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Alzheimer Disease, Familial or Cerebral Amyloid Angiopathy via the APP Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
4557 APP 81406 81406,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4557APP81406 81406,81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Li Fan, MD, PhD, FCCMG, FACMG

Clinical Features and Genetics

Clinical Features

Familial Alzheimer disease (FAD) is a neurodegenerative disorder characterized by onset of dementia at a relatively young age. Dementia initially presents in FAD patients as short term memory problems or disorientation between 30 and 60 years of age. Cognitive decline is observed over the next 10-20 years with apraxia, progressive memory loss and impaired spatial skills being common presentations (Wallon et al. 2012). Motor disturbances such as cerebellar ataxia and spastic paraparesis are also observed in a subset of patients. The key neuropathology of FAD includes: amyloid plaques, neurofibrillary tangles, neuronal loss and brain atrophy (Wu et al. 2012). An important feature of the FAD diagnosis is that an individual has at least one affected family member.

Cerebral amyloid angiopathy APP-related (CAA): Select pathogenic variants in the APP gene can also cause severe cerebral amyloid angiopathy, where amyloid fibrils accumulate in blood vessels and can lead to cerebral hemorrhage, stroke and progressive dementia. Clinical and neuropathologic symptoms of cerebral amyloid angiopathy overlap with Alzheimer disease. Several variants such as Dutch, Iowa, Italian, Flemish, Arctic, etc. have been reported (Revesz et al. 2009; Biffi and Greenberg 2011; Kumar-Singh et al 2002).

Genetics

Familial Alzheimer disease is inherited in an autosomal dominant manner and can be caused by pathogenic variants in the APP gene. Almost all reported APP pathogenic variants are missense, frameshift and small deletion variants contained within Exons 16 and 17 of the APP gene, except rare large duplications. These variants disrupt processing of APP into mature amyloid-beta protein (Janssen et al. 2003; Mullan et al. 1992; Tomiyama et al. 2008). Large duplications encompassing the entire APP gene have also been identified in FAD patients (McNaughton et al. 2012). A rare recessive pathogenic variant in the APP gene was reported to cause FAD (Di Fede et al. 2009).

Cerebral amyloid angiopathy APP-related is inherited in an autosomal dominant manner. The causative pathogenic variants in cerebral amyloid angiopathy are missense variants and large duplications in APP gene. Most pathogenic variants such as Dutch, Iowa, Italian, Flemish Arctic etc. are concentrated in exon 17 (Biffi and Greenberg 2011; Sleegers et al 2006; Kumar-Singh et al 2002). APP encodes amyloid-beta precursor protein (APP). Numerous studies suggest that APP has a trophic function and it may be involved in neuronal stem cell development, neuronal survival, neurite outgrowth, neurorepair and memory formation (Dawkins and Small 2014; Bourdet et al. 2015). APP protein is post-translationally processed into two amyloid-beta isoforms: AB40 and AB42. The gamma-secretase complex that processes APP contains the proteins PSEN1 and PSEN2, which also play a role in FAD pathogenesis (Sua'rez-Calvet et al. 2014). Pathogenic variants in the APP gene that disrupt the gamma-secretase cleavage site can result in increased levels of the AB42 isoform relative to the AB40 isoform. This imbalance promotes amyloid-beta aggregation (Kumar-Singh et al. 2000). Pathogenic variants in the APP gene also result in hyperphosphorylation of the microtubule associated protein, tau (Umeda et al. 2014). Hyperphosphorylation causes tau to form long filaments and neurofibrillary tangles. The presence of amyloid plaques and neurofibrillary tangles leads to neuroinflammation and neuronal cell death, which underlie the dementia phenotype.

Clinical Sensitivity - Sequencing with CNV PG-Select

Point variants in the APP gene are identified in ~ 15% of familial Alzheimer disease cases (Wallon et al. 2012; Janssen et al. 2003). Detection rate of pathogenic variants in the APP gene in cerebral amyloid angiopathy is unknown as no large-scale molecular studies have been done. APP-related cerebral amyloid angiopathy is the most common form of cerebral amyloid angiopathy.

Testing Strategy

This test provides full coverage of all coding exons of the APP gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

APP testing should be considered for individuals with early onset dementia who have at least one affected family member and for which no PSEN1 mutation has been identified (Loy et al. 2013). APP sequencing can also be used to determine carrier status of individuals for a known familial mutation. APP testing is also recommended for individual who are suspected to have cerebral amyloid angiopathy.

Gene

Official Gene Symbol OMIM ID
APP 104760
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Cerebral Amyloid Angiopathy, App-Related AD 605714

Related Test

Name
Alzheimer Disease, Familial, Panel

Citations

  • Biffi A., Greenberg SM. 2011. Journal of Clinical Neurology (seoul, Korea). 7: 1-9. PubMed ID: 21519520
  • Bourdet I. et al. 2015. The Journal of Neuroscience : the Official Journal of the Society For Neuroscience. 35: 1043-51. PubMed ID: 25609621
  • Dawkins E., Small DH. 2014. Journal of Neurochemistry. 129: 756-69. PubMed ID: 24517464
  • Di Fede G. et al. 2009. Science. 323: 1473-7. PubMed ID: 19286555
  • Janssen JC. et al. 2003. Neurology. 60: 235-9 PubMed ID: 12552037
  • Kumar-Singh S. et al. 2000. Human Molecular Genetics. 9: 2589-98. PubMed ID: 11063718
  • Kumar-Singh S. et al. 2002. The American Journal of Pathology. 161: 507-20. PubMed ID: 12163376
  • Loy CT. et al. 2014. Lancet. 383: 828-40. PubMed ID: 23927914
  • McNaughton D. et al. 2012. Neurobiology of Aging. 33: 426.e13-426.e21 PubMed ID: 21193246
  • Mullan M. et al. 1992. Nature Genetics. 1: 345-7. PubMed ID: 1302033
  • Revesz T. et al. 2009. Acta Neuropathologica. 118: 115-130 PubMed ID: 19225789
  • Sleegers K. et al. 2006. Brain. 129: 2977-2983 PubMed ID: 16921174
  • Suárez-Calvet M. et al. 2014. Journal of Neurochemistry. 128: 330-9 PubMed ID: 24117942
  • Tomiyama T. et al. 2008. Annals of Neurology. 63: 377-87. PubMed ID: 18300294
  • Umeda T. et al. 2014. Acta Neuropathologica. 127: 685-98. PubMed ID: 24531886
  • Wallon D. et al. 2012. Journal of Alzheimer's Disease. 30: 847–856 PubMed ID: 22475797
  • Wu L. et al. 2012. The Canadian Journal of Neurological Sciences. 39: 436–445 PubMed ID: 22728850

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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