BIOMARKERS

Biomarkers & Imaging

Biomarkers, which reflect pathological changes associated with AD, are likely to become instrumental in obtaining an early diagnosis of AD.1 Changes in these biomarkers have been found to correspond to phases of cognitive decline during AD progression.2 Biomarker data can support a clinical diagnosis of dementia due to AD and may be useful for monitoring treatment response.1,3 However, these tests are not yet definitive diagnostic tools, and certain criteria should be met for their use to be appropriate.1,3

biomarkers-1

Reference 2

Cerebrospinal fluid (CSF) biomarkers include tau, which reflects the intensity of neurodegeneration, and phosphorylated-tau, which correlate with tangle pathology.4 Also measured in CSF is phosphorylated-tau, which correlates with tangle pathology.4 Research is ongoing on biomarkers of neurodegeneration available in blood plasma, such as neurofilament light.5,6 These markers may become useful for screening patients for further diagnostic tests and/or monitoring response to treatment; however, these uses are still several years away.

Among the neuroimaging biomarkers of AD, 18F-fluorodeoxyglucose (FDG) PET reveals a progressive decrease in glucose brain metabolism with worsening of cognitive function.7

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The most important biomarkers integrated in the new staging system for AD are those identifying and tracking accumulation of β-amyloid and hyperphosphorylated tau protein in the brain.8 Amyloid-positron emission tomography (PET) detects β-amyloid neuritic plaques using 18F (fluoride 18)-labeled radiotracers with an affinity for fibrillary β-amyloid. Among these tracers, florbetapir, flutemetamol, and florbetaben are approved by the FDA, and another (NAV4694) is under development.3,7 There are also three families of specific tau tracers for PET in development: aryquinoline derivatives, pyrido-indole derivatives, and phenyl/pyridinyl-butadienyl-benzothiazole/benzothiazolium derivatives. These tracers can cross the cell membrane to bind both extra- and intra-cellular tau protein and have encouraging specificity and expected regional distribution in early clinical studies.8

Best Practices for Amyloid PET

A positive amyloid-PET scan has a high correlation with clinical diagnosis of AD.2 Amyloid PET can contribute to differentiating AD from frontotemporal lobar degeneration (FTLD), which is not associated with Aβ plaques, but it cannot distinguish AD from other dementia, including Lewy body dementia and cerebral amyloid angiopathy.3 Clinical trials—including the IDEAS study—are underway to determine whether a diagnosis of AD supplemented with amyloid-PET changes treatment patterns, patient behavior, and/or disease outcomes.9,10

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Reference 11

The present guidance suggests considering amyloid PET in patients who meet the following criteria:3

  • A cognitive complaint with objectively confirmed impairment;
  • Alzheimer’s disease as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and
  • Knowledge of the presence or absence of Aβ pathology is expected to increase diagnostic certainty and alter management.

These criteria are generally interpreted to indicate amyloid PET would be appropriate for patients:3

  • With persistent or progressive unexplained MCI;
  • Who satisfy core clinical criteria for possible AD because of unclear clinical presentation, either an atypical clinical course or an etiologically mixed presentation; or
  • With progressive dementia and atypically early age of onset (≤65 years).

However, amyloid PET would not be appropriate for:3

  • Patients with core clinical criteria for probably AD with typical age of onset;
  • Determining dementia severity;
  • Patients without cognitive impairment but who have a positive family history of dementia or with the mutation apolipoprotein E (APOE)ε4;
  • Patients with a self-reported cognitive complaint that has not been confirmed with clinical examination;
  • Use in lieu of genotyping for patients with suspected autosomal mutations,
  • Asymptomatic patients; or
  • Nonmedical use (eg, legal, insurance coverage, or employment screening).

References

  1. Alzheimer’s Association. Alzheimer’s Association Report: 2017 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2017;13:325-373. Full report available at www.alz.org/documents_custom/2017-facts-and-figures.pdf
  2. Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9:119-128.
  3. Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: A report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimer’s Dement. 2013;9:e1-e16.
  4. Sutphen CL, Jasielec MS, Shah AR, et al. Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer Disease during Middle Age. JAMA Neurol. 2015;72:1029-1042.
  5. Bacioglu M, Maia LF, Preische O, et al. Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases Neuron. 2016;91:56-66.
  6. Mattsson N, Andreasson U, Zetterberg H, et al. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 2017 Mar 27. doi: 10.1001/jamaneurol.2016.6117.
  7. Johnson KA, Fox NC, Sperling RA, Klunk WE. Brain imaging in Alzheimer’s disease. Cold Spring Harb Perspect Med. 2012;2:a006213.
  8. Saint-Aubert L, Lemoine L, Chiotis K, et al. Tau PET imaging: Present and future directions. Mol Neurodegeneration. 2017;12:19.
  9. Alzheimer’s Association. News release in IDEAS study: Major new research study to demonstrate value of PET scans in Alzheimer’s disease diagnosis. Available at www.alz.org/documents_custom/IDEAS_study_news_release_041615.pdf
  10. Boccardi M, Altomare D, Ferrari C, et al. Assessment of the incremental diagnostic value of florbetapir F 18 imaging in patients with cognitive impairment: The incremental diagnostic value of amyloid PET with [18F]-florbetapir (INDIA-FBP) Study. JAMA Neurol. 2016;73:1417-1424.
  11. Amyvid [package insert]. Indianapolis, IN; Eli Lilly and Company; 2013.

Epidemiology

Challenges

Diagnosis

Biomarkers

Treatments

Additional Reading