New research: This protein is the key to carrying Alzheimer's disease mutations but not developing the disease?

Alzheimer's disease (AD), as the most common neurodegenerative disease in the world, not only seriously threatens the quality of life of the elderly, but also brings a heavy burden to families and society. With the acceleration of social aging, the incidence of AD is increasing year by year. However, the current treatment methods for AD are still limited and far from meeting clinical needs.

In this context, scientists are committed to exploring the pathogenesis of AD in order to find effective prevention and treatment strategies. Recently, a case report published in the journal Nature Medicine pointed out the key - tau protein. The purpose of this study is to further explore the potential relationship between tau protein pathology and AD cognitive protection, by analyzing a rare case of a person who carries a pathogenic gene mutation but has not developed the disease at the age of 70, to explore whether tau pathology restriction is a key factor in cognitive protection.

Research methods and process

**1.** Case selection and background investigation

The subject of the study was a male individual with the presenilin 2 (PSEN2) p.Asn141Ile mutation (a known mutation site on the PSEN2 gene that is associated with an increased risk of AD). Normally, this mutation is strongly associated with dominantly inherited AD, usually causing the onset of the disease before the age of 50. However, the subject still maintained completely normal cognitive abilities at the age of 71 and did not carry a gene known to protect against AD.

The researchers conducted a detailed investigation of the family history of the case and found that his mother and 11 of his 13 siblings were also carriers of the PSEN2 p.Asn141Ile mutation, and they generally developed the disease around the age of 50, with the latest person being 58 years old. However, the subject did not show any cognitive or clinical symptoms of AD until he was 71 years old (2021).

2. Cognitive assessment and follow-up

At the age of 61, the subject participated in the Dominant Alzheimer's Disease Network Study, a large research project dedicated to the study of dominantly inherited AD. In the subsequent years of follow-up, the researchers regularly evaluated his cognitive ability and daily living ability. The results showed that the subject's cognitive test had always been normal, and only occasionally experienced right hand tremors in 2017, but the Parkinson's disease rating scale results have always been within the normal range.

3. Imaging and biomarker analysis

In order to gain a deeper understanding of the brain pathological changes of the subjects, the researchers used a variety of imaging techniques for testing. PiBPET testing (a neuroimaging technology used for AD diagnosis and research) found that the subjects had obvious Aβ deposition in their brains (Aβ deposition is one of the early pathological features of AD), which is consistent with the typical manifestations of PSEN2 p.Asn141Ile mutation carriers. However, AV1451PET testing showed that tau protein deposition in the subjects' brains was mainly confined to the occipital lobe area and did not spread to other cognitive areas.

In addition, the results of FDGPET detection of glucose metabolism in the brain showed that the subjects' brain metabolism was also reduced locally, especially in the occipital lobe area where tau protein was deposited, which was different from the typical manifestation of tau deposition in multiple cognitive areas of the brain in AD patients.

The study also collected cerebrospinal fluid from the subjects for biomarker analysis. The results showed that the levels of Aβ markers such as Aβ42:40 were comparable to those of other carriers, while the levels of phosphorylated tau protein were between those of carriers and non-carriers.

**4.** Gene, proteomics and metabolomics analysis

The researchers conducted a detailed analysis of the genes of the subjects and found that, except for the PSEN2 p.Asn141Ile mutation, the APOE genotype was APOE3 homozygous and did not carry any known protective mutations.

To further explore possible protective mechanisms, the researchers also conducted proteomic and metabolomic analyses. The results showed that among the nearly 300 proteins with high abundance, pathways related to protein folding were enriched and included multiple members of the heat shock protein family. Comprehensive analysis found that the three pathways related to protein synthesis, anti-aging and anti-oxidation were significantly different.

Practical implications of the findings

1. Discovery of rare cases

The most significant finding of this study is the rare case of a 70-year-old patient who carries a pathogenic gene mutation but has not developed the disease. This finding challenges the traditional understanding of the pathogenesis of AD and suggests that there may be undiscovered cognitive protection mechanisms.

2. Tau **** pathology limitation and cognitive protection

Imaging and analysis showed that the subjects had Aβ pathology consistent with other PSEN2 p.Asn141Ile mutation carriers, but tau pathology was confined to the occipital lobe and not diffuse, a finding that suggests that limited tau pathology may be a key factor in cognitive protection.

**3.** Potential role of cytoprotective mechanisms such as heat shock proteins

Proteomic and metabolomic analyses revealed that the subjects showed differences in pathways related to protein folding, anti-aging, and anti-oxidation. In particular, the enrichment of members of the heat shock protein family revealed that these cell protection mechanisms may play an important role in cognitive protection.

**4.** Environmental factors and individual differences

The subject's unique experience - working in a hot environment for a long time and using cold water showers - also provides a possible explanation for cognitive protection. This environmental factor may be related to his tolerance and activation of cellular protection mechanisms.

Future Outlook

This study reveals a new perspective on the relationship between tau pathology and cognitive protection, and also brings new hope for the prevention and treatment of AD. Although this is only an individual case at present, the scientific value behind it cannot be ignored. In the future, we look forward to more studies to further verify and improve this discovery, and to limit the spread of tau pathology as a new strategy for early intervention and treatment of AD. At the same time, in-depth research on cell protection mechanisms such as heat shock proteins may also open new treatment doors for us.

More importantly, this study reminds us that everyone's life is unique. Even when facing the same genetic risk, different fates may be revealed due to various unknown factors. This is not only a revelation for scientific research, but also a profound respect for biodiversity and complexity. We believe that with the continuous advancement of science and technology, mankind will eventually defeat Alzheimer's disease and allow every elderly person to have a healthy and dignified later life.

References: Llibre-Guerra, JJ, Fernandez, MV, Joseph-Mathurin, N, et al. Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia. Nat Med (2025).