the effect of CLU could be on the later stages of SP development and related to removal of A?? [31-34] being reduced in efficiency. The PICALM T allele appears to have a protective effect on SP prevalence, true also for TT genotypes, versus CC genotypes in the oldest age group. This may be due to more efficient intracellular trafficking and clear-up of A??, or the components or pathways that induce A?? build-up or production [24-27]. The protective effect of the T carriers was seen also for SP coverage; however, it was only significant for moderate SP. CR1 CC genotype carriers were associated with an increased risk of having sparse compared to no SP; however, the trend was not consistent for increasing coverage of SP (data not shown), which was also true for the analysis grouping the rare homozygote with the heterozygotes.

This suggests the effect of CR1 is complex and not as straight-forward as increasing SP risk and requires Dacomitinib further investigation. The lack of robust and numerous associations with the GWAS SNPs and brain lesions, alongside the strong APOE??4 results, questions the sellectchem involvement of SP in AD pathology. It may be a coincidence that SP are found in AD brains with evidence suggesting that they may be a part of normal aging [16,17]. In light of this, SP treatments have so far failed to improve patients’ cognitive abilities [35] and current theories are moving away from SP and suggest soluble oligomeric A?? may be the culprit in AD [36-39]. The scarcity of associations may be due to the small number of cases with SP within the TASTY series (31.1%), resulting in low power; however, we have a 600 case-strong cohort, which revealed strong associations between APOE with SP. It may also be due to the low strength of these prior associations in the original studies, which should be investigated in future cohorts of a similar nature.

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