From precision medicine to precision care: Choosing and using precision medicine in the context of multimorbidity.

Rapid advances in precision medicine promise dramatic reductions in morbidity and mortality for a growing array of conditions. To realize the benefits of precision medicine and minimize harm, it is necessary to address real-world challenges encountered in translating this research into practice. Foremost among these is how to choose and use precision medicine modalities in real-world practice by addressing issues related to caring for the sizable proportion of people living with multimorbidity. Precision medicine needs to be delivered in the broader context of precision care to account for factors that influence outcomes for specific therapeutics. Precision care integrates a person-centered approach with precision medicine to inform decision making and care planning by taking multimorbidity, functional status, values, goals, preferences, social and societal context into account. Designing dissemination and implementation of precision medicine around precision care would improve person-centered quality and outcomes of care, target interventions to those most likely to benefit thereby improving access to new therapeutics, minimize the risk of withdrawal from the market from unanticipated harms of therapy, and advance health equity by tailoring interventions and care to meet the needs of diverse individuals and populations. Precision medicine delivered in the context of precision care would foster respectful care aligned with preferences, values, and goals, engendering trust, and providing needed information to make informed decisions. Accelerating adoption requires attention to the full continuum of translational research: developing new approaches, demonstrating their usefulness, disseminating and implementing findings, while engaging patients throughout the process. This encompasses basic science, preclinical and clinical research and implementation into practice, ultimately improving health. This article examines challenges to the adoption of precision medicine in the context of multimorbidity. Although the potential of precision medicine is enormous, proactive efforts are needed to avoid unintended consequences and foster its equitable and effective adoption.

Resistance and resilience to Alzheimer's disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort.

Alzheimer's disease neuropathologic change (ADNC) is defined by progressive accumulation of ß-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia. ADNC criteria for resistance and resilience are not well-defined, so we developed stringent pathologic cutoffs for non-demented subjects to eliminate cases of borderline pathology. We identified 14 resistant (85+ years old, non-demented, Braak stage ≤ III, CERAD absent) and 7 resilient (non-demented, Braak stage VI, CERAD frequent) individuals out of 684 autopsies from the Adult Changes in Thought study, a long-standing community-based cohort. We matched each resistant or resilient subject to a subject with dementia and severe ADNC (Braak stage VI, CERAD frequent) by age, sex, year of death, and post-mortem interval. We expanded the neuropathologic evaluation to include quantitative approaches to assess neuropathology and found that resilient participants had lower neocortical pTau burden despite fulfilling criteria for Braak stage VI. Moreover, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was robustly associated with clinical dementia and was more prevalent in cases with high pTau burden, supporting the notion that resilience to ADNC may depend, in part, on resistance to pTDP-43 pathology. To probe for interactions between tau and TDP-43, we developed a C. elegans model of combined human (h) Tau and TDP-43 proteotoxicity, which exhibited a severe degenerative phenotype most compatible with a synergistic, rather than simply additive, interaction between hTau and hTDP-43 neurodegeneration. Pathways that underlie this synergy may present novel therapeutic targets for the prevention and treatment of AD.