Amyloid PET scan
The LA Times recently published a fairly negative appraisal of the construct of preclinical Alzheimer’s disease (AD). The article described the recent effort by an international committee to update diagnostic criteria that date back to 1984, updated in 2011 and again in 2018. The most recent updates have been presented at meetings and published online and have indeed been the source of debate and disagreement in the field. But the LA Times article goes quite a bit further, essentially asking if one particular aspect of the criteria—the definition of preclinical AD—exists mainly to benefit pharmaceutical and medical testing companies.
So what is preclinical AD? This idea also dates back decades, to early autopsy studies that observed about 20-30% of the brains of older individuals who died with normal cognition had the characteristic signs of AD. The proportion increased with age, just like the frequency of disease and the question loomed: Were these people special or resilient in some way, or were they destined to develop cognitive impairment and dementia if they had lived longer?
Progress in AD biomarkers helped answer this question. Many studies have now shown that having the pathology of AD in the brain is not “normal.” The risk of developing cognitive problems in the future is much higher in people for whom biomarker tests suggest disease biology is present, compared to people who don’t have these brain changes. Formal research diagnostic criteria for preclinical AD were first proposed more than a decade ago and have now been implemented in multiple clinical trials to test medications for their ability to potentially delay or prevent cognitive problems in people at this higher risk. One of the first of these studies was the Anti-Amyloid treatment in Asymptomatic AD (A4) Study, which concluded a little more than a year ago. Though the A4 trial did not demonstrate a benefit of the drug it tested, solanezumab, it did demonstrate the utility of preclinical AD as an ideal disease stage to intervene. In fact, some of the most important learnings from the trial include that the amount of amyloid present in the brain of a person with preclinical AD was strongly associated with the risk of developing cognitive problems over the course of the trial.
So, preclinical AD is not a business product, it is a product of decades of research progress. At least two ongoing clinical trials are testing drugs that have demonstrated efficacy in slowing disease progression once a person has memory and other thinking problems. One of those trials was mentioned in the LA Times article and is ongoing at UCI MIND—the AHEAD Study of lecanemab in preclinical AD. Many in the field believe that these trials are key steps toward the ultimate goal of preventing AD.
If preclinical AD is a real thing and not just a business product, why don’t we make the diagnosis routinely? There are many reasons. First, the recommendations made for an older person who shows biological evidence of disease compared to one who does not are no different. We recommend everyone do everything they can to maximize brain health and lower risk for later cognitive problems. Second, beyond these recommendations, there are not yet treatment options for people with preclinical AD. So the immediate clinical implications are for now extremely limited. And third, there are risks for stigma and discrimination associated with the diagnosis of preclinical AD. That’s why the study materials in the AHEAD Study, which in full disclosure I helped develop, recommend that people considering purchasing long-term care insurance policies do so before entering the study. Right now, there are no laws in this country to protect people from being discriminated against by insurance companies because of a biomarker test. More broadly, we simply do not live in a dementia-friendly society and progress on many levels will be needed to ensure the safety, rights, and optimal outcomes in the care of people with preclinical AD.
Thus, preclinical AD is a complex topic. But it likely represents the future of clinical practice for AD. Much work remains needed. Beside finding treatments that work to delay clinical presentation of disease, the tools to identify people needing to be treated must be more precise, including sorting out the best time to start such treatments and how long they are needed. We remain committed to this work, and efforts to find preventions. It will take a collaborative effort, including pharmaceutical companies, diagnostic testing companies, funding agencies like the National Institute on Aging and Alzheimer’s Association, academic investigators, and most importantly people enrolling in trials like the AHEAD Study. Those people, many of whom have a family history of disease and remarkable motivation to help us advance the field, know how important this effort is.
