When you hear “Alzheimer’s disease” what comes to mind? Understandably, most people picture an older adult with dementia. But new insights are leading us to reimagine what it means to have Alzheimer’s disease.

Alzheimer’s disease is being reconceptualized as a continuum that begins in a “preclinical” phase. Preclinical Alzheimer’s disease is characterized by the presence of pathology—amyloid plaques, tau tangles, and neurodegeneration—in the absence of cognitive impairment. Though preclinical Alzheimer’s disease is not yet diagnosed clinically, the label offers insights into a patient’s risk of developing dementia years or even decades before the onset of cognitive symptoms.

APOE is a susceptibility gene for Alzheimer’s disease. There are at least three alleles, or variants, of the APOE gene: ε2, ε3, and ε4. Whereas APOE ε2 and ε3 alleles are protective or neutral, respectively, APOE ε4 alleles increase the carrier’s risk of developing dementia. Clinical guidelines currently recommend against genetic testing for Alzheimer’s disease. Participants in Alzheimer’s disease research, however, often undergo APOE testing and learn those results.

What is it like to learn that you are at increased risk for developing dementia caused by Alzheimer’s disease? For years, our team has sought to understand this patient experience.

We have conducted qualitative studies examining how cognitively unimpaired older adults respond to learning dementia-risk information. The Study of Knowledge and Reactions to Amyloid Testing (SOKRATES I) followed individuals after the disclosure of an amyloid PET scan result. The Study of Knowledge and Reactions to APOE Testing (SOKRATES II) followed individuals who had learned an APOE result. Our team has also studied how family members react when they learn about an older adult’s risk for dementia caused by Alzheimer’s disease.

Across these studies, we have seen that individuals view information about dementia risk as distinct from other kinds of health information. Strikingly, older adults talk about the unique implications for their identity and sense of self because amyloid and APOE are about their brains. Although individuals recognize that dementia-risk information is not medically actionable, many still describe feeling empowered by learning this information. Individuals who learn they are at increased risk for dementia are more likely than others to make changes in diet and exercise—and also to revise their future plans to account for the possibility of cognitive decline.

Older adults who participated in SOKRATES I and SOKRATES II wrestled with whether or not to share their dementia-risk information with others. Many raised concerns that sharing would result in stigma and discrimination: in personal relationships and in the workplace, as well as in purchasing insurance or housing. These concerns appear to be justified, as negative attitudes appear to attach to biomarkers like amyloid even in the absence of cognitive impairment. In Alzheimer’s disease, the unfortunate reality is that law and policy lag scientific progress. While the Genetic Information Non-Discrimination Act affords some (albeit incomplete) protections to individuals with APOE ε4 alleles, there are no comparable protections for individuals who learn they have elevated amyloid. This is a serious gap and one that should be remedied before biomarker and APOE testing become widespread.

The SOKRATES I and II studies have proven particularly timely in light of the U.S. Food and Drug Administration’s controversial June 2021 announcement that it had granted accelerated approval to aducanumab (Aduhelm; Biogen), which targets amyloid plaques. Although not addressed in the FDA-approved label, amyloid testing and APOE testing will arguably be an important part of prescribing aducanumab—amyloid testing to see who is a good candidate for the drug and APOE testing because ε4 carriers are at increased risk of brain edema and microhemorrhages due to aducanumab. If these tests become the norm, it will represent a significant change in clinical practice, and it will be essential to design education and disclosure practices around what we know of the patient experience.

Various payers and providers have pushed back on aducanumab due to high costs and uncertain benefits—for example, the Department of Veterans Affairs has announced that the VA won’t include aducanumab on its national formulary. Many are waiting for the Centers for Medicare and Medicaid Services to announce a national coverage decision. But if it’s not aducanumab, it will be another drug. FDA has opened the door for other anti-amyloid therapies, and pharmaceutical companies are eagerly knocking. Thus, there is reason to think testing will soon be more widespread. While the first patients will likely have mild cognitive impairment or dementia, it’s reasonable to anticipate that cognitively unimpaired older adults will also seek testing, whether to receive a drug off-label or to receive another as yet unknown new drug.

The implications for our health system loom large. It’s estimated that 45 million Americans have preclinical AD. If amyloid or APOE testing become widespread, and if there is a disease-modifying therapy, demands on the already over-taxed health care system will substantially increase. More work is needed to understand how to redress disparities in memory care and increase capacity to meet the needs of older adults with Alzheimer’s disease and their caregivers.

The studies:

Disclosing Genetic Risk of Alzheimer’s Disease to Cognitively Unimpaired Older Adults: Findings from the Study of Knowledge and Reactions to APOE Testing (SOKRATES II), was published in Journal of Alzheimer’s Disease in September 2021. Authors include Emily A. Largent, Twisha Bhardwaj, Maramawit Abera, Shana D. Stites, Kristin Harkins, Alan J. Lerner, Angela R. Bradbury, and Jason Karlawish.

Family Members’ Perspectives on Learning Cognitively Unimpaired Older Adults’ Amyloid-β PET Scan Results, was published in Journal of the American Geriatrics Society in July 2021. Authors include Emily A. Largent, Maramawit Abera, Kristin Harkins, Sara J. Feldman, Wendy R. Uhlmann, J. Scott Roberts, Jason Karlawish, and The REVEAL-SCAN Team.

Cognitively Unimpaired Adults’ Reactions to Disclosure of Amyloid PET Scan Results, was published in PLoS One in February 2020. Authors include Emily A. Largent, Kristin Harkins, Christopher H. van Dyck, Sara Hachey, Pamela Sankar, and Jason Karlawish.


Emily Largent

Emily Largent, JD, PhD, RN

Assistant Professor, Medical Ethics and Health Policy, Perelman School of Medicine

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