Amyloid β Deposition and Suspected Non-Alzheimer Pathophysiology and Cognitive Decline Patterns for 12 Years in Oldest Old Participants Without Dementia
Authors: Yujing Zhao, Dana L. Tudorascu, Oscar L. Lopez, Ann D. Cohen, Chester A. Mathis, Howard J. Aizenstein, Julie C. Price, Lewis H. Kuller, M. Ilyas Kamboh, Steven T. DeKosky, William E. Klunk, Beth E. Snitz
Journal: JAMA Neurology (2017)

<h3>Importance</h3> The prevalence of pathologic conditions of the brain associated with Alzheimer disease increases strongly with age. Little is known about the distribution and clinical significance of preclinical biomarker staging in the oldest old, when most individuals without dementia are likely to have positive biomarkers. <h3>Objective</h3> To compare the patterns of long-term cognitive decline in multiple domains by preclinical biomarker status in the oldest old without dementia. <h3>Design, Setting, and Participants</h3> A longitudinal observational study with a mean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conducted in an academic medical center from August 24, 2000, to January 14, 2016, including and extending observations from the Ginkgo Evaluation of Memory study. A total of 197 adults who had completed the Ginkgo Evaluation of Memory study, were free of dementia, and were able to undergo magnetic resonance imaging were eligible for a neuroimaging study in 2009. Of these patients, 175 were included in the present analyses; 140 (80%) were cognitively normal and 35 (20%) had mild cognitive impairment. <h3>Main Outcomes and Measures</h3> Biomarker groups included amyloid β negative (Aβ<sup>−</sup>)/neurodegeneration negative (ND<sup>−</sup>), amyloid β positive (Aβ<sup>+</sup>)/ND<sup>−</sup>, Aβ<sup>−</sup>/neurodegeneration positive (ND<sup>+</sup>), and Aβ<sup>+</sup>/ND<sup>+</sup>based on Pittsburgh Compound B retention and hippocampal volume in 2009. Participants completed baseline neuropsychological testing from 2000 to 2002 and annual testing from 2004 to 2016. Domains included memory, executive function, language, visual-spatial reasoning, and attention and psychomotor speed. Slopes of decline were evaluated with linear mixed models adjusted for age, sex, and years of education. <h3>Results</h3> Of the 175 participants (71 women and 104 men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). A total of 42 participants (24.0%) were Aβ<sup>−</sup>/ND<sup>−</sup>, 32 (18.3%) were Aβ<sup>+</sup>/ND<sup>−</sup>, 35 (20.0%) were Aβ<sup>−</sup>/ND<sup>+</sup>, and 66 (37.7%) were Aβ<sup>+</sup>/ND<sup>+</sup>. On all cognitive measures, the Aβ<sup>+</sup>/ND<sup>+</sup>group showed the steepest decline. Compared with the Aβ<sup>−</sup>/ND<sup>−</sup>group, the amyloid deposition alone (Aβ<sup>+</sup>/ND<sup>−</sup>) group showed faster decline on tests of verbal and visual memory (–0.3513; 95% CI, –0.5269 to –0.1756), executive function (0.0158; 95% CI, 0.0013-0.0303), and language (–0.1934; 95% CI, –0.3520 to –0.0348). The Aβ<sup>−</sup>/ND+ group showed faster visual memory decline than the Aβ<sup>−</sup>/ND<sup>−</sup>reference group (–0.3007; 95% CI, –0.4736 to –0.1279). <h3>Conclusions and Relevance</h3> In the oldest old without dementia, presence of either or both Aβ and hippocampal atrophy is typical (&gt;75%). Isolated hippocampal volume atrophy is associated only with greater decline in memory. However, isolated Aβ is associated with decline in memory plus language and executive functions. These findings suggest different underlying pathophysiologic processes in the Aβ<sup>+</sup>/ND<sup>−</sup>and Aβ<sup>−</sup>/ND<sup>+</sup>groups.