Medical Policy

This document addresses the use of cerebrospinal fluid and serum (blood-based) testing for biochemical markers as a tool to assist in the diagnosis or guide the clinical management of Alzheimer disease.

Note: This document does not address imaging tests, including MRI and PET. For criteria related to MRI and PET, refer to applicable guidelines used by the plan.

Note: For a high-level overview of this document, please see "Summary for Members and Families" below.

Medically Necessary: 

Testing for Alzheimer disease (AD) using biochemical markers is considered medically necessary when ALL of criteria set I (A, B, and C) and criteria set II or III are met:

1. General Criteria (applies to criteria II and III).
   1. The individual has cognitive impairment consistent with possible AD, including BOTH of the following:
      1. Measurable mild cognitive impairment (MCI) or dementia; and
      2. Signs and symptoms presented with insidious onset and progressive decline;
         and
   2. The diagnosis remains unclear following standard evaluation, including but not limited to all of the following:
      1. History and neurologic exam (including imaging, if indicated); and
      2. Cognitive testing (for example, Montreal Cognitive Assessment [MoCA], Mini-Mental State Examination [MMSE]); and
      3. Evaluation for reversible causes of cognitive impairment; (for example, thyroid dysfunction, vitamin B12 deficiency, depression, medication effects, etc.);
         and
   3. Results are likely to guide management, including but not limited to one or more of the following clinical scenarios:
      1. As an aid to help differentiate AD from non-AD dementias (for example, frontotemporal dementia, vascular dementia, Lewy body disease); or
      2. Evaluate atypical or early-onset presentation of AD or dementia or mild cognitive impairment (MCI); or
      3. Resolve discordance between clinical findings and imaging or cognitive testing results; or
      4. Improve diagnostic confidence affecting prognosis and care planning; or
      5. Treatment with disease targeting therapy is being considered (for example, amyloid beta targeting therapy).
2. Cerebrospinal Fluid Biomarker Testing
   1. The test measures ANY of the following cerebrospinal fluid (CSF) biomarkers:
      1. Aβ42 or Aβ42/Aβ40 ratio; or
      2. Phosphorylated tau (p-tau181 or p-tau217); or
      3. Total tau (t-tau); or
      4. Tau/Aβ ratio combinations.
3. Blood-Based Biomarker Testing
   1. Blood-based biomarker (BBM) testing is being requested and ALL of the following criteria (1, 2, and 3) are met:
      1. The individual is 50 years of age or older; and
      2. The test meets either of the following criteria (a or b):
         1. FDA-cleared or approved*; or
         2. Measures p-tau217 or %p-tau217;
            and
      3. Any of the following:
         1. To triage the need for CSF testing or PET imaging; or
         2. As an alternative when CSF testing is not feasible (for example, coagulopathy and bleeding disorders or structural and anatomical concerns); or
         3. To assess for neuropsychiatric referral or evaluation.

*Note: At the time of review, only the Lumipulse p-tau217/Aβ42 and Elecsys p-tau181 BBM tests have received FDA clearance to be used as an aid in the initial assessment for AD and other causes of cognitive decline in adult patients presenting with signs, symptoms, or complaints of cognitive decline. Please see Discussion section for additional information.

Not Medically Necessary:

1. Measurements of biochemical markers for AD are considered not medically necessary when the medically necessary criteria above are not met and for ANY of the following:
   1. Asymptomatic screening (including testing solely based on family history of AD); or
   2. A clear alternative diagnosis exists that explains the degree of cognitive impairment; or
   3. No expected impact on management, including repeat testing without new indication.

This document describes clinical studies and expert recommendations, and explains whether biochemical marker testing for Alzheimer disease (AD) is clinically appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Alzheimer Disease and Biomarker Testing

Alzheimer disease (AD) is a brain condition that gets worse over time and affects memory, thinking, and behavior. It is linked to buildup of proteins called amyloid plaques and tau tangles in the brain. Doctors use different tests to help diagnose this condition. These include brain scans, spinal fluid tests, and newer blood tests for proteins called biomarkers. Blood tests are easier to perform, but they are newer and not as well studied as other methods. Spinal fluid tests and an imaging test called positron emission tomography, also called PET scans, have been used for many years and are still important, especially when deciding if a person may benefit from treatments with drugs. Each test has benefits and limits, and results are usually combined with other clinical information.

What the Studies Show

The measurement of biomarkers for AD in the spinal fluid has been used for many years and is considered one of the most reliable ways to identify AD. However, it requires a medical procedure called a lumbar puncture that requires insertion of a needle into the back to get the spinal fluid. That procedure is uncomfortable and involves a small risk of problems.

As an alternative to spinal fluid testing the use of blood-based biomarker tests have been developed, including the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio and Elecsys pTau181. Those tests have been cleared by the FDA to help with diagnosis in adults with memory problems. Studies showed these tests can correctly identify Alzheimer-related changes in many cases, with accuracy often close to 85% to 95%. However, they are not 100% accurate. Positive results may still need confirmation with PET scans or spinal fluid tests. Negative results may help rule out AD in some people.

Other newer biomarkers, such as MTBR-tau243, brain-derived tau, neurofilament light, and urine or skin tests, are still being studied. Early results are promising, but many studies were small or done in limited groups. Better studies are needed to know if these tests improve health or should be used in routine care. Some markers may also be elevated in other brain diseases or even in healthy older adults, which can make results harder to interpret.

Biomarker testing in people without symptoms is not well supported. Studies show that some healthy older adults can have amyloid in the brain without having AD. This means test results can be misleading. Unnecessary or unproven tests can lead to needless worry, or to treatment that does not help.

When is Biomarker Testing Clinically Appropriate?

Biomarker testing may be appropriate in these situations:

• The person has symptoms of cognitive decline, such as memory loss or changes in thinking; and
• Testing is being used as part of a full clinical evaluation that includes exams and cognitive testing; and
• Results will help with diagnosis or treatment decisions, such as determining if the person may benefit from amyloid-targeting therapy; and
• Testing is done using validated methods, such as CSF testing, PET imaging, or certain FDA-cleared blood tests; and
• Results are interpreted along with other clinical information, not used alone.

When is this not Clinically Appropriate?

Biomarker testing is not clinically appropriate in these situations:

• Testing people who do not have symptoms outside of research settings. Studies show that amyloid can be present in healthy older adults, so results may not reflect disease and can be misleading.
• Using blood tests alone to confirm a diagnosis. Studies show these tests are not fully accurate and often require confirmation with PET scans or spinal fluid testing.
• Using new or experimental tests that have not been well studied. Better studies are needed to know if these tests improve health.
• Using biomarker tests without a full clinical evaluation. These tests cannot replace a complete assessment by a healthcare professional.

Biomarker testing is not clinically appropriate in scenarios other than those listed above.

(Return to Description/Scope)

Summary

Alzheimer disease (AD) is a progressive brain disease causing cognitive decline due to the buildup of amyloid beta (Aβ) plaques/deposits and tau tangles in the brain. At this time, there are inadequate data regarding the role of biochemical testing for AD in asymptomatic individuals. With regard to symptomatic individuals, testing for the presence of Aβ in cerebrospinal fluid (CSF) or on PET imaging have long been the standards in diagnosing AD and is required for the selection of appropriate candidates for treatment with Aβ targeting therapy (for example, lecanemab-irmb [Leqembi^™]). Clinically validated blood-based biomarker (BBM) testing allows for accurate in vivo detection of amyloid and tau pathology, but is only recommended for selected, symptomatic individuals being evaluated for cognitive impairment. Currently Lumipulse^® G pTau217/ß-Amyloid 1-42 Plasma Ratio^® (Fujirebio Diagnostics, Inc., Malvern, PA) and Elecsys^® (Roche Diagnostics, Indianapolis, In) are the only FDA-cleared serum biomarker tests to assist in the diagnosis of AD.   

Discussion

AD, the most prevalent form of dementia, is a progressive, neurodegenerative disease that affects memory, behavior, and cognitive abilities. by distinct neurologically-defined clinical stages as well as the presence of Aβ plaques/deposits and tau tangles in the brain. In the early stage of AD, Aβ plaques and tau tangles contribute to the development of mild cognitive impairment. However, as the disease progresses into the middle and late stages, the cognitive decline becomes more noticeable with the manifestation of the progressive loss of memory, language, behavioral and decision making skills. Eventually, the accumulation and growth of Aβ plaques/deposits and tau tangles worsen dementia, cognitive decline, and neuropathological changes and brain atrophy.

Recent advances in blood-based biomarkers (BBMs), including, but not limited to Aβ and phosphorylated tau (p-tau), offer less invasive and more accessible options for early AD detection and improved patient management (including the selection of appropriate candidates for treatment with Aβ targeting therapy).

Diagnosis of AD

AD is an age-related disease caused by unrelenting neurodegeneration and brain atrophy. Behaviorally, AD is characterized by progressive memory loss and cognitive decline. Pathologically, AD is characterized by local accumulations of Aβ peptide and neurofibrillary tangles (NFTs) comprised of tau protein in the brain. At present, a definitive diagnosis of AD requires postmortem verification of Aβ deposits (plaques) and NFTs in the brain. In current clinical practice, a diagnosis of AD is based on clinical presentations, a detailed clinical history, and other information including physical and neurological exams, cognitive assessments, brain imaging (CT, MRI, PET) as well as CSF or BBM testing to make an accurate diagnosis. Clinical diagnostic criteria (for example, the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association [NINCDS-ADRDA] guidelines and the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition [DSM-IV]) may also be used to make a diagnosis of AD. However, the diagnostic accuracy of these AD criteria is not perfect. Diagnosis of AD is often a diagnosis of exclusion and is challenging for both physicians and patients (Alzheimer’s Association, 2026a).

Based on the 2011 guidelines from the National Institute on Aging (NIAA) and the Alzheimer’s Association (AA), the diagnosis of AD is a clinical diagnosis, focusing on the exclusion of other causes of senile dementia. Ancillary imaging studies such as computed tomography [CT], magnetic resonance imaging [MRI], single-photon emission CT [SPECT], or positron emission tomography [PET]) and laboratory tests may be used to aid in the diagnosis. These tests help rule out other possible causes for dementia (for example, cerebrovascular disease, cobalamin [vitamin B12] deficiency, syphilis, and thyroid disease) (McKahn, 2011).

In 2018, the NIA-AA published an updated biological definition of AD that focuses on the underlying pathological activities of the disease, which can be identified either in living individuals (via biomarkers) or during autopsy. The NIA-AA framework proposed using three groups of biomarkers (Aβ deposition, pathologic tau, and neurodegeneration) that can be measured by obtaining spinal fluid and/or special radiological imaging tests. The new definition was intended for research purposes only (to identify and stage research participants) and was meant to provide a flexible framework amenable to new (yet to be discovered) biomarker tests. The definition was not intended to be used in routine clinical care, as further investigation was required to establish the role and utility of biomarkers (Jack, 2018).

In 2024, Jack and associates published an update to the 2018 research framework for diagnosing and staging AD. The framework integrates research and clinical care, categorizing biomarkers into Core 1 (early detection) and Core 2 (later detection) types. It emphasizes the need for high accuracy in biomarkers and incorporating clinical judgments with biomarker results. The document provides guidance for the utilization of biomarkers in clinical trials and therapeutic decision-making. Although blood-based testing is progressively approaching the diagnostic accuracy of CSF testing, it currently exhibits less clinical robustness compared to CSF assays and has a limited diagnostic range. With regard to clinically validated blood-biomarker testing, the guideline notes:

Only biomarkers that have been proven to be accurate with respect to an accepted reference standard should be used for clinical diagnostic purposes, and the same criteria apply to PET, CSF, or blood-based biomarkers. We recommend, as a minimum requirement, an accuracy of 90% for the identification of moderate/frequent neuritic plaques at autopsy (or an approved surrogate, which, at this point, would be amyloid PET or CSF) in the intended-use population.

The Global CEI Initiative on AD published a consensus statement outlining recommendations for the minimum acceptable performance metrics for BBM testing of amyloid pathology in clinical practice (Schindler, 2024). Amyloid PET and CSF biomarker testing have long been the standards in diagnosing AD. To maintain diagnostic accuracy and timeliness, the committee recommends that BBM tests demonstrate sensitivity and specificity comparable to CSF tests. With the approval of FDA-sanctioned treatments, there has been a shift towards developing more accessible BBM testing methodologies.

The committee did not evaluate any specific tests but instead provided general performance standards. The group recommends that BBM tests used in primary care settings achieve a minimum of 90% sensitivity and 85% specificity. In secondary care settings, these tests should exhibit sensitivity and specificity in the range of 75% to 85% when employed as triaging tools. For confirmatory testing without the need for follow-up procedures, BBM tests should demonstrate sensitivity and specificity approximating 90%, similar to CSF tests.

Key Clinically Validated Blood-Biomarkers for AD include the following:

• Aβ 42/40 ratio;
• p-tau217 (or %p-tau217);
• p-tau 181.

Biomarkers for AD

The use of diagnostic tools to identify AD continues to evolve. A definitive diagnosis of AD is made through postmortem examination. Unlike clinical assessments or imaging alone, autopsy findings can provide direct evidence of the neuropathological hallmark features of AD such as amyloid plaques and neurofibrillary tau tangles in the brain tissue. For decades, the options for ante mortem detection of AD pathology were limited to tests that are either expensive and not widely available, such as positron emission tomography (PET) imaging, or invasive but safe when properly performed tests, such as cerebrospinal fluid (CSF)-based biomarker analysis. While highly accurate, these tests are either invasive or not accessible to many individuals.

More recently, research has demonstrated that some blood-based biomarkers have the potential to improve the accuracy and speed of AD diagnosis when used as a complement to other tests, representing a significant advancement in the early and accessible detection of AD. While minimally invasive and generally more accessible, BBMs do not currently serve as a standalone diagnostic tool.

Amyloid Beta (Aβ) Peptide

Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of AD, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia.

Aβ in Plasma 

In May 2025, the FDA granted 510(k) premarket notification clearance for Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio (Fujirebio Diagnostics Inc., Malvern, Pennsylvania) as the first blood test to assist in diagnosing AD. The Lumipulse G pTau217/ß-Amyloid 1-42 is designed to detect signs of AD by identifying amyloid plaques in the plasma. According to the FDA 510(k) premarket notification, the test is cleared for use in adults 50 years and older who are being evaluated for AD and other causes of cognitive decline. The test measures the ratio of two pTau 217 and β-Amyloid 1-42 proteins in plasma. This ratio correlates with the presence of amyloid plaques in the brain. The FDA emphasizes that the test is not 100% accurate and cannot be used alone to confirm a diagnosis. Results must be interpreted in conjunction with other clinical information and are not for general screening of healthy individuals. Additional testing, such as PET brain scans or CSF analysis, is often required to verify the presence of Alzheimer-related changes in the brain. The test serves as a preliminary testing option to indicate whether other tests may be necessary.

The FDA clearance of the Lumipulse G pTau217/ß-Amyloid 1-42  test (K242706) was based on a study involving 499 adults with cognitive impairment. Researchers compared the Lumipulse blood test results with PET scan and CSF findings. The study found that approximately 92 % of individuals who tested positive on the Lumipulse G pTau217/ß-Amyloid 1-42 test had confirmed amyloid plaque buildup, while more than 97% of those with negative results demonstrated negative findings on the confirmatory tests. Less than 20% of participants received inconclusive results. This study demonstrated that while Lumipulse G pTau217/ß-Amyloid 1-42  test is highly reliable for both positive and negative results, it is not definitive and may require follow-up testing for clarification.

Monane and colleagues (2025) conducted a single-arm, multisite, prospective cohort study to evaluate how the PrecivityAD2 (C2N Diagnostics, St. Louis, MO) BBM test impacted clinical decision-making for 203 individuals (median age, 74 years; 53% women) who displayed signs of dementia or mild cognitive impairment consistent with AD. The test measures plasma Aβ42/Aβ40 and p-tau217/np-tau217 ratios to generate an Amyloid Probability Score 2 (APS2), which estimates the likelihood of brain amyloid plaque presence. Clinicians completed surveys on patient management before and after receiving the BBM test results to assess its clinical utility. The study’s primary outcome focused on two key aspects: patient selection and test result interpretation. Patient selection was measured by determining how closely clinicians’ decisions to order the PrecivityAD2 blood test aligned with its intended use criteria. Test interpretation was evaluated by examining changes in clinical decision-making after receiving the Amyloid Probability Score 2 (APS2) results. Specifically, researchers measured shifts in clinicians’ estimated probability of AD (rated from 0-100%), as well as changes in prescribing Alzheimer-related medications and in ordering additional amyloid brain imaging before and after the BBM test.

With regards to the primary outcome, concordance with the intended use of the BBM test was 99% (200/203). Reasons for non-concordance were test use outside of the intended use, including participants below the age of 55 (n=1) and participants without symptoms of MCI or dementia (n=2). The study found that the composite primary endpoint, defined as any change in diagnostic certainty, drug therapy, or the need for additional brain amyloid evaluation pre- and post-BBM testing, was 75% (153/203, p<0.0001 vs. a pre-specified threshold of 20% clinically meaningful change). Among participants with negative APS2 results, use of anti-Alzheimer medications and further amyloid imaging decreased, while both increased among participants with positive APS2 results (p<0.0001). The findings indicate that the PrecivityAD2 blood test effectively refines diagnostic confidence, reduces unnecessary confirmatory testing, and helps guide the initiation or discontinuation of Alzheimer-specific treatments, ultimately improving decision-making in memory care settings.

There are some limitations related to this study’s design and scope. First, it assessed clinicians’ intended changes in clinical management after receiving the BBM test results, rather than confirming whether those changes were actually implemented. This was due to the study’s real-world, survey-based design conducted under an IRB exemption, which relied on clinician-reported data. Second, the study’s outcomes were limited to clinician-reported measures, such as changes in diagnostic confidence, treatment decisions, and use of additional amyloid testing. It did not directly evaluate patient-level outcomes like cognitive function, daily living performance, or quality of life improvements.

Aβ in CSF

Researchers are investigating the use of CSF biomarkers to predict the conversion from MCI to dementia and to diagnose AD. The most explored CSF biomarkers include tau protein or phosphorylated tau protein and Aß42 peptide, which may be represented by a low ratio of Aß42 to Aß40 levels, or a low ratio of Aß42 to tau levels or elevated levels of tau or tau protein phosphorylated at threonine 181.

Schmand and colleagues (2010) reported the results of a meta-analysis that sought to determine if biomarkers can detect preclinical AD prior to the onset of behavioral (for example, memory) symptoms. The researchers included relevant longitudinal studies of CSF and MRI biomarkers published between January 2003 and November 2008. Study participants were not demented at baseline, but some declined to MCI or to AD. A total of 21 MRI studies and 14 CSF studies were included in the analysis. The effect sizes of Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) ranged from 0.91 to 1.11. The effect size of medial temporal lobe (MTL) atrophy was 0.75. Memory performance had an effect size of 1.06. Memory impairment and MTL atrophy tended to increase when measured closer to the time of diagnosis, whereas effect sizes of CSF biomarkers tended to increase when measured longer before the diagnosis. The researchers concluded that memory impairment is a more accurate predictor of early AD than atrophy of MTL on MRI, whereas CSF abnormalities and memory impairment are about equally predictive. Therefore, the MRI and CSF biomarkers are not very sensitive to preclinical AD. While CSF markers have shown promise, additional studies with long follow-up periods in elderly participants who are normal at baseline are needed to evaluate this promise.

Roe and colleagues (2013) investigated whether Aβ42, tau, phosphorylated tau at threonine 181 (ptau181), tau/Aβ42, and ptau181/Aβ42 predict future decline in non-cognitive outcomes among individuals who were cognitively normal at baseline. Longitudinal data from 430 participants who donated CSF within 1 year of a clinical assessment indicating normal cognition and were 50 years of age or older were analyzed. Mixed linear models were used to assess whether baseline biomarker values predicted future decline in function (instrumental activities of daily living), weight, behavior, and mood. Clinical Dementia Rating Sum of Boxes (CDR-SB) and Mini-Mental State Examination (MMSE) scores were also assessed. Abnormal levels of each biomarker were related to greater impairment with time in behavior (p<0.035) and mood (p<0.012) symptoms, and increased difficulties with independent activities of daily living (p<0.012). However, biomarker levels were not linked to a change in weight with time (p>0.115). Abnormal biomarker values also forecasted more rapidly changing MMSE (p<0.041) and CDR-SB (p<0.001) scores compared with normal values. The investigators concluded that CSF biomarkers among cognitively normal individuals correlate with future decline in some, but not all, non-cognitive AD symptoms studied. The authors acknowledged that additional work is needed to determine the extent to which these findings generalize to other samples. The investigators also noted that future research should explore whether the ratio of tau/Aβ42 and ptau181/Aβ42 are better predictors of decline in non-cognitive outcomes compared with individual molecular markers alone.

Rivero-Santana and colleagues (2017) conducted a systematic review of studies analyzing the diagnostic performance of CSF Aβ42, t-tau, and p-tau in the discrimination between AD and frontotemporal lobar degeneration (FTLD) dementias. A Hierarchical Summary Receiver Operating Characteristic (HSROC) model was applied, which circumvents methodological problems of meta-analyses based on summary points of sensitivity and specificity values. They also examined relevant confounders of CSF biomarkers' diagnostic performance such as age, disease duration, and global cognitive impairment. The p-tau/Aβ42 ratio demonstrated the best diagnostic performance. No statistically significant effects of the confounders were detected. Nonetheless, the investigators found the p-tau/Aβ42 ratio may be especially indicated for younger subjects; p-tau may be preferable for less cognitively impaired individuals (high MMSE scores) and the t-tau/Aβ42 ratio for more cognitively impaired individuals (low MMSE scores). The researchers concluded that p-tau/Aβ42 ratio has potential for being implemented in the clinical routine for the differential diagnosis between AD and FTLD. The authors also recommended that future studies report information on confounders such as age, disease duration, and cognitive impairment.

In the Decision Summary section of the Centers for Medicare & Medicaid Services (CMS) National Coverage Analysis of Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (2022), the authors point out the following limitations of Aβ as a biomarker of AD:

1. Amyloid is associated with normal physiologic processes. Normal functions of Aβ include disease prevention by protecting against oxidative stress and regulating cholesterol transport and anti-microbial activity. Additionally, Aβ protects the brain from infections, promotes recovery from injury and repairs leaks in the blood-brain barrier.
2. Amyloid plaques are seen in other diseases, such as cerebral amyloid angiopathy, dementia with Lewy bodies, Parkinson’s disease, Huntington’s disease, and inclusion body myositis.
3.  Amyloid plaques can be identified in cognitively normal older adults. Autopsy studies demonstrate that approximately 1/3 of cognitively normal older individuals (20-65% depending on age) have amyloid accumulation at levels consistent with AD pathology (CMS, 2022).

In 2023, Nisenbaum published the results of a follow-up study of the EMERGE and ENGAGE clinical trials used in the FDA application for the anti-amyloid drug aducanumab. As noted below, those studies did not use measurement of CSF Aβ42, p-tau, or t-tau as clinical trial inclusion criteria or for subject selection purposes. The Nisenbaum study assessed the use of these biomarkers as an alternative to amyloid PET for confirmation of brain pathology using data from 350 subjects (EMERGE n=208, ENGAGE n=142) who had an evaluable baseline CSF screening value and baseline PET scan. A total of 308 subjects were identified as PET positive and 42 were identified as PET negative. Compared with the PET negative group, the mean CSF Aβ42 level was numerically lower in the PET positive group (484.4 pg/mL in the CSF group vs. 933.3 pg/mL in the PET negative group). The p-tau181 level was numerically higher (91.42 pg/mL in the PET positive group vs.40.09 pg/mL in the PET negative group). The t-tau level was numerically higher in the PET positive group (594.8 pg/mL in the PET positive group vs. 374.6 pg/mL in the PET positive group). In contrast, Aβ40 levels were similar between groups (10,973.9 pg/mL in the PET positive group vs.11,251.0 pg/mL in the PET negative group). The Aβ42/Aβ40 ratio was numerically lower in the PET positive group (0.048 in the PET positive group vs. 0.087 in the PET negative group). The p-tau181/Aβ42 and t-tau/Aβ42 ratios were numerically higher in the PET positive group (0.203 in the PET positive group vs. 0.050 in the PET negative group for and t-tau181/Aβ42; and 1.329 in the PET positive group vs. 0.433 in the PET negative group for t-tau/Aβ42). The area under the curve (AUC) for Aβ42, p-tau and t-tau were calculated by receiver operating characteristic curve (ROC curve), which indicated high accuracy for all three (AUCs ≥ 0.90; p<0.0001). In contrast, Aβ40 was found to have an unfavorable AUC and deemed not useful for the detection of the visual status of PET scans (AUC, 0.49; p=0.782). Finally, the combination of Aβ42 with Aβ40 demonstrated high diagnostic accuracy with PET visual assessment (AUCs, 0.90; p<0.0001). The sensitivity, specificity and overall percent agreement (OPA) was calculated using optimal cutoff values that maximize the Youden J index in the ROC analysis. The maximum Youden J index was observed at a cutoff of 664 pg/mL for Aβ42. For the Aβ42/Aβ40 ratio the best cut-off was 0.062. With these cutoffs, Aβ42 showed the highest diagnostic accuracy as a single biomarker with an OPA of 89.4%. Additionally, the sensitivity and specificity were improved when Aβ42 was combined with a second analyte (94.4% and 88.1% for Aβ42/Aβ40, 95.4% and 83.3% for p-tau181/Aβ42, and 92.3% and 81.6% for t-tau/Aβ42. The authors concluded that their data supported the use of CSF biomarkers as reliable alternatives to PET imaging for brain Aβ pathology confirmation.

MTBR-tau243

Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and monitoring the effects of treatment. The MTBR-tau243 protein is associated with toxic tau tangles that build up in the brain as part of AD. MTBR-tau243 has been investigated as a BBM that can not only aid in the diagnosis of AD but can also indicate how far the brain condition has progressed. The MTBR test tracks levels of the MTBR-tau243 protein, in the blood. In studies of individuals with cognitive decline, the eMTBR-tau243 plasma test was able to differentiate between early and later stages of AD and also distinguish AD from other neurodegenerative conditions.

Horie and colleagues (2025) validated a plasma-based eMTBR-tau243 assay for identifying tau-related pathological changes in AD across three cohorts, totaling over 900 participants, including cognitively unimpaired, MCI, and AD dementia groups. Researchers analyzed three different cohorts:

1. Pilot BioFINDER-2 cohort (n=108), participants were divided into 3 categories as follows:
   1. Cognitively impaired (CU) either Aβ-negative or -positive (CU− (n=57) or CU+ (n=4), respectively),
   2.  Mild cognitive impairment (MCI) Aβ-positive (MCI+; n=10) and
   3. AD dementia Aβ-positive (AD+; n=37).
2. Pilot Knight ADRC cohort (n=55:
   1. CU− (n=15) and
   2. CU+ (n=4) with Clinical Dementia Rating (CDR) = 0, very mild AD dementia (CDR = 0.5), Aβ-positive (n=18) or AD+ with CDR ≥ 1 (n=8).
3. BioFINDER-2 validation cohort (n=739),
   1. CU− (n=110),
   2. CU+ (n=198),
   3. MCI+ (n=169),
   4. AD+ (n=134),
   5. Parkinson’s disease or Lewy body dementia (PD or DLB) (n=18),
   6. Progressive supranuclear palsy or corticobasal syndrome (PSP or CBS) (n=6),
   7. Vascular dementia (VaD); n=4),
   8. Frontotemporal dementia (FTD; n=2),
   9. R406W MAPT mutation carriers (n=2) (one tau-PET positive and the other tau-PET negative),
   10. MCI without Aβ-positive (MCI−) (n=86) and
   11. Other neurodegenerative dementia (n=12).

Across the AD spectrum in three different cohorts (n=108, 55 and 739, respectively), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and escalated further in dementia. Plasma eMTBR-tau243 demonstrated strong associations with tau positron emission tomography binding (β = 0.72, R² = 0.56) and cognitive performance (β = 0.60, R² = 0.40), outperforming other plasma tau (%p-tau217 and %p-tau205) biomarkers. In the three cohorts tested, the assay distinguished between early versus later-stage AD and separated AD from non-Alzheimer tauopathies.

A key limitation of this initial assay version is the substantial plasma volume (1.5 ml) required to ensure accurate results. Future studies should focus on validating this novel biomarker in larger, real-world cohorts that include diverse demographic (racial and ethnic) backgrounds and individuals with various comorbidities or other neurodegenerative or psychiatric conditions, as these factors may influence biomarker measurements.

In a prospective study, Mattson-Calgren (2026) investigated if, among participants positive for plasma p-tau217 and plasma eMTBR-tau243 improves classification of established AD and predicts cognitive decline and tau tangle accumulation. The study included adult participants 40 years of age or older with subjective cognitive decline, mild cognitive impairment, or dementia, based on cognitive test results and clinical assessments. Individuals were consecutively recruited at two memory clinics in Sweden, as part of the Swedish BioFINDER-2 study. The researchers validated the results by using a group of participants from the Knight AD Research Center, including individuals that were determined to be cognitively unimpaired as well as those with cognitive impairment. Using mass spectrometry techniques, plasma p-tau217 was calculated as a ratio to a non-phosphorylated peptide (%p-tau217), and eMTBR-tau243 was calculated as a concentration. Predefined cutoff levels were used to determine positive results. The primary outcome was established AD based on both AD pathology-specific CSF or PET biomarkers and clinical assessment, in accordance with the International Working Group definition.

A total of 572 individuals with cognitive symptoms (142 with subjective cognitive decline, 259 with mild cognitive impairment, and 171 with dementia) were enrolled with 291 (51%) female participants and 281 (49%) male participants. A total of 350 (61%) of 572 participants had positive plasma %p-tau217. Among these, 341participants (97%) were amyloid β (Aβ)-positive by CSF biomarkers or PET and 199 (57%) had established AD (positive predictive value [PPV], 57%; 95% CI, 51-61, for %p-tau217 alone). A total of 194 (55%) of 350 %p-tau217-positive patients were also positive for eMTBR-tau243, with an accuracy of 81% (95% CI, 76-84), PPV of 84% (95% CI, 78-88), negative predictive value (NPV) of 77% (95% CI, 68-82), and sensitivity of 82% (95% CI, 76-87) for established AD, in cross-sectional analyses. Findings were comparable in the validation cohort. Positive eMTBR-tau243 was associated with worse longitudinal cognitive decline and longitudinal tau tangle accumulation in %p-tau217 positive cohort. Among %p-tau217 positive individuals, eMTBR-tau243 identified participants with high tau PET load with an accuracy of 87%, PPV 76%, and NPV 90%. The researchers concluded that while plasma %p-tau217 can confirm Aβ-positivity, eMTBR-tau243 can confirm clinically symptomatic AD. The researchers proposed that when used in combination with %p-tau217, eMTBR-tau243 in %p-tau217 could help gauge whether AD pathology is causing symptoms and suggested that plasma eMTBR-tau243 might be valuable in determining the severity of tau tangle burden and guiding therapeutic decisions.

A limitation of this study is the sample composition which consisted of Swedish participants referred to secondary memory clinics. Additional cross-validation which includes participants from diverse populations and primary care settings could strengthen the generalizability of study results, given that biomarker performance may be influenced by demographic factors and comorbidities.

Early studies evaluating eMTBR-tau 243 have demonstrated a strong correlation with tau PET binding and cognitive performance. As a promising BBM, eMTBR-tau 243 could potentially provide a less invasive alternative to PET scans for detecting tau pathology, diagnosing and staging AD as well as discerning between AD and other causes of cognitive decline. Additional studies that include demographically diverse populations and individuals with medical comorbidities are needed.

Neural Thread Protein (NTP)

Neural thread protein is a protein that is associated with neurofibrillary tangles. Both CSF and urine levels of this protein have been investigated as a potential biochemical marker of AD.

Zhang et al (2014) conducted a systematic review and meta-analysis of urinary AD -associated neural thread protein (NTP) for diagnosing AD in individuals with suspected AD. Nine studies met the inclusion criteria (n=841 individuals with probable or possible AD; 37 individuals with MCI, 992 with non- AD dementia or controls without dementia). The reference standard consisted of a clinical diagnosis in eight studies and not described in another. Varying cutoffs for positive diagnosis were used amongst included studies. Controls were both healthy volunteers and individuals with other dementias. For a probable AD D, pooled sensitivity and specificity were 89% (95% CI, 86% to 92%) and 90% (95% CI, 88% to 92%), respectively. Pooled positive and negative likelihood ratios were 8.9 (95% CI, 7.1 to 11.1) and 0.12 (95% CI, 0.09 to 0.16), respectively. The authors concluded that urinary AD7c-NTP is both a sensitive and specific test for the diagnosis of probable AD. However, whether urinary AD7c-NTP can be used as an early marker is still uncertain. 

Neurofilament Light (NF-L)

Neurofilaments are intermediate filaments that serve as structural components of neuronal axons, in particular large, myelinated axons. NF-L has been studied in individuals with neuronal injury and neurodegenerative diseases because it is released into CSF and systemic circulation when neurons are damaged. Sjogren and colleagues (2000) reported that CSF NF-L levels are increased in subjects with frontotemporal dementia (FTD) and late onset AD compared with control subjects, and the increase in FTD subjects is higher than in late onset AD.

In a meta-analysis, Olsson and colleagues (2016) found that NF-L has a large effect size for differentiating individuals with AD from control subjects. Additionally, Zetterberg and colleagues (2016) demonstrated that higher CSF NF-L concentrations are associated with cognitive deterioration and brain atrophy over time in AD and MCI groups and concluded that CSF NF-L could be used as a marker for AD progression. However, elevated CSF levels of NF-L are also found in other neurodegenerative diseases, such as normal-pressure hydrocephalus, multiple sclerosis, Parkinson disease and amyotrophic lateral sclerosis. Therefore, CSF NF-L could be a representative marker of neurodegeneration, but not a precise marker for distinguishing AD from other neurological disorders.

Skin Fibroblast

Researchers are also exploring the use of skin fibroblast testing as a means to detect and differentiate AD from other dementias. The Discern^™ Alzheimer's disease test (NeuroDiagnostics, Rockville, MD) examines skin fibroblast cells to identify and quantify three biomarkers (the phosphorylated Erk1 and Erk2, quantitatively measure skin fibroblast networks and protein kinase C€ levels), each of which is reported to independently identify and differentiate AD. At the time of this review, peer-reviewed studies assessing the analytical validity of this test were limited (Chirila, 2013; Chirila, 2014; Nelson, 2017). Large, randomized, controlled trials demonstrating this test is as accurate as autopsy results (the gold standard in the definitive diagnosis of AD) are needed in order to assess the clinical utility of the test.

Tau Protein in CSF

CSF t-tau and p-tau are frequently studied in neurodegenerative disorders. CSF t-tau levels can serve as a neuronal injury marker and are elevated in many neurodegenerative diseases, such as Creutzfeldt-Jakob disease, AD, and FTD, whereas CSF p-tau 181 or p-tau 231 (tau phosphorylated at threonine 181 or threonine 231) levels are elevated more specifically in AD than in other neurodegenerative diseases. Like CSF Aβ42, t-tau and p-tau tests are difficult to use in healthy people at the preclinical stage because of the limitation of obtaining CSF samples. 

Tau Protein in Plasma

Mattsson and colleagues (2016) investigated if plasma tau is altered in AD and whether it is related to alterations in cognition, CSF biomarkers of AD pathology (Aβ and tau), brain metabolism and brain atrophy. This was a study of plasma tau in prospectively followed subjects with AD (n=179), subjects with MCI (n=195), and cognitive healthy controls (n=189) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and cross-sectionally studied subjects with AD (n=61), MCI (n=212), and subjective cognitive decline (n=174) and controls (n=274) from the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden. A total of 1284 participants were evaluated. Tested associations were between plasma tau and diagnosis, CSF biomarkers, MRI measures, 18fluorodeoxyglucose-PET, and cognition. The researchers reported that higher plasma tau was associated with AD dementia, higher CSF tau, and lower CSF Aβ42, but the correlations were weak and differed between ADNI and BioFINDER. The longitudinal analysis in ADNI demonstrated significant associations between plasma tau and worse cognition, more atrophy, and more hypo-metabolism during follow-up. The researchers concluded that plasma tau partly reflected AD pathology, but the overlap between normal aging and AD was large, especially in subjects without dementia. They also concluded that despite group-level differences, these results did not support plasma tau as an AD biomarker in individual people.

The authors noted that while this was the largest published study on plasma tau, there were some drawbacks. For example: some ADNI participants had plasma tau below the lower limit of quantification of the assay. Although these measurements were uncertain, they were included because excluding them would have biased the data toward higher plasma tau. Also, the researchers utilized only one plasma tau assay, but it is possible that other assays capture tau fragments that are less sensitive to peripheral degradation and more likely to reflect AD pathology.

Olsson and colleagues (2020) reported the results of a systematic review and meta-analysis for 15 biomarkers in both CSF and blood to assess which of these were most altered in AD. Of the eligible studies, 151 provided data on T-tau in CSF. These studies consisted of 164 cohorts with AD and 153 control cohorts representing a total of 11,341 AD subjects and 7086 controls. The authors found that increased levels of CSF t-tau and p-tau were strongly associated with AD and MCI subjects that developed AD.

Building upon the premise that blood total-tau originates primarily from peripheral, non-brain sources, Gonzalez-Ortiz and colleagues (2022) investigated if an anti-tau antibody that selectively binds brain-derived tau (BD-tau) and avoids the peripherally expressed 'big tau' isoform could be used as a biomarker to identify AD -type neurodegeneration. The researchers validated their assay in five cohorts that included a total of 609 patient samples. The researchers’ observations included the following:

1. Blood-based BD-tau demonstrated equivalent diagnostic performance to both CSF total-tau and CSF brain-derived tau in distinguishing biomarker-positive Alzheimer’s disease participants from biomarker-negative controls.
2. Plasma-based BD-tau accurately differentiated autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases with an area under the receiver operating curve (AUC) of 86.4%, while plasma neurofilament light was not significantly increased (AUC 54.3%).
3. Serum BD-tau distinguished Alzheimer's from other neurodegenerative disorders -- including frontotemporal lobar degeneration and atypical parkinsonian disorders -- with AUCs up to 99.6%.
4. Plasma/serum BD-tau correlated with neurofilament light only in Alzheimer's disease, but not in the other neurodegenerative diseases.

Researchers plan to conduct large-scale clinical validation of blood brain-derived-tau in a wide range of cohorts including individuals with diverse racial and ethnic backgrounds. Studies will incorporate older adults with no biological evidence of AD as well as those at different stages of the disease. The authors also acknowledge that more research is needed to address the characteristics of this biomarker, longitudinal changes across the AD continuum in both sporadic and familial AD. Additionally, research is needed to verify the generalizability of the biomarker in diverse, multi-ethnic cohorts from a variety of populations.

For additional information, please see the discussion regarding the study by Nisenbaum (2023) above.

Barthélemy (2024) investigated whether a BBM test could perform as well as established CSF tests in identifying amyloid-β (Aβ) plaques and tau tangles. The plasma ratio of phosporylated-tau217 (plasma %p-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in two groups: the Swedish BioFINDER-2 (n=1,422) cohort and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n=337). Matched CSF samples were evaluated with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology, respectively, utilizing PET imaging as the reference standard. Primary analyses were concentrated on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying agents. Plasma %p-tau217 was clinically equivalent to CSF tests in classifying Aβ PET status, with an area under the curve (AUC) for both between 0.95 and 0.97. Plasma %p-tau217 performed better than CSF tests in the classification of tau-PET with AUCs of 0.95-0.98. In cognitively impaired individuals (BioFINDER-2: n=720; Knight ADRC: n=50), plasma %p-tau217 demonstrated accuracy, a PPV and a NPV of 89-90% for Aβ PET and 87-88% for tau PET status, which was clinically equivalent to CSF tests, further increasing to 95% using a two-cutoffs approach. Blood plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. The researchers concluded that the adoption of high-performance BBMs would permit improved detection of AD and better access to AD-specific treatments.

Palmqvist and associates (2024) reported on the diagnostic accuracy of blood tests for AD using plasma phosphorylated tau 217 (p-tau217) ratios and the Aβ 42 to 40 ratio (APS2, the PrecivityAD2 test). A total of 1213 individuals with cognitive symptoms (subjective cognitive decline, mild cognitive impairment or dementia underwent plasma analysis using mass spectrometry assays. The APS2 test demonstrated superior diagnostic accuracy compared to standard clinical evaluations. Specifically, APS2 achieved accuracies of 89-90% for Alzheimer pathology and 91% for clinical outcomes, with positive predictive values (PPV) of 97-99% in individuals with cognitive impairment. These findings suggest that APS2 and p-tau217 could potentially replace more invasive and expensive diagnostic methods like CSF testing and PET scans in the future. Further research is needed to evaluate the clinical impact and validate the results.

In a subsequent study (Palmqvist, 2025) researchers evaluated the performance of the Lumipulse plasma pTau217 immunoassay test in 1219 participants in secondary care and 548 in primary care settings across several sites in Italy, Spain, and Sweden. The primary outcome was AD pathology defined as abnormal CSF Aβ42:p-tau181. Researchers used the fully automated Lumipulse plasma pTau217 immunoassay test to measure p-tau217 plasma levels, comparing results to CSF markers of AD (abnormal Aβ42:p-tau181 ratio). The diagnostic performance of the Lumipulse plasma pTau217 immunoassay test across all cohorts demonstrated AUC ranging from 0.93 to 0.96. In the secondary care settings, accuracy ranged from 89% to 91%, with PPV 89-95% and negative predictive values (NPV) from 77-90%. In the primary care setting, accuracy was slightly lower at 85%, with positive and negative predictive values of 82% and 88%, respectively. Accuracy was somewhat reduced in participants 80 years of age or older (83%) but remained stable regardless of sex, APOE genotype, diabetes, kidney disease, or cognitive stage. Implementing a two-cutoff approach (defining clear positive and negative thresholds) improved overall accuracy to 92-94%, while excluding 12-17% of participants with intermediate results. Using the ratio of plasma p-tau217 to Aβ42 did not increase accuracy but reduced indeterminate outcomes to 10% or less. The authors acknowledged that the generalizability of the study results are limited due to the lack of inclusion of non-European individuals. Further validation, including populations from other regions of the world is needed. Additionally, the somewhat reduced performance relative to % p-tau217 in primary care populations and older adults emphasizes the need for additional research.

In October 2025 the FDA granted 510(k) premarket notification clearance for another BBM test, the Elecsys pTau181 test (Roche Diagnostics), to assist in the diagnosis of AD (K252163). According to the FDA premarket notification summary:

The Elecsys Phospho-Tau (181P) Plasma assay result is intended to be used as an aid in the initial assessment for Alzheimer’s disease and other causes of cognitive decline in adult patients aged 55 years and older, presenting with signs, symptoms, or complaints of cognitive decline. The result should be interpreted in conjunction with other clinical information.

A negative test result is consistent with a negative amyloid positron emission tomography (PET) scan result and reduced likelihood that a patient's cognitive impairment is due to amyloid pathology. These patients should be investigated for other causes of cognitive decline.

A positive test result may not be consistent with a positive amyloid PET scan result. Patients with an initial positive result should be further investigated to determine whether the amyloid pathology can be a cause of cognitive impairment (FDA Premarket Notification, Elecsys, 2025).

The FDA premarket clearance also indicates that the Elecsys Phospho-Tau (181P) Plasma assay is not recommended for individuals with signs, symptoms, or complaints of cognitive decline, who have already been referred to a specialist. Additionally, the clearance states that Elecsys Phospho-Tau (181P) Plasma assay has not been proven effective for predicting dementia or other neurological conditions, nor for monitoring treatment responses.

The FDA clearance of the Elecsys Phospho-Tau (181P) Plasma assay was based on the results of a multicenter, prospective, non-interventional clinical study (Roche study RD006263) that evaluated 312 participants ranging from 55-80 years of age that presented with cognitive complaints or impairment of unknown cause at 8 geographically diverse enrollment sites in the U.S. and Europe. The study population consisted of 40.7% males and 59.3% females, both groups averaging 69.1 years of age. Most participants were White (59%), followed by Black or African American (34%), Asian (1.6%), Middle Eastern (0.3%), and Other (5.1%). Ethnically, 66.3% were non-Hispanic or Latino, 29.5% were Hispanic or Latino, and 4.2% had missing data. Common comorbidities included cardiovascular disease (56.1%), diabetes (25.6%), depression (19.9%), kidney disease (2.2%), prior stroke (3.5%), and cancer (12.5%). Data collected from participants included cognitive assessments (Quick Dementia Rating System [QDRS], Mini-Mental State Examination [MMSE], Clinical Dementia Rating [CDR], imaging results [amyloid PET and MRI]), and questionnaires covering medical history, medications, quality of life, physical activity, and socio-demographic information. Participants were classified into three diagnostic groups: 41.0% with subjective cognitive decline (SCD), 56.1% with mild cognitive impairment (MCI), and 1.0% with mild dementia. Diagnosis was unknown for 1.9% of participants. Overall, 97.1% of the study population fell into the pre-dementia AD categories (SCD and MCI).

A total of 313 participants received amyloid PET scans using FDA-approved tracers (18F-Florbetapir, 18F-Florbetaben, or 18F-Flutemetamol). Each scan was independently reviewed by three of five trained readers, blinded to all clinical data. Using majority voting, 41 scans (13.1%) were classified as amyloid positive and 271 (86.9%) as negative. Reader agreement was high, with positive concordance in 28 cases (9%) and negative concordance in 260 cases (83%). Discordant readings were rare, occurring in 24 cases total (7.7%). Only one scan had missing ratings, leaving 312 usable PET scans for analysis. On average, reader agreement was high: the Positive Percent Agreement (PPA) was 81.6%, the Negative Percent Agreement (NPA) was 97.1%, and the Total Percent Agreement (TPA) was 94.9%, indicating strong consistency among readers. Among the 41 participants with a positive PET scan, 3 (7.3%) showed false-negative Phospho-Tau (181) Plasma results. Results demonstrated that in early-stage, low-prevalence populations similar to primary care settings, Elecsys pTau181 Plasma assay effectively ruled out Alzheimer pathology, showing a 97.9% negative predictive value (NPV).

Hortsch and colleagues (2026) evaluated the performance of the pTau217 (Elecsys pTau181 Plasma assay in an unselected cohort of participants representative of clinical practice. Participants were recruited at several primary and secondary clinical care sites. Plasma was prospectively collected from 588 participants, aged 55 to 80 years with either subjective or objective cognitive impairment, under evaluation for AD. The plasma pTau217 concentrations were measured using the prototype pTau217 plasma immunoassay and compared with amyloid PET results using a centiloid-based classification system, with further analyses conducted at centiloid cutoff 30.

Of the 588 participants, plasma pTau217 demonstrated high concordance with centiloid-based classification at selected cutoffs. The discriminative ability of plasma pTau217 to identify Aβ pathology peaked at centiloid cutoff 32 (area under the curve=0.933). Subgroup analyses at centiloid cutoff 30 showed good discrimination of Aβ positivity/negativity by age, sex and clinical diagnosis. Moderately decreased kidney function to kidney failure was found to affect plasma pTau217 levels. Study results demonstrated that the prototype pTau217 plasma immunoassay exhibited high accuracy in reflecting Aβ burden among participants presenting with cognitive complaints across diverse clinical settings. The researchers concluded that these findings support the potential implementation pTau217 plasma immunoassay into routine clinical practice for early detection of AD, alongside standard neuropsychologic and clinical assessments.

Amyloid Beta Targeted Therapy

On June 7, 2021, the United States Food and Drug Administration (FDA) granted accelerated approval of the anti-amyloid drug aducanumab based on results of EMERGE and ENGAGE clinical trials. The two trials of 18-month duration were conducted in participants with MCI due to AD or mild AD, mean age of 70 years. The ENGAGE trial demonstrated no benefit while the high-dose EMERGE trial initially also exhibited no benefit but with longer follow-up demonstrated a significant decrease in amyloid plaque on PET scans. The inclusion criteria for both of these trials required participants to have a positive amyloid PET scan and to consent to apolipoprotein E (ApoE) genotyping, as part of trial entry. Researchers conducted biomarker substudies in subgroups of participants in each trial to assess the effects of Aduhelm on brain amyloid pathology as well as CSF Aβ and tau levels; however, biomarker evaluations did not constitute defined endpoints in either of the trials and only included 30% and 35% of the participants in EMERGE and ENGAGE, respectively. Furthermore, use of CSF Aβ and tau levels were not used as clinical trial inclusion criteria, or for patient selection purposes. Because the cognitive deterioration associated with MCI and mild AD dementia often occurs over the span of years, the 78-week follow up duration period of EMERGE and ENGAGE complicates the ability to draw conclusions regarding the effectiveness of Aduhelm for treating early AD.

In April 2022, CMS announced a National Coverage Determination (NCD) that provides coverage for FDA-approved monoclonal antibodies directed against amyloid for the treatment of AD when furnished in accordance with Section B (Coverage Criteria) (CMS, 2022).

On January 6, 2023, the FDA granted accelerated approval of another anti-amyloid drug, lecanemab-irmb (Leqembi), for the treatment of individuals diagnosed with AD with mild cognitive impairment or mild dementia stage of disease. Full approval was granted on July 6, 2023 based on results of an 18-month long double-blind, placebo-controlled, parallel-group, dose-finding study of 856 subjects aged 50 to 90 years with AD-related mild cognitive impairment or mild dementia stage of disease and confirmed presence of Aβ pathology (van Dyck, 2022). Inclusion criteria required amyloid positivity determined by either PET imaging or CSF measurement of Aß42 peptide. Subjects receiving the treatment were reported to have a change of 0.45 points on an 18-point scale in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) over 18 months. A sub study of amyloid burden on PET imaging involving 698 subjects found a significant decrease in mean amyloid level from baseline to 18 months (-55.48 centiloids in the lecanemab group vs. 3.64 centiloids in the placebo group, p<0.001).

A third AD drug therapy, donanemab-azbt (Kisunla) was approved on July 2, 2024, for affected individuals with mild cognitive impairment or mild dementia stage of disease. The approval was based on a double-blind, placebo-controlled, parallel-group study of 1736 participants. The prescribing information includes a boxed warning for amyloid-related imaging abnormalities. The presence of amyloid beta pathology should be confirmed prior to the initiation of therapy. Monitoring within the study was done via amyloid PET imaging and plasma p-tau217 levels.

Recommendations from Authoritative Organizations

In a collaborative position statement, the joint committee of the American Academy of Neurology (AAN), American Neurological Association (ANA), and Child Neurology Society (CNS) stated that biomarker testing in asymptomatic individuals is recommended only in a research setting, in part due to the potential harms and the absence of interventions that can favorably alter the natural history of the disease. For symptomatic individuals, the author indicated that “CSF and PET biomarkers of amyloid and tau aggregation are now also being used to diagnose symptomatic patients with atypical presentations of dementia” (Chiong, 2021).

The Alzheimer’s Association supports the use of BBM tests for diagnosing AD, but only when conducted by qualified specialists as part of a comprehensive clinical assessment of patients with cognitive impairment presenting to specialized care for memory disorders. This panel provides the following guidance for utilizing BBM tests:

For triage purposes, a BBM test with at least 90% sensitivity and 75% specificity may help rule out Alzheimer’s when results are negative, while positive results should be confirmed with additional biomarker testing, such as amyloid PET scans or cerebrospinal fluid (CSF) analysis. However, for blood-based biomarker tests to serve as a direct replacement for PET or CSF tests in confirming amyloid pathology, they must demonstrate ≥90% sensitivity and specificity, ensuring diagnostic accuracy equivalent to established methods.

The panel alerts users of this guideline that there is significant variation in diagnostic test accuracy and many commercially available BBM tests do not meet these thresholds, especially using a single cutoff. Additionally, these tests do not serve as a substitute for comprehensive clinical evaluation by a healthcare professional and should be used only as part of a full diagnostic workup of patients with cognitive impairment presenting to specialized care settings, and with careful consideration of pretest probability of AD pathology (Palmqvist 2025).

AD is a progressive and ultimately fatal dementia that can be familial or idiopathic (no family history). The majority of AD is late-onset, but there is also a less common early-onset form of AD, which appears before the age of 65 and is associated with a rapid decline, cognitive and behavioral changes, and severe neurochemical and neuropathological changes.

Cognitive assessment tools are important tools in the evaluation of cognitive function. These tools range from brief screening tests to comprehensive evaluations, and allow clinicians to detect and measure cognitive. Cognitive assessments tools are used to evaluate memory, thinking and simple problem-solving abilities, and may quickly identify changes in behaviors and symptoms. Some of these tests are brief, while others can be more time complex. Cognitive assessments are frequently administered by a neuropsychologist to evaluate executive function, judgment, attention and language. Examples of cognitive assessments tools include:

• The Montreal Cognitive Assessment (MoCA): A brief (10-12 minute) screening tool used to identify early signs of AD and mild cognitive impairment (MCI). It assesses memory, language, executive functions, and orientation. The MoCA is better suited for the early detection of cognitive decline.
• The Mini-Mental State Examination (MMSE): A 30-point, 5-10 minute pen-and-paper test intended to screen for cognitive impairment and dementia, including AD. It assesses memory, orientation, attention, language, and visuospatial skills.
• The Ascertain Dementia 8 (AD8): A screening test designed to identify early cognitive impairment. The test assesses memory, orientation, judgment, and function, and is sensitive to early signs of dementia regardless of the underlying etiology.
• The Saint Louis University Mental Status (SLUMS): A cognitive screening tool developed to identify mild cognitive impairment and dementia, primarily in adults aged 60 and older.
• The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): A screening tool used to identify dementia and Alzheimer’s by interviewing a friend or close relative about a patient’s changes in functional ability and memory over the past 10 years.

Biomarkers represent biological changes that can be quantified to indicate the absence or presence of a disease or the risk of developing a disease. Biomarkers may be used to help researchers and medical practitioners diagnose diseases and health conditions, identify health risks in an individual, monitor responses to treatment, and see how an individual’s disease or health condition changes over time. Researchers continue to explore the use of biomarkers as an accurate and conclusive means to diagnose and screen for AD.

Alzheimer disease: A progressive neurological condition, including dementia, which primarily affects memory.

A 510(k) clearance: A process by which the FDA allows a medical device manufacturer to market a new device by demonstrating it is substantially equivalent to a legally marketed predicate (already on the market) device.

Amyloid beta 42 (Aβ42): A protein that accumulates abnormally in the brains of individuals with AD; the major component of amyloid plaques in the brain.

Biomarker: A naturally occurring, measurable substance in an organism whose presence is indicative of a normal physiological state, pathological processes, or pharmacologic responses to therapy; Objective medical signs that are used to measure the presence or progress of disease, or the effects of treatment.

Dementia: A general term for a range of symptoms, commonly including memory loss, that reflect a significant decline in cognitive function serious enough to interfere with daily life. These symptoms, which can also include difficulties with communication, reasoning, and problem-solving, are caused by abnormal changes in the brain.

Frontotemporal dementia: A broad term for a group of brain disorders that primarily affect the frontal and temporal lobes of the brain.

Mild cognitive impairment (MCI): A condition that falls between normal age-related memory changes and more serious dementia. Individuals with MCI have noticeable problems with thinking, such as memory or language, that they or others can recognize, but they are still able to manage their daily activities independently.

Neurofilament light chain (NFL) protein, A biomarker associated with neurodegeneration, neuronal damage.

Objective cognitive impairment (OCI): Distinct problems with thinking and memory that can be measured using standard tests. Unlike subjective cognitive decline, which is based on what a person feels, OCI is identified by healthcare professionals through formal testing that evaluate skills such as memory, attention, language, and problem-solving to determine if there is real impairment.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met for testing in CSF specimen:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or when the code describes a procedure indicated in the Position Statement section as not medically necessary.

When services may be Medically Necessary when criteria are met for testing in blood-based specimen:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or when the code describes a procedure indicated in the Position Statement section as not medically necessary.

When services are also Not Medically Necessary:
For the following procedure and diagnosis codes, or when the code describes a procedure indicated in the Position Statement section as not medically necessary.

Peer Reviewed Publications:

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23. McDade EM, Barthélemy NR, Wang G, et al. The relationship of soluble tau species with Alzheimer's disease amyloid plaque removal and tau pathology. Alzheimers Dement. 2025; 21(9):e70689.
24. Monane M, Maraganore DM, Carlile RM, et al. Clinical utility of an Alzheimer's disease blood test among cognitively impaired patients: results from the Quality Improvement PrecivityAD2 (QUIP II) Clinician Survey Study. Diagnostics (Basel). 2025; 15(2):167.
25. Nam E, Lee YB, Moon C, Chang KA. Serum tau proteins as potential biomarkers for the assessment of Alzheimer's disease progression. Int J Mol Sci. 2020; 21(14):5007.
26. Nelson TJ, Sun MK, Lim C, et al, Chirila FV, Alkon DL. Bryostatin effects on cognitive function and PKCɛ in Alzheimer's disease Phase IIa and expanded access trials. J Alzheimers Dis. 2017; 58(2):521-535.
27. Nisenbaum L, Martone R, Chen T, et al. CSF biomarker concordance with amyloid PET in phase 3 studies of aducanumab. Alzheimers Dement. 2023; 19(8):3379-3388.
28. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 2016, 15(7);673-684.
29. Palmqvist S, Tideman P, Mattsson-Carlgren N, et al. Blood biomarkers to detect Alzheimer disease in primary care and secondary care. JAMA. 2024; 332(15):1245-1257.
30. Palmqvist S, Warmenhoven N, Anastasi F, et al. Plasma phospho-tau217 for Alzheimer's disease diagnosis in primary and secondary care using a fully automated platform. Nat Med. 2025; 31(6):2036-2043.
31. Rabinovici GD, Gatsonis C, Apgar C, et al. Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia. JAMA. 2019; 321(13):1286-1294.
32. Rivero-Santana A, Ferreira D, Perestelo-Pérez L, et al. Cerebrospinal fluid biomarkers for the differential diagnosis between Alzheimer's disease and frontotemporal lobar degeneration: systematic review, HSROC analysis, and confounding factors. J Alzheimers Dis. 2017; 55(2):625-644.
33. Roe CM, Fagan AM, Grant EA, et al. CSF biomarkers of Alzheimer disease: "noncognitive" outcomes. Neurology. 2013; 81(23):2028-2031.
34. Schindler SE, Petersen KK, Saef B, et al. Head-to-head comparison of leading blood tests for Alzheimer's disease pathology. Alzheimers Dement. 2024; 20(11):8074-8096.
35. Schmand B, Huizenga HM, van Gool WA. Meta-analysis of CSF and MRI biomarkers for detecting preclinical Alzheimer's disease. Psychol Med. 2010; 40(1):135-145.
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Government Agency, Medical Society, and Other Authoritative Publications:

1. American Academy of Family Physicians. Blood biomarkers and early detection of Alzheimer’s disease and related dementias (2025). Available at: https://www.aafp.org/pubs/fpm/issues/2025/0500/alzheimers-detection.pdf. Accessed on March 23, 2026.
2. American Psychological Association. Guidelines for the evaluation of dementia and age-related cognitive change. Am Psychol. 2012; 67(1):1-9.
3. Atri A, Dickerson BC, Clevenger C, et al. Alzheimer's Association clinical practice guideline for the diagnostic evaluation, testing, counseling, and disclosure of suspected Alzheimer's disease and related disorders (DETeCD-ADRD): executive summary of recommendations for primary care. Alzheimers Dement. 2025 Jun;21(6):e14333.
4. Arevalo-Rodriguez I, Smailagic N, Roqué-Figuls M, et al. Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2021 Jul 27;7(7):CD010783.
5. Biogen. Aducanumab. (Combined FDA and Applicant PCNS Drugs Advisory Committee Briefing Document. https://fda.report/media/143503/PCNS-20201106-CombinedFDABiogenBackgrounder_0.pdf. Accessed on March 23, 2026.
6. Burton JK, Fearon P, Noel-Storr AH, et al. Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the detection of dementia within a general practice (primary care) setting. Cochrane Database Syst Rev. 2021; 7(7):CD010771.
7. Centers for Disease Control and Prevention. Alzheimer’s disease and dementia. about Alzheimer's. August 15, 2024. Available at: https://www.cdc.gov/alzheimers-dementia/about/alzheimers.html. Accessed on March 23, 2026.
8. Centers for Medicare and Medicaid Services (CMS). National Coverage Analysis (NCA), Decision Memo. CAG-00460N. Monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease. April 7, 2022. Available at: https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&NCAId=305. Accessed on March 23, 2026.
9. Chiong W, Tsou AY, Simmons Z, et al. Ethics, Law, and Humanities Committee (a joint committee of the American Academy of Neurology, American Neurological Association, and Child Neurology Society). Ethical considerations in dementia diagnosis and care: AAN Position Statement. Neurology. 2021; 97(2):80-89.
10. Dubois B, Villain N, Frisoni GB, et al. Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group. Lancet Neurol. 2021; 20(6):484-496.
11. Herukka SK, Simonsen AH, Andreasen N, et al. Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment. Alzheimers Dement 2017; 13(3):285-295.
12. Jack CR Jr, Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024; 20(8):5143-5169.
13. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018; 14(4):535-562.
14. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7(3):263-269.
15. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001; 56(9):1143-1153.
16. Palmqvist S, Whitson HE, Allen LA, et al. Alzheimer's Association clinical practice guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer's disease within specialized care settings. Alzheimers Dement. 2025; 21(7):e70535.
17. Petersen RC, et al. Practice guideline update summary: mild cognitive impairment. Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2018; 90:126-135.
18. Roche Diagnostics. News Release. Roche’s Elecsys pTau181 becomes the only FDA-cleared blood test for use in primary care to rule out Alzheimer’s-related amyloid pathology. Release Elecsys p Tau 181 Oct 2025. Available at: https://diagnostics.roche.com/us/en/news-listing/2025/fda-cleared-ptau181-alzheimers-blood-test.html. Accessed on March 23, 2026.
19. Schindler SE, Galasko D, Pereira AC, et al. Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease. Nat Rev Neurol. 2024; 20(7):426-439.
20. U.S. Food and Drug Administration (FDA). 510(k) Premarket Notification Database. Elecsys Phospho-Tau (181P) Plasma (Roche Diagnostics, Indianapolis, In). K252163. Rockville, MD: FDA. October 8, 2025. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf25/K252163.pdf. Accessed on March 23, 2026.
21. U.S. Food and Drug Administration (FDA). 510(k) Premarket Notification Database. Summary of safety and effectiveness. Lumipulse G pTau217/b-Amyloid 1-42 Plasma Ratio (Fujirebio Diagnostics, Inc. Malvern, PA). K242706. Rockville, MD: FDA. May 16, 2025. Available at: https://www.accessdata.fda.gov/cdrh_docs/reviews/K242706.pdf. Accessed on March 23, 2026
22. U.S. Food and Drug Administration (FDA). 510(k) Substantial Equivalence Determination Decision Summary. Elecsys pTau 181 Plasma (Roche Diagnostics, Indianapolis, IN). K252163. Rockville, MD. FDA. October 8, 2025. Available at: https://www.accessdata.fda.gov/cdrh_docs/reviews/K252163.pdf. Accessed on March 23, 2026.
23. U.S. Food and Drug Administration (FDA). Denovo Notification Database. Lumipulse G β-Amyloid Ratio (1-42/1-40) Summary of safety and effectiveness. DEN200072. Rockville, MD: FDA. May 4, 2022. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/denovo.cfm?id=DEN200072. Accessed March 23, 2026.
24. U.S. Food and Drug Administration (FDA). FDA News Release. FDA clears first blood test used in diagnosing Alzheimer’s disease. May 16, 2025. Available at: https://www.fda.gov/news-events/press-announcements/fda-clears-first-blood-test-used-diagnosing-alzheimers-disease. Accessed on March 23, 2026.
25. U.S. Food and Drug Administration (FDA). FDA to recommend additional, earlier MRI monitoring for patients with Alzheimer’s disease taking Leqembi (lecanemab). Available at: https://www.fda.gov/media/188468/download?attachment. Accessed on March 23, 2026.
26. U.S. Food and Drug Administration (FDA). Product Label. Accessed on March 23, 2026.
    • Aducanumab (Aduhelm). Biogen; Rockville, MD: FDA. July 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s003lbl.pdf.
    • Donanemab-azbt (Kisunla). Eli Lilly; Indianapolis, IN; FDA. July 2024. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf.
    • Lecanemab-irmb (Leqembi^™) Product label. Eisai; Nutley, NJ: FDA. Revised January 2026. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761269s011lbl.pdf .
27. World Health Organization (WHO). Preferred product characteristics of blood-based biomarker diagnostics for Alzheimer disease (2024). Available at: https://iris.who.int/server/api/core/bitstreams/43c83ef7-7a34-4b56-ae17-b584f2fc0798/content. Accessed on March 23, 2026.

1. Alzheimer’s Association.
   • Medical Tests for Diagnosing Alzheimer's. Available at: https://www.alz.org/alzheimers-dementia/diagnosis/medical_tests#blood. Accessed on April 1, 2026a.
   • What is Alzheimer's disease? Available at: https://www.alz.org/alzheimers-dementia/what-is-alzheimers. Accessed on March 23, 2026b.
2. National Institutes of Health (NIH) Biomarkers for dementia detection and research. Last reviewed January 21, 2022. Available at: https://www.nia.nih.gov/health/biomarkers-dementia-detection-and-research#CSF. Accessed on March 23, 2026.

AB-42
ADmark^® Alzheimer’s Evaluation
Aducanumab
Aduhelm
Alzheimer Disease
ApoE
Apolipoprotein E
C₂N Diagnostics
Discern^™
Donanemab-azbt
Elecsys pTau181
Kisunla
Lecanemab-irmb
Leqembi
Lumipulse G β-Amyloid Ratio (1-42/1-40)
Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio
Neural Thread Protein
PrecivityAD^™
Tau Protein

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

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