Behind the Basics: Nontraditional Biomarkers with Big Clinical Impact in Primary Care

 

NURSE PRACTITIONER CHRONICLES Clinical Education for NP Students & New Grads

 

Behind the Basics: Nontraditional Biomarkers with Big Clinical Impact in Primary Care

When the standard panel isn’t enough — a practical guide to Lp(a), ApoB, hs-CRP, coronary calcium, uACR, cystatin C, blood eosinophils, APOE, plasma p-Tau/amyloid ratios, and multi-cancer early detection tests.

Reviewed against: Baldor R. Behind the Basic: Nontraditional Markers with Big Clinical Impact in Primary Care. Pri-Med Institute CME activity, UMassChan Medical School, 2026; plus the primary guidelines and studies cited in the References section below.

A biomarker is any cellular, biochemical, or molecular change that can be measured in blood, urine, or tissue and used to assess risk, make a diagnosis, estimate prognosis, or track disease over time. In primary care, that almost always means a blood test. The panels most of us order daily — lipids, A1c, basic metabolic panel — are the traditional workhorses. But a growing set of “nontraditional” markers is moving from research labs into everyday practice, and knowing when one of them actually changes management (rather than just adding noise and cost) is now a core primary care skill.

This post walks through five domains where nontraditional biomarkers are reshaping primary care decision-making: cardiovascular risk refinement, chronic kidney disease, COPD management, dementia risk assessment, and multi-cancer early detection. For each, the goal is the same question a patient or a colleague might ask you in clinic: when should I actually order this, and what do I do with the result?

Cardiovascular Risk Refinement

Nontraditional cardiac biomarkers are not a replacement for the standard workup — they’re a tool for the gray zone. Start every risk conversation the way you always have: a lipid panel and A1c, blood pressure and BMI, and a history of smoking and family cardiovascular disease. Feed that into the AHA’s PREVENT equations to estimate 10-year ASCVD risk.

•  Low risk (<3%): no biomarkers needed — focus on preventive lifestyle counseling.

•  High risk (>10%): no biomarkers needed right now — the answer is to start medication and treat aggressively.

•  Borderline risk (3–10%): this is where nontraditional biomarkers earn their place.

Deciding whether to test in the borderline zone

Within that borderline group, look for risk enhancers or genuine uncertainty before ordering anything: a first-degree relative with an MI, stroke, or revascularization before age 55 (men) or 65 (women); metabolic syndrome; or evidence of chronic inflammation. If any of those are present, a targeted biomarker can help decide how aggressively to treat.

Biomarker	What it adds	Practical note
Lipoprotein(a) — Lp(a)	An LDL-like, genetically determined particle that is proatherogenic and proinflammatory, independent of standard lipid values.	Check once in every adult — levels are stable over a lifetime and fasting isn’t required.
Apolipoprotein B — ApoB	Counts every atherogenic particle (LDL, VLDL, IDL, Lp(a)); predicts ASCVD risk more accurately than LDL alone.	Most useful when LDL is at goal but risk still feels unresolved — elevated ApoB signals persistent particle burden.
hs-CRP	A marker of low-grade chronic inflammation, including the inflammatory component of atherosclerotic plaque.	Order when the patient is free of acute infection, injury, or active autoimmune flare.
Coronary artery calcium (CAC)	A low-dose CT quantifying calcified plaque, scored with the Agatston system.	Directly visualizes plaque burden — useful when risk-factor data alone leaves real uncertainty.

Lipoprotein(a): what the number means

Lp(a) is largely genetic (autosomal codominant inheritance) and is minimally affected by diet or exercise, which is exactly why it’s worth checking just once. Levels run highest in people of African and Southeast Asian ancestry, and a markedly elevated result is a reasonable cue to screen first-degree relatives. A level above 125 nmol/L (roughly 50 mg/dL) is associated with about a 1.4-fold increase in ASCVD risk, and above 250 nmol/L (roughly 100 mg/dL) that risk roughly doubles. Because lifestyle changes barely move Lp(a), an elevated result is a signal to intensify statin therapy, consider non-statin agents, and manage every other modifiable risk factor more aggressively — not a target to chase down directly. Keep in mind that kidney, liver, or thyroid disease, pregnancy, menopause, and some medications can secondarily raise Lp(a), and that inflammation can push it in either direction.

Reading hs-CRP and CAC results

hs-CRP level	Interpretation
Below 1.0 mg/L	Low cardiovascular risk
1.0–3.0 mg/L	Average/intermediate risk
Above 3.0 mg/L	High risk
Above 10 mg/L	Likely reflects an acute process — recent infection, injury, or major surgery; recheck later

Diet, exercise, weight loss, and smoking cessation can lower hs-CRP, and statins help as well. For CAC, an Agatston score of 1–100 signals mild, early plaque and reinforces preventive measures; 100–300 marks a moderately elevated risk of a cardiac event over the next several years; and above 300 indicates a plaque burden comparable to someone who has already had an MI — the response is to lower LDL aggressively and treat every other risk factor without delay.

CLINICAL BOTTOM LINE — CARDIOVASCULAR Start with the PREVENT calculator every time. Order nontraditional biomarkers only for borderline (3–10%) 10-year risk with a genuine risk enhancer or clinical uncertainty — not as a routine add-on to every lipid panel.

Renal Biomarkers

The traditional starting point for kidney disease is still eGFR alongside blood pressure, BMI, and family history. An eGFR above 90 mL/min is considered normal (CKD Grade 1); 60–90 mL/min is mildly decreased (Grade 2); and anything below 60 mL/min (Grades 3–5) meets criteria for chronic kidney disease.

Urine Albumin-to-Creatinine Ratio (uACR)

Guidelines call for pairing eGFR with a uACR to screen for CKD in anyone over 60, and in anyone with diabetes, hypertension, or established cardiovascular disease. Per the ADA, CKD is present if eGFR is below 60 mL/min or uACR exceeds 30 mg/g. Because albuminuria typically appears before GFR starts to fall, uACR functions as an early-warning marker rather than a confirmatory one. A spot urine sample is sufficient, though a first morning void is preferred.

uACR category	Range	Interpretation
A1	Under 30 mg/g	Normal to mildly increased
A2	30–299 mg/g	Moderately increased
A3	300 mg/g or higher	Severely increased

Treatment thresholds follow the uACR result. Above 30 mg/g, start an ACE inhibitor or ARB in patients with hypertension to slow progression, and add a GLP-1 receptor agonist in patients with type 2 diabetes for its added cardiovascular and mortality benefit. Above 200 mg/g, add an SGLT2 inhibitor to the ACE-I/ARB in patients with type 2 diabetes or heart failure.

Cystatin C: an alternative to creatinine-based eGFR

Cystatin C is produced at a steady rate and is catabolized in the renal tubules rather than returning to the bloodstream, which makes it a more muscle-mass-independent marker than creatinine. The National Kidney Foundation suggests using it in patients where creatinine-based eGFR is likely to be misleading because of low muscle mass — children, older adults, and patients on chronic steroid therapy are the classic examples. Availability remains limited in the US, so this is a targeted rather than routine order.

CLINICAL BOTTOM LINE — RENAL Pair eGFR with a uACR in anyone over 60 or with diabetes, hypertension, or cardiovascular disease. Reach for cystatin C only when low muscle mass makes creatinine-based eGFR unreliable.

Pulmonary Biomarkers: Blood Eosinophil Count in COPD

Blood eosinophil count (BEC) helps identify an inflammatory endotype within COPD. Patients with higher circulating eosinophil counts tend to have a higher risk of exacerbations and respond better to inhaled corticosteroids (ICS); very high counts can also prompt consideration of biologic therapy such as dupilumab.

BEC threshold	2025 GOLD guidance
Under 100 cells/µL	Do not add ICS — consider roflumilast or a macrolide instead
100–300 cells/µL	Consider ICS only if exacerbations persist and the benefit outweighs pneumonia risk
300 cells/µL or higher	Strongest indication for triple therapy (LABA/LAMA/ICS)

Dementia Biomarkers: Risk Assessment and the New Blood Tests

Picture a 67-year-old woman at her annual wellness visit who mentions trouble finding words — her mother was diagnosed with dementia in her early 70s, and she’s heard there’s now a blood test for Alzheimer’s. This is becoming a routine primary care conversation, and it’s worth understanding what APOE, beta-amyloid, and phosphorylated tau (p-Tau) actually tell you, because none of these are yet standard-of-care primary care screening tools, and most are not widely covered by insurance.

APOE and the APOE-4 allele

The APOE gene has three common alleles — ε2, ε3, and ε4 — all of which are normal inherited variants, not mutations. The ε2 allele may be modestly protective; ε3 is the most common and considered neutral; ε4 raises Alzheimer’s risk, and roughly 15% of people carry at least one copy. Because everyone inherits two APOE alleles (one from each parent), the specific combination sets an individual’s risk profile: ε3/ε3 is essentially neutral risk, one copy of ε4 raises risk about 2–3-fold, and two copies of ε4 raise risk roughly 10–15-fold along with an earlier typical age of onset.

APOE testing is available direct-to-consumer, but on its own it has limited predictive value — it’s a risk factor, not a diagnosis. Plenty of ε4/ε4 homozygotes never develop Alzheimer’s, and plenty of people with no ε4 allele do. Where APOE testing becomes clinically necessary is before starting anti-amyloid therapies such as lecanemab or donanemab: the FDA requires it, because ε4 homozygotes carry roughly a 9.2% risk of symptomatic brain swelling on these agents, versus about 1.4% in non-carriers.

Plasma p-Tau and beta-amyloid: the new FDA-cleared blood tests

Two newly available blood tests — Lumipulse G, which reports the ratio of p-Tau217 to beta-amyloid 1-42, and Elecsys, which reports plasma p-Tau181 — are FDA-cleared for patients already showing cognitive decline. Both replace what previously required a lumbar puncture or PET scan, and both help determine eligibility for anti-amyloid therapy.

The biology behind the ratio test is worth understanding: as Alzheimer’s pathology progresses, more phosphorylated tau spills into the blood while less beta-amyloid does (it’s being sequestered into brain plaques instead), so the p-Tau/beta-amyloid ratio rises. Because the ratio captures the relationship between the two proteins rather than either one in isolation, it holds up better across patients despite confounders like chronic kidney disease or obesity, which can independently shift the raw values.

In a 25-year follow-up of nearly 2,800 cognitively normal women in the Women’s Health Initiative Memory Study, those with higher baseline plasma p-Tau217 were significantly more likely to later develop mild cognitive impairment or dementia, with risk rising steadily alongside the biomarker level — and the association was strongest in women who also carried an APOE-4 allele.

On interpretation: a negative Elecsys result carries a 97.9% negative predictive value, meaning cognitive symptoms are unlikely to be Alzheimer’s-related and other causes (depression, thyroid disease, medication effects, vascular or Lewy body dementia) deserve a look. A positive result is not diagnostic on its own and still requires confirmatory testing. For the Lumipulse ratio, a high result strongly suggests amyloid pathology and a low result strongly argues against it, but roughly 20% of results fall in an intermediate zone that still needs PET or CSF confirmation. Real-world performance also matters here: in a risk-enriched research cohort the Lumipulse test showed 99% sensitivity and 85% specificity, but in a real-world clinic population specificity fell to just 23% — which means false positives climb fast in patients with a low pretest probability. That’s why these tests are recommended only for patients over 50 who already have cognitive symptoms, not for screening asymptomatic adults.

A NUANCE WORTH FLAGGING Specificity that looks strong in an enriched research cohort can collapse in a general clinic population. A test’s published performance numbers only apply to a population that resembles the one it was validated in — always ask what population generated the number before trusting it for the patient in front of you.

CLINICAL BOTTOM LINE — DEMENTIA Don’t order APOE testing without genetic counseling available. Reserve p-Tau/amyloid blood tests for patients over 50 with actual cognitive symptoms, not as a screen for the worried-well — and keep a full clinical work-up (cognitive screening, medication review, mood, sleep, vascular risk factors) as the foundation regardless of any biomarker result.

Cancer Biomarkers: Beyond PSA, CEA, and CA-125

Multi-cancer early detection (MCED) tests are blood- or urine-based “liquid biopsies” that look for circulating tumor DNA, RNA, or protein fragments, aiming to catch cancer before symptoms appear — including cancers like pancreatic or ovarian that have no standard screening test today. None of them are FDA-approved for population-wide screening, and out-of-pocket cost typically runs $700–$950 since most insurers don’t yet cover them.

Test		Cancers detected	Sensitivity	Specificity	FDA status
Galleri (GRAIL)		Many	~51% (<20% for Stage I)	~99.5%	Not approved (laboratory-developed test)
CancerGuard (Exact Sciences)		Many	Varies by cancer type	Varies by cancer type	Not approved
Prenetics CIRCLE		5	Variable	Variable	FDA-approved
DELFI Diagnostics		Lung	~80%	~58%	FDA-approved
Freenome		Many	Not disclosed	Not disclosed	In development
	CASE FROM PRACTICE A 54-year-old man, asymptomatic, comes in after ordering a CancerGuard test online. The result is positive: “cancer signal detected.” He has no symptoms but is visibly anxious. With sensitivity around 51–64% and specificity around 97.4%, a positive result in a low-prevalence, asymptomatic population works out to a positive predictive value of roughly 21% — meaning only about 1 in 5 people with a positive result actually have cancer. A negative result, by contrast, carries a reassuring negative predictive value near 99.7%. The core challenge with a positive liquid biopsy is that, unlike a palpable lump or an abnormal scan, you don’t know where to look. There’s no established guideline for the imaging work-up that follows a positive MCED result. A reasonable approach: a thorough history and physical focused on possible cancer symptoms, bringing age- and risk-based screening (colonoscopy, mammography, low-dose lung CT, PSA, etc.) fully up to date, then an IV-contrast CT of the chest, abdomen/pelvis, and soft-tissue neck. If that’s unrevealing, an 18F-FDG PET-CT from skull base to mid-thigh is a reasonable next step, with further targeted imaging or endoscopy guided by whatever the initial work-up turns up.

Key Takeaways

•  For ASCVD risk, start with traditional risk factors and the PREVENT calculator. Reserve nontraditional biomarkers for the borderline (3–10%) risk group with a genuine risk enhancer.

•  The AHA/ACC recommend measuring Lp(a) at least once in every adult — it’s stable for life, so one measurement is enough.

•  Pair eGFR with a uACR to diagnose and guide treatment of chronic kidney disease, especially in patients over 60 or with diabetes, hypertension, or cardiovascular disease.

•  Order a blood eosinophil count in COPD patients to guide whether inhaled corticosteroids are likely to help.

•  Don’t order APOE testing without genetic counseling in place — a risk factor is not a diagnosis, and the result carries real emotional and insurance implications.

•  For patients worried about memory or cognitive decline, a comprehensive clinical evaluation — cognitive screening, medication review, mood, sleep, vascular risk factors — remains the foundation, not a blood test.

•  Most insurers still do not cover most of these emerging tests, including Alzheimer’s blood panels and multi-cancer early detection tests — talk cost through with patients before ordering.

References

Mayeux R. Biomarkers: potential uses and limitations. NeuroRx. 2004;1(2):182-188. doi:10.1602/neurorx.1.2.182

Blumenthal R, Morris P, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia. JACC. 2026. doi:10.1016/j.jacc.2025.11.016

Arroyo-Espliguero R, Viana-Llamas MC, Silva-Obregón A, Avanzas P. The Role of C-reactive Protein in Patient Risk Stratification and Treatment. Eur Cardiol Rev. 2021;16:e28. doi:10.15420/ecr.2020.49

Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy (PROVE IT–TIMI 22). N Engl J Med. 2005;352:20-28. doi:10.1056/NEJMoa042378

American Heart Association. Coronary Artery Calcium Test. heart.org.

American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. 2024;48(Suppl 1):S239-S251. doi:10.2337/dc25-S011

Chronic kidney disease evaluation and management guidance. Ann Intern Med. doi:10.7326/ANNALS-25-03499

Sacks DB, Arnold M, Bakris GL, et al. Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus. Diabetes Care. 2023;46(10):e151-e199. doi:10.2337/dci23-0036

Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2025 report guidance on blood eosinophil-guided therapy. PMID: 30592902.

Rajič Bumber J, Rački V, Mežnarić S, Pelčić G, Mršić-Pelčić J. Clinical Significance of APOE4 Genotyping. J Clin Med. 2025;14(17):6047. doi:10.3390/jcm14176047

Lehmann S, Gabelle A, Duchiron M, et al. Comparative performance of plasma pTau181/Aβ42, pTau217/Aβ42 ratios, and individual measurements in detecting brain amyloidosis. eBioMedicine. 2025;117.

Shadyab AH, Zhang B, LaCroix AZ, et al. Plasma Phosphorylated Tau 217 and Incident Mild Cognitive Impairment and Dementia in Older Women. JAMA Netw Open. 2026. doi:10.1001/jamanetworkopen.2026.1295

Accuracy of FDA-Cleared Alzheimer’s Blood Test Evaluated in a Real-World Cohort. Practical Neurology.

American Cancer Society. Multi-Cancer Early Detection Tests. cancer.org.

Exact Sciences. Data Showing Promise of Multi-Cancer Early Detection Presented at AACR.

Lennon AM, Buchanan AH, Kinde I, et al. Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science. 2020;369(6499):eabb9601.

Kisiel JB, et al. Shifting the cancer screening paradigm: developing a multi-biomarker class approach to multi-cancer early detection testing. Life. 2024;14(925). doi:10.3390/life14080925

 

This post is intended for clinical education purposes and does not replace individualized clinical judgment. Guideline endorsement, insurance coverage, and validation status vary across the emerging biomarker tests discussed here — confirm current recommendations and coverage before ordering.

By Dr. Valerie Watters-Burke, FNP-BC, GNP-BC, PPCNP-BC