LAUSR

Brain diseases represent the main cause of disability throughout human life and pose a major global threat for public health and the sustainability of human societies. According to a report on the future of health and health care published by The World Economic Forum, it is estimated that direct and indirect costs of brain diseases already amount to >5% of global gross domestic product, more than the cost of cancer, diabetes, and chronic pulmonary diseases combined. Most importantly, however, brain diseases cause enormous human suffering: 1 in 4 people in the world suffers from neurological or psychiatric disabilities, and not “only” are patients affected, but also their families, neighbors, friends, and communities. Hippocrates reportedly taught his disciples that if they had to choose between learning about the disease a patient had or about the patient who had a disease, they should choose the latter. William Osler echoed this admonition: “The good physician treats the disease; the great physician treats the patient who has the disease.” The study by Ward and colleagues in this issue of Annals of Neurology reminds us of this important lesson, revealing that the prognosis of mild cognitive impairment (MCI) and the rate and risk of progression to dementia do not depend solely on the brain, but rather on the entire person. According to the 2021 Alzheimer’s Disease Facts and Figures report from the Alzheimer’s Association, Americans >60 years of age fear dementia more than any other disease, including cancer, stroke, and cardiac disease. Alzheimer’s disease (AD) is the most common cause of dementia, a major cause of death, and the leading reason for disability amongst older adults in the USA. AD affects >5 million people in the USA alone and nearly 50 million people worldwide. As the population ages, the prevalence of AD is expected to increase further, with estimates of 7.1 million Americans with AD by 2025 and 15 million by 2050. Despite substantial efforts, available therapies offer limited benefits, and we lack disease-modifying treatments that have any meaningful impact on the progressive disability caused by AD. We are in urgent need of a different approach, and a shift from focusing on the “disease” to focusing on the “individual patient” seems essential. Mild cognitive impairment is broadly considered a precursor to dementia, although not all patients with a diagnosis of MCI go on to develop dementia. Much attention has been paid to different subtypes of MCI and their relative prognostic risk to progress to dementia. When MCI is characterized primarily by memory deficits (amnestic MCI [aMCI]), the risk of progression to dementia is thought to be particularly high, and the underlying pathology is typically AD. However, in assessing the risk of dementia and resulting disability faced by a given patient, it is imperative to go beyond the disease or even the brain and consider other aspects of the person’s health and lifestyle. Ward, Wallace, and colleagues had previously shown that an individual’s degree of frailty influences the risk of progression from MCI to dementia and is correlated with the extent to which those with AD manifest the clinical symptoms of dementia. In the present study, Ward and colleagues leverage data from the National Alzheimer’s Coordinating Center (NACC), including nearly 3,500 individuals >65 years of age with a diagnosis of MCI and ≥2 follow-up visits. They confirmed that those with aMCI were about twice as likely to progress to dementia over the course of a 12-year follow-up period as those with nonamnestic MCI (naMCI). However, the important and new finding is that patients with aMCI and high frailty progressed substantially faster than those with low frailty, and those with naMCI and high frailty were twice as likely to develop dementia as those with low frailty. In other words, high frailty was associated with an accelerated progression to dementia in patients with aMCI, and with an increased risk of progression in patients with naMCI. Frailty is a challenging concept, because many authors include in the construct factors that are clearly related to cognitive function, and in that case its utility to assess its contribution to the progression or risk of dementia is limited. In the 45-item frailty index from the NACC Uniform Data Set, which was used by Ward and colleagues, many of the factors can directly compromise cerebrovascular function (eg, cardiac disease or hypertension) or be manifestations of mental and cognitive impairment attributable to brain pathology. For example,