Llibre-Guerra, JJ;
Fernandez, MV;
Joseph-Mathurin, N;
Bian, S;
Carter, K;
Li, Y;
Aschenbrenner, AJ;
... Ikeuchi, T; + view all
(2025)
Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia.
Nature Medicine
, 31
(4)
pp. 1267-1275.
10.1038/s41591-025-03494-0.
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Abstract
We conducted an in-depth longitudinal study on an individual carrying the presenilin 2 p.Asn141Ile mutation, traditionally associated with dominantly inherited Alzheimer’s disease (AD), who has remarkably remained asymptomatic past the expected age of clinical onset. This study combines genetic, neuroimaging and biomarker analyses to explore the underpinnings of this resilience. Unlike typical progression in dominantly inherited AD, tau pathology in this case was confined to the occipital region without evidence of spread, potentially explaining the preservation of cognitive functions. Genetic analysis revealed several variants that, although not previously associated with protection against AD, suggest new avenues for understanding disease resistance. Notably, environmental factors such as significant heat exposure and a unique proteomic profile rich in heat shock proteins might indicate adaptive mechanisms contributing to the observed phenotype. This case underscores the complexity of Alzheimer’s pathology and suggests that blocking tau deposition could be a promising target for therapeutic intervention. The study highlights the need for further research to identify and validate the mechanisms that could inhibit or localize tau pathology as a strategy to mitigate or delay the onset of Alzheimer’s dementia.
| Type: | Article |
|---|---|
| Title: | Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41591-025-03494-0 |
| Publisher version: | https://doi.org/10.1038/s41591-025-03494-0 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, TREM2 VARIANTS, TAU PATHOLOGY, ONSET, GENE |
| 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 Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10208548 |
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