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Donohue MC, Sperling RA, Petersen R, Sun CK, Weiner MW, Aisen PS, Alzheimer’s Disease Neuroimaging Initiative. Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons. JAMA. 2017 Jun 13;317(22):2305-2316. PubMed.
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University of Gothenburg
This study corroborates the strong association of APOE ε4 with amyloid buildup in the brain. Already at baseline the amyloid-positive group shows signs of neuronal impairment in the form of increased CSF concentrations of both total- and phospho-tau. Although cognitively similar at baseline, the follow-up data clearly show functional neuronal impairment in the amyloid-positive group; those group members do worse at cognitive testing and get more dementia drugs prescribed during followup.
Although the study design does not allow for drawing conclusions on causality, the data show that amyloid positivity is very common and should not to be neglected. Finally, I think it is fair to state that the study shows we have tools to detect the group that might benefit from amyloid-targeting treatments, which will be clinically important once such drugs are available.
View all comments by Henrik ZetterbergCommonwealth Scientific and Industrial Research Organisation
Donohue and colleagues present an interesting study on the longitudinal clinical and cognitive profiles of participants with and without an abnormal burden of neocortical Aβ-amyloid. It appears that differences in cognitive testing between those with and without abnormal neocortical Aβ-amyloid burden can be detected four years after baseline examination. The clinical significance of the findings is not clear, as stated by Donohue et al. This suggests that, while baseline abnormal neocortical amyloid burden is in itself indicative of clinical and cognitive decline, it may need to be augmented by other measures of pathological burden, i.e., tau and neurodegeneration (Burnham et al., 2016; Vos et al., 2013), to elicit clinically significant decline.
The earlier differentiation between groups with and without abnormal neocortical amyloid burden on PACC, MMSE, and the CDR Sum of Boxes over the Logical Memory Delayed Recall may indicate that clinical, rather than episodic memory, measures may be more sensitive to detecting decline in preclinical populations, also identified in our paper on prodromal AD (Burnham et al., 2015). Larger studies with longer follow-up would be required to validate this.
Another interesting observation is the similar profiles of the biomarker data, regardless of high or low neocortical amyloid burden. This suggests that decline on clinical and cognitive measures is associated with abnormal pathology but not necessarily increasing pathology. The authors suggest that the presence of an APOEε4 allele is associated with faster cognitive decline; however, I wonder if the presence of an APOEε4 allele is actually associated with the baseline level of pathology (within high and low groupings) which in turn is associated with rates cognitive decline.
References:
Burnham SC, Bourgeat P, Doré V, Savage G, Brown B, Laws S, Maruff P, Salvado O, Ames D, Martins RN, Masters CL, Rowe CC, Villemagne VL, AIBL Research Group. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer's disease pathophysiology (SNAP) or Alzheimer's disease pathology: a longitudinal study. Lancet Neurol. 2016 Sep;15(10):1044-53. Epub 2016 Jul 20 PubMed.
Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, Cairns NJ, Morris JC, Holtzman DM, Fagan AM. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2013 Oct;12(10):957-65. PubMed.
Burnham SC, Raghavan N, Wilson W, Baker D, Ropacki MT, Novak G, Ames D, Ellis K, Martins RN, Maruff P, Masters CL, Romano G, Rowe CC, Savage G, Macaulay SL, Narayan VA, Alzheimer’s Disease Neuroimaging Initiative, AIBL Research Group. Novel Statistically-Derived Composite Measures for Assessing the Efficacy of Disease-Modifying Therapies in Prodromal Alzheimer's Disease Trials: An AIBL Study. J Alzheimers Dis. 2015;46(4):1079-89. PubMed.
View all comments by Samantha BurnhamMake a Comment
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