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A path forward for dementia research: Highlights from the 2019 ADRD Summit

Alzheimer’s disease (AD) is a top funding priority for the U.S. National Institutes of Health (NIH), due to the growing dementia epidemic among our aging population, and to the remaining obstacles along the path to developing accurate diagnostic tools and effective treatments. To identify the largest gaps in our understanding of dementia, and to refine guidelines for research priorities, experts in the field recently convened to devise recommendations for the path forward in dementia research. Their conclusions were presented March 14-15 during the AD and related dementias (ADRD) Summit at the NIH. Attendees ranged from prominent AD researchers and clinicians to caregivers and patients. The engaging format of pairing key problems with roadmaps for solutions allowed attendees of all backgrounds to appreciate the AD forest, rather than its trees. Below are selected highlights* of this inspiring meeting.

Multiple etiologies

A recurring theme throughout the summit was the multiple etiologies underlying the overlapping variants of aging-related dementias. Though age is the primary risk factor for dementia, data suggest that once we account for the contributing pathologies (think amyloid, tau, α-synuclein and TDP-43), the causal link between older age and dementia disappears. This finding offers hope that if we can minimize the fundamental converging pathologies, we may eradicate these devasting age-dependent conditions.

These intersecting causal pathways coupled with the lack of precise assessment techniques for differential diagnosis preclude optimal clinical care. Improved diagnostic methods, perhaps in the form of refined cognitive tests, or self-assessment tools, could transform patient management and reduce economic burdens associated with unemployment and health-related costs that typically increase 5-10 years before diagnosis. With improved screening, targeted interventions for reversible causes will be critical. Various lifestyle factors have been found to protect against dementia, including exercise, cardiovascular health, adherence to a Mediterranean diet, alcohol consumption, and education. Conversely, established risk factors include the APOE4 allele, diabetes, hearing loss, depression, delirium, poor sleep and anti-cholinergic drugs. These findings call for urgent intervention trials, several of which are underway, to evaluate whether structured lifestyle interventions may prevent disease progression, or even reverse symptoms.

Disparities

Accurate diagnosis and appropriate care are further complicated by racial, cultural and health disparities. Most dementia research has focused on relatively high socioeconomic status, educated, white individuals, limiting applications to underrepresented groups. However, the data speak loudly that increasing study sample diversity, by improving participant engagement and retention for minority communities, will drive equity in dementia care. Striking differences in dementia risk factors among races underscores the need for this diversification. For instance, risk from low socioeconomic status and stroke are greater in black populations, whereas risk from the APOE4 allele is stronger for whites. Cultural differences in performance on standardized cognitive tests, and stigma against cognitive impairment that tends to be culture-specific, further amplify these disparities.

Lewy body dementias

Lewy body dementias (LBD), which comprise both dementia with Lewy bodies and Parkinson’s disease dementia, exemplify the multiple etiologies challenge. LBD are characterized by build-up of the protein α-synuclein. However, α-synuclein also manifests in the AD brain, and the AD hallmarks amyloid and tau also accumulate in LBD, blurring the etiological lines among these dementias. Current LBD biomarkers, including cortical hypometabolism, striatal dopamine terminal markers, or cardiac norepinephrine transporters show poor specificity to LBD. Classic proteins, namely amyloid, tau, α-synuclein and TDP-43, are similarly uninformative, as they are elevated in many overlapping etiologies. LBD clinical trials have run the gamut, from serotonergic agents, dopamine agonists, and phosphodiesterase inhibitors, to brain stimulation and lifestyle interventions, though none have demonstrated compelling cognitive outcomes to date. Therefore, more specific imaging and pathological LBD biomarkers, and better characterization of LBD neuropathology and mechanism of pathological spread, are needed for unraveling these intertwined dementias.

Vascular contributions

Despite the established connection between poor vascular health and dementia, the pathways linking these conditions are unclear. Vascular dysfunction increases risk for white matter degeneration, but why is white matter more susceptible than gray matter? There’s some evidence for lower capillary flow, and reduced perfusion in hypoxic conditions in white matter, but better animal models are needed to clarify the associations among vascular function, neuropathological burden and white matter damage. A prime culprit in this system is altered peri- or paravascular flow, through which cerebrospinal fluid (and its contents like amyloid) moves through the spaces surrounding blood vessels and brain tissue. Sluggish flow could prevent amyloid clearance from the brain, eventually leading to toxic build-up.

Regardless of the mechanisms, it’s crucial to develop sensitive biomarkers of vascular contributors to white matter damage or neuropathology which lead to cognitive decline. An array of markers, such as blood flow, blood-brain barrier leakage, proteomics, or imaging measures of white matter damage, are candidates for further exploration. So far, increased mean diffusivity and hyperintensities in white matter, both measurable with MRI, show high promise for detecting white matter damage that tracks closely with cognitive deficits.

Given the mounting evidence that poor vascular health is a key driver of cognitive decline, identifying vascular risk factors that can be modified through lifestyle could radically transform dementia prevention methods. It’s now believed that cerebrovascular risk accumulates throughout life, as factors such as high blood pressure during early adulthood predict faster cognitive decline decades later. Trials to improve vascular health through lifestyle interventions like exercise and a healthy diet have shown promise, but need refining to target the strongest cerebrovascular risk factors.

Nomenclature

The importance of diagnostic nomenclature was vividly expressed by two speakers personally touched by dementia. An eloquent woman struggling with AD explained that labels have ramifications on both how clinicians treat, and how friends and family perceive, the dementia patient. She shared how stigma regarding cognitive problems can interfere with patient care, and why improved diagnoses that accurately define a patient’s condition should constitute the foundation of patient care. Another speaker offered a heartbreaking account of his father’s descent into his ultimately fatal dementia. Meeting attendees, including myself, teared up alongside him as he described how, after a painful period of diagnostic uncertainty, his father’s diagnosis was revised from AD to LBD. This clarity was vital for his family’s understanding of his father’s behavior and their own genetic links to the disease. These personal stories illustrate the devastating toll dementia takes on our loved ones, underscoring the urgent need for progress in dementia research, which may hopefully be achieved by prioritizing the recommendations outlined in the ADRD Summit.

* Note that I unfortunately missed the final sessions due to travel, but a webcast of the summit is available in full online.


Any views expressed are those of the author, and do not necessarily reflect those of PLOS.

Emilie Reas received her PhD in Neuroscience from UC San Diego, where she used fMRI to study memory. As a postdoc at UCSD, she currently studies how the brain changes with aging and disease. In addition to her tweets for @PLOSNeuro she is @etreas.

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