AD Should Be Treated as a Clinical-Biological Construct

The International Working Group (IWG) recommends approaching Alzheimer disease (AD) as a clinical-biological construct, according to a Special Communication published in JAMA Neurology.

The recently revised Alzheimer Association (AA) diagnostic criteria for AD proposed that AD be defined on a biological basis alone. According to the AA criteria, an AD diagnosis can be applied to cognitively normal individuals with evidence of core 1 AD biomarkers, which include cerebrospinal fluid (CSF) amyloid β and tau ratios and plasma phosphorylated tau (p-tau) 217 confirmed with amyloid in positron emission tomography (PET).

The IWG, however, advocated that AD is a clinical-biological construct and that biomarkers alone are not sufficient to diagnose AD. Instead, the IWG argued, an AD diagnosis should be made when biomarkers are complemented by cognitive deficits.

The IWG stated that the presence of core 1 AD biomarkers alone is not sufficient to account for the complex mechanisms and interactions underlying AD. In the clinical setting, diagnosing a patient who has normal cognition with AD on the basis of only core 1 AD biomarkers is the most concerning extension of the purely biologic definition of AD offered by the AA.

The IWG posited that using purely biologic markers in the early stages to diagnose other diseases, such as some cancers, has clinical utility. In AD, however, core 1 biomarker positivity does not ensure progression to AD. For example, a 65-year-old man who is cognitively normal and positive for amyloid vs a biomarker-negative 65-year-old man only has a 1.7-times higher lifetime risk for AD dementia. There is no societal benefit of diagnosing someone with a disease for which they may never develop symptoms, according to the IWG.

Instead, the presence of core 1 biomarkers should be viewed as an AD risk factor among individuals with normal cognition.

The IWG recommended referring to cognitively normal individuals with a core 1 biomarker as at risk of progressing to cognitive decline. Individuals who are cognitively normal and have a significant biomarker-positive profile should be considered as having pre-symptomatic AD. Examples of significant biomarker-positive profiles include:

• Highly penetrant autosomal dominant genetic variants with a near 100% lifetime risk for AD (eg, amyloid-β precursor protein [APP], presenilin 1 [PSEN1], presenilin 2 [PSEN2]);
• Down syndrome;
• Homozygous sortilin-related receptor 1 (SORL1) loss of function in apolipoprotein E (APOE)e4; and,
• Sporadic AD pathology biomarker changes.

A diagnosis of AD should only be made when patients present with cognitive impairment in combination with either common or uncommon clinical phenotypes and positivity for AD CSF or PET. Plasma biomarkers may eventually enter the routine clinical workup.

The IWG acknowledged that AD diagnostic criteria will likely evolve with more research.

“The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future,” the authors concluded.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.