The Neuropsychology of Preclinical Alzheimer's Disease
The Preclinical Alzheimer Cognitive Composite: Measuring Amyloid-Related Decline
Importance: As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes. Objective: To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study). Design, Setting, and Participants: With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies.Main Outcomes and Measures: For the 2 studies that collected data on Aβ levels (ADNI and AIBL), we estimate decline in a preclinical AD “Aβ-positive” placebo group and compare them with an “Aβ-negative” group. For the study that did not include data on Aβ levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-ε4 and by clinical progression. Results: In ADNI, Aβ-positive participants showed more decline than did Aβ-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, −1.239 [0.522] [95% CI, −2.263 to −0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (−1.009 [0.406] [95% CI, −1.805 to −0.213]; P = .01) and 36 months (−1.404 [0.452] [95% CI, −2.290 to −0.519]; P = .002). In the ADCS-PI study, APOE-ε4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, −0.742 [0.294] [95% CI, −1.318 to −0.165]; P = .01) and 36 months (−1.531 [0.469] [95% CI, −2.450 to −0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, −4.471 [0.702] [95% CI, −5.848 to −3.094]; P < .001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% α level, we project 80% power to detect effects in the range of Δ = 0.467 to 0.733 on the ADCS-PACC. Conclusions and Relevance: Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials. [Donahue, M. C., Sperling, R. A., Salmon, D. P., Rentz, D. M., Raman, R., Thomas, R. G., Weiner, M., & Aisen, P. S. (2014),JAMA Neurology, 71(8), 961-970.] http://www.ncbi.nlm.nih.gov/pubmed/24886908
New Frontier: Developing Outcome Measures for Pre-dementia Trials - Thursday, February 28, 2013 at 12:00 AM US EST:http://www.alzforum.org/webinars/new-frontier-developing-outcome-measures-pre-dementia-trials
As researchers push into the frontier of early-stage and preventative Alzheimer's disease clinical trials, they will have to measure whether a drug works in people who do not have dementia yet. Traditional outcome measures were designed for moderate AD, and do not detect cognitive change at early stages of the disease. Therefore, leaders of the Dominantly Inherited Alzheimer Network (DIAN), Alzheimer’s Prevention Initiative (API), and the Anti-Amyloid Treatment in Asymptomatic AD Trial (A4) each have analyzed separate sets of longitudinal data to find those test items that are most sensitive to change in presymptomatic disease. They combined these into new composites. Pharmaceutical companies focusing on prodromal AD follow a similar strategy. These novel composites are being used in trials now underway, but the FDA has not yet formally validated them. It has issued a brand-new guidance on the topic, though. Does it jibe with what the trials are doing now? Will the agency accept change as measured by these batteries as sufficient for drug approval? With so many groups designing their own composites, will the field arrive at a common standard, or will it be allresearchers for themselves for some time to come? On 28 February, 2013, leaders from these initiatives addressed these questions.
Promising developments in neuropsychological approaches for the detection of preclinical Alzheimer’s disease: a selective review. [Rentz, D. M., Parra Rodriguez, M. A., Amariglio, R., Stern, Y., Sperling, R., & Ferris, S. (2013), Alzheimer’sResearch & Therapy, 5(6), 58-68.] http://www.ncbi.nlm.nih.gov/pubmed/24257331
Neuropsychological features of mild cognitive impairment and preclinical Alzheimer’s disease. [Salmon, D. P. (2012),Current Topics in Behavioral Neurosciences, 10, 187-212.] http://www.ncbi.nlm.nih.gov/pubmed/22042707
Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. [Sperling et al. (2011). Alzheimer’s & Dementia, 7(3), 280-292.] http://www.sciencedirect.com/science/article/pii/S1552526011000999