APP, PSEN1, and PSEN2

What these genes do

APP provides instructions for amyloid precursor protein. When APP is processed, it can produce amyloid beta fragments. PSEN1 and PSEN2 provide instructions for proteins that are part of gamma-secretase, one of the enzyme complexes involved in processing APP.

Certain pathogenic variants alter this biology in a way that leads to the development of Alzheimer's disease. The discovery of these families helped establish the importance of amyloid biology in Alzheimer's research.

The presence of a DNA difference in one of these genes is not automatically a diagnosis. The laboratory must determine whether the specific variant has enough evidence to be classified as pathogenic or likely pathogenic. A variant of uncertain significance should not be treated as a familial cause.

What the family pattern may look like

Autosomal dominant Alzheimer's disease often appears in successive generations. An affected parent may have affected children, and both women and men can inherit and pass on the variant.

Symptoms frequently begin before age 65 and often in the 30s, 40s, or 50s, depending on the gene and variant. PSEN2 can have a wider and sometimes later range of onset. Family members with the same variant may still differ in the age symptoms begin and in the features that appear first.

A small family, early deaths from other causes, adoption, incomplete medical information, or reduced penetrance can make a dominant pattern difficult to see. Conversely, several relatives with late-life dementia do not by themselves prove that APP, PSEN1, or PSEN2 is involved.

How inheritance works

APP, PSEN1, and PSEN2 pathogenic variants associated with familial Alzheimer's disease are usually inherited in an autosomal dominant manner. If a person carries a confirmed familial pathogenic variant, each child has a 50 percent chance of inheriting that variant.

That is a probability for each pregnancy, not a prediction that half of the children in one family will necessarily inherit it. Sons and daughters have the same chance.

Inheriting the variant may confer a very high likelihood of developing disease, but it usually does not provide an exact date of onset or a detailed forecast of symptoms and progression.

Who should be tested first

When possible, testing should begin with a relative who has symptoms. A confirmed pathogenic variant in an affected person establishes the familial finding. Other adult relatives can then decide whether to pursue a targeted test for that exact variant.

Testing an unaffected relative first with a broad panel can be difficult to interpret. A negative result may not identify whether the family has an undiscovered cause, a type of change not detected by that method, or a condition that was clinically misclassified.

The testing strategy may include sequencing and deletion or duplication analysis. APP duplications are one reason the laboratory method matters. In a family with overlapping dementia, language, behavior, movement, or motor-neuron symptoms, the clinician may recommend a broader panel rather than testing only these three genes.

Diagnostic testing and predictive testing are different

In someone who has symptoms, a pathogenic result may help explain the diagnosis and direct family counseling. The genetic result should still be interpreted alongside the clinical pattern and, when appropriate, Alzheimer's biomarkers.

In an adult relative without symptoms, testing is predictive. The person is choosing whether to learn if the known familial variant was inherited before disease is clinically apparent. That decision can affect emotional health, family relationships, long-term planning, insurance considerations, and reproductive choices.

Formal genetic counseling helps a person consider these outcomes before testing and plan how the result will be disclosed. Predictive testing of children for an adult-onset condition is generally avoided when the result would not change medical care during childhood.

What a result can change

A confirmed pathogenic variant may:

• establish the cause of Alzheimer's disease in a family;
• allow adult relatives to choose targeted predictive testing;
• clarify eligibility for some observational studies or gene-specific trials;
• inform reproductive options and long-term planning;
• prevent repeated broad testing in other relatives.

It does not measure current memory, the amount of amyloid or tau in the brain, or the present stage of disease. A genetic result and a biomarker result answer different questions.

What a negative result means

If the family's pathogenic variant is known and a relative tests negative for that exact variant, that person did not inherit that familial cause.

If no family variant has been identified, a negative APP, PSEN1, and PSEN2 panel does not prove that the condition is non-genetic. It also does not rule out Alzheimer's disease as the cause of a symptomatic person's illness.