Biomarkers.

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Autosomal dominant Alzheimer Disease (ADAD) typically causes dementia in individuals aged 30s-50s.
• A deep phenotyping study focused on a highly resilient mutation carrier (rMC) with the presenilin 2 p.Asn141Ile mutation.
• This rMC remained non-demented over two decades past their expected dementia onset.

Purpose of the Study:

• To investigate the biological mechanisms underlying cognitive resilience in a rare ADAD mutation carrier.
• To understand how atypical tau pathology distribution influences dementia onset and progression.

Main Methods:

• Dementia status assessed via Clinical Dementia Rating (CDR).
• Tau PET imaging (flortaucipir) and amyloid imaging (PiB) were utilized.
• Task-based functional MRI (fMRI) from the Human Connectome Project Aging (HCP Aging) study was performed.

Main Results:

• The rMC maintained cognitive unimpaired status (CDR=0).
• Elevated global amyloid levels (SUVR ~3.6) with a typical ADAD spatial distribution were observed.
• An atypical tau pathology pattern was noted, primarily restricted to the visual cortex and asymmetrically lateralized to the left hemisphere.

Conclusions:

• High amyloid levels confirm preserved mutation penetrance.
• Atypical tau pathology distribution, with limited spread, is associated with preserved cognition.
• Further fMRI analysis is needed to determine if underlying tissue is impaired or if resilience stems from reduced tau toxicity or spread.