Alzheimer’s escape: How one man defied his genetic fate for nearly two decades

Scientists discovered a rare case of a Gendr carrier of Alzheimer’s who remained symptom-free for 18 years after the expected beginning, which revealed potential genetic, environmental and proteomic resilience factors.

Study: Longitudinal analysis of a dominant inherited Alzheimer’s -Diseases Higher Dementia Protected. Image Credit: Kateryna Kon / Shutterstock

In a recent study in the magazine Nature MedicineResearchers have conducted an in-depth multi-Oomics longitudinal study into a dominant hereditary Alzheimer Network (Dian) participant who showed exceptional resilience against Alzheimer’s disease (AD). Despite wearing a dominant preseniline 2 (PSEN2) P.ASN141ILE mutation, a well -known genetic link with Alzheimer’s disease (AD), the participant showed no AD symptoms, even 18 years after the expected start of the condition.

To unravel the reasons for this remarkable resilience, the study used various genetic and molecular analyzes (whole-vexome and whole genome seal) on the participant and their closest family members in addition to high resolution in Vivo Neuroimaging (MRI and PET scans) and Biofluid Assays ( LC-MS/MS, Lumipulse G1200 immunoassays and cerebrospinal liquid (CSF) Proteomic/metabolomic profiling). In addition to genetic factors, the study investigated the role of environmental influences, in particular the long-term exposure of the participant to extreme heat conditions while working as a navy mechanic. Study -findings revealed various potential genetic and proteomic associations for future validation, which opened a new avenue in preventive and therapeutic AD research.

Background

Alzheimer’s disease (AD) is a progressive neurological condition due to the breakdown and degeneration of brain cell connections and neurons. The most important symptoms include a decrease in memory and cognitive skills that aggravate over time, so that daily functioning is considerably impeded.

Unfortunately, despite decades of research, a remedy for AD still has to be discovered, with current therapeutic interventions aimed at early detection and delayed symptom this. However, this research has identified important genetic signatures of AD, with various allelical mutations that are now known to contribute to the risk of medical expenses and age at the beginning (AAO).

An appropriate example of this is “dominant inherited in Alzheimer’s disease (Diad)”, a relatively rare subset of ad -patients whose genetics – mutations in preseniline 1 (PSEN1), preseniline 2 (Psen2) or amyloid precursor protein (app) – al – Most warranty ad -manifestation. These genes play a crucial role in the processing of amyloid precursors (app) and amyloid-β-pathology and can, in addition to family history, predict AAO with high accuracy.

Dian and the subject of the Case Study

The dominant inherited Alzheimer Network (Dian) is a large cohort, multinational, longitudinal research aimed at creating a worldwide register of Diad patients and their family members. Since its foundation in 2008, Dian has recruited more than 530 participants, all of whom have been developed one except for or around predicted Aaos.

Entire exome sequencing of the two previously discovered from bijters discovered Homozygote Genetic Mutations (APOE3-Christchurch (P.Arg136Ser) and Reln-Colbos (P.HIS3447ARG)) who proved strong protection against advertisements and led their indication as “designation as” Mutation as “Exceptional Resilience Mutation. Carriers. “The third from the best is the case of the current study, which will remain diad -free, despite the fact that it is between 15 and 22 years past the predicted AAO. In contrast to the previous bijters, this person misses these known protective mutations, making their resilience even more remarkable is becoming.

“The P.ASN141ile variant has an average symptomatic aao of 53.7 years (reach 39-58), and its origin can be traced to people who originally live in two small German villages.”

About the study

The current study uses longitudinal clinical, genetic, neuroimaging and biomarker data from the Dian study to investigate potential protective mechanisms that prevent Diad manifestation in a participant with a strong genetic predisposition and a family history of the condition.

Study data includes detailed neurological and neuropsychological assessments for a period of 10 years, which did not reveal signs of cognitive disorders. The participant consistently scored 30 on the mini -mental state exam (MMSE) and 0 on the Clinical Dementia Rating (CDR) scale, which indicates full cognitive function.

Genetic and molecular data include whole-vexome sequencing and entire genomesquencing of the participant and their close family members (N = 4 and 14 respectively).

In Vivo, neuroimaging was carried out using high resonance magnetic resonance imaging (MRI) scans to detect atrophic processes, micro -hemorrhacesses, amyloid burden or small vessel disorders. The Positron Emission Tomography (PET) scans of the participant revealed an unusual finding: Tau -Pathology was limited to the left occipital area without proof of spread to other brain areas, a pattern that is not typically seen in Diad patients.

Finally, cerebrospinal fluid (CSF) tested a high amyloid load, similar to other Dian’s participants with diad mutations, which suggests that only amyloid accumulation does not determine the disease progression.

Study findings

Immunological tests confirmed that the participant showed a high amyloid deposit, similar to symptomatic diadings mutation carriers. In contrast to other cases, however, Tau -Pathology was limited to the occipital lob, without the widespread spread typically associated with cognitive decline in AD.

Moreover, the participant has not developed significant spatial or visual impairments, despite TAU taxes equal to or found in posterior cortical atrophy. Interestingly, this limited Tau deposition pattern was also seen in the two previously reported APOE3-Christchurch and Reln-Colbos carriers, suggesting a possible shared resilience mechanism.

The study also identified various genetic variants that may contribute to resilience, including Upregulation of the enzyme GPCPD1 (involved in cholinemetabolism), a variant in the CD33 gene (previously linked to AD risico modulation) and adjustments in the MAPThaplotype, that is possible influence that can influence tau pathology.

In addition, proteomic analysis revealed an overrepresentation of heat shook proteins that play an important role in folding proteins and cellular stress reactions. These findings suggest a possible link between exposure to chronic heat in the participant’s profession and improved resilience mechanisms at the molecular level.

Conclusions

The current study included an in-depth analysis of genetic, clinical, neuroimaging and proteomic factors in an “exceptional resilience mutation carrier” that remains diad-free despite the fact that it is ~ 18 years beyond the expected aao.

Although the study identified various promising genetic and proteomic markers, it has not established any protective factor that is responsible for the resilience of the participant.

“This research could have broad implications for the development of treatments aimed at reducing tau pathology in the wider AD population. Insight into the mechanisms that limit TAU ​​spread in this person, can offer crucial insights into possible therapeutic goals To prevent or delay the progression of AD.