Yes. A follow-up PSEN2 genetic test can change dementia care decisions when the first result is borderline.
PSEN2 is a gene linked to early-onset Alzheimer disease, and clarifying the result can open trials and family planning. A borderline result usually means a variant of uncertain significance, called a VUS. A systematic review in Frontiers in Aging Neuroscience found 5.09% of previously reported APP, PSEN1 and PSEN2 variants were actually VUS, so borderline calls are common, described in the systematic re-evaluation.
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
- Who is PSEN2 testing meant for?
- What does a borderline result mean?
- How can a clearer answer change care?
- What are the limits of PSEN2 testing?
Who is PSEN2 testing meant for?
PSEN2 variants cause autosomal-dominant early-onset Alzheimer disease. They affect families with dementia across generations. The American College of Medical Genetics and National Society of Genetic Counselors joint guideline reports about 95% penetrance and typical onset from age 40 to 75, detailed in the joint ACMG and NSGC guideline.
Testing is recommended for dementia onset before about age 60 to 65. It is also recommended for people with three or more affected relatives. These groups are most likely to carry PSEN2, according to the University of Pennsylvania Perelman School of Medicine.
What does a borderline result mean?
Borderline does not mean positive or negative. It means the lab cannot yet call the variant harmful or harmless. That label often changes after expert review, family data, or updated records.
PSEN2 is hard to interpret. Even established variants show incomplete penetrance and variable expression within and between families. One example is PSEN2-N141I, with a wide onset range such as 39 to 75 years in the AlzForum database.
How can a clearer answer change care?
A confirmed pathogenic result can establish eligibility for Dominantly Inherited Alzheimer Network trials. Those trials enroll carriers of pathogenic PSEN1, PSEN2 or APP variants and at-risk relatives, according to Neuroscience Research Australia, described in the DIAN trial summary. For a family facing early dementia, that can mean a concrete next appointment.
A confirmed result also changes care for relatives. It triggers cascade predictive testing, reproductive and family-planning counseling, and long-term care planning for first-degree relatives. Those are often the main practical benefits beyond the patient. Families can take these practical steps:.
- Ask for genetics referral and variant re-review
- Share family history across three generations when possible
- Ask whether relatives can give samples to aid interpretation
- Ask about trial referral if the variant is reclassified as pathogenic
What are the limits of PSEN2 testing?
Testing yield is modest. Studies report a hereditary cause in 5 to 13% of early-onset cases tested, with PSEN2 explaining about 5% of familial early-onset cases. Most families tested will not get a definitive inherited cause.
PSEN2 testing cannot predict onset age, severity, symptom type or progression rate. A negative result without a known familial mutation does not exclude genetic risk. Decisions still require counseling and biomarkers.
