How a former navy mechanic defied the genetic odds of inherited Alzheimer’s disease microbiologystudy

Researchers at Washington University School of Medicine in St. Louis have conducted a longitudinal study on an individual carrying the presenilin 2 (PSEN2) p.Asn141Ile mutation, a genetic variant known to cause dominantly inherited Alzheimer’s disease (DIAD). The high risk individual, despite being 18 years past the expected age of clinical onset, has remained cognitively intact. Researchers investigated genetic, neuroimaging, and biomarker data to understand potential protective mechanisms.

Unlike typical DIAD progression, tau pathology in this case was confined to the occipital lobe without spreading, suggesting a possible explanation for the lack of cognitive decline.

DIAD results from highly penetrant mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), or PSEN2, which lead to abnormal amyloid-β processing and early-onset Alzheimer’s disease. The Dominantly Inherited Alzheimer Network (DIAN) was established to track DIAD mutation carriers and assess clinical, cognitive, and biomarker changes over time.

Previous studies have identified rare genetic variants that may confer resistance to AD in mutation carriers, but such cases remain extremely rare.

In the study titled “Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia,” published in Nature Medicine, researchers examined the participant’s genetic profile, cognitive function, neuroimaging data, and biomarker levels over a decade.

The participant, a member of a large family carrying the PSEN2 p.Asn141Ile mutation, remained asymptomatic well beyond the expected age of disease onset. Family history analysis showed that 11 of the participant’s 13 maternal aunts and uncles developed AD by age 50. Based on family-specific data, the average symptomatic age at onset for this mutation is 53.7 years, yet this individual remains cognitively normal at age 71.

Clinical and cognitive assessments since enrollment in the DIAN study in 2011 have consistently shown no signs of impairment. The participant maintained a Clinical Dementia Rating of 0 and a Mini-Mental State Examination score of 30 in multiple evaluations between 2011 and 2021. Neuropsychiatric and functional assessments revealed no significant decline, although some cognitive test scores showed minor reductions in processing speed and executive function. Neurological examinations detected only a mild postural tremor in the right hand, first noted in 2017.

Neuroimaging revealed an atypical pattern of tau deposition localized to the occipital lobe, a finding inconsistent with typical DIAD progression. While amyloid-β deposition was comparable to symptomatic DIAD mutation carriers, tau accumulation did not spread beyond the occipital cortex, potentially explaining the absence of cognitive decline.

Magnetic resonance imaging showed a gradual, age-appropriate decline in hippocampal volume, while positron emission tomography (PET) imaging confirmed limited metabolic changes in glucose uptake compared to symptomatic DIAD carriers.

Whole-genome sequencing did not identify previously known protective variants such as APOE3-Christchurch (p.Arg136Ser) or RELN p.His3447Arg, which have been associated with resilience in other autosomal dominant Alzheimer’s Disease cases.

However, genetic analysis identified rare coding variants in genes such as FAM151B, CHST15, CEP290, GPCPD1, and PRICKLE3, which could play a role in resistance to AD. The participant also carried a TREM2 p.Asp87Asn variant with an unclear association with AD risk and a MAPT variant (p.Tyr441His) that may influence tau pathology.

Environmental factors

The participant had prolonged occupational exposure to high heat as a naval diesel mechanic, requiring frequent cooling measures. Proteomic analysis revealed elevated levels of heat shock proteins, which could play a role in protein folding and neuroprotection. This experience at an early age, and the body’s reaction to it, may have contributed to the lifelong resilience.

Longitudinal cerebrospinal fluid and plasma biomarker analyses showed that amyloid-β levels and amyloid-β42/40 ratios were within the range observed in symptomatic DIAD carriers. Phosphorylated tau markers (pTau181, pTau217, pTau205) were intermediate between DIAD carriers and non-carriers, suggesting potential modifications in tau pathology.

Proteomic and metabolomic analyses identified alterations in pathways related to protein synthesis, metabolism, and anti-oxidative stress responses, which could contribute to resistance against neurodegeneration.

It is a rare example of a DIAD mutation carrier defying the expected clinical course, raising new questions about the interplay between genetic, biological, and environmental factors in AD progression. While the exact mechanisms of resistance remain unclear, restricted tau pathology may play a crucial role. Further research is needed to determine whether blocking tau spread could serve as a therapeutic strategy for delaying or preventing Alzheimer’s disease.

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