Molecular fluid biomarkers
Cerebrospinal fluid (CSF) analysis is currently the most readily available and reimbursed test to aid in diagnosing AD, with appropriate-use criteria for patients with suspected AD. CSF biomarkers for AD are useful in cognitively impaired patients when the etiologic diagnosis is equivocal, there is only an intermediate level of diagnostic confidence, or there is very high confidence in the etiologic diagnosis. Testing for CSF biomarkers is also recommended for patients at very early clinical stages (for example, early MCI) or with atypical clinical presentations.
A decreased concentration of amyloid-beta 42 in CSF is a marker of amyloid neuritic plaques in the brain. An increased concentration of total tau in CSF reflects injury to neurons, and an increased concentration of specific isoforms of hyperphosphorylated tau reflects neurofibrillary tangles. Presently, the ratios of t-tau to amyloid-beta 42, amyloid-beta 42 to amyloid-beta 40, and phosphorylated-tau 181 to amyloid-beta 42 are the best-performing markers of AD neuropathologic changes and are more accurate than assessing individual biomarkers. These CSF biomarkers of AD have been validated against autopsy, and ratio values of CSF amyloid-beta 42 have been further validated against amyloid PET, with overall sensitivity and specificity of approximately 90% and 84%, respectively.
Some of the most exciting recent advances in AD center around the measurement of these proteins and others in plasma. Appropriate-use criteria for plasma biomarkers in the evaluation of patients with cognitive impairment were published in 2022. In addition to their use in clinical trials, these criteria cautiously recommend using these biomarkers in specialized memory clinics in the diagnostic workup of patients with cognitive symptoms, along with confirmatory CSF markers or PET. Additional data are needed before plasma biomarkers of AD are used as standalone diagnostic markers or considered in the primary care setting.
We have made remarkable progress toward more precise molecular diagnosis of brain diseases underlying cognitive impairment and dementia. Ongoing efforts to evaluate the utility of these measures in clinical practice include the need to increase diversity of patients and providers. Ultimately, the tremendous progress in molecular biomarkers for the diseases causing dementia will help the field work toward our common goal of early and accurate diagnosis, better management, and hope for people living with these diseases.
Bradford C. Dickerson, MD, MMSc, is a professor, department of neurology, Harvard Medical School, and director, Frontotemporal Disorders Unit, department of neurology, at Massachusetts General Hospital, both in Boston.
A version of this article first appeared on Medscape.com.