Bibliographic record
Abstract
The sporadic form of Alzheimer’s disease (AD) is a multifactorial disease influenced by a multitude of factors. Among the most important factors are genetics and studies suggest that AD is highly heritable. Despite recent advances in discovering loci underlying this heritability, known loci only account for about a third of the genetic variance. Thus, the majority is still to be identified; an important process, as this can contribute to the identification of disease-causing mechanisms that in turn can lead to the development of potential drugs. As there is still no cure for AD, such new treatment options are sorely needed. AD is also influenced by modifiable factors and of special interest for this thesis is hypercholesterolemia as it pertains to cholesterol metabolism that has been further implicated in AD. For example, midlife hypercholesterolemia associates with increased risk of developing AD later in life while the use of cholesterol lowering statins have been shown to associate with reduced risk. Similarly, in vitro and in vivo studies have shown cholesterol to increase Aβ pathology.With ample evidence implicating altered cholesterol metabolism as one of the mechanisms contributing to AD and many genetic variants still to be identified, this thesis aimed at investigating genetics relating to cholesterol metabolism in AD and was assessed in three studies. In the first study, genetic variants in the gene encoding the rate-limiting step in cholesterol synthesis, HMGCR, was investigated in relation to both cholesterol metabolism and AD. We identified rs72633963, that showed evidence of a protective phenotype in two Quebec based cohorts; the A allele associated with reduced Aβ pathology and with better cognition in a pre-clinical AD cohort. This was accompanied by reductions in blood total cholesterol and LDL cholesterol. The second study investigated the cellular effects of a previously discovered HMGCR variant, rs3846662, whose AA genotype has been shown to associate with protection in AD. It is hypothesized to act by increasing alternative splicing of the HMGCR transcript, resulting in a transcript lacking exon 13 (Δ13-HMGCR). Induced pluripotent stem cells were produced from either AA or GG carriers, that were then used for differentiation into neural progenitor cells and neurons. Effects of genotype and cell type were assessed on HMGCR RNA and protein expression, HMGCR activity, intracellular TAU levels, and extracellular Aβ peptides. We found that rs3846662 genotype influenced indices of HMGCR – AA carriers had lower levels of full length HMGCR and increased levels of Δ13-HMGCR, which was accompanied by increased protein levels, but had no effect on measures of TAU or Aβ. Findings on rs72633963 (reported here) and rs3846662 (reported in the literature) indicate that they are protective in AD and associate with reduced blood cholesterol, leading us to hypothesize that the effects on AD is mediated through their effect on cholesterol levels. In the third and final study we devised a blood cholesterol polygenic score for evaluation in AD. The score associated well with total cholesterol levels and improved prediction of hypercholesterolemia. These relationships were strongly influenced by statin use and sex, such that the best effect was observed in statin free females. However, we could not find any significant effect on either AD risk, AD biomarkers, or AD pathology. In conclusion, this thesis provides insights into the role of cholesterol related genetics in AD. While the literature and our findings on rs72633963 and rs3846662 support a role for cholesterol related genetics in AD our findings with the total cholesterol polygenic score were negative. These findings highlight the complexity of the relationship between cholesterol related genetics and AD and implores more research to determine the mechanisms of cholesterol related variants
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".