LAUSR

Over the last century, Alzheimer’s disease has proven a highly malleable concept. Initially an obscure diagnosis pertaining to rare cases of young onset dementia, by the latter half of the 20th century the label had replaced “senility” as the global shorthand for age-related memory loss—a discreet end-of-life disease amenable to cure (Whitehouse and George 2008). However, failures to develop effective therapies in the 21st century have, as McKeown, Malhi, and Singh (2021) write, engendered another paradigmatic shift away from late-stage treatments and toward a pre-symptomatic model aimed at identifying the condition upstream using biomarkers/ genes and interceding with “personalized” treatments. New socially-constructed “pre-disease” categories such as Mild Cognitive Impairment (MCI), Subjective Cognitive Decline (SCD), and preclinical Alzheimer’s have emerged to promote treatment of milder-and-milder forms of memory loss—the latter construct representing a situation wherein Alzheimer’s-associated biomarkers are present in the absence of clinical signs and symptoms. This early intervention paradigm is fraught with practical, philosophical, and ethical challenges. At the core sits an inconvenient truth: that what we have singularly called “Alzheimer’s disease” for the last halfcentury is defined by its heterogeneous, age-related, and multi-factorial nature, and thus more appropriately regarded as a syndrome, i.e., “Alzheimer’s diseases”. Consequently, for a condition where pathology is not destiny (to the point where AD is difficult to diagnose at autopsy given use of variable criteria and methods) (Hyman et al. 2012), it is daunting to imagine a future where early-stage biomarkers assume predictive power. Invariably, as McKeown et al. (2021) write, pursuit of early diagnostics will be burdened with potential for false positives/negatives until proven adequately reliable, specific, sensitive, and valid. So too does the conceptual move upstream to earlier “diagnostic” labeling risk excess medicalization, especially when some degree of memory loss and accumulation of neuropathology associated with socalled “Alzheimer’s disease” is the statistical norm for aging brains beyond sixty-five years. Do we wish to extend one of society’s most feared and stigmatizing labels to people, especially when present treatments are so limited and a “cure” non-existent and even unlikely given complexities with heterogeneity/overlap with aging? Ultimately, it is sentient human beings with fragile, finite lives and relational bonds who must bear the consequences of medical labels, and we must approach telling people they are “at-risk” for dementia (or becoming caregivers) with requisite caution, sensitivity, and humanity (George 2010). There are also valid concerns about industry’s influence within the “upstream” paradigm. Early intervention tests (e.g., amyloid-imaging) can be lucrative for commercial providers even as their use offers unclear diagnostic accuracy and creates anxiety, ambiguity, and uncertainty for patients and families. Moreover, it is possible that “pre-disease” categories will augment offlabel use of current FDA-approved (but rather ineffective) Alzheimer’s drugs. Professional organizations and big pharma have funded expert panels that have established diagnostic parameters for MCI and preclinical Alzheimer’s, frequently producing biased articles reifying the categories that justify therapeutic trials for patients with pre-disease labels. As this “diagnostic creep” occurs, there are inevitably increasing opportunities for companies offering treatment/diagnostics to enlarge market share, and any engagement with the ethics of early intervention must grapple with the conflicts