Test Id : C2AD2

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.

1. Specimens must be shipped frozen on dry ice.

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

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 degrees C.

1.5 mL

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

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

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 to100 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.

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

Negative: 0-47

Positive: 48-100

Abeta42/40 Ratio:

> or =0.095 Consistent with absence of amyloid plaques

Percent p-tau217:

<4.2% consistent with absence of brain amyloid plaques

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. Amyloid Probability Score and Interpretation

The APS2 result should be interpreted in conjunction with other patient information. Clinical correlation is recommended.

This test is not a standalone test; Positive or negative APS2 values alone neither rule in nor rule out a diagnosis of Alzheimer disease (AD).

Test results should be used in conjunction with other diagnostic tools, such as neurological examination, neurobehavioral tests, imaging, and routine laboratory tests.

False-positive and false-negative test results may occur.

This test uses interpretive data that were derived from clinical studies in a predominantly White US population of patients with mild cognitive impairment or early dementia. The extent of the differences in results (if any) based on individuals of other racial and ethnic groups has not yet been firmly established.

Currently, there is insufficient evidence to support serial testing for the assessment of longitudinal changes in biomarkers, including monitoring response to therapy.

The results of other analyte tests using other methodologies cannot be interpreted in the context of the PrecivityAD2 test.

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

Plasma specimens undergo immunoprecipitation followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) for the quantification of amyloid beta (Abeta) 42 and Abeta 40 peptide isoform concentrations and phosphorylated and non-phosphorylated tau at amino acid threonine, position 217 (p-tau271 and np-tau217) peptide concentrations. The percent tau phosphorylated at threonine-217 (%p-tau217) is calculated using the following equation: p-tau271/np-tau217*100. A statistical algorithm combines the Abeta42/40 and %p-tau217 to generate the Amyloid Probability Score 2 (APS2).(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)

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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.

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