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Background <p>This study systematically investigated phenotypes causally associated with Alzheimer’s disease (AD) across the phenome and validated the findings at cognitive and neuroimaging levels using real-world clinical data.</p> Methods <p>We performed phenome-wide Mendelian Randomization (MR) analyses on genetic proxies for over 860 disease phenotypes to identify traits causally associated with AD. Lipid metabolism-related phenotypes identified through MR were further examined in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to assess associations with AD risk, brain structure, and cognition.</p> Results <p>MR analyses revealed a significant causal association between lipid metabolism, particularly low-density lipoprotein cholesterol (LDL-C), and the risk of AD (OR: 1.05, 95% CI: 1.03–1.07). In ADNI, higher LDL-C indicators correlated with increased AD risk, reduced hippocampal and entorhinal volumes, and poorer cognitive performance. Notably, elevated cholesterol-to-total lipid ratios in small LDL particles were negatively associated with the entorhinal-hippocampal complex. Among cognitively normal individuals, higher LDL-C indicators were associated with smaller hippocampus-amygdala transition area (HATA) and CA3 head volumes. In those with mild cognitive impairment, higher LDL-C was associated with reduced entorhinal surface area.</p> Conclusions <p>Our findings suggest that disrupted LDL-C metabolism may play a causal role in the development and progression of AD.</p>

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A phenome-wide hunt for risk factors of Alzheimer’s disease: from metabolic clues to neuroimaging evidence

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月5日

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  • Dongming Liu,
  • Ancha Baranova,
  • Wenxi Sun,
  • Hongbao Cao,
  • Bing Zhang,
  • Fuquan Zhang

摘要

Background

This study systematically investigated phenotypes causally associated with Alzheimer’s disease (AD) across the phenome and validated the findings at cognitive and neuroimaging levels using real-world clinical data.

Methods

We performed phenome-wide Mendelian Randomization (MR) analyses on genetic proxies for over 860 disease phenotypes to identify traits causally associated with AD. Lipid metabolism-related phenotypes identified through MR were further examined in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to assess associations with AD risk, brain structure, and cognition.

Results

MR analyses revealed a significant causal association between lipid metabolism, particularly low-density lipoprotein cholesterol (LDL-C), and the risk of AD (OR: 1.05, 95% CI: 1.03–1.07). In ADNI, higher LDL-C indicators correlated with increased AD risk, reduced hippocampal and entorhinal volumes, and poorer cognitive performance. Notably, elevated cholesterol-to-total lipid ratios in small LDL particles were negatively associated with the entorhinal-hippocampal complex. Among cognitively normal individuals, higher LDL-C indicators were associated with smaller hippocampus-amygdala transition area (HATA) and CA3 head volumes. In those with mild cognitive impairment, higher LDL-C was associated with reduced entorhinal surface area.

Conclusions

Our findings suggest that disrupted LDL-C metabolism may play a causal role in the development and progression of AD.