Probable Novel APP Met671Leu Mutation in a Chinese Han Family with Early-Onset Alzheimer’s Disease

Medical Laboratory Science Neurology Basic Medical Sciences Life Sciences Medicine Genetics
Alzheimer's disease biomarker APP early-onset Alzheimer’s disease gene mutation

A Study Exploring a New Mutation in Early-Onset Alzheimer’s Disease

Alzheimer’s Disease (AD) is a common neurodegenerative disorder, accounting for 60-70% of all dementia cases. In recent years, with global population aging and environmental changes, the incidence of AD has been increasing annually. It is predicted that by 2050, the number of patients will reach three times the current level. Statistics show that about 50 million people worldwide are affected by dementia, a number expected to grow rapidly in the coming decades. However, research on Early-Onset Alzheimer’s Disease (EOAD) is still relatively lacking. EOAD refers to AD with clinical symptoms appearing before the age of 65, with about 10% showing autosomal dominant inheritance.

Among the many pathogenic genes, APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common gene mutations associated with AD. The APP gene was the first discovered to be related to EOAD, and the amyloid-beta peptide (Aβ) produced in its abnormal processing is the main component of senile plaques in the brains of AD patients. Studies have reported 54 known missense or nonsense mutations in the APP gene worldwide.

This report explores a newly discovered APP gene mutation in a Chinese Han family and its association with EOAD.

Authors and Research Publication Information

The study was conducted by Limin Ma and his team at the People’s Hospital Affiliated to Zhengzhou University in Henan, China. The article was published in the journal “Neuromolecular Medicine”, Volume 26, Issue 6, 2024. The research team members mainly come from the hospital’s Health Management Center, Department of Neurology, and Department of Radiology. The paper was submitted on September 27, 2023, accepted on November 19, 2023, and exclusively published by Springer Science+Business Media, LLC.

Research Workflow

The research team conducted an in-depth study of a family with 13 members. Among these members, three had passed away, and the remaining nine provided blood samples. The proband was a 54-year-old right-handed woman who had gradually developed memory loss and cognitive impairment over the past four years, with clinical symptoms progressively worsening, manifesting as getting lost and inability to operate a printer.

To comprehensively understand the pathogenesis of AD in this family, the research team carried out the following steps:

  1. Clinical Evaluation Detailed medical and family history data were obtained through communication with the patient and relatives. The proband underwent various examinations, including brain MRI, 18F-FDG-PET, brain MRA, brain 18F-Florbetapir (AV-45) PET imaging, cerebrospinal fluid (CSF) amyloid protein, and neuropsychological assessments.

  2. Genetic Testing Gene testing was performed on the proband and her family members, 100 unrelated normal individuals, and 100 sporadic AD patients, mainly using whole-exome sequencing and Sanger sequencing.

  3. CSF Biomarker Analysis CSF was collected through lumbar puncture, and the levels of Aβ1-42, Aβ1-40, total tau protein (t-tau), and phosphor-tau at t181 protein (p-tau) were quantitatively detected using solid-phase enzyme-linked immunosorbent assay (ELISA).

In whole-exome sequencing, a novel missense mutation was detected, namely a point mutation from A to T at position 2011 (c.2011A > T) in exon 16 of the APP gene, resulting in the replacement of methionine (M) with leucine (L). Through co-separation analysis, the mutation was verified to exist in three patients in the family (all three carrying the mutation but not yet symptomatic) and three other normal members, but was not found in three other unaffected family members, 100 unrelated normal individuals, or 100 sporadic AD patients.

Research Results

The results showed that the proband’s brain MRI revealed brain atrophy, especially in the entorhinal cortex, temporal lobe hippocampus, and lateral ventricle expansion. 18F-FDG-PET showed hypometabolism in the frontotemporal lobe, parietal lobe, and hippocampal region. 18F-florbetapir (AV-45) PET imaging showed Aβ protein deposition in the cerebral cortex. CSF test results showed a decreased Aβ42/Aβ40 ratio and increased levels of pathological phospho-tau protein.

The new mutation site of the APP gene (c.2011A > T, p.M671L) in this family was not found in 100 normal controls and 100 sporadic AD patients. Through multiple sequence alignments and comparisons of sequences from different organisms, it was found that the mutation led to a highly conserved amino acid change. Furthermore, after analysis using 23 prediction software, 70% (16⁄23) considered the p.M671L mutation to be harmful. Martin Citron et al. found that cells with the Swedish family’s double mutation unit (app670/671) produced 6-8 times more Aβ than normal cells, with the M671L mutation being the main cause.

Conclusions and Significance

This study reports for the first time a new mutation p.M671L (c.2011A > T) in the APP gene in a Chinese Han family. The changes in biomarkers detected through CSF and 18F-Florbetapir (AV-45) PET imaging are consistent with the pathological manifestations of AD. The data suggest that the APP gene p.M671L mutation may be the main cause of pathogenicity in the Swedish APP double mutation (K670N and M671L). The study shows that the pathogenic mechanism of this mutation needs to be verified through further animal experiments.

This study not only provides a new research direction for the pathogenesis of AD but also provides an important theoretical basis for early diagnosis and treatment strategy formulation. Through in-depth research on the family, it reveals the connection between new gene mutations and AD, providing new ideas for personalized treatment of AD in the future.

Research Highlights

  1. Discovery of a new APP gene mutation associated with early-onset Alzheimer’s disease in a Chinese Han family.
  2. Detailed brain imaging and CSF biomarker analysis revealing the pathological mechanism.
  3. The high conservation of the mutation and its determination as harmful by most prediction software enhance the credibility and importance of the research results.

In future research, further animal experiments and long-term follow-up will help to confirm the biological effects of this mutation and its specific mechanism in the pathogenesis of AD. The study is significant for understanding the genetic basis of AD and promoting personalized medicine.