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Alzheimer's Disease, Familial, Plus APOE Panel

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
15781 APOE 81479,81479 Order Options and Pricing
APP 81406,81479
PSEN1 81405,81479
PSEN2 81406,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
15781Genes x (4)81479 81405(x1), 81406(x2), 81479(x5) $990 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. 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.

We only report the following APOE genotypes: E4/E4, E4/E2 and E4/E3.

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

Testing run on PG-Select capture probes does not include exome-wide CNV analysis. Reflex is available to PGxome or an exome-based panel, or you can use this gene list to create a custom panel (click here).

Click here for costs to reflex to whole PGxome.

Turnaround Time

3 weeks on average for standard orders or 2 weeks 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's disease is a neurodegenerative disorder characterized by onset of dementia at a relatively young age. Dementia initially presents in patients with familial Alzheimer's disease 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. PubMed ID: 22475797). Motor disturbances such as cerebellar ataxia and spastic paraparesis are also observed in a subset of patients. The key neuropathology of familial Alzheimer's disease includes amyloid plaques, neurofibrillary tangles, neuronal loss, and brain atrophy (Wu et al. 2012. PubMed ID: 22728850). An important feature of a familial Alzheimer's disease diagnosis is that an individual has at least one affected family member.

Patients with familial Alzheimer's disease caused by PSEN2 pathogenic variants typically show a later age of onset in the 50s or 60s as compared to onset in the 30s or 40s as seen in familial Alzheimer's disease caused by APP or PSEN1 variants (Jayadev et al. 2010. PubMed ID: 20375137). In addition, patients with PSEN2-related familial Alzheimer's disease have a higher frequency of behavioral and psychotic symptoms of dementia, such as hallucinations or delusions (Canevelli et al. 2014. PubMed ID: 24594196).

Genetics

Familial Alzheimer's disease is inherited in an autosomal dominant manner and can be caused by pathogenic variants in the APP, PSEN1, and PSEN2 genes.

Reported APP pathogenic variants include missense, frameshift, and small deletion variants mainly located in exons 16 and 17 of the APP gene. These variants disrupt the processing of APP into mature amyloid-beta protein (Janssen et al. 2003. PubMed ID: 12552037; Mullan et al. 1992. PubMed ID: 1302033; Tomiyama et al. 2008. PubMed ID: 18300294). Large duplications and large deletions encompassing the entire APP gene have also been identified in patients with familial Alzheimer's disease (McNaughton et al. 2012. PubMed ID: 21193246). A rare recessive pathogenic variant in the APP gene has been reported to cause familial Alzheimer's disease (Di Fede et al. 2009. PubMed ID: 19286555). APP encodes amyloid-beta precursor protein (APP). APP is post-translationally processed into two amyloid-beta isoforms: AB40 and AB42. The gamma-secretase complex that processes APP contains the proteins PS1 and PS2, which play a role in pathogenesis of familial Alzheimer's disease (Suárez-Calvet et al. 2014. PubMed ID: 24117942).

Most causative PSEN1 variants are missense variants distributed throughout the gene, though frameshifts, splice site variants, and large deletions in PSEN1 have also been identified in patients with familial Alzheimer's disease (Rogaeva et al. 2001. PubMed ID: 11524469; Janssen et al. 2003. PubMed ID: 12552037). PSEN1 encodes the presenilin-1 (PS1) protein. PS1 is the catalytic subunit of the gamma-secretase complex which cleaves the Alzheimer's-associated alpha-beta precursor protein (APP). PSEN1 variants are believed to act in a dominant negative manner to interfere with wildtype PS1 activity and to cause familial Alzheimer's disease via impaired APP processing by gamma-secretase (Nornes et al. 2008. PubMed ID: 17981814; Heilig et al. 2013. PubMed ID: 23843529).

The major causative PSEN2 variants are missense variants. Two variants, p.N141I and p.M239V, account for 74% of all PSEN2-related familial Alzheimer's disease cases (Canevelli et al. 2014. PubMed ID: 24594196). No large deletions or duplications have been reported to date. PSEN2 encodes the presenilin-2 (PS2) protein. PS2 is a subunit of the gamma-secretase complex which cleaves the Alzheimer's-associated alpha-beta precursor protein (APP). Although PSEN2 knockout mice do not show amyloid-beta processing defects, pathogenic PSEN2 variants were shown to alter AB40:AB42 ratios in in vitro cell-based assays (Herreman et al. 1999. PubMed ID: 10518543; Walker et al. 2005. PubMed ID: 15663477). 

APOE is a susceptibility gene for late onset Alzheimer's disease. In particular, the E4 allele is a risk factor for late-onset Alzheimer's disease. Note, however, that APOE genotyping is not fully specific or sensitive. APOE is just one of many risk factors for Alzheimer's disease (Desikan et al. 2017. PubMed ID: 28323831). Many individuals with the APOE E4/E4 genotype do not develop Alzheimer's disease during their lifetimes (Goldman et al. 2011. PubMed ID: 21577118; Bird. 2018. PubMed ID:20301340). Of note, several recent notable studies investigated APOE E4 effect on pathophysiology and therapeutic strategies (for example Koutsodendris and Rao. 2022. PubMed ID: 34460318; Raulin et al. 2022. PubMed ID: 36348357). 

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in PSEN1 account for 30%-70% of early-onset familial Alzheimer's disease while pathogenic variants in APP are identified in ~15% of familial Alzheimer's disease cases. Fewer pathogenic variants are found in PSEN2, which account for about 5% of all early-onset familial Alzheimer's disease (Marcon et al. 2009. PubMed ID: 19276543; Campion et al. 1999. PubMed ID: 10441572; Wallon et al. 2012. PubMed ID: 22475797; Janssen et al. 2003. PubMed ID: 12552037).

In cohorts of autosomal dominant early-onset Alzheimer's disease, the clinical sensitivity of APP locus duplications can be roughly estimated to be 8% (Rovelet-Lecrux et al. 2006. PubMed ID: 16369530). Large deletions in PSEN1 in a large cohort of patients with autosomal dominant early-onset Alzheimer's disease is unavailable in the literature because large deletions have only been reported in individual cases. No large deletions/duplications in PSEN2 have been reported.

Testing Strategy

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

We only report the following APOE genotypes: E4/E4, E4/E2 and E4/E3.

Indications for Test

Patients whose symptoms are consistent with familial Alzheimer’s disease are candidates for this panel.

Genes

Official Gene Symbol OMIM ID
APOE 107741
APP 104760
PSEN1 104311
PSEN2 600759
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Bird. 2018. PubMed ID: 20301340
  • Campion et al. 1999. PubMed ID: 10441572
  • Canevelli et al. 2014. PubMed ID: 24594196
  • Desikan et al. 2017. PubMed ID: 28323831
  • Di Fede et al. 2009. PubMed ID: 19286555
  • Goldman et al. 2011. PubMed ID: 21577118
  • Heilig et al. 2013. PubMed ID: 23843529
  • Herreman et al. 1999. PubMed ID: 10518543
  • Janssen et al. 2003. PubMed ID: 12552037
  • Jayadev et al. 2010. PubMed ID: 20375137
  • Koutsodendris and Rao. 2022. PubMed ID: 34460318
  • Marcon et al. 2009. PubMed ID: 19276543
  • McNaughton et al. 2012. PubMed ID: 21193246
  • Mullan et al. 1992. PubMed ID: 1302033
  • Nornes et al. 2008. PubMed ID: 17981814
  • Raulin et al. 2022. PubMed ID: 36348357
  • Rogaeva et al. 2001. PubMed ID: 11524469
  • Rovelet-Lecrux et al. 2006. PubMed ID: 16369530
  • Suárez-Calvet et al. 2014. PubMed ID: 24117942
  • Tomiyama et al. 2008. PubMed ID: 18300294
  • Walker et al. 2005. PubMed ID: 15663477
  • Wallon et al. 2012. PubMed ID: 22475797
  • Wu et al. 2012. 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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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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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