Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

Author:

Lane Roger M.,Darreh-Shori Taher,Junge Candice,Li Dan,Yang Qingqing,Edwards Amanda L.,Graham Danielle L.,Moore Katrina,Mummery Catherine J.

Abstract

AbstractBackgroundWe wished to examine the impact of the K-variant ofbutyrylcholinesterase(BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) inAPOE4carriers.MethodsIn 45 patients, aged 50-74 years, with cerebrospinal fluid (CSF) biomarker confirmed mild AD, recruited into a clinical trial (NCT03186989), baseline demographics, disease characteristics, and biomarkers were evaluated byBCHE-KandAPOE4allelic status.ResultsInAPOE4carriers (N = 33), mean age-at-diagnosis of AD inBCHE-Kcarriers (n = 11) was 6.4 years earlier than inBCHE-Knoncarriers (n = 22,P <.001, ANOVA). InAPOE4noncarriers (N = 12) there was no similar influence ofBCHE-K. InAPOE4carriers with versus those withoutBCHE-K, mean age-at-baseline was over 6 years earlier and accompanied by slightly higher amyloid and tau accumulations. A predominant amyloid, limited tau pathophysiology, and limbic-amnestic phenotype was exemplified byAPOE4homozygotes withBCHE-K. Multiple regression analyses demonstrated association of amyloid accumulation withAPOE4carrier status (P <.029), larger total brain ventricle volume (P <.021), less synaptic injury (Ng,P <.001), and less tau (p-tau181,P <.005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL,P= .002), more synaptic injury (Ng,P <.001), and higher levels of glial activation (YKL-40,P= .01).ConclusionFindings concern the genetic architecture of prognosis in early AD, that is fundamental for patients and the design of clinical trials, and that is less well established than the genetics of susceptibility. In mild AD patients aged less than 75 years, the mean age-at-diagnosis of AD inAPOE4carriers was reduced by over 6 years inBCHE-Kcarriers versus noncarriers. Functional activation of glia may explain much of the effects ofAPOE4andBCHE-Kon the phenotype of early AD.

Publisher

Cold Spring Harbor Laboratory

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