Ma, Yuan;
Zhang, Allena;
Asri, Sabrina;
Curtis, David;
(2025)
Health effects of loss of function variants in gene targets for Alzheimer’s disease prevention.
Neurological Sciences
, 46
pp. 6535-6541.
10.1007/s10072-025-08578-w.
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Abstract
Treatments for Alzheimer’s disease (AD) have to date met with limited success but potentially promising approaches involve attempting to reduce expression of one of the genes coding for key proteins involved in AD pathogenesis. Potential targets for such interventions include APOE, APP and MAPT but there is little published evidence to help assess whether reducing expression of one of these genes might cause adverse effects. We investigated 470,000 exome-sequenced UK Biobank participants to identify those carrying a naturally occurring loss of function (LOF) variant in these genes to see if they had impaired general health or educational attainment. For APOE we additionally tested for association with hyperlipidaemia and for APP and MAPT we tested for associations with mental health and epilepsy. For APOE, APP and MAPT there were respectively 56, 118 and 333 carriers of LOF variants. For each gene, there was no association between carrying a LOF variant and any of the phenotypes tested and for some phenotypes confidence intervals of effect size were small, ruling out any large effect. The findings provide some reassurance that interventions aimed at reducing expression of one of these genes may not necessarily be associated with significant adverse effects, though the small number of phenotypes examined means we cannot be confident that such treatments would be completely safe. Since LOF variants are very rare, further investigation of the effects of reduced gene expression can be undertaken within the context of clinical trials. This research has been conducted using the UK Biobank Resource.
| Type: | Article |
|---|---|
| Title: | Health effects of loss of function variants in gene targets for Alzheimer’s disease prevention |
| Location: | Italy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1007/s10072-025-08578-w |
| Publisher version: | https://doi.org/10.1007/s10072-025-08578-w |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Alzheimer’s disease; Coding variant; APP; MAPT; APOE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10219478 |
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