Early-Onset Alzheimer's Panel, Sequencing

Last Literature Review: December 2019 Last Update:
  • Confirm diagnosis of early-onset AD in symptomatic individuals
  • Perform presymptomatic testing in individuals with a family history of early-onset AD
  • Contraindications for ordering:
    • Test should not be ordered in individuals whose symptoms developed later than age 65

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Alzheimer’s disease (AD) is characterized by progressive memory loss leading to dementia. Up to 25% of AD may be hereditary. Less than 2% of cases are the early-onset familial form, defined as a diagnosis of AD before age 65, while 15-25% of cases are a late-onset familial form. Although symptoms of familial early-onset AD are similar to late-onset (sporadic AD), there is a greatly increased chance of identifying a genetic etiology with early-onset AD. Diagnosis of AD requires autopsy or a molecular genetic confirmation.

Disease Overview

Symptoms of Early-Onset AD

Symptom onset typically occurs between 30 and 60 years of age. Duration of disease is approximately 8-10 years.

  • Progressive dementia beginning as subtle failure of memory (mild cognitive impairment)
  • Confusion
  • Poor judgment
  • Loss of language skills
  • Agitation
  • Depression and withdrawal
  • Hallucination
  • Occasionally: seizures, Parkinson-like movements, hypertonia, and other movement disorders

Prevalence

Less than 2% of individuals with a diagnosis of AD have the early-onset familial form diagnosed before age 65. 

Etiology

Pathogenic variants in the APP, PSEN1, and PSEN2 genes

Inheritance

Autosomal dominant

Genotype-Phenotype Correlation

PSEN2 has been shown to have reduced penetrance. 

Test Description

See Genes Tested table for genes included in this panel.

Clinical Sensitivity

This test will identify a cause for familial early-onset AD in approximately 60-80% of cases. Clinical sensitivity is inversely related to age of onset. 

Familial early-onset AD is due to pathogenic variants in the following genes:

  • PSEN1 (20-70%)  
  • APP (10-15%)
  • PSEN2 (5%)
  • Unknown (20-40%) 

Limitations

  • A negative result does not exclude a heritable form of early-onset Alzheimer’s disease.  
  • This assay only detects variants within the coding regions and intron-exon boundaries of the targeted genes.
  • Regulatory region variants and deep intronic variants will not be identified. Noncoding transcripts will not be analyzed.
  • Deletions/duplications/insertions of any size may not be detected by massive parallel sequencing.
  • Diagnostic errors can occur due to rare sequence variations. In some cases, variants may not be identified due to technical limitations in the presence of pseudogenes and repetitive or homologous regions.
  • This assay may not detect low-level mosaic or somatic variants associated with disease.
  • Interpretation of this test result may be impacted if this patient has had allogeneic stem cell transplantation.
  • The following regions are not sequenced due to technical limitations of the assay: APP (NM_001136016.3) exon 1

Analytic Sensitivity 

For massively parallel sequencing:

Variant Class Analytic Sensitivity (PPA) Estimatea (%) Analytic Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Testing Strategy

Genes Tested
Gene MIM Number Disorder and Subtype (Abbreviation) Inheritance

APP

104300

Familial Alzheimer's disease, type 1

AD

PSEN1

607822

Alzheimer's disease, type 3

AD

PSEN2

606889

Alzheimer's disease, type 4

AD

References

Related Information
Alzheimer's Disease