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

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Feb 11 2025

Scientists discovered a rare case of an Alzheimer’s gene carrier who remained symptom-free for 18 years beyond the expected onset, revealing potential genetic, environmental, and proteomic resilience factors.

Study: Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia. Image Credit: Kateryna Kon / Shutterstock

In a recent study in the journal Nature Medicine, researchers carried out an in-depth multi-omics longitudinal study on a Dominantly Inherited Alzheimer Network (DIAN) participant who exhibited exceptional resilience to Alzheimer's disease (AD). Despite carrying a dominant Presenilin 2 (PSEN2) p.Asn141Ile mutation, a known genetic link to Alzheimer's disease (AD), the participant displayed no AD symptoms even 18 years beyond the expected onset of the condition.

To unravel the reasons for this remarkable resilience, the study employed several genetic and molecular analyses (whole-exome and whole-genome sequencing) on the participant and their close relatives alongside high-resolution in vivo neuroimaging (MRI and PET scans) and biofluid assays (LC-MS/MS, LUMIPULSE G1200 immunoassays, and cerebrospinal fluid (CSF) proteomic/metabolomic profiling). In addition to genetic factors, the study explored the role of environmental influences, particularly the participant's long-term exposure to extreme heat conditions while working as a naval mechanic. Study findings revealed several potential genetic and proteomic associations for future validation, opening a new avenue in preventive and therapeutic AD research.

Background

Alzheimer's disease (AD) is a progressive neurological condition resulting from the breakdown and degeneration of brain cell connections and neurons. Its main symptoms include declines in memory and cognitive ability that worsen over time, significantly hampering daily functioning.

Unfortunately, despite decades of research, a cure for AD has yet to be discovered, with current therapeutic interventions aimed at early detection and delayed symptom progression. This research has, however, identified key genetic signatures of AD, with several allelic mutations now known to contribute to disease risk and age at onset (AAO).

An apt example of this is “dominantly inherited Alzheimer's disease (DIAD),” a relatively rare subset of AD patients whose genetics—mutations in Presenilin 1 (PSEN1), Presenilin 2 (PSEN2), or Amyloid Precursor Protein (APP)—almost guarantee AD manifestation. These genes play critical roles in amyloid precursor protein (APP) processing and amyloid-β pathology and, alongside family history, can predict AAO with high accuracy.

DIAN and the Case Study Subject

The Dominantly Inherited Alzheimer Network (DIAN) is a large cohort, multinational, longitudinal study aimed at creating a global registry of DIAD patients and their family members. Since its establishment in 2008, DIAN has recruited more than 530 participants, all but three of whom have developed DIAD at or around predicted AAOs.

Whole-exome sequencing of the two previously discovered outliers revealed homozygous genetic mutations (APOE3-Christchurch (p.Arg136Ser) and RELN-COLBOS (p.His3447Arg)) that conferred strong protection against AD onset and led to their designation as “exceptional resilience mutation carriers.” The third outlier is the present study's case subject, who remains DIAD-free despite being between 15 and 22 years beyond the predicted AAO. Unlike the previous outliers, this individual lacks these known protective mutations, making their resilience even more remarkable.

"The p.Asn141Ile variant has a mean symptomatic AAO of 53.7 years (range 39–58), and its origin can be traced to people originally living in two small adjacent Volga German villages."

About the Study

The present study leverages longitudinal clinical, genetic, neuroimaging, and biomarker data from the DIAN study to investigate potential protective mechanisms preventing DIAD manifestation in a participant with a strong genetic predisposition and a family history of the condition.

Study data included detailed neurological and neuropsychological assessments over a 10-year period, revealing no signs of cognitive impairment. The participant consistently scored 30 on the Mini-Mental State Examination (MMSE) and 0 on the Clinical Dementia Rating (CDR) scale, indicating full cognitive function.

Genetic and molecular data included whole-exome sequencing and whole-genome sequencing of the participant and their close family members (n = 4 and 14, respectively).

In vivo neuroimaging was carried out using high-resolution magnetic resonance imaging (MRI) scans to detect atrophic processes, microhemorrhages, amyloid burden, or small-vessel disease markers. The participant’s positron emission tomography (PET) scans revealed an unusual finding: tau pathology was confined to the left occipital region with no evidence of spread to other brain regions, a pattern not typically seen in DIAD patients.

Finally, cerebrospinal fluid (CSF) assays demonstrated a high amyloid burden, comparable to other DIAN participants with DIAD mutations, suggesting that amyloid accumulation alone does not determine disease progression.

Study Findings

Immunological assays confirmed that the participant exhibited high amyloid deposition, similar to symptomatic DIAD mutation carriers. However, unlike other cases, tau pathology remained restricted to the occipital lobe, without the widespread spread typically associated with cognitive decline in AD.

Furthermore, the participant did not develop any significant spatial or visual impairments despite tau loads equal to or exceeding those found in posterior cortical atrophy. Interestingly, this restricted 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 several genetic variants potentially contributing to resilience, including upregulation of the enzyme GPCPD1 (involved in choline metabolism), a variant in the CD33 gene (previously linked to AD risk modulation), and modifications in the MAPT haplotype, which may influence tau pathology.

Additionally, proteomic analysis revealed an overrepresentation of heat shock proteins, which play key roles in protein folding and cellular stress responses. These findings suggest a possible link between chronic heat exposure in the participant’s profession and enhanced resilience mechanisms at the molecular level.

Conclusions

The present study comprised an in-depth analysis of genetic, clinical, neuroimaging, and proteomic factors in an “exceptional resilience mutation carrier” who remains DIAD-free despite being ~18 years beyond the expected AAO.

While the study identified several promising genetic and proteomic markers, it did not pinpoint a single protective factor responsible for the participant’s resilience.

"This research could have broad implications for the development of treatments aimed at mitigating tau pathology in the wider AD population. Understanding the mechanisms that restrict tau spread in this individual could provide crucial insights into potential therapeutic targets for preventing or slowing the progression of AD. We invite researchers to join us in this search."