ACOT7 Biomarker May Help in Early Diagnosis of Alzheimers Disease (2024 Study)

ACOT7 shows promise as a non-invasive serum biomarker for Alzheimer’s disease (AD) with high diagnostic accuracy.

Highlights:

Increased Expression: ACOT7 levels were significantly elevated in AD patients and animal models compared to controls.
Correlation with Cognitive Decline: A strong negative correlation was observed between serum ACOT7 levels and MMSE scores (r = -0.85; p < 0.001), indicating that higher ACOT7 levels are associated with more severe cognitive impairment.
Diagnostic Accuracy: ACOT7 demonstrated a high diagnostic accuracy with an AUC of 0.83, a sensitivity of 80%, and a specificity of 74% at an optimal cut-off point of 62.5 pg/mL.
Superiority Over Traditional Markers: ACOT7 outperformed the traditional AD marker Aβ42/40 ratio in diagnostic accuracy.

Source: Frontiers in Aging Neuroscience (2024)

Major Findings: ACOT7 as a Biomarker for Alzheimer’s Disease (2024)

Wang et al. investigated ACOT7 as a non-invasive biomarker for accurately diagnosing Alzheimer’s disease (AD).

1. Increased Expression of ACOT7 in Alzheimer’s Disease

In both human patients with Alzheimer’s disease (AD) and animal models of the disease, the levels of ACOT7 were found to be significantly higher compared to control groups.

Specifically, in the cortical tissues of APP/PS1 transgenic mice (an animal model of AD), ACOT7 expression increased by 26%, and in the hippocampus, it increased by 35%.

The serum levels in these mice were also 45% higher. In human patients, serum ACOT7 levels were elevated by 47% as detected through Western blot and ELISA analyses.

This suggests that ACOT7 is markedly upregulated in AD, indicating its potential as a biomarker.

2. Strong Correlation with Cognitive Decline

A significant negative correlation was observed between serum ACOT7 levels and Mini-Mental State Examination (MMSE) scores, a measure of cognitive function.

The correlation coefficient was -0.85 (p < 0.001), meaning that as ACOT7 levels increased, MMSE scores decreased, indicating worse cognitive function.

This strong inverse relationship underscores the potential of ACOT7 levels to reflect the severity of cognitive impairment in AD patients.

3. High Diagnostic Accuracy of ACOT7

The analysis of the receiver operating characteristic (ROC) curve revealed that ACOT7 has a high diagnostic accuracy for distinguishing AD patients from healthy individuals.

The area under the curve (AUC) was 0.83, which indicates good diagnostic performance.

At an optimal cut-off point of 62.5 pg/mL, ACOT7 achieved a sensitivity of 80% and a specificity of 74%.

Sensitivity refers to the test’s ability to correctly identify those with the disease (true positive rate), while specificity refers to its ability to correctly identify those without the disease (true negative rate).

Thus, ACOT7 can accurately identify a significant proportion of AD patients and healthy controls.

4. Superiority Over Traditional Biomarkers

When compared to the traditional AD marker, the Aβ42/40 ratio, ACOT7 demonstrated superior diagnostic performance.

The Aβ42/40 ratio had an AUC of 0.70 with a diagnostic accuracy of 72%, sensitivity of 69%, and specificity of 76%.

In contrast, ACOT7 had a higher AUC (0.83) and better overall diagnostic accuracy (77%).

This suggests that ACOT7 is a more reliable serum biomarker for AD than the traditional Aβ42/40 ratio.

5. Role in Amyloidogenic Pathway of APP Metabolism

ACOT7 plays a role in the amyloidogenic pathway of amyloid precursor protein (APP) metabolism, which is a critical pathway in AD pathogenesis.

RNA interference experiments in neuroblastoma cells (SK-N-SH APPwt) showed that reducing ACOT7 levels led to significant decreases in β-secretase (BACE1), Aβ42, and βCTF levels, which are involved in the production of amyloid-beta plaques characteristic of AD.

However, ACOT7 knockdown did not affect the non-amyloidogenic pathway, suggesting that ACOT7 specifically influences the disease-related pathway of APP metabolism.

This finding points to ACOT7’s potential as a target for therapeutic intervention in AD.

Study Overview: Diagnostic Value of ACOT7 in Alzheimer’s Disease (2024)

The primary aim of this study was to evaluate the diagnostic value of acyl-Coenzyme A thioesterase 7 (ACOT7) as a serum biomarker for predicting Alzheimer’s disease (AD).

Sample

The study included a total of 682 participants, divided into two groups:

AD Group: 366 patients diagnosed with Alzheimer’s disease.
Control Group: 316 cognitively normal, age-matched, and gender-matched individuals.

Methods

Participant Selection: Participants were categorized based on cognitive impairment levels, confirmed through medical history, neurological examination, and cognitive function tests such as the Mini-Mental State Examination (MMSE). Diagnostic criteria included NINCDS-ADRDA and DSM-IV-TR standards, supplemented by cerebrospinal fluid examination, MRI, PET scans, and routine laboratory tests.
Blood Sample Collection: Venous blood samples were collected from all participants. Serum was separated and stored at −20°C until analysis.
Animal Models: APP/PS1 double transgenic mice and age-matched wild-type (WT) mice were used to study ACOT7 expression in brain tissues and serum.
RNA Interference & Western Blot Analysis: SK-N-SH and SK-N-SH APPwt neuroblastoma cells were used to investigate the effects of ACOT7 knockdown on APP metabolism. Protein levels were analyzed using Western blot and enzyme-linked immunosorbent assay (ELISA).
Statistical Analysis: Data were analyzed using SPSS software. Correlation analysis between ACOT7 levels and MMSE scores was conducted using the Spearman correlation coefficient. ROC curve analysis was performed to evaluate the diagnostic accuracy of ACOT7.

Limitations

Sample Diversity: The study did not differentiate between mild cognitive impairment (MCI) and AD in participants, which could affect the specificity of ACOT7 as an early biomarker.
Longitudinal Analysis: The study did not conduct a longitudinal analysis to observe changes in ACOT7 levels over time, which could provide insights into its potential as a predictive biomarker.
Broader Population: The study was conducted in a specific geographic region (Shandong, China), and the results may not be generalizable to broader, more diverse populations.
Mechanistic Insights: While the study explored ACOT7’s role in the amyloidogenic pathway of APP metabolism, it did not fully elucidate the underlying molecular mechanisms.

Accuracy of ACOT7 as a Biomarker for Alzheimer’s Disease Diagnosis

1. Receiver Operating Characteristic (ROC) Curve Analysis

The accuracy of ACOT7 as a biomarker for Alzheimer’s disease (AD) was evaluated using receiver operating characteristic (ROC) curve analysis.

The ROC curve is a graphical representation of the diagnostic ability of a biomarker, plotting the true positive rate (sensitivity) against the false positive rate (1-specificity) at various threshold settings.

Area Under the Curve (AUC): The AUC for ACOT7 was found to be 0.83.

The AUC value ranges from 0 to 1, with 1 indicating perfect diagnostic accuracy and 0.5 indicating no diagnostic ability.

An AUC of 0.83 signifies a high level of diagnostic performance, indicating that ACOT7 is a reliable biomarker for distinguishing AD patients from healthy controls.

2. Sensitivity & Specificity

The sensitivity and specificity of ACOT7 were determined at an optimal cut-off point of 62.5 pg/mL.

Sensitivity: ACOT7 demonstrated a sensitivity of 80%. This means that 80% of individuals with AD were correctly identified by the biomarker (true positives).
Specificity: ACOT7 showed a specificity of 74%. This indicates that 74% of healthy individuals without AD were correctly identified as not having the disease (true negatives).

These values indicate that ACOT7 has a strong ability to correctly identify both AD patients and healthy controls, making it a highly effective diagnostic tool.

3. Diagnostic Accuracy

The overall diagnostic accuracy of ACOT7 was calculated to be 77%, with a 95% confidence interval (CI) of 72–82%.

Diagnostic accuracy is the proportion of true positive and true negative results among the total number of cases examined.

An accuracy of 77% means that the biomarker correctly classified 77% of all individuals (both AD patients and healthy controls).

4. Comparison with Traditional Biomarkers

When compared to the traditional AD marker, the Aβ42/40 ratio, ACOT7 demonstrated superior diagnostic performance.

Aβ42/40 Ratio: The AUC for the Aβ42/40 ratio was 0.70, with a sensitivity of 69% and specificity of 76%.
ACOT7: With an AUC of 0.83, sensitivity of 80%, and specificity of 74%, ACOT7 outperformed the Aβ42/40 ratio in terms of diagnostic accuracy (77% vs. 72%).

This comparison highlights ACOT7’s greater reliability and effectiveness as a diagnostic biomarker for AD.

Why ACOT7 Correlates with Alzheimer’s Disease: Likely Reasons

1. Involvement in Fatty Acid Metabolism

ACOT7 is a member of the acyl-Coenzyme A thioesterases family, which plays a critical role in the metabolism of long-chain fatty acids.

It catalyzes the hydrolysis of acyl-CoA into free fatty acids (FFA) and coenzyme A (CoA), regulating their levels within cells.

In Alzheimer’s disease (AD), disturbances in lipid metabolism are commonly observed.

The brain, having high metabolic demands, is particularly sensitive to such disturbances.

Elevated ACOT7 levels in AD may reflect a compensatory response to metabolic stress or an attempt to manage disrupted fatty acid metabolism, which is a hallmark of AD pathology.

2. Protection Against Neuronal Toxicity

ACOT7 is highly expressed in neurons and oligodendrocytes and has been shown to protect nerve cells from the toxicity of accumulated long-chain fatty acids.

In AD, there is substantial neuronal damage and death, partially due to the toxic effects of amyloid-beta (Aβ) plaques and tau tangles.

Increased expression of ACOT7 may be a cellular defense mechanism against this toxicity, aiming to maintain neuronal integrity and function in the face of AD-related stressors.

3. Role in Myelin Development and Maintenance

ACOT7 is essential for myelin development and maintenance.

Myelin is crucial for proper neuronal function and signal transmission.

In AD, demyelination and myelin damage are frequently observed, contributing to cognitive decline and other symptoms.

Elevated ACOT7 levels in AD patients might be associated with attempts to preserve or repair myelin integrity, counteracting the demyelinating effects of the disease.

4. Energy Metabolism Regulation

The cytoplasmic activity of ACOT7 is regulated by ATP, aligning with the high sensitivity of myelination to energy metabolism.

In AD, mitochondrial dysfunction and altered energy metabolism are prominent features.

Increased ACOT7 expression could be linked to attempts by cells to adjust their energy metabolism in response to mitochondrial impairments, aiming to support cellular functions and mitigate the effects of energy deficits in the brain.

5. Modulation of Amyloid Precursor Protein (APP) Metabolism

The study found that ACOT7 is involved in the amyloidogenic pathway of APP metabolism, which leads to the production of amyloid-beta (Aβ) peptides, central to AD pathology.

Knockdown of ACOT7 resulted in reduced levels of β-secretase (BACE1), Aβ42, and βCTF, components involved in Aβ production.

Elevated ACOT7 levels in AD might indicate an upregulation of this pathway, contributing to the increased production and accumulation of Aβ plaques characteristic of AD.

Conclusion: ACOT7 May Predict Alzheimer’s Disease

This study highlights the potential of acyl-Coenzyme A thioesterase 7 (ACOT7) as a promising serum biomarker for Alzheimer’s disease (AD).

The findings demonstrate that ACOT7 levels are significantly elevated in both human AD patients and animal models, and show a strong negative correlation with cognitive function, as measured by MMSE scores.

With an area under the curve (AUC) of 0.83, and diagnostic accuracy of 77%, ACOT7 offers high sensitivity and specificity, surpassing traditional biomarkers such as the Aβ42/40 ratio.

The involvement of ACOT7 in the amyloidogenic pathway of APP metabolism further supports its relevance in AD pathology.

These results suggest that ACOT7 could be a valuable tool for the early and accurate diagnosis of AD, paving the way for more effective intervention and management strategies.

Further research is needed to explore its full diagnostic and therapeutic potential.

References

Study: ACOT7, a candidate and novel serum biomarker of Alzheimer’s disease (2024)
Authors: Jintao Wang et al.