Cholesterol related genetics in sproadic Alzheimer's disease
Notice bibliographique
Résumé
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
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,001 | 0,002 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».