Dementia: A new era in diagnosis and treatment

To help support clinical decision-making, a growing number of healthcare centers are adopting a multi-disciplinary team approach. Psychiatrists, neurologists, radiologists, and other clinical specialists meet to review cases.
Peter Jaret
Published on December 14, 2021

One of the most devastating disorders associated with aging, dementia causes a progressive loss of the ability to think, remember, and reason. Early disease stages may cause only minor memory lapses and difficulty paying attention. But over time, it can rob patients of speech, movement, and even the capacity to recognize loved ones. Eventually, the underlying disease can prove fatal.

<p>Over 50 million people in the world have dementia, according to a recent report from Alzheimer’s Disease International. Because the risk rises with age – and because people are living longer than ever – the number of people with dementia is expected to double every two decades.<br>By 2050, dementia is predicted to affect 152 million people.[1]&nbsp;What makes it even more difficult is that there is not one “dementia”; there is a set of underlying diseases that cause dementia. After decades of research, these diseases remain challenging disorders to diagnose and treat. But important progress is being made on many fronts.</p>
Researchers now know that the symptoms of dementia, such as memory loss and impaired thinking, can be caused by a variety of disorders of the brain. The most common form of dementia is Alzheimer’s disease, which accounts for 60 to 80 percent of all dementias. Others include Lewy body dementia, frontotemporal dementia, vascular dementia, and mixed dementia.
Each of these disorders is marked by characteristic changes in the brain. Yet diagnosing dementia remains a challenge. “Most patients are first seen by a primary care physician, who takes a medical history and may perform a simple cognitive test,” explained Nick Fox, MD, director of the Dementia Research Centre at University College London, UK. “But because dementia causes a loss of insight, the patient isn’t usually a good historian of their own medical history.”<br><p>Instead, physicians must rely on family members such as a spouse or adult child.<br></p>

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<p>With many disparate sources of clinical data, bringing all the relevant information together in a form that specialists can easily review is challenging. “Doctors tend to overestimate their own potential to integrate all the available data,” said Oskar Hansson, PhD, a professor at Lund University in Sweden, where he conducts dementia research. To help support clinical decision-making, a growing number of centers are adopting a multi-disciplinary team approach, where psychiatrists, neurologists, radiologists, and other clinical specialists meet to review cases. Integrated dashboards designed to assemble and present all relevant data about a patient with the help of artificial intelligence (AI), which are increasingly used by tumor boards, promise to support clinical decision-making in dementia as well.<br>Algorithms may also prove to be helpful in analyzing multiple disease markers. The ATX(N) classification system, for example, currently used solely in research but potentially useful in the clinic, categorizes patients using three pathophysiologic pathways: beta-amyloid (A), tau (T), and neurodegeneration (N). The X has recently been added to represent novel biomarkers such as synaptic dysfunction and blood-brain barrier alterations, which may prove useful in diagnosis.[7]<br></p>

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Advanced tools like these could prove especially useful for analyzing complex cases. As Dr. Fox noted, “In some cases, we can confidently rule out dementia. In others, we can diagnose Alzheimer’s disease or another dementia. The pinch point is those patients where the clinical data is contradictory or unreliable. Especially when handling multiple parameters, there may be uncertainly when some results are within the normal range and others are outside normal range.” <br>Even when the diagnosis is Alzheimer’s disease or another form of dementia, offering a prognosis is difficult. “Really what we’re being asked to do is predict the future, based on the past – working out how someone has changed from the previous self is key,” explained Dr. Fox. Imaging data, medical history, and results of tests for tau in CSF can serve as a guide. In a recent study, for example, researchers reported that tau PET imaging accurately predicted cognitive decline in asymptomatic patients who were beta-amyloid positive, outperforming both volumetric MRI and amyloid PET.[8]
<p>Even with these advances, the task of offering a prognosis to patients is far from simple, said Andrew Saykin, PsyD, director of the Indiana University (IU) Alzheimer’s Disease Research Center and IU Center for Neuroimaging, Indianapolis, USA. “The truth is, in the absence of a rare causative gene mutation, we don’t understand what drives Alzheimer’s disease in a given individual. We can detect amyloid and tau, but the key issue is why these pathological proteins are upregulated in the first place. Dysregulation of the immune system, lipid metabolism, brain energetics, and several other pathways are prime suspects. We also need a better understanding of why patients differ in age of onset and rate of progression, with some patients having an earlier onset and rapid progression and others showing very slow progression. These differences underscore the need for a precision medicine of dementia where treatment can be fine-tuned to the individual.”</p>
<p>Today, refinements in brain imaging, the development of new and more precise biomarkers for dementia, and the use of predictive AI hold out the promise of far greater diagnostic precision.<br>One area of interest is genetics. “Alzheimer’s disease has a strong genetic component,” said Dr. Saykin. “<a href="APOE e4">APOE e4</a> is the strongest genetic risk factor. But many of us are interested in the possibility of developing polygenic scores for dementia, similar to what we have for prostate and breast cancer and for diabetes. DNA extracted from blood can be used for a genome-wide scan yielding a composite score that sums up all genetic variations that contribute to increased risk.” <br>Meanwhile, the identification and development of new blood biomarkers for Alzheimer’s disease, such as p-tau, could lead to minimally invasive tests that could be more widely used than today’s CSF tests. In a recent review article, researchers cited “substantial progress” in novel blood biomarkers over the past four years.”[9]</p>
Studies show that the APOE e4 gene strongly affects the deposition of beta amyloid to form plaques and cause cerebral amyloid angiopathy (CAA), two major hallmarks in AD brains.
<p>A wide variety of other potentially useful biomarkers for diagnosis are also under investigation, including exosomes. “Exosomes are vesicles shed from brain cells that are able to cross the blood-brain barrier,” explained Saykin. “Exosomes carry molecular signatures that reflect what’s going on in the brain. The hope is that we may be able to use them to noninvasively identify changes in the brain far earlier than we can now.”&nbsp;</p>

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Even something as seemingly simple as basic cognitive testing – which today is often done with a questionnaire filled out by hand – may become much more precise. “Digital tools such as smartphones and wearable devices allow patients to do memory tests at home, every week or two,” said Dr. Hansson. “This could be very informative for the medical doctor when the patient returns to the clinic, to determine if memory function has deteriorated or remained stable.” Prognostic algorithms powered by AI could be helpful in spotting telltale changes in a patient’s cognition over time.
For now, treatment options for Alzheimer’s disease are extremely limited. <a href="Cholinesterase inhibitors">Cholinesterase inhibitors</a> can prevent the breakdown of acetylcholine and slow or delay the worsening of symptoms in Alzheimer’s disease, although these medications do not slow the underlying progression of pathology in the brain.[2,3] Memantine, which is approved for patients with moderate to severe Alzheimer’s disease, can improve memory, attention, reason, language, and the ability to perform simple tasks. The drug is believed to work by regulating the activity of glutamate, a chemical that plays a role in information processing, storage, and retrieval.[10] In the case of vascular dementia, which is caused by damage to parts of the brain due to reduced blood supply from blood vessels, treatments to modify risk factors such as high cholesterol and elevated blood pressure can help prevent further damage. <br>Medications are also used to ease symptoms. Antidepressants and anti-anxiety drugs, for instance, can help relieve mood disorders linked to dementia. Sleep medications can help treat insomnia and alterations in sleep-wake cycles, another common feature of Alzheimer’s disease. Non-drug approaches such as memory training, physical activity, and psychological counseling may also help some patients.[2,3]
AD is marked by a decrease in levels of acetylcholine, which plays a key role in memory, thought, judgment, and alertness. Cholinesterase inhibitors prevent its breakdown, boosting levels in the brain and temporarily improving cognitive function.
The Holy Grail of research, of course, is finding a way to dramatically slow or stop the progress of Alzheimer’s, by far the most common form of dementia. With one new therapy recently approved by the FDA [11] and others in the pipeline, experts are hopeful that more effective treatments may soon become available. Nothing on the horizon yet offers a cure, they caution. “But as new therapeutic approaches become available, clinicians may be able to use diagnostic data such as family history and biomarkers to optimize interventions, using combination therapies, much like the successful approach to AIDS,” said Dr. Saykin. “We don’t know yet whether combination therapies for Alzheimer’s need to be administered together as a therapeutic cocktail or sequentially based on stage of disease, for example, anti-amyloid treatment administered early followed by another drug to block tau or inflammation. Research is needed to optimize the approach, including how to best tailor the strategy to the individual patient,” said Saykin. Ironically, the approval of disease-altering therapies will pose its own challenges. Currently, most of the emphasis is on supporting patients and families as Alzheimer’s disease worsens. “In the UK, we’re anticipating that the systems we have in place may be overburdened if a therapy does become available. We’re all scrambling to think about how we bring the services up to the level we’re going to need,” said Dr. Mackay. In Sweden, Dr. Hansson anticipates similar challenges. “The approval of an effective therapy will mean that even more patients go to their primary care physicians,” he said.

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<p>Once patients are started on a therapy, the experts noted, they will need to be monitored to evaluate both its effectiveness and possible side effects, adding to the complexity of long-term clinical care.<br>The arrival of a genuinely effective treatment is also likely to shift the prevailing perception of Alzheimer’s disease, according to Dr. Mackay. “There’s still something of a taboo about dementia, a sense that it’s something to be ashamed of, and that there’s nothing that can be done. But we are already beginning to see efforts to change the public health messaging around brain health, to encourage people to take their brain health seriously, and to do everything they can to preserve it.”<br>With advances on many fronts, clinicians may soon have more tools to offer.</p>

By Peter Jaret

Peter Jaret is the author of several health-related books, including In Self-Defense: The Human Immune System, Nurse: A World of Care, and Impact: On the Frontlines of Public Health. A frequent contributor to National Geographic, The New York Times, Reader’s Digest, Health magazine, More, AARP Bulletin, and dozens of other periodicals, Jaret is the recipient of an American Medical Association award for journalism and two James Beard awards. He lives in Petaluma, California.