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

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.