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Test ID: AD2AR PrecivityAD2, Reflex to Apolipoprotein E, Plasma


Ordering Guidance


This blood test is intended for use in patients aged 55 and older with signs or symptoms of mild cognitive impairment or dementia who are undergoing evaluation for Alzheimer disease or other forms of cognitive decline, and who have not had prior apolipoprotein E proteotyping or APOE genotyping.



Shipping Instructions


1. Specimens must be shipped frozen on dry ice.

2. Place labeled aliquot tubes inside a larger tube or vial for transport.



Specimen Required


Supplies: Screw cap micro tube, 2 mL, PCR Performance Tested, Low protein-binding (T983)

Collection Container/Tube: 10 mL Purple top (K EDTA)

Submission Container/Tube: Two 2-mL screw cap micro tubes

Specimen Volume: 3 mL in 2 tubes, each containing 1.5 mL

Collection Instructions:

1. Centrifuge within two hours of collection.

2. Label two 2-mL screw-cap micro tubes.

3. Aliquot 1.5 mL of plasma into each labeled micro tube.

4. Freeze plasma (no longer than 2 hours after collection) at or below -20° C.


Useful For

Assisting in the evaluation of adult patients, aged 55 years and older, with signs or symptoms of mild cognitive impairment or dementia who are being assessed for Alzheimer disease and other causes of cognitive decline

 

Determining APOE E4 status to aid in medical management and treatment decisions when the PrecivityAD2 blood test result is positive

 

This test is not intended for patients younger than 55 years, or for use as a screening test in patients without signs or symptoms of cognitive, or for serial testing for assessment of longitudinal changes.

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
C2NAP Precivity-ApoE No No

Testing Algorithm

When this test result is positive, then apolipoprotein E testing will be performed at an additional charge.

Method Name

Immunoprecipitation/Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS)

Reporting Name

PrecivityAD2 Reflex to ApoE

Specimen Type

Plasma

Specimen Minimum Volume

See Specimen Required

Specimen Stability Information

Specimen Type Temperature Time
Plasma Frozen

Clinical Information

Alzheimer disease (AD) is defined pathologically by the presence of amyloid plaques and neurofibrillary tangles in the brain. Clinical characteristics include gradual onset of Mild cognitive impairment (MCI), behavioral changes such as apathy, withdrawal, or agitation, and disease progression to middle and later stage dementia.(1,2) Currently, no test detects AD with 100% accuracy; definitive diagnosis occurs at brain autopsy.

 

Recent availability of anti-amyloid therapies increases the importance of detection of AD at an early stage.(3-5) MCI impacts 12% to 18% of people in the United States over age 60 and is often an initial clinical sign of AD.(6) Establishing or excluding an AD diagnosis with a high degree of certainty at first signs of memory decline may optimize medical management.

 

Brain amyloid pathology is detectable by amyloid positron emission tomography (PET) scan, cerebrospinal fluid testing, or liquid chromatography tandem mass spectrometry blood biomarker testing with high sensitivity and specificity in patients with MCI and early dementia.(7-12) In all testing modalities, healthcare providers interpret test results in the context of the patient's clinical findings and other clinical work-up, as the neuropathological changes associated with AD can be seen in other forms of dementia and in unaffected individuals.(7,8,13)

 

The PrecivityAD2 test is an analytically and clinically validated blood test that aids healthcare providers in ruling in or ruling out AD in patients presenting with MCI or dementia. This evaluation simultaneously quantifies specific plasma amyloid beta (Abeta) and tau peptide concentrations to calculate the Abeta42/40 ratio and percent tau phosphorylated at threonine-217 (% p-tau217).(12) The inclusion of plasma analyte ratios has been shown to mitigate the effects of confounding factors such as chronic kidney disease.(14,15) The ratios are combined into a proprietary statistical algorithm to calculate the Amyloid Probability Score 2 (APS2), a numerical value ranging from 0 to 100, that determines whether a patient is positive (has high likelihood) or negative (has low likelihood) for the presence of brain amyloid plaques by amyloid PET scan.

 

For patients with a positive PrecivityAD2 blood test result, apolipoprotein E (ApoE) proteotyping is performed to determine APOE E4 status.

 

ApoE is a component of several classes of lipoprotein particles, including chylomicron remnants, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and high-density lipoprotein (HDL) and is highly expressed in the liver and brain.(16) The protein has seven isoforms (ApoE1-7), the most common of which are ApoE2, ApoE3 and ApoE4. ApoE isoforms are encoded by the APOE gene alleles E1-E7. The E3 allele, most frequent in all populations, has a frequency range of 50% to 90%, whereas E4 and E2 allele frequencies range from 5% to 35% and 1% to 5%, respectively.(17)

 

ApoE isoforms differentially influence the buildup of amyloid beta plaques and tau neurofibrillary tangles in the brain. Determination of APOE proteotype/genotype status may aid in clinical evaluation for AD in symptomatic patients and can inform decision-making for optimal treatment pathways.(18-21) In recent clinical trials for amyloid-reducing therapies, the E4 allele showed an association with the development of amyloid-related imaging abnormalities (ARIA): cerebral edema (ARIA-E), and cerebral microhemorrhages (ARIA-H).(3,4)

Reference Values

Amyloid Probability Score 2 (APS2) (range of 0-100):

Negative: 0-47

Positive: 48-100

 

Abeta42/40 Ratio:

≥0.095 Consistent with absence of amyloid plaques

 

Percent p-tau217:

<4.2% consistent with absence of brain amyloid plaques

 

ApoE Proteotype

E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4

-E3 is the most common allele.

-E4 allele is associated with increased risk of amyloid plaques.

-E2 allele is associated with lower risk of amyloid plaques.

Interpretation

The Amyloid Probability Score 2 (APS2) result is a composite score ranging from 0 to 100 that demonstrates the strongest correlation with brain amyloid pathology compared to the individual biomarkers (amyloid beta [Abeta] 42/40 ratio or percent tau phosphorylated at threonine-217 [%p-tau217]), considered separately. Discordance of the individual biomarkers can occur.

 

Table 1. Amyloid Probability Score and Interpretation

APS2

Interpretation

0-47

Negative

Consistent with a negative amyloid positron emission tomography (PET) scan; reflects a low likelihood of brain amyloid plaques and is therefore not consistent with a neuropathological diagnosis of Alzheimer disease (AD).

48-100

Positive

Consistent with a positive amyloid PET scan; reflects a high likelihood of brain amyloid plaques, one of the neuropathological findings of AD.

 

For apolipoprotein E (ApoE) testing, there are six possible allele combinations for AD risk interpretation.

 

ApoE proteotyping determines which ApoE protein types are present in the submitted sample. The protein types detected determine the presence of E2, E3, and/or E4 alleles, corresponding to the patient's APOE genotype (see Table 2).

 

Table 2. Proteotype Interpretation

Proteotype result

Corresponding genotype

Interpretation

ApoE2/ApoE2

APOE2/APOE2

E2/E2 homozygous individuals have a significantly decreased risk for AD compared to E3/E3 and E4 carriers.

ApoE2/ApoE3

APOE2/APOE3

E2/E3 heterozygous individuals have a decreased risk for AD compared to E3/E3, and E4 carriers.

ApoE2/ApoE4

APOE2/APOE4

E2/E4 heterozygous individuals have an increased risk for AD compared to E3/E3, E2/ E2, and E2/E3 proteotypes/ genotypes.

ApoE3/ApoE3

APOE3/APOE3

E3/E3 homozygous individuals are most common and have decreased risk for AD com- pared to E4 carriers, and increased risk compared to E2/E2 and E2/ E3 proteotypes/genotypes.

ApoE3/ApoE4

APOE3/APOE4

E3/E4 heterozygous individuals have an approximately three-fold increased risk for AD compared to E4 noncarriers.

ApoE4/ApoE4

APOE4/APOE4

E4/E4 homozygous individuals have an approximately eight- to twelve-fold increased risk for AD compared to E4 noncarriers.

Clinical Reference

1. Centers for Disease Control and Prevention. Alzheimer's Disease and Related Dementias. CDC; Updated October 26,2020. Accessed March 25, 2024. Available at www.cdc.gov/aging/aginginfo/alzheimers.htm

2. Bird TD. Alzheimer Disease Overview. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews. University of Washington, Seattle; October 23, 1998. Updated December 20, 2018. Accessed March 13, 2024. Available at www.ncbi.nlm.nih.gov/books/NBK1161/

3. Cummings J, Aisen P, Apostolova LG, Atri A, Salloway S, Weiner M. Aducanumab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2021;8(4):398-410. doi:10.14283/jpad.2021.41

4. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948

5. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527. doi:10.1001/jama.2023.13239

6. Alzheimer's Association. Mild Cognitive Impairment (MCI). Accessed July 21, 2023. Available at https://www.alz.org/alzheimers-dementia/what-is-dementia/related_conditions/mild-cognitive-impairment

7. Johnson KA, Minoshima S, Bohnen NI, et al. Update on appropriate use criteria for amyloid PET imaging: dementia experts, mild cognitive impairment, and education. Amyloid Imaging Task Force of the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging. Alzheimers Dement. 2013;9(4):e106-e109. doi:10.1016/j.jalz.2013.06.001

8. Shaw LM, Arias J, Blennow K, et al. Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer's disease. Alzheimers Dement. 2018;14(11):1505-1521. doi:10.1016/j.jalz.2018.07.220

9. Kirmess KM, Meyer MR, Holubasch MS, et al. The PrecivityAD test: Accurate and reliable LC-MS/MS assays for quantifying plasma amyloid beta 40 and 42 and apolipoprotein E proteotype for the assessment of brain amyloidosis. Clin Chim Acta. 2021;519:267-275. doi:10.1016/j.cca.2021.05.011

10. West T, Kirmess KM, Meyer MR, et al. A blood-based diagnostic test incorporating plasma Abeta42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: findings from a multi cohort validity analysis. Mol Neurodegener. 2021;16(1):30. Published 2021 May 1. doi:10.1186/s13024-021-00451-6

11. Hu Y, Kirmess KM, Meyer MR, et al. Assessment of a plasma amyloid probability score to estimate amyloid positron emission tomography findings among adults with cognitive impairment. JAMA Netw Open. 2022;5(4):e228392. Published 2022 Apr 1. doi:10.1001/jamanetworkopen.2022.8392

12. Meyer MR, Kirmess KM, Eastwood S, et al. Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Abeta42/40 ratio to identify presence of brain amyloid. Alzheimers Dement. Published online March 16, 2024. doi:10.1002/alz.13764

13. Jansen WJ, Janssen O, Tijms BM, et al. Prevalence estimates of amyloid abnormality across the Alzheimer disease clinical spectrum [published correction appears in JAMA Neurol. 2022 Mar 1;79(3):313]. JAMA Neurol. 2022;79(3):228-243. doi:10.1001/jamaneurol.2021.5216

14. Janelidze S, Barthelemy NR, He Y, Bateman RJ, Hansson O. Mitigating the associations of kidney dysfunction with blood biomarkers of Alzheimer disease by using phosphorylated tau to total tau ratios [published correction appears in JAMA Neurol. 2023 Aug 1;80(8):873]. JAMA Neurol. 2023;80(5):516-522. doi:10.1001/jamaneurol.2023.0199

15. Pichet Binette A, Janelidze S, Cullen N, et al. Confounding factors of Alzheimer's disease plasma biomarkers and their impact on clinical performance. Alzheimers Dement. 2023;19(4):1403-1414. doi:10.1002/alz.12787

16. Mahley RW, Rall SC Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507-537. doi:10.1146/annurev.genom.1.1.507

17. Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 2011;10(3):241-252. doi:10.1016/S1474-4422(10)70325-2

18. Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer's disease. Neuron. 2009;63(3):287-303. doi:10.1016/j.neuron.2009.06.026

19. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921-923. doi:10.1126/science

20. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;43(8):1467-1472. doi:10.1212/wnl.43.8.1467

21. Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy [published correction appears in Nat Rev Neurol. 2013. doi:10.1038/nmeurol.2013.32. Liu, Chia-Chan [corrected to Liu, Chia-Chen]]. Nat Rev Neurol. 2013;9(2):106-118. doi:10.1038/nrneurol.2012.263

22. Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer's disease. Annu Rev Med. 1996;47:387-400. doi:10.1146/annurev.med.47.1.387

Day(s) Performed

Monday through Friday

Report Available

15 days post sample receipt from MCL

Test Classification

C2N Diagnostics has developed and determined the analytical and clinical validity performance characteristics of this Laboratory Developed Test (LDT). This assay has been validated pursuant to CLIA regulations and is used for clinical purposes. This assay has not been cleared or approved by the FDA.

CPT Code Information

0503U

LOINC Code Information

Test ID Test Order Name Order LOINC Value
AD2AR PrecivityAD2 Reflex to ApoE Not Provided

 

Result ID Test Result Name Result LOINC Value
C2RG Amyloid Probability Score 2 (APS2) Not Provided
C2RGF APS2 Result Not Provided
C2RH APS2 Result Interpretation Not Provided
C2RI APS2 Result Reference Interval Not Provided
C2RJ APS2 Description Not Provided
C2RK Percent p-tau217 Not Provided
C2RL Percent p-tau217 Reference Interval Not Provided
C2RLD Percent p-tau217 Description Not Provided
C2RM Abeta42/40 Ratio Not Provided
C2RN Abeta42/40 Ratio Reference Interval Not Provided
C2RND Abeta42/40 Ratio Description Not Provided
C2RO Test Description Not Provided
C2RP Limitations of Test Result Not Provided
C2RQ Methods and Assay Category Not Provided
C2RR References Not Provided
C2RRC Report Comment Not Provided
C2RRF Performing Site Not Provided