In patients with Alzheimer disease (AD), once β-amyloidosis begins, additional pathologies may develop less than 10 years later, but more than 15 years before symptom onset, an important factor to consider when exploring interventions intended to alter the course of the disease. The investigators of the current longitudinal analysis sought to evaluate the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of AD via use of the Dominantly Inherited Alzheimer Network (DIAN) study and to compare their results with those derived from cross-sectional estimates. Study findings were published in Neurology.

Researchers conducted longitudinal, clinical, cognitive, cerebrospinal fluid, and neuroimaging evaluations (mean number of visits, 2.7±1.1) in a total of 217 participants from the DIAN study. They used linear mixed effects models to assess changes in each measure relative to estimated years to symptom onset and to compare mutation carriers vs noncarriers.

Results demonstrated that longitudinal β-amyloid measures change first (beginning 25 years before estimated symptom onset), which was followed by declines in measures of cortical metabolism (approximately 7-10 years later), and then by cognitive and hippocampal atrophy (about 20 years later). Significant differences were observed in the estimates of cerebrospinal fluid p-tau181 and tau (P <.0001 for both), with elevations from cross-sectional estimates preceding longitudinal estimates by more than 10 years. Moreover, longitudinal estimates identified a significant decline in p-tau181 near symptom onset, as opposed to continued elevations (P <.0001).

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The investigators concluded that these longitudinal estimates elucidate the sequence and temporal dynamics of presymptomatic pathologic changes in patients with autosomal dominant AD, information that is key to an improved understanding of the disease. The data derived from this study imply that the therapeutic window for disease prevention and modification in AD may start 20 years or more before the onset of dementia symptoms, especially in the case of a single therapeutic target (eg, amyloid), and may begin to close within several years before cognitive decline.


McDade E, Wang G, Gordon BA, et al; Dominantly Inherited Alzheimer Network. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology. 2018;91(14):e1295-e1306.