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Determining clinically meaningful decline in preclinical Alzheimer disease

Insel, Philip S. LU ; Weiner, Michael; Mackin, R. Scott; Mormino, Elizabeth; Lim, Yen Ying; Stomrud, Erik LU ; Palmqvist, Sebastian LU ; Masters, Colin L.; Maruff, Paul T. and Hansson, Oskar LU , et al. (2019) In Neurology 93(4). p.322-333
Abstract

OBJECTIVE: To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)-related decline. METHODS: In 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect. RESULTS: Cognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on... (More)

OBJECTIVE: To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)-related decline. METHODS: In 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect. RESULTS: Cognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aβ to predict cognitive decline; however, these findings were all cohort-specific. Despite design differences across the cohorts, with large sample sizes and sufficient follow-up time, the Aβ+ groups declined consistently on cognitive composite measures. CONCLUSIONS: A preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%-50% delays clinically relevant impairment by 3 years-a potentially meaningful treatment effect. However, assuming a 40%-50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required sample size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aβ status were inconsistent and not readily generalizable.

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published
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Neurology
volume
93
issue
4
pages
322 - 333
publisher
American Academy of Neurology
external identifiers
  • scopus:85070183172
ISSN
1526-632X
DOI
10.1212/WNL.0000000000007831
language
English
LU publication?
yes
id
f0d48c19-db95-4aa9-9df9-674956513d58
date added to LUP
2019-08-29 14:36:28
date last changed
2019-10-27 05:24:59
@article{f0d48c19-db95-4aa9-9df9-674956513d58,
  abstract     = {<p>OBJECTIVE: To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)-related decline. METHODS: In 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect. RESULTS: Cognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aβ to predict cognitive decline; however, these findings were all cohort-specific. Despite design differences across the cohorts, with large sample sizes and sufficient follow-up time, the Aβ+ groups declined consistently on cognitive composite measures. CONCLUSIONS: A preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%-50% delays clinically relevant impairment by 3 years-a potentially meaningful treatment effect. However, assuming a 40%-50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required sample size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aβ status were inconsistent and not readily generalizable.</p>},
  author       = {Insel, Philip S. and Weiner, Michael and Mackin, R. Scott and Mormino, Elizabeth and Lim, Yen Ying and Stomrud, Erik and Palmqvist, Sebastian and Masters, Colin L. and Maruff, Paul T. and Hansson, Oskar and Mattsson, Niklas},
  issn         = {1526-632X},
  language     = {eng},
  month        = {07},
  number       = {4},
  pages        = {322--333},
  publisher    = {American Academy of Neurology},
  series       = {Neurology},
  title        = {Determining clinically meaningful decline in preclinical Alzheimer disease},
  url          = {http://dx.doi.org/10.1212/WNL.0000000000007831},
  volume       = {93},
  year         = {2019},
}