Abstract
Familial Alzheimer’s disease (AD) is a rare disease caused by autosomal-dominant mutations. APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common genes cause dominant inherited AD. This study aimed to demonstrate a Chinese early-onset AD pedigree presenting as progressive memory impairment, apraxia, visual-spatial disorders, psychobehavioral disorders, and personality changes with a novel APP gene mutation. The family contains four patients, three carries and three normal family members. The proband underwent brain magnetic resonance imaging (MRI), 18F-fludeoxyglucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid amyloid detection, 18F-florbetapir (AV-45) Positron Emission Computed Tomography (PET) imaging, whole-exome sequencing and Sanger sequencing. Brain MRI images showed brain atrophy, especially in the entorhinal cortex, temporal hippocampus, and lateral ventricle dilation. The FDG-PET showed hypometabolism in the frontotemporal, parietal, and hippocampal regions. 18F-florbetapir (AV-45) PET imaging showed cerebral cortex Aβ protein deposition. The cerebrospinal fluid amyloid protein test showed Aβ42/Aβ40 ratio decreases, pathological phosphor-tau level increases. Whole-exome sequencing detected a new missense mutation of codon 671 (M671L), which was a heterozygous A to T point mutation at position 2011 (c.2011A > T) in exon 16 of the amyloid precursor protein, resulting in the replacement of methionine to Leucine. The co-separation analysis was validated in this family. The mutation was found in 3 patients, 3 clinical normal members in the family, but not in the other 3 unaffected family members, 100 unrelated normal subjects, or 100 sporadic patients with AD. This mutation was probably pathogenic and novel in a Chinese Han family with early-onset AD.
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The authors are very grateful for the cooperation of the family members.
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Limin Ma wrote the main manuscript with the help of Fengyu Wang,Mingrong Xia, Yongli Li, Huimin Ma,Jiewen Zhang and Junkui Shang. Shuai Chen and Shenghui Wang prepared the clinical figures.Zhenzhen Wang prepared the figures. All authors reviewed the manuscript.
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The study was approved by The Institutional Review Board of People’s Hospital of Zhengzhou University.
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Ma, L., Wang, F., Chen, S. et al. Probable Novel APP Met671Leu Mutation in a Chinese Han Family with Early-Onset Alzheimer’s Disease. Neuromol Med 26, 6 (2024). https://doi.org/10.1007/s12017-023-08770-1
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DOI: https://doi.org/10.1007/s12017-023-08770-1