J Med Genet

. 2024 Apr 19;61(5):435-442.

doi: 10.1136/jmg-2023-109295.

Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank

Francesco Casanova ¹, Qu Tian ², Janice L Atkins ¹, Andrew R Wood ¹, Daniel Williamson ³, Yong Qian ², David Zweibaum ², Jun Ding ², David Melzer ¹, Luigi Ferrucci ⁴, Luke C Pilling ⁵

Affiliations expand

• PMID: 38191510

PMCID: PMC11041574 DOI: 10.1136/jmg-2023-109295

Abstract

Background: Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter.

Methods: We analysed UK Biobank participants clustered into European (N=451284), African (N=7477) and South Asian (N=9570) groups by genetic similarity to the 1000 genomes project. Using Mendelian randomisation methods, we estimated the association between genetically predicted serum iron (transferrin saturation [TSAT] and ferritin), grey matter volume and genetic liability to clinically defined dementia (including Alzheimer's disease [AD], non-AD dementia, and vascular dementia) from hospital and primary care records. We also performed time-to-event (competing risks) analysis of the TSAT polygenic score on risk of clinically defined non-AD dementia.

Results: In Europeans, higher genetically predicted TSAT increased genetic liability to dementia (Odds Ratio [OR]: 1.15, 95% Confidence Intervals [CI] 1.04 to 1.26, p=0.0051), non-AD dementia (OR: 1.27, 95% CI 1.12 to 1.45, p=0.00018) and vascular dementia (OR: 1.37, 95% CI 1.12 to 1.69, p=0.0023), but not AD (OR: 1.00, 95% CI 0.86 to 1.15, p=0.97). Higher TSAT was also associated with increased risk of non-AD dementia in participants of African, but not South Asian groups. In survival analysis using a TSAT polygenic score, the effect was independent of apolipoprotein-E ε4 genotype (with adjustment subdistribution Hazard Ratio: 1.74, 95% CI 1.33 to 2.28, p=0.00006). Genetically predicted TSAT was associated with lower grey matter volume in caudate, putamen and thalamus, and not in other areas of interest.

Discussion: Genetic evidence supports a causal relationship between higher TSAT and risk of clinically defined non-AD and vascular dementia, in European and African groups. This association appears to be independent of apolipoprotein-E ε4.




In December 2022 ATH told about new patented molecules:

The patent, entitled, “Compounds for and methods of treating diseases”, provides Alterity with
20 years of exclusivity and expands its intellectual property estate for treating major
neurodegenerative diseases. The patent is based on a new scaffold that is distinct from recent
patents granted to Alterity and includes more than 100 novel compounds, at least one of which
has demonstrated efficacy in an animal model of dementia.