Should EOAD patients be included in clinical trials?

Alzheimer disease (AD) is the most common form of dementia, affecting 5.5 million people in the US. Progressive neurodegeneration results in relentless cognitive decline, posing a substantial public health burden, and has major implications at the individual level. AD phenotypes are divided into early-onset (EOAD) and late-onset (LOAD) AD with the arbitrary cut-off 65 years in most studies [1].Approximately 1% to 6% of all AD is early-onset. Genetics plays a more significant role in EOAD, as this subset is enriched for familial disease in 60% of the cases [2]. Furthermore, 13% of EOAD has an autosomal dominant inheritance pattern, and three genes - the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) - have been identified as having mutations that cause EOAD. These genes contribute to approximately 80% of the autosomal dominant EOAD cases [2-4]. Although these mutations are rare and affect a small percentage of AD cases, the discovery of these three genes gave molecular genetic evidence supporting the amyloid hypothesis. As the amyloid cascade is the leading hypothesis, this cohort would be ideal for proof-of-principle studies in amyloid-based drug therapy. However, their low prevalence and geographic dispersion make any trial exclusively with familial AD patients logistically challenging. The organization of the Dominantly Inherited Alzheimer Network [5] has been a major accomplishment in creating the logistic basis of such clinical trials, although owing to the small sample size, it is not likely that all drugs can be tested in this specific population.On clinical grounds, EOAD and LOAD are distinguished on the basis of age of onset (AOO) alone. Several studies attempted to delineate the clinical, neuropsycho-logical, imaging, pathological, and biomarker differences between EOAD and LOAD based on the 65-year arbitrary cutoff proposed by Amaducci and colleagues [1] in 1986. The age of disease onset of patients with AD ranged from 50 t