Care for Alzheimer’s patients in the U.S. is estimated to reach $1.1 trillion in Medicare and Medicaid costs by 2050 if a treatment, or cure, is not found, according to the Alzheimer’s Association. With over 27 million cases worldwide, the neurodegenerative disease touches many lives and the demand for better care has never been greater.

Medical imaging has shown promise in recent years for visualizing the way Alzheimer’s spreads and opening up a greater understanding of the condition. Using biomarkers, researchers aim to widen the scope of diagnostic options available and facilitate earlier detection of the disease.

“Biomarkers for amyloid and tau are necessary for positively diagnosing Alzheimer’s in a patient. It takes time for biomarkers to be recognized and accepted, first by the scientific community, then by the clinical community, and eventually, bodies such as CMS and private insurers for reimbursement,” Carlo Medici, CEO of Alzeca Biosciences told HCB News. “But we’re in a phase now where the need for biomarkers is increasingly recognized by the scientific community. So, there will be more research, more publications and more validation of these biomarkers.”

Earlier detection is a key focus for Alzeca, which is currently developing two new MR imaging agents for detection, one for amyloid plaques, the other for tau tangles.

But developing these markers means facing financial and regulatory obstacles while demonstrating that all these efforts will ultimately help move the needle on solving a global problem.

Three types of biomarkers
Years of research around the presence of amyloid plaques and its association with Alzheimer’s has led to the development of diagnostic agents that have earned approval from the FDA. A shift, however, is now underway from amyloid-centric to non-amyloid imaging targeting, especially around tau tangles, which must be present alongside amyloid plaques to confirm a diagnosis of Alzheimer’s.

“These changes in the brain occur 15-20 years before the onset of clinical symptoms. A patient may have amyloid plaques in the brain, without having any symptoms whatsoever,” said Medici. “So, the presence of the plaques does not necessarily mean they’ll develop dementia due to Alzheimer’s. It’s the beginning of what I call a physiopathological journey that could lead to dementia.”

One biomarker included in the classification of Alzheimer’s is neurodegeneration, which is characterized by the destruction of neurons and synapses that connect various neurons to one another. These are associated with amyloid plaques and tau tangles.

The use of imaging biomarkers in making an Alzheimer’s diagnosis has led to the shift in the last few years from amyloid-centric to non-amyloid imaging targeting, and introduced new forms of imaging, such as synaptic imaging and neuroinflammation imaging, for assessing. While not specific to Alzheimer’s, neuroinflammation is believed to play a major role in the neurodegeneration process of many neurological conditions, but what that role is, remains unclear.

“We do not know yet if the neuroinflammation is helping or trying to mitigate the disease process, or if the host reaction or neuroinflammation is making neurological diseases worse,” Dr. Satoshi Minoshima, 2018-2019 president of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and chairman of radiology and imaging sciences at the University of Utah, told HCB News. “To better understand these questions, we really need to have an in vivo imaging marker,” he said.

New classes of such drugs have been developed, according to Minoshima, and looking ahead they should provide greater insight on the role of neuroinflammation in Alzheimer’s diagnoses.

Echoing this sentiment is Dr. Jason Cai, an assistant professor from the Yale PET Center at Yale School of Medicine, and part of a team that recently developed a radiotracer for measuring synaptic density, an early and robust biomarker for Alzheimer’s. “I think in the future we will see a combination of amyloid, tau and neurodegeneration PET as biomarkers for AD, hopefully together with structural information from MR imaging.”

Factors currently limiting research
With no treatment or cure in sight for Alzheimer’s, efforts to justify the development of diagnostic agents are sometimes met with skepticism.

“If there is no therapeutic to change the course of the disease, it is hard to justify complex diagnostic tests, especially when they are expensive,” said Minoshima. “With no approved outcome benefit of a therapeutic drug, we cannot change the course of the disease and make a sustainable impact on patients. I think this challenge is going to continue for a while.”

A lack of treatment also means insurers are less inclined to reimburse for diagnostic exams, said Dr. Henryk Barthel, assistant medical director at the department of nuclear medicine at the University of Leipzig, who added that once such a drug becomes available, it’s predicted that the use of molecular imaging in Alzheimer’s will “massively increase” in both clinical routine and research.

“Until then, this issue creates another challenge to the field, in which being able to offer new imaging tools to a wider clinical population is hindered by the underestimated ‘value of knowing’ among payers,” said Barthel. “An accurate diagnosis is wrongfully not considered as a value of its own when it comes to reimbursement discussions.”

In addition to allowing patients and families to better plan for the onset of Alzheimer’s, using imaging to obtain an earlier diagnosis may support the development of effective treatments for the disease.

“Most treatment trials likely start too late in the course of the disease,” said Dr. Matthias Brendel, a researcher in the department of nuclear medicine at Ludwig-Maximilians-University of Munich. “Brain function will probably not be restored by any therapy, as there is little potential at this stage for the neurons to recover; if the full-blown cascade is already running, it will be difficult to improve the outcome.”

Strong government restrictions related to the use of radiopharmaceuticals are another factor hindering new efforts to diagnose and treat the disease.

“These [restrictions] really hamper the use of molecular imaging in clinical trials and even led to exclusion of strongly regulated countries in some investigations,” said Brendel.

A better future for Alzheimer’s patients
“In my eyes, the most exciting imaging modality innovation in the last few years is the introduction of hybrid PET/MR,” said Barthel. “By that, it is now possible to image Alzheimer’s and other patients on a multimodality base in one session. This ‘one-stop shop’ imaging approach improves patient and caregiver convenience, and potentially also Alzheimer’s diagnosis itself.”

Medici, at Alzeca Biosciences, is also excited about the prospect of MR-based imaging and expects his imaging agents to be available by 2025. He believes their introduction, along with that of other imaging agents for MR, will significantly increase Alzheimer’s research and diagnoses at earlier stages.

Personalized medicine is an overarching trend in modern medicine, but the ability of nuclear medicine to find the best treatment for a specific patient falls in line perfectly with efforts to tackle Alzheimer’s.

“Molecular imaging could serve to stratify patients to their individualized ideal therapy,” said Brendel. “For treatments targeting neuroinflammation, it is probably necessary to analyze the current activation state of the innate immune system of the brain, as there is evidence that too low and too high response of the immune system to proteinopathies can damage the brain.”

While a cure may not be available for some time, Minoshima is confident that the research being done today can have a direct and positive impact on the patient outcomes of tomorrow.

“We may not be able to cure Alzheimer’s disease within the next 10 years, but if we better understand the multiple pathways and targets, we may be more effective at intervening in, and slowing down, its progression,” he said.

For now, researchers continue their efforts to better understand the disease and detect it before it’s already done significant damage.

“If we are able to do a better job of diagnosing Alzheimer’s disease, then hopefully we’ll be able to treat this population early on before full blown dementia takes place,” said Cai. “This is similar to cancer or cardiovascular therapies. The earlier we find the disease, the better the outcome will be.”