The role of genetics in vascular dementia (VaD) is increasingly recognized as a crucial factor influencing the risk, progression, and underlying mechanisms of this complex neurocognitive disorder. Vascular dementia arises primarily from brain damage caused by impaired blood flow, often due to strokes, small vessel disease, or other vascular injuries. While environmental and lifestyle factors such as hypertension, diabetes, and atherosclerosis are well-established contributors, genetic predispositions significantly modulate individual susceptibility and disease characteristics.
**Genetic Contributions to Vascular Dementia**
Vascular dementia is not caused by a single gene mutation but rather involves a multifactorial genetic architecture. Current research suggests that genetic risk factors converge with vascular insults to drive cerebral small vessel disease (CSVD), a major pathological substrate of VaD. CSVD progression is influenced by both vascular and genetic risk factors, which together lead to chronic brain ischemia, white matter damage, and neuronal loss[1].
Some rare monogenic forms of vascular dementia exist, caused by mutations in single genes. For example, mutations in the NOTCH3 gene cause CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a hereditary small vessel disease leading to early-onset vascular dementia. These monogenic forms highlight how specific genetic defects can directly impair vascular integrity and brain function[2].
Beyond rare mutations, common genetic variants also contribute to vascular dementia risk. Genome-wide association studies (GWAS) have identified multiple loci associated with vascular dysfunction, inflammation, and neurodegeneration pathways that overlap with dementia phenotypes. Genes involved in innate immunity, vascular endothelial function, and neuroinflammation appear particularly relevant[2].
**Shared Genetic Risk with Other Cardiovascular Diseases**
There is mounting evidence that vascular dementia shares genetic risk factors with other cardiovascular diseases, such as coronary artery disease (CAD). Both conditions share modifiable and nonmodifiable risk factors, including genetic variants that influence lipid metabolism, blood pressure regulation, and inflammatory responses. This genetic overlap suggests that some pathways contributing to vascular pathology in the heart also affect cerebral vessels, increasing dementia risk[4].
For instance, lipoprotein(a), a genetically determined lipid particle, is a known causal risk factor for atherosclerosis and has been implicated in dementia risk, although the exact relationship remains complex and under investigation[8].
**Genetics and Metabolic Factors**
Genetic predisposition to metabolic disorders like type 2 diabetes (T2D) also plays a role in vascular dementia. Insulin resistance and related metabolic dysfunctions, which have a strong genetic component, contribute to vascular damage and cognitive decline. Studies show that genetic scores related to insulin resistance correlate with increased risk of Alzheimer’s disease and likely vascular dementia, reflecting the intertwined nature of metabolic and vascular pathways in neurodegeneration[5].
**Mechanisms Linking Genetics to Vascular Dementia**
Genetic factors influence vascular dementia through several biological mechanisms:
– **Vascular Integrity and Function:** Genes regulating endothelial cell function, blood-brain barrier integrity, and vascular remodeling affect susceptibility to ischemic injury and microvascular damage[1].
– **Neuroinflammation:** Genetic variants modulating immune responses can exacerbate inflammation in cerebral vessels, promoting damage and cognitive decline[2].
– **White Matter Damage:** Genetic predispositions may affect the brain’s white matter connectivity by influencing susceptibility to ischemia and infarcts, key features of vascular dementia pathology[6].
– **Interaction with Amyloid Pathology:** Although primarily associated with Alzheimer’s disease, amyloid-beta accumulation can impair vascular function, and genetic factors influencing amyloid processing may indirectly contribute to vascular dementia[7].
**Research and Clinical Implications**
Understanding the genetic underpinnings of vascular dementia is vital for improving diagnosis, risk stratification, and treatment. Genetic profiling may help identify individuals at high risk, especially those with family histories or early-onset disease. Moreover, recognizing the share
