Identifying Biomarkers for Alzheimer’s Disease

Alzheimer’s disease affected an estimated 5.5 million Americans in 2014, according to the Alzheimer’s Association, including approximately 200,000 individuals aged younger than 65 years.

These numbers are expected to increase rapidly over the next several years as the baby boomer generation ages — tripling to as many as 16 million people with Alzheimer’s disease (AD) or a related dementia by 2050.¹

Current procedures for AD diagnosis include a primary Mini Mental Status Examination (MMSE) to screen for and confirm cognitive impairment and neuropsychological tests to exclude other age-related dementias. However, definitive diagnosis is only possible at autopsy.

“The analysis of postmortem brain tissue is necessary to verify AD by immunohistochemical analysis of amyloid-b plaques and tangles (tau). Postmortem analysis or, alternatively, brain biopsies might also allow screening for general pathological changes in the AD brain, but these are not useful methods of routine biomarker analysis,” said Meena Chintamaneni, PhD, a pharmacologist and associate dean and chairperson at the Narsee Monjee Institute of Management Studies in Mumbai, India.

Public interest in methods to diagnose AD in its early stages is growing in hopes of slowing disease progression and facilitating better planning to care for loved ones.

This interest has fueled a research push to identify AD biomarkers via cerebrospinal fluid (CSF), positron emission tomography (PET) and magnetic resonance imaging (MRI) neuroimaging, and blood and skin peripheral tissues.

Cerebrobrospinal Fluid Biomarkers

“CSF is a very useful for AD diagnosis because it reflects metabolic processes in the brain owing to direct contact between the brain and CSF,” Chintamaneni said.

“Several biomarkers in CSF have been identified so far, such as decreased amyloid-b-peptides, increased total tau (T-tau), and increased phosphorylated tau (P-tau),” said Carmen Burtea, PhD, a research advisor and clinical lecturer at the University of Mons in Belgium.

Study findings indicate some relationship between these biomarkers and AD, but not at the level of statistical significance needed for them to be considered unequivocally diagnostic. Despite evidence of significant changes in CSF biomarkers, the changes occur in total absence of any cognitive or symptomatic changes in patients.³

“The obtained results are highly variable and not directly interpretable, most likely because a clinical standard technique has yet to be developed,” Burtea said.

Daniel Alkon, MD, of Blanchette Rockefeller Neurosciences Institute in Morgantown, West Virginia, told Neurology Advisor that studies of autopsy brains stained with markers for synapses demonstrated minimal relationships between level of plaques and cognitive performance. “There was, however, a clear, direct relationship between the numbers of synapses and the levels of cognitive function.”

This relationship between the loss of synapses and cognitive deficits has held up in many subsequent studies. But this finding has yet to move the industry, partly because there has not been much that can be done about synaptic loss, according to Akon, whose research efforts continue to move in this direction.

In another study published in Frontiers in Aging Neuroscience, Daniel Ferreira, MD, of Karolinska Institutet in Stockholm, Sweden, and colleagues evaluated the capacity of core CSF biomarkers to predict conversion from mild cognitive impairment (MCI) to AD.

“Several confounding factors have an important influence on CSF biomarkers’ diagnostic performance for predicting progression from MCI to AD,” Ferreira said.

Primarily, CSF biomarkers have a better predictive capacity in cases of amnestic MCI, in patients that convert from MCI to AD in a short period of time, and younger MCI patients. The predictive value and utility of biomarkers is still strongly linked to the stage of the disease and the time to conversion.

The amyloid-ß 42/p-tau ratio showed promise, especially for predicting progression from MCI to AD in patients aged younger than 70 years, the researchers found. p-tau alone had high capacity to identify MCI cases converting to AD in the short-term.⁵

Due to the differences of predictive value over time, the researchers recommended that CSF biomarkers be utilized in tandem with others, such as neuroimaging biomarkers that have a higher efficiency closer to AD diagnosis.

Another challenge is that CSF biomarkers are not really practical for clinical practice diagnosis, especially for older or middle-aged patients, because they require lumbar punctures — an invasive procedure with potential side effects ranging from backache to headache to internal bleeding and infections. Routine screening with this method would be difficult as well as follow-up analysis of the same patient over several years.

Other diagnostic methods involving brain imaging and peripheral biomarkers in the blood and skin cells are also being explored, Alkon said.