Laboratory Section - Biochemical Markers of Alzheimer's Disease

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

Currently the diagnosis of Alzheimer's disease (AD) is a clinical diagnosis, focusing on the exclusion of other causes of senile dementia. In 1988 the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's and Related Disorders Association (ADRDA) published clinical criteria for the diagnosis of AD. These organizations defined three categories: possible, probable, and definite AD. The only difference between probable and definite AD is that the definite category requires a brain biopsy confirming the presence of characteristic neurofibrillary tangles. Therefore, definite AD is typically identified only at autopsy. The categories are defined as follows:

1. Possible Alzheimer's Disease
   1. May be made on the basis of the dementia syndrome in the absence of other neurological, psychiatric, or systemic disorders sufficient to cause dementia, and in the presence of variations in the onset, in the presentation, or in the clinical course
   2. May be made in the presence of a second systemic or brain disorder sufficient to produce dementia, which is not considered to be the cause of the dementia
   3. Should be used in research studies when a single gradually progressive severe cognitive deficit is identified in the absence of other identifiable cause
2. Probable Alzheimer's Disease

   The criteria for the clinical diagnosis of probable AD include:

1. Dementia, established by clinical examination and documented by the Mini-Mental State Examination, the Blessed Dementia Scale, or some similar examination and confirmed by neuropsychological tests
2. Deficits in two or more areas of cognition
3. Progressive worsening of memory and other cognitive functions
4. No disturbance of consciousness
5. Onset between ages 40 and 90, most often after the age of 65
6. Absence of systemic disorders or other brain diseases that in and of themselves could account for the progressive deficits in memory and cognition

   The diagnosis of probable AD is supported by:

1. Progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia), and perception (agnosia)
2. Impaired activities of daily living and altered patterns of behavior
3. Family history of similar disorders, particularly if confirmed neuropathologically
4. Laboratory results: normal lumbar puncture as evaluated by standard techniques, normal pattern or non-specific changes in the EEG, and evidence of cerebral atrophy on CT scanning with progression documented by serial observation

Other clinical features consistent with the diagnosis of probable AD, after exclusion of causes of dementia other than AD, include

1. Plateaus in the course of progression of the illness;
2. Associated symptoms of depression, insomnia, incontinence, delusions, illusions, hallucinations, sexual disorders, weight loss, and catastrophic verbal, emotional, or physical outbursts
3. Other neurologic abnormalities in some patients, especially with more advanced disease and including motor signs such as increased muscle tone, myoclonus, or gait disorder
4. Seizures in advanced disease CT normal for age

Features that make the diagnosis of probable AD uncertain or unlikely include:

1. Sudden apoplectic onset
2. Focal neurological findings such as hemiparesis, sensory loss, visual field deficits, and incoordination early in the course of the illness
3. Seizures or gait disturbances at the onset or very early in the course of the illness

3. Definite Alzheimer's Disease
   1. Clinical criteria for probable Alzheimer's disease AND
   2. Histopathologic evidence obtained from a biopsy or autopsy

Diagnosis by exclusion is frustrating for physicians, patients and families, and there has been considerable research interest in identifying an inclusive laboratory test for AD, particularly for use early in the course of disease. Abnormal levels in cerebrospinal fluid (CSF) of the tau protein (phosphorylated [P-tau] or with a threonine moiety [T-tau]) or an amyloid beta (AB) peptide such as AB-42, have been found in patients with AD, and thus these two proteins have been investigated for their diagnostic utility. The tau protein is a microtubule-associated molecule that is found in the neurofibrillary tangles that are typical of Alzheimer's disease. This protein is thought to be related to degenerating and dying neurons, and high levels of tau proteins in the CSF have been associated with AD. AB-42 stands for a subtype of amyloid beta peptide that is produced following the metabolism of an amyloid precursor protein. AB-42 is the key peptide deposited in the amyloid plaques characteristic of AD. Low levels of AB-42 in the CSF have been associated with AD, perhaps because the AB-42 is deposited in the amyloid plaques instead of remaining in solution.

Neural thread protein is another protein that is associated with neurofibrillary tangles of Alzheimer's disease. Both CSF and urine levels of this protein have been investigated as a biochemical marker of Alzheimer's disease. Urine and CSF tests for neural thread protein may be referred to as the AD7CTM test, as developed by Nymox Pharmaceutical Corporation.

Genetic testing for Alzheimer's disease has also been investigated. Genetic tests are considered separately in Regence policy Genetic Testing , Laboratory, Policy No. 20.

Policy/Criteria

1. Measurement of cerebrospinal fluid biomarkers of Alzheimer's disease, including but not limited to tau protein, amyloid beta peptides, or neural thread proteins, is considered investigational.
2. Measurement of urinary biomarkers of Alzheimer's disease, including but not limited to neural thread proteins, is considered investigational.

Scientific Background

Genetic testing for Alzheimer's disease has also been investigated. Genetic tests are considered separately in Regence policy Genetic Testing , Laboratory, Policy No. 20.

• improve diagnostic accuracy or
• predict conversion from mild cognitive impairment (MCI) to AD

Evidence of clinical utility (i.e., improved health outcomes) requires that the testing being evaluated demonstrate all of the following:

• Incremental improvement in diagnostic or prognostic accuracy over current practice
• Incremental improvements lead to improved health outcomes (e.g., by informing clinical management decisions)
• Generalizability

Evaluation of evidence of clinical utility requires consideration of the following:

• Reference Standard

The gold standard for definitive diagnosis of Alzheimer’s Disease (AD) is autopsy. The accuracy of testing for AD is best established by comparison with this gold standard; therefore, the gold standard must be employed to accurately assess incremental diagnostic improvement.

• Predicting Conversion from mild cognitive impairment (MCI) to AD

Predicting conversion from MCI to AD may rely on a clinical diagnosis, albeit with some attendant error and misclassification, because the prediction of interest is conversion and not the gold standard diagnosis.

• Incremental Diagnostic Improvement.

Incremental diagnostic or prognostic improvement is best demonstrated through evidence that the proposed predictor can correctly reclassify individuals with and without AD, or those with MCI who will and will not progress to AD. (5) Alternative approaches such as classical ROC analyses, while providing some insight, do not allow directly translating improvements in diagnostic or prognostic accuracy to changes in health outcomes. (4)

• Improved Health Outcomes (Clinical Utility)

Although not without controversy because of modest efficacy, cholinesterase inhibitors are used to treat mild-to-moderate Alzheimer’s disease. (5) Memantine, a NMDA receptor antagonist, appears to provide a small benefit in those with moderate-to-advanced disease. (6) Given available therapies, in principle more accurate diagnosis might allow targeting treatment to those most likely to benefit. However, clinical trial entry criteria and benefit have been based on clinical diagnosis. While the possibility that more accurate diagnosis might lead to improved outcomes is plausible, it is not based on current evidence. Pharmacologic interventions for MCI have not demonstrated benefit in reducing progression to Alzheimer’s disease. (7)

• Test Cutoffs

Almost all studies employ optimal (data-driven) test cutoffs to define test accuracy (sensitivity and specificity). This approach is typically accompanied by a degree of optimism and potentially overstates test accuracy.

• Sample Definition

Clear description of whether samples included consecutive patients or were selective is required to evaluate potential bias and generalizability but almost absent in this literature.

• Validation

Validation in independent samples is required to establish generalizability of markers but has been scant.

Few studies have included autopsy confirmation; instead, they employed clinical AD diagnosis as the referent standard. Although not directly informative of potential benefit, they are of some interest primarily from revealing possible inaccuracies. Formichi and colleagues identified studies examining diagnostic accuracy of CSF markers for AD: T-tau (41 studies; 2,287 AD patients and 1,384 controls; sensitivities 52% to 100%; specificities 50% to 100%), P-tau (12 studies; 760 AD patients and 396 controls; sensitivities 37% to 100%; specificities 80% to 100%), AB-42 (14 studies; 688 AD patients and 477 controls; sensitivities 55% to 100%; specificities 80% to 100%). (8) While primarily a descriptive review, test accuracies varied widely and only one study included a majority of autopsy-confirmed AD diagnoses.

Diagnostic Accuracy of CSF Markers with AD Autopsy Confirmation

Engelborghs and colleagues assayed P-tau and AB-42 in banked CSF. (9) Samples were examined from 100 patients with and 100 without dementing illness seen between 1992 and 2003. All dementia diagnoses were autopsy proven (65 pure AD, 8 mixed, 37 non-AD dementias). Details of the sample selection were not provided; none indicated if CSF testing was routine or selective. Of those with dementia, 76 were evaluated in a memory clinic and the remainder in referring centers; all underwent clinical, neuropsychological, and imaging evaluations. The non-demented group was substantially younger (mean age 47 versus 76 years of age). Laboratory technicians performing assays were blinded to clinical diagnoses. Samples from 52 subjects required retesting due to questionable results. The sensitivity of clinical evaluation for a pure AD diagnosis was 83% with 75% specificity; of CSF P-tau and AB-42 80% and 93%, respectively. In models, the CSF biomarkers did not provide incremental diagnostic accuracy over the clinical diagnosis—“[a]lthough biomarkers did not perform significantly better comparing all unique clinical diagnoses, they were also not significantly worse, and could therefore add certainty to an established diagnosis.” Four of seven listed authors were employees of the test manufacturer.

Clark and colleagues examined CSF from 106 patients with autopsy-confirmed dementia evaluated at 10 referral clinics and 73 controls (four pathologically examined). Laboratory technicians were blinded to clinical diagnoses. (10) An optimal cutoff of 234 pg/mL for total tau had sensitivity and specificity of 85% and 84%, respectively, for distinguishing those with AD (n=73) from cognitively normal individuals (n=74); AB-42 offered no incremental diagnostic value to total tau in ROC analyses. An optimal cutoff of 361 pg/mL had sensitivity and specificity of 72% and 69% for distinguishing AD (n=74) from frontotemporal dementia (FTD) (n=3) and DLB (n=10). Bian and colleagues assembled a sample from two institutions including 30 patients with FTD (19 autopsy-proven and 11 with known causal genetic mutations) and autopsy proven AD (n=19). (11) Using an optimal cutoff total tau had sensitivity and specificity of 68% and 90%, respectively, for distinguishing FTD from AD. While the tau/AB-42 ratio appeared 100% sensitive distinguishing FTD from AD, it lacked specificity (53%).

As previously noted, among patients with clinically diagnosed AD some have suggested the tau/AB-42 ratio a more accurate measure than either alone. For example, using optimal cutoffs de Jong and colleagues reported sensitivities and specificities for the ratio of 95% and 90% in a sample with clinically diagnosed AD (n=61) and VaD (n=61). (12) In contrast, Le Bastard and colleagues suggested the p-tau/AB-42 ratio lacked specificity distinguishing AD from vascular dementia (VaD) in a sample of 85 subjects (VaD [n=64] or AD [n=21]; 76/85 autopsy-confirmed diagnoses)—specificity 52% at a sensitivity of 91% to 95%. (13)

There is limited existing evidence examining incremental diagnostic accuracy of CSF biomarkers for AD diagnosis employing autopsy as a referent standard. The evidence does not demonstrate improvement over a clinical diagnosis, or whether diagnosis using CSF biomarkers would lead to improved net health outcomes.

Neural Thread Protein

Data have been limited on neural thread protein as a marker for AD. Kahle and colleagues reported on the diagnostic potential of CSF levels of total tau protein and neural thread protein in a group of 35 patients with dementia (30 with probable or definite AD), five patients with Lewy body disease, 29 patients with Parkinson’s disease, and 16 elderly healthy control patients. (14) Levels of both tau and neural thread protein were elevated in patients with AD compared to controls—sensitivities and specificities for tau (63% and 93%) and neural thread protein (70% and 80%). In a prospective multicenter study conducted at eight sites, Goodman and colleagues enrolled 168 patients with recent referral to memory clinics. (15) The urinary neural thread test was 91.4% sensitive for a diagnosis of probable AD (32/35) and 90.1% specific among healthy subjects. However, it was unclear whether the marker changed management or what the potential consequences of a 9.9% false-positive rate might be.

CSF Markers and Progression of Mild Cognitive Impairment

There have been a number of studies of patients with mild cognitive impairment (MCI) for whom the distinction between early stage AD and other etiologies may be more important. Riemenschneider and colleagues assayed AB and tau levels in 28 patients with MCI who were followed up for 18 months. (16) Of the 28 patients, ten progressed to AD, two developed frontotemporal dementia, six had progressive mild cognitive impairment, and ten remained stable. Using previously defined cutoffs combining AB and tau results, sensitivity and specificity for conversion to AD were both 90%. Andreasen and colleagues studied 32 controls and 44 patients with mild cognitive impairment who, after a 1-year follow-up, had progressed to probable AD. (17) At the start of the study, the investigators evaluated total and p-tau and beta amyloid levels. At baseline, 79.5%, 70.4%, and 77.3% had abnormal levels of total tau, P-tau, and AB, respectively. More relevant results would have derived from including patients with mild cognitive development that did not progress to AD.

Hansson and colleagues obtained 137 CSF samples from a larger group of 180 consecutive individuals with MCI evaluated at a referral memory clinic between 1998 and 2001. (18) CSF was also obtained from 39 controls. In the analytical sample (n=137) patients were 50 to 86 years of age at baseline, 55% were female, they were followed a median of 5.2 years, and 57 (42%) progressed to AD. Using a predictor composed of T-tau and AB-42/P-tau181 employing optimal cutoffs, sensitivity and specificity for progression to clinical AD were 95% (95% CI: 86% to 98%) and 87% (95% CI: 78% to 93%), respectively. Patients were not categorized by the presence of amnestic MCI conferring increased risk of conversion to AD. (21) Bouwman and colleagues followed up 59 patients with MCI a mean of 19 months (range 4 to 45 months) obtaining baseline of CSF AB-42 and tau. (19) Abnormal levels for AB-42 (<495 pg/mL) and tau (>356 pg/mL) were accompanied by increased, but imprecise, relative risks for progression to AD—5.0 (95% CI: 1.4 to 18.0) and 5.3 (95% CI: 1.5 to 19.2), respectively. Parnetti and colleagues examined 55 patients with MCI. (20) At baseline, CSF AB-42, total tau, and p-tau were measured—38% had abnormal values. After one year, four of 33 stable patients had abnormal markers. Of those progressing to AD, Lewy body or frontotemporal dementia, 10 of 11 had two or more abnormal markers. While results from these studies are consistent with potential prognostic utility of markers, sample sizes were small. In addition, the type of MCI (amnestic or nonamnestic) was not distinguished but has important predictive value for progression to dementia. (21)

Herrukka and colleagues reported on a sample of 106 patients evaluated at a university neurology department and 33 “from an ongoing prospective population-based study”; selection criteria other than agreeing to a lumbar puncture were not further described. (22) Of the 106 patients, 79 were diagnosed with MCI, 47 with amnestic type, 33 converting to dementia; 60 were included as controls. Average follow-up ranged from 3.5 years (MCI converters), 3.9 years (controls), to 4.6 years (stable MCI). CSF AB-42, P-tau and total tau were measured. Graphical representation of AB-42, P-tau, and total tau suggested considerable overlap between controls, those with stable MCI, and progressive MCI. Test accuracy was not reported. From four international clinical research centers, Ewers and colleagues retrospectively assembled a sample of 88 patients with amnestic MCI based on both the availability of CSF samples and at least one follow-up between one and three years after initial evaluation; 57 healthy controls with baseline evaluations only were also included. (23) Forty-three patients (49%) in the MCI group converted to AD over an average 1.5-year follow-up. Using a cutoff of 27.32 pg/mL sensitivity and specificity of p-tau for conversion were 87% (95% CI: 73% to 93%) and 73% (95% CI: 55% to 84%). It should be noted that the conversion rate to AD in the sample was between two- and threefold the typical 15% found in amnestic MCI.

In summary, this evidence suggests that testing may define increased risk of conversion from MCI to AD. The lack of clearly defined patient samples and distinction of amnestic MCI are significant limitations. Moreover, evidence that earlier diagnosis leads to improved health outcomes through delay of AD onset or improved quality of life is lacking.

Clinical Practice Guidelines

American Academy of Neurology

In 2001, the Quality Standards Committee of the American Academy of Neurology issued the following evidence-based practice parameters related to laboratory testing for AD (24):

• "...no laboratory tests have yet emerged that are appropriate or routine use in the clinical evaluation of patients with suspected AD. Several promising avenues genotyping, imaging and biomarkers are being pursued, but proof that a laboratory test has value is arduous. Ultimately, the putative diagnostic test must be administered to a representative sample of patients with dementia who eventually have pathologic confirmation of their diagnoses. A valuable test will be one that increases diagnostic accuracy over and above a competent clinical diagnosis."

"There are no CSF or other biomarkers recommended for routine use in determining the diagnosis of AD at this time."

Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD)

In July 2007, final approval of the recommendations of the third CCCDTD included the following guidelines related to biomarkers (25):

Biological markers for AD should not be used by primary care physicians as part of a battery of testing for evaluation of memory loss. Referral to a specialist in dementia evaluation is recommended.

There currently are no blood- or urine-based AD diagnostics that can be unequivocally endorsed for routine evaluation of memory loss.

Due to their invasiveness and the availability of other fairly accurate diagnostic modalities (e.g., clinical, neuropsychological), cerebrospinal fluid (CSF) biomarkers should not be routinely performed in all subjects undergoing evaluation for memory loss.

Although the guideline states that CSF biomarkers may be considered in differential diagnosis of AD where there are atypical features and diagnostic uncertainty (e.g., differentiating frontal variants of AD from frontotemporal dementia).

CSF biomarker data in isolation are insufficient to diagnose or exclude AD.

National Institute for Health and Clinical Excellence (NICE) and Social Care Institute for Excellence (SCIE) (26):

This guideline concluded that “the majority of studies come from specialist centres, making widespread interpretation of results difficult, and there remain concerns and difficulties about reliability and standardisation of assays between different laboratories. It also remains to be seen whether lumbar puncture to obtain CSF would be widely acceptable to people with dementia as a routine investigation”.

Summary

Evidence is insufficient to determine whether testing for AD-related biomarkers can improve health outcomes. For the diagnosis of AD, evidence does not demonstrate incremental improvement in diagnostic accuracy over a clinical diagnosis. For predicting conversion from MCI to AD, limited evidence suggests testing might define increased risk; however, further validation studies are needed. Whether earlier diagnosis leads to improved health outcomes through delay of AD onset or quality of life is also unknown. Guidelines are consistent with these conclusions.

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.04.14
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Cross References

Genetic Testing, Regence Medical Policy Manual, Laboratory No. 20

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