Preclinical Alzheimer Disease Prevalence and Outcomes

To examine the prevalence of preclinical Alzheimer disease (AD) and to determine clinical progression and mortality outcomes, researchers studied 311 people aged ≥65 who were deemed cognitively normal (Clinical Dementia Rating [CDR] score = 0) at enrollment. Participants underwent baseline cognitive and cerebrospinal fluid (CSF) testing, which were used to identify preclinical AD, according to criteria proposed by the National Institute on Aging and the Alzheimer's Association (NEJM JW Neurol May 17 2011). These criteria include three stages that emphasize the presumed chronology of biomarker changes in the evolution of AD: stage 1, amyloid abnormalities, defined in the current study by low CSF amyloid-beta 1-42 in CSF; stage 2, abnormal amyloid and evidence of neuronal injury, defined in the study by both low CSF amyloid and elevated total tau or phosphorylated tau in CSF; stage 3, low CSF amyloid, high CSF tau, and measurable cognitive change without functional impairment, characterized in the present study by a deficit on a composite score of episodic memory tasks. Participants had at least one annual follow-up assessment (median follow-up, 3.9 years).

The primary outcome was the proportion of individuals in each stage at baseline. Stage 1 was identified in 15% of participants, stage 2 in 12%, and stage 3 in 4%; 23% had suspected non-AD pathology, and 5% were unclassified. Secondary outcomes included a positive correlation between preclinical AD stage and likelihood of progression to symptomatic AD (defined as CDR >0.5) and an increased risk for death during follow-up in participants with preclinical AD. Additionally, eight of nine autopsies in participants classified with preclinical AD confirmed the presence of AD neuropathological changes.