Language and Meaning: Asymptomatic Alzheimer’s Disease in the Clinic and Society

Patients who know they have an abnormal Alzheimer’s disease (AD) biomarker result but have no cognitive or behavioral symptoms have already presented to many clinical practices. And their numbers will soon rise. Cognitively normal older adults who have abnormal amyloid PET or cerebrospinal fluid AD biomarkers identified through research participation, or an abnormal AD blood biomarker from one of several commercially available tests, are trickling into both specialty and general care clinics. The question of whether they have a disease, or are simply at risk for one, has already challenged clinicians’ and researchers’ conceptions of AD. The way that this “asymptomatic, biomarker positive” state is characterized outside of care and research has consequences that require study and navigation.

Consensus appropriate use criteria for obtaining AD biomarkers for patients without objective cognitive impairment are mixed. Guidelines include some differences between those who have subjective cognitive decline and those with no symptoms who have normal cognition by testing [1–3]. As of this writing, obtaining AD biomarkers for the latter group is clearly not recommended. But, like prediabetes and prehypertension have shown us, the line between normal and abnormal in medicine is almost, by nature, not sharp. Further, this challenge of early and accurate detection of AD is magnified by clinical practice realities of minimal patient-facing time, variable expertise for detailed cognitive assessment and interpretation, and by our often blunt even if validated tools.

The way that clinicians conceive of AD, the use of biomarkers, and the evaluation of symptoms is on the precipice of a sea change, if it not well in to one already. The Alzheimer’s Association Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease is currently being finalized, after a period of public comment [4]. In these criteria, asymptomatic AD (sometimes equated with “preclinical AD”) as we have known it is codified as part of the disease. Clinical “Stage 1” of a proposed 6-stage model of AD is defined as “asymptomatic, biomarker evidence only”, where objective cognitive performance is within expected range on cognitive tests. These criteria envision a landscape where more precise, alphanumeric stages for AD will be used, mirroring the evolution of cancer care and nosology, combining a clinical stage (CS, 1–6) and a biologic stage (BS, A–D).

Disease labels and diagnostic codes confer certain medical-legal statuses on individuals. Thus, the question of when AD “starts” is not just a biological one or a quandary for philosophers of medicine [5]. It is practical. And the answer has consequences that will be felt outside of our health care systems. The way that clinicians understand and use labels, document them in the medical record, and view the appropriateness of disclosing them outside of care likely has an outsized role in the way that health systems, employers, and insurance carriers treat the labeled. For example, in the U.S., the Affordable Care Act (2010) aims to protect individuals from discrimination or refusal of coverage related to a health problem that they had prior to enrolling in a new insurance plan (where this problem is termed a “pre-existing condition”). As others have pointed out, since a pre-existing condition is defined as a “condition resulting from [a prior] illness, injury (whether or not the injury is accidental), pregnancy, or congenital malformation,” it is not clear by existing AD diagnostic criteria in early 2024 that an elevated biomarker alone would meet this definition [6]. In a similar vein, AD biomarker positivity may not be considered a “disability” as defined by the Fair Housing Act or the Americans with Disabilities Act in the U.S., which prohibit discrimination against individuals due to their disability by providers of housing, and in areas of employment, communications and access to government programs and services [7]. In these ways, individuals with asymptomatic AD, vulnerable in their having a higher risk of developing symptoms (and accompanying life challenges) of AD than their age-matched peers, may not enjoy legal protections against inflated health insurance premiums or against discriminatory hiring and firing practices in the workplace. As asymptomatic biomarker positivity shifts from pre-disease to disease, and becomes classified and documented as early AD, these legal risks and protections may also shift.

The way clinicians conceptualize and document AD matters. In a recent study published in the Journal of Alzheimer’s Disease, Vaishnav et al. have contributed novel work to better understand this landscape [8]. Looking ahead presciently to our current era of biologically-defined AD and disease-modifying therapies, almost 9 years ago now, the authors conducted a qualitative, interview-based study of 17 dementia care experts at centers across the U.S. A central aim, and one that should continue to motivate further investigation, was to try to capture these experts’ perspectives and consequent conceptions of asymptomatic AD (termed “preclinical AD” in the paper) and the language they use in their practice to describe it. In turn, the study also shed light on how experts’ conceptions of asymptomatic, elevated AD biomarker status align with their views on disclosing that status outside of care.

For Vaishnav et al. [8], the main worry is that patients identified with abnormal AD biomarker(s) who are not classified as having AD (i.e., a new, “unprotected class”) are still at risk for employment- or insurance-related discrimination associated with the disease. On the other side, if there are any legal-financial “benefits” to gain with asymptomatic AD being classified as a disease, like supportive services or health insurance coverage before any symptoms or disability, these would not be realized.

In the study, experts were given three hypothetical, clinical scenarios, including psychosocial factors, that involved patients with asymptomatic AD [8]. Experts were asked two questions about each scenario: What language would you use when documenting this patient’s condition, and should this information be disclosed to employers or insurers? The authors analyzed 51 unique sets of responses to these questions across the 17 experts, coding for themes related to AD diagnostic certainty and disclosure.

Interestingly, results were mixed. There were certainly patterns that emerged. In around 80% of responses, experts said they would document these biomarker-positive, asymptomatic patients as not having active AD; in the remaining 20% of responses, they would document amyloid positivity in “preclinical AD” as having AD (described as an “active disease process”). In a prophetic view to the present, an expert in this active AD group remarked, “I would say they have biomarker evidence of Alzheimer’s disease.” Of the responses in the not active AD group, most said the data conferred “increased susceptibility to AD” (∼60%).

For the study’s second question regarding disclosure, experts favored withholding disclosure outside of care in over 70% of the scenarios and disclosing asymptomatic AD in about 15% (the remainder with no preference) [8]. As the authors point out, while acknowledging the small sample size, in all scenarios where disclosure was favored, documentation patterns were either “susceptibility to AD” or “active AD”. When a biomarker result was thought to provide no prognostic information, no disclosure was favored. A conclusion may be that if information was enough to make a diagnosis or be meaningful about prognosis, there was no reason to shield it outside of care. In a couple of scenarios, experts expressed a sense of ethical obligation to not “withhold meaningful information” (biomarker positivity) from employers, and maybe insurance carriers. Thus, disease conceptions and labels and their documentation have consequences.

This study provides valuable insights, even if derived from a small sample of experts’ practices from almost a decade ago. Its results are a helpful guide but a mere first step. To fully understand the social and legal consequences of “biomarkers before symptoms” today, of how this earliest phase of the AD continuum is conceived of and put on record, we must update and widen this knowledge, across practice settings, geographic locations, and providers’ level of experience. We have to gain a thorough understanding of the real-world landscape of views at the same time that we strive to adapt practices or policy.

As the biological criteria for AD take firmer hold, we see how much has changed in AD care in a relatively short period of time. This reflects our exploding knowledge about the pathophysiology of the disease and how we are, finally, intervening with disease-modifying drug therapies. In many ways we are at the beginning again. Internists, geriatricians, and specialty providers in neurology and psychiatry around the world are poised to positively impact care, perhaps more so than ever before. We must remember that while criteria and guidelines shape clinicians’ conceptions, it is clinicians’ conceptions and actual practice that may most meaningfully shape the medical-legal and social landscape for patients.