Associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease: a Mendelian randomization study

Abstract

Previous observational studies reported that midlife clustering of cardiovascular risk factors and lifestyle behaviors were associated with neurodegenerative disease; however, these findings might be biased by confounding and reverse causality. This study aimed to investigate the causal associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease, using the two-sample Mendelian randomization design. Genetic variants for the modifiable risk factors and neurodegenerative disease were extracted from large-scale genome-wide association studies. The inverse-variance weighted method was used as the main analysis method, and MR-Egger regression and leave-one-out analyses were performed to identify potential violations. Genetically predicted diastolic blood pressure (DBP: OR per 1 mmHg, 0.990 [0.979–1.000]), body mass index (BMI: OR per 1 SD, 0.880 [0.825–0.939]), and educational level (OR per 1 SD, 0.698 [0.602–0.810]) were associated with lower risk of late-onset Alzheimer’s disease (LOAD), while genetically predicted low-density lipoprotein (LDL: OR per 1 SD, 1.302 [1.066–1.590]) might increase LOAD risk. Genetically predicted exposures (including LDL and BMI) applied to familial AD showed the same effect. The association of LDL was also found with Amyotrophic lateral sclerosis (ALS) (LDL: OR per 1 SD, 1.180 [1.080–1.289]). This MR analysis showed that LDL, BMI, BP, and educational level were causally related to AD; a significant association between LDL and ALS risk, as well as the potential effect of sleep duration on PD risk, were also revealed. Targeting these modifiable factors was a promising strategy of neurodegenerative disease prevention.

Investigation of the Circular Transcriptome in Alzheimer’s Disease Brain

“…Previous studies have demonstrated implications of downregulated circFASTKD1 and circGF2I (Gao WQ et al 2020 ; Yuan C et al 2022 ) associated with myocardial infarction. Similarly, these circRNAs have also been observed in an intersection between cardiovascular and neurodegenerative disease pathways (Huang L-Y et al 2023 ). Furthermore, the linear counterpart of the PICALM’s dysregulation influences the risk of AD development by impacting APP processing, Aβ transcytosis and tau progression, highlighting its multifaceted influence on AD pathogenesis (Ando K et al 2022 ).…”

Adiponectin Gene Polymorphisms: A Case–Control Study on Their Role in Late-Onset Alzheimer’s Disease Risk

“…Midlife adiposity and late-life weight loss are frequently linked to a higher risk of cognitive decline and AD in observational studies [ 9 , 10 ]. However, the exact nature of this relationship remains a source of controversy and may even involve reverse causation between a decline in body mass index (BMI) in later life and AD [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Beyond serving as a depot for energy storage, white adipose tissue also functions as an endocrine organ, secreting a variety of biologically active substances.…”