A Case of Early-Onset Alzheimer's Disease with MAPT P301L Mutation and Literature Review


 Background: Early-onset Alzheimer's disease is defined as Parkinson's disease that begins at an age of 65 or younger. Currently, among the reports on early-onset Alzheimer's disease related genes, mutations of APP, PSEN1 and PSEN2 genes are relatively common, However, the mutation of MAPT P301L causes early-onset Alzheimer's disease, which has not been reported so far. Case report: We have found a clinical case of a 30-year-old male who suddenly developed cognitive impairment and progressed rapidly within 2 years, leaving him unable to take care of himself. The patient underwent examinations of blood and cerebrospinal fluid routine, biochemistry and immunoassay, as well as imaging examinations of MRI, FDGPET and PIBPET. PIB-PET indicated diffuse heterogeneous radionuclivity in cerebral cortex, and positive PIB imaging was considered. Sequencing results suggested that there was a heterozygous mutation in the MAPT gene of the patient, which was located in Chr17-44087755, and c.902C>T. Conclusion: We speculated that EOAD of this patient may be related to the P301L mutation on MAPT.


Background
Alzheimer's disease (AD) is a common neurodegenerative disease. AD patients are divided into the early onset group (E O AD, age≤65 years) and the late onset group (L O AD, age>65 years) according to the age of onset. Early-onset Alzheimer's disease accounts for 4%-6% of AD, which is characterized by the relative de ciency of attention, executive function, practical function and visuospatial function, and a higher prevalence of traumatic brain injury (TBI) [1] . Whereas late-onset Alzheimer's disease is a complex disease with a 70-80% heritability, early-onset Alzheimer's disease is a disease almost entirely genetically determined, whose heritability is between 92% and 100%. It has been reported that 35%-60% of E O AD patients have at least one rst-degree relative with E O AD, and 10%-15% of familial E O AD patients have autosomal dominant inheritance [2] . APP, PSEN 1, PSEN 2 and other gene mutations are relatively common in E O AD-related reports, but a few cases have been reported to be associated with mutations in the MAPT gene [3] . However, E O AD caused by MAPT P301L mutation has not been reported.
We have found a clinical case of a 30-year-old male who suddenly developed cognitive impairment and progressed rapidly within 2 years, leaving him unable to take care of himself. Advanced neurological examination indicated multiple cognitive domains were impaired. The patient underwent examinations of blood and cerebrospinal uid routine, biochemistry and immunoassay, as well as imaging examinations of MRI, FDGPET and PIBPET. Combined with his various laboratory test results and structural and functional imaging ndings, E O AD was con rmed. In order to further clarify whether the etiology was related to genes, gene sequencing for the patient and their parents was conducted by adopting the methods of target region capture + high-throughput sequencing, and found that there was a hybridized mutation at locus chr17-44087755 of MAPT gene, c.902C>T, leading to the change of amino acid p.P301L (proline > leucine). We hypothesized that E O AD may be associated with this gene mutation.

2.case Presentation
The patient was a 30-year-old male who sought medical aid in our hospital for the reason that he began to forget what had just happened , lose things and got lost lost frequently 2 years ago. His family members found that his reactions were slow. He had di culty understanding other people's words and expressing his own intentions. His speaking speed was getting slower, and it was di cult to nd words to express himself. He lost the abilities to write and recognize time. His memory was getting poor, which caused him to forget what had happened just now. He forgot whether he had eaten food or not. When he was out, he could not nd his way home. It was hard for him to nish simple movements, such as getting dressed, eating, or else. Neurological examination showed that the main symptoms were impaired cognitive function, including severe impairment of visual space and executive function (1/5), impaired attention (1/6), impaired verbal repetition and uency (0/3), impaired delayed recall (1/5), impaired directivity (2/6), impaired clock drawing test, MMSE (10/30), and MoCA (5/30).
No abnormalities were found in the blood routine, biochemistry, immunoassay, small-molecule metabolic indicators, heavy metals, poisons, tumor and paraneoplastic markers. No abnormalities were found in CEREBRO spinal uid routine, biochemistry, immunoassay and viral antibody tests.
Head MRI indicated severe atrophy in temporal lobes and parietal lobes. FDG PET showed moderate and severe reduction in laminar radioactive uptake in bilateral frontal lobes, parietal lobes, inferior temporal lobes and caput nuclei caudati, especially in temporal lobes. PIB-PET indicated diffuse heterogeneous radionuclivity in cerebral cortex, and positive PIB imaging was considered. (Figure 1) To further clarify the etiology, the genes of the patients and their parents are sequenced. The results are shown in Table 1.
Sequencing results suggested that there was a heterozygous mutation in the MAPT gene of the patient, which was located in Chr17-44087755, and c.902C>T. Family veri cation results showed that the heterozygous mutation was from his mother, and his father had no mutation.
By the time of submission, the patient had been taking donepezil and citicoline orally for nearly 2 years, and the cognitive impairment of the patient had not been signi cantly alleviated.
3.discussion AD is the most common age-related neurodegenerative disease among the elderly, affecting 23 million to 35 million people worldwide [4] . The patients with the onset of early-onset Alzheimer's disease (E O AD) is less than 65 years old, and it is the most common early neurodegenerative dementia. As patients approached the age of 65, the incidence and prevalence of E O AD increase exponentially [5] . Existing studies have shown that there are three kinds of genes involved in the pathogenesis of E O AD, namely APP [6] , PSEN 1 [7] and PSEN 2 [8] . However, they explain only a small proportion (5-10%) of E O AD cases [9] , leaving most families and a large number of E O AD patients with unknown involved genes, showing that other causal genes remain to be determined.
We reported a young E O AD patient, a 30-year-old man with sudden onset of impaired memory and numeracy, and loss of writing ability, which progressed rapidly over a 2-year period. The patient showed signi cant brain atrophy on head MRI, and FDGPET indicated low metabolism. The patient was con rmed to have early-onset Alzheimer's disease by PIB-PET examination. Gene sequencing revealed that the patient had a P301L heterozygous mutation on the MAPT gene, and family analysis suggested that the heterozygous mutation originated from his mother. MAPT encodes the microtubule-associated protein τ, and the clinical phenotype caused by different mutations has considerable heterogeneity. We speculated that E O AD of this patient may be related to the P301L mutation on MAPT.
The encoding gene MAPT of microtubule-associated protein τ is located on chromosome 17q21.3 and consists of 16 exons. Protein τ is translated from a 6 kb mRNA transcript, and produces a series of 6 subtypes of protein τ with 37-46 kDa, ranging in length from 352 to 441 amino acids, which are expressed in neurons. Among the six subtypes mentioned above, half of the them showed three repeated sequences (3Rτ) of 3 microtubule-binding region and the other half contained four repeated sequences (4Rτ). Normally, the ratio of 3Rτ and 4Rτ in the adult brain is roughly equal. For patients with AD, this ratio remained normal, but MAPT mutations can lead to AD-like tauopathies with a 4R or 3R predominance [10] .
The mutants of MAPT may cause hyperphosphorylation, insolubility as well as structural and functional abnormalities in concentrated τ. These pathological changes play a crucial role in the pathogenesis of τ related neurodegenerative diseases [11] . Many tauopathies, especially AD, regard the occurrence of τ deposition as the typical pathological characteristic. The Braak stage of neuropathology of AD is also related to the severity of neuro brillary tangles in different brain areas. It has been con rmed that MAPT is able to cause neurodegenerative diseases [12] . Different types of MAPT mutations may lead to different clinical diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Frontotemporal dementia with parkinsonism-17 (FTDP-17) and Amyotrophic lateral sclerosis (ALS).
AD caused by MAPT mutation is rare. Since 2005, fewer than 100 AD patients with MAPT mutation have been reported in the literature, as shown in the Table 2. P301L mutation is more common in patients in western countries, mainly related to FTD and PD, while two P301L families in China present bvFTD or PNFA (Progressive non uent aphasia ) [13] . P301L mutation in AD patients has not been reported in the world.
E O AD with MAPT P301L mutation has been reported for the rst time in this paper. Unfortunately, based on the available clinical data, it is not clear whether this mutation is responsible for E O AD in patients.
Next, an E O AD animal model with MAPT P301L mutation will be constructed to further investigate whether this mutation is associated with the onset of early-onset Alzheimer's disease.

Consent for publication
The consent for publication was obtained from all participants. And written consent for publication was also obtained.

Availability of data and material
The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This study was supported by Jilin Science and Technology Department Project (No.20200201451JC and 20200602045ZP) JF and JL analyzed and interpreted the patient data, and was a major contributor in writing the manuscript.CJ guided the writing. HS helped to analyz and interpret the patient data. All authors read and approved the nal manuscript. Figure 1 Imaging manifestations and the gene sequencing results A, B: Head MRI indicated severe atrophy in temporal lobes and parietal lobes.

Figures
E, F: FDG PET showed moderate and severe reduction in laminar radioactive uptake in bilateral frontal lobes, parietal lobes, inferior temporal lobes and caput nuclei caudati, especially in temporal lobes.
C, D, G, H: PIB-PET indicated diffuse heterogeneous radionuclivity in cerebral cortex, and positive PIB imaging was considered.
I, J, K: the patient, the patient' father and the patient' mother are shown from I to K.

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