A 2022 study explored the relationship between Alzheimer's disease (AD), cardiovascular and cerebrovascular risk factors (CVRFs), and the gene FMNL2.

The abstract provides a comprehensive overview of the research findings and their implications for understanding the pathogenesis of AD.

Here’s a detailed explanation of the study based on the abstract:

Background and Rationale

Alzheimer's disease, a neurodegenerative condition, has previously been linked with cardiovascular and cerebrovascular risk factors particularly noticeable in middle age or later stages of life. These risk factors often coincide with cerebrovascular pathology observable upon autopsy.

The study proposes that the interaction between these risk factors and genetic variants could be critical in the development of AD.

Research Objective

The primary aim of the study was to identify gene variants that interact with cardiovascular and cerebrovascular risk factors to influence the development and progression of Alzheimer’s disease.

Methodology

• Study Population: The study involved a genome-wide interaction analysis with a sample size comprising 6,568 patients diagnosed with AD and 8,101 control subjects without AD.
• Genetic Analysis: The focus was on identifying any significant interactions between gene variants and CVRFs that are associated with AD. The gene FMNL2 was identified through this analysis with a significant p-value (6.6 × 10^–7), suggesting a strong interaction.

Key Findings

• FMNL2 Expression: Increased expression of FMNL2 was noted in the brains of patients who had both brain infarcts (a type of stroke) and AD pathology. This expression was correlated with the accumulation of amyloid plaques and phosphorylated tau proteins, which are hallmark features of AD.
• Localization in Astroglia: FMNL2 was predominantly found in astroglia (star-shaped glial cells in the brain and spinal cord) in cases of AD with cerebrovascular pathology.
• Experimental Models:
  • Zebrafish: Amyloid toxicity induced higher expressions of fmnl2a (zebrafish equivalent of human FMNL2) in astroglia. Additionally, this led to the detachment of the astroglial end-feet from blood vessels.
  • Mice Models: APP/PS1dE9 AD mice (a common model for AD research) showed increased Fmnl2 expression. This expression disrupted gliovascular contacts, crucial for maintaining the integrity of the blood-brain barrier.

Implications of FMNL2 Function

The increased expression and disruption caused by FMNL2 suggest that it plays a crucial role in regulating the plasticity of the blood-brain barrier under pathological conditions like AD.

By controlling the gliovascular interactions, FMNL2 influences the clearance mechanisms for extracellular aggregates such as amyloid and tau proteins.

Conclusion and Hypothesis

The study proposes that cerebrovascular risk factors exacerbate cerebrovascular pathology which, in turn, interacts with FMNL2 leading to altered astroglial-vascular mechanisms.

This alteration hampers the efficient clearance of amyloid and tau, thereby increasing their accumulation and contributing to the progression of AD.

Future Directions

This finding opens up potential pathways for targeting FMNL2-mediated pathways to improve the clearance of amyloid and tau in AD patients, potentially offering new therapeutic or preventive strategies against the progression of Alzheimer's disease.

This study highlights a critical genetic interaction that could be instrumental in the development and exacerbation of Alzheimer's disease, offering a new avenue for research into disease-modifying treatments.