Published Date: 1/1/25
Key words: Β-Amyloid Ratio (1-42/1-40); Alzheimer disease biomarkers
Recommendation
Medically Necessary
Testing of β-Amyloid Ratio in the cerebrospinal fluid (CSF) as a biomarker for AD dementia when used to register patient for treatment with aducanumab or other anti-amyloid monoclonal antibodies.
Investigational
Testing of β-Amyloid Ratio in the CSF for any other reason, serum or other fluids as a biomarker for AD dementia.
Background
The clinical criteria for Alzheimer Disease (AD) include a history of insidious onset and progressive course of cognitive decline, exclusion of other etiologies, and documentation of cognitive impairments in one or more domains. Definitive diagnosis of AD requires histopathologic examination, which is rarely done in life.
Role of biomarkers — There are several widely investigated biomarkers for the molecular and degenerative process of AD that can be supportive of a diagnosis of AD but are not yet recommended for routine diagnostic purposes.
Such testing can add incremental confidence to a clinical diagnosis of AD, however, and can be useful in certain circumstances, including early-onset dementia and atypical presentations of AD in which the differential diagnosis includes other non-amyloid neurodegenerative diseases such as FTD.
Accepted biomarkers indicating evidence of the presence of amyloid include imaging scans and CSF amyloid measurements. Such evidence is a requirement for registration of patients to receive aducanumab, which specifically targets this protein. Molecular biomarkers of Aβ protein deposition include:
●Low cerebrospinal fluid (CSF) Aβ42(or Aβ42:Aβ40 ratio)
●Positive amyloid PET imaging using one of the amyloid PET tracers
Appropriate use guidance states that one of these tests should be positive in patients who are treated with aducanumab. Biomarkers of tau deposition (a key component of neurofibrillary tangles) include:
●Increased CSF total tau and phospho-tau
●Tau PET imaging using flortaucipir F-18
In addition to these molecular biomarkers, there are several topographic or neurodegenerative biomarkers used to assess the downstream brain changes that correlate with the regional distribution of neuronal dysfunction and eventual neuronal death associated with AD. These include medial temporal lobe atrophy on MRI and reduced glucose metabolism in the temporoparietal regions on FDG-PET.
In general, the topographic biomarkers are less specific than the molecular biomarkers but correlate better with the emergence of clinical symptoms. None of these tests is valid as a standalone diagnostic test and their combination may best predict outcomes. Research criteria have begun to incorporate these biomarkers in the definition of AD with the goal of providing a biologically based diagnosis rather than a purely clinical diagnosis. These criteria define AD based on the presence of Aβ and tau biomarkers and are irrespective of the patient’s clinical impairments. Markers of neurodegeneration also provide information about disease staging, and, taken together, this has been referred to as the amyloid, tau, and neurodegeneration (ATN) framework.
Plasma biomarkers show promise but do not currently have an established role in clinical practice; more studies are needed. Decreased APOE and APOE ε4 plasma levels as well as a variety of other plasma/serum and CSF proteins have been assessed for predictive value for AD in persons without dementia and in patients with MCI. Ongoing research is investigating the role of such biomarkers that may help distinguish AD from other forms of dementia. In particular, measures of plasma phospho-tau181and phospho-tau217 have demonstrated strong correlation with CSF phospho-tau measures and association with amyloid and tau PET imaging. Similarly, a plasma measure of β42/β40 using an immunoprecipitation and liquid chromatography-mass spectrometry assay has shown promise in detection of amyloid and can be commercially ordered, although it is not currently considered to have clinical utility.
Other laboratory testing — Routine laboratory tests are not useful in the positive diagnosis of AD; however, some laboratory tests are indicated to exclude contributing secondary causes or conditions that may exacerbate cognitive impairment.
Genetic testing – Genetic testing is not recommended in the routine evaluation of patients with AD. APOE genotyping adds marginally to the predictive value of clinical criteria for AD and may stratify risk of progression of amnesic MCI to AD, but both false positives and negatives occur.
Genetic testing for APP, PSEN1, and PSEN2 mutations is commercially available but should be reserved for cases in which young-onset dementia occurs in the setting of a family history positive for an autosomal-dominant distribution of early-onset cases. This should not be performed in asymptomatic family members or patients without appropriate professional genetic counseling, since there would be implications for family members as well as the patient.
Imaging Studies in AD
A consensus opinion of the Amyloid Imaging Task Force, the Society of Nuclear Medicine, and the Alzheimer’s Association concluded that amyloid imaging is not appropriate in patients who meet the core clinical criteria for probable AD and have a typical age of onset, and such a scan should not be used to determine dementia severity. However for registration trial for treatment of AD with aducanumab or other anti-amyloid monoclonal antibodies, a positive amyloid scan or CSF amyloid test is a prerequisite.
Tau PET imaging – A number of tau PET imaging tracers have been in development and hold potential as markers of the tauopathy of AD. A number of studies have demonstrated that these tracers better track disease progression and more highly associate with patterns of atrophy and clinical features than amyloid PET does.
One such tracer, flortaucipir F-18, was approved by the FDA for determining the burden of neurofibrillary tangles in individuals being evaluated for AD; this tracer is not useful for measuring non-AD tauopathies such as frontotemporal lobar degeneration (FTLD). As with amyloid PET, there is limited insurance coverage of this agent.
Clinical Criteria and Features of AD
The diagnosis of AD in practice depends on the clinical criteria outlined below.
Alzheimer disease dementia — Criteria for the diagnosis of probable AD dementia have been established by the National Institute on Aging and the Alzheimer’s Association (NIA-AA) .
●NIA-AA criteria for probable AD dementia require the presence of dementia and the following characteristics:
•Interference with ability to function at work or at usual activities
•A decline from a previous level of functioning and performing
•Not explained by delirium or major psychiatric disorder
•Cognitive impairment established by history-taking from the patient and a knowledgeable informant; and objective bedside mental status examination or neuropsychologic testing
•Cognitive impairment involving a minimum of two of the following domains:
-Impaired ability to acquire and remember new information
-Impaired reasoning and handing of complex tasks, poor judgment
-Impaired visuospatial abilities
-Impaired language functions
-Changes in personality, behavior, or comportment
•Other core clinical criteria include:
-Insidious onset
-Clear-cut history of worsening
-Initial and most prominent cognitive deficits are one of the following: amnestic presentation (ie, impairment in learning and recall of recently learned information) or nonamnestic presentations (including either a language presentation, with prominent word-finding deficits; a visuospatial presentation, with visual cognitive deficits; or a dysexecutive presentation, with prominent impairment of reasoning, judgment, and/or problem solving).
•No evidence of substantial concomitant cerebrovascular disease, core features of dementia with Lewy bodies (DLB), prominent features of behavioral variant frontotemporal dementia (FTD) or prominent features of semantic or nonfluent/agrammatic variants of primary progressive aphasia (PPA), or evidence of another concurrent, active neurologic or non-neurologic disease or use of medication that could have a substantial effect on cognition
●NIA-AA criteria for possible AD dementia include either of the following clinical scenarios:
•Atypical course – The core clinical criteria above are met in terms of the nature of the cognitive deficits, but there is either a sudden onset of cognitive impairment or insufficient historical detail or objective documentation of progressive decline.
•Etiologically mixed presentation – All of the core clinical criteria for AD dementia are met, but the individual also has evidence of concomitant cerebrovascular disease, features of DLB other than the dementia itself, or evidence for another neurologic or medical comorbidity or medication that could have a substantial effect on cognition.
●The Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for AD are also commonly used. Criteria for AD were revised in 2013. The DSM-5 definition of probable AD (now called major neurocognitive disorder due to AD) differs from prior versions in that the cognitive domains have been renamed and expanded to include learning and memory, language, executive function, complex attention, perceptual-motor, and social cognition. Previously, the criteria recognized five domains (memory, aphasia, apraxia, agnosia, and executive function). Like prior versions, the criteria continue to require both memory impairment and evidence of decline in at least one other cognitive domain. New to the criteria is the recognition of genetic testing results, if known, as supportive of a diagnosis of probable AD.
While less substantially validated compared with the NIA-AA criteria, the DSM-IV criteria appeared to have similar accuracy. The performance characteristics of the DSM-5 criteria compared with the DSM-IV and NIA-AA criteria are not yet known.
Basis for FDA approval and use of aducanumab
The pivotal trials included patients with early AD (mild cognitive impairment due to AD and mild AD dementia) who had confirmed brain amyloid using amyloid positron tomography. The expert panel recommended that use of aducanumab be restricted to this population in which efficacy and safety have been studied.
Amyloid pathology can also be established by assessment of Aβ levels or Aβ ratios in the CSF: Aβ 42/40; Aβ 42/total tau; Aβ 42/phospho-tau [p-tau]). These measures provide an alternative to amyloid PET. There is good correspondence between amyloid plaque burden as determined by amyloid PET and CSF amyloid abnormalities in the diagnosis of AD.
References
Leuzy A, Mattsson-Carlgren N, Palmqvist S, Janelidze S, Dage JL, Hansson O. Blood-based biomarkers for Alzheimer’s disease. EMBO Mol Med. 2022;14(1):e14408; 10.15252/emmm.202114408.
Palmqvist S, Zetterberg H, Mattsson N, Johansson P, Alzheimer’s Disease Neuroimaging I, Minthon L, et al. Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology. 2015;85(14):1240-1249; 10.1212/WNL.0000000000001991).
Applicable Code(s) (This list may not be all inclusive)
0358U – Neurology (mild cognitive impairment), analysis of β-amyloid 1-42 and 1-40, chemiluminescence enzyme immunoassay, cerebral spinal fluid, reported as positive, likely positive, or negative (Lumipulse® G βAmyloid Ratio (1-42/1- 40) Test, Fujirebio Diagnostics, Inc)
0412U – Beta amyloid, Aβ42/40 ratio, immunoprecipitation with quantitation by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and qualitative ApoE isoform- specific proteotyping, plasma combined with age, algorithm reported as presence or absence of brain amyloid pathology (PrecivityAD® blood test, C2N Diagnostics LLC)
0547U – Neurofilament light chain (NfL), chemiluminescent enzyme immunoassay, plasma, quantitative
0551U – Tau, phosphorylated, pTau217, by single-molecule array (ultrasensitive digital protein detection), using plasma
DSM-5 criteria for major neurocognitive disorder due to Alzheimer disease
| A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains*: |
| Learning and memory. |
| Language. |
| Executive function. |
| Complex attention. |
| Perceptual-motor. |
| Social cognition. |
| B. The cognitive deficits interfere with independence in everyday activities. At a minimum, assistance should be required with complex instrumental activities of daily living, such as paying bills or managing medications. |
| C. The cognitive deficits do not occur exclusively in the context of a delirium. |
| D. The cognitive deficits are not better explained by another mental disorder (eg, major depressive disorder, schizophrenia). |
| E. There is insidious onset and gradual progression of impairment in at least two cognitive domains. |
| F. Either of the following: |
| Evidence of a causative Alzheimer disease genetic mutation from family history or genetic testing. |
| All three of the following are present: |
| 1) Clear evidence of decline in memory and learning and at least one other cognitive domain. |
| 2) Steadily progressive, gradual decline in cognition, without extended plateaus. |
| 3) No evidence of mixed etiology (ie, absence of other neurodegenerative disorders or cerebrovascular disease, or another neurological, mental, or systemic disease or condition likely contributing to cognitive decline). |