Biomarkers can be an early indicator of change¹

The accumulation of amyloid beta and tau are regarded as one of the earliest signs and the pathological hallmarks of Alzheimer's disease (AD).² Accumulation of both amyloid and tau starts 15 years prior to symptom onset.³

These biomarkers reflect the specific pathological accumulation of amyloid beta in plaques and tau in neurofibrillary tangles in the brain, serving as detectable signs of AD pathogenesis.²

Biomarkers enhance diagnostic accuracy and physician confidence in early diagnosis.⁴

A positive pTau181/Abeta42 ratio result in CSF does not establish a diagnosis of Alzheimer's disease (AD) and should always be interpreted in conjunction with clinical information.

CSF biomarkers are well established⁵

Amyloid beta (1-42) (Abeta42), phosphorylated tau (pTau181) and total tau (tTau) cerebrospinal fluid (CSF) biomarkers have been used in the research field for over 20 years.⁵

In 2018, the National Institute of Aging-Alzheimer's Association (NIA-AA) provided an unbiased, classification scheme, the amyloid/tau/neurodegeneration (AT(N) framework), that recognized three general groups of fluid biomarkers based on the nature of the pathological process that each measures.⁵

NIA-AA has included Abeta42, pTau and tTau CSF biomarkers as core biomarkers to aid in the diagnosis of mild cognitive impairment (MCI) and AD.⁵

Clinical diagnostic criteria for AD and guidelines have been developed by several organizations including:

• FDA⁶
• EMA⁷
• The American Psychiatric Association (DSM5)⁸
• NINCDS-ADRDA⁹
• IWG¹⁰
• NIA-AA⁵

Per the IWG-2 criteria, in vivo evidence of AD pathophysiology is defined as increased brain amyloid retention on PET imaging (and perhaps of tau ligand on tau imaging PET), or as decreased Abeta42 together with increased tTau or pTau in CSF.¹⁰

Updates to these guidelines in recent years reflect an increased focus on the utility of biomarkers to aid the timely and accurate diagnosis of AD.^6-10

Clinical trials support biomarker use^11,12

In order for patients to meet eligibility criteria for enrollment in clinical trials, a diagnosis of AD is required. Biomarkers can aid in the diagnosis of AD.^11,12

Fluid biomarkers are reliable alternatives to PET in clinical trials due to their modifications in the early stages of disease, concordance with amyloid PET, wide availability, and low cost.^11,12

Although they cannot guarantee the success of a drug in late-phase trials, biomarkers can be used in earlier phases to select the most promising drug candidates and most optimal dose to move forward to late-phase clinical trials.^11,12

Assessment of various biomarkers may also provide supportive evidence for a drug that has an established clinically meaningful benefit.⁶

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