A confirmed disease-causing PSEN1 result can change dementia care decisions, but a borderline result alone should not. PSEN1 is a gene that provides instructions for presenilin-1, a key part of an enzyme that processes amyloid precursor protein, according to the U.S.
National Library of Medicine MedlinePlus Genetics gene guide. Borderline usually means a variant of uncertain significance, often called a VUS. It signals that the lab found a change but the evidence does not yet show whether it causes disease.
Medical information disclaimer: This article is for general educational purposes only and does not provide medical advice, diagnosis, or treatment. Always consult a physician or other qualified health professional about symptoms, medications, tests, or treatment decisions.
Table of Contents
- What does a borderline PSEN1 result mean?
- Why do clinicians hold off on VUS-based changes?
- What can a confirmed PSEN1 result change?
- What steps help resolve a borderline finding?
What does a borderline PSEN1 result mean?
A borderline result means the variant lacks enough evidence for a clear benign or pathogenic call. The gene has dozens of variants tied to early-onset Alzheimer disease before age 65. A VUS sits between those poles.
Reclassification happens. A 2021 systematic re-evaluation found that most prior pathogenic calls in APP, PSEN1 and PSEN2 stayed pathogenic or likely pathogenic, but a small share moved down to uncertain significance, according to the Frontiers in Aging Neuroscience team systematic variant re-analysis. That shift explains why one report may look less definite than an older family report.
Why do clinicians hold off on VUS-based changes?
Clinicians treat a VUS as non-actionable because the result does not prove disease risk. A review of ACMG variant guidance states that a variant of uncertain significance should not be used in clinical decision-making, according to the Journal of the Advanced Practitioner in Oncology review ACMG guidance review.
Care continues based on symptoms, exam, cognitive testing and brain imaging. This pause protects families from wrong choices. Starting or stopping a drug, moving a relative into care, or making permanent family-planning choices on a VUS risks harm if later data show the variant is harmless.
What can a confirmed PSEN1 result change?
A confirmed pathogenic PSEN1 variant can sharpen diagnosis and family planning. Joint guidelines from the American College of Medical Genetics and the National Society of Genetic Counselors note that such a result can confirm early-onset familial Alzheimer diagnosis, guide predictive counseling and testing of at-risk relatives after testing an affected relative first, and shape reproductive and long-term care choices ACMG and NSGC practice guidelines.
In practice, that means clearer talks about who should consider testing, when children or siblings may want counseling, and what support to arrange. It also helps families separate inherited risk from age-related memory change.
What steps help resolve a borderline finding?
Families can pursue clarity without acting as if the VUS is positive. Useful next actions include: Added monitoring may be prudent while reclassification proceeds, but intervention based only on the VUS is not advised. Keep copies of reports, family history and test dates so any future review starts with complete records.
- Ask for referral to genetics for pedigree review and counseling
- Ask whether relatives with dementia can provide samples for segregation testing
- Ask whether the lab will re-review the variant against updated databases
- Ask what symptom monitoring and follow-up schedule fits now
