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

Background We wished to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers.

In 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 by BCHE-K and APOE4 allelic status.

In APOE4 carriers (N = 33), mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P < .001, ANOVA). In APOE4 noncarriers (N = 12) there was no similar influence of BCHE-K. In APOE4 carriers with versus those without BCHE-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 by APOE4 homozygotes with BCHE-K. Multiple regression analyses demonstrated association of amyloid accumulation with APOE4 carrier 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).

Findings 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 in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. Functional activation of glia may explain much of the effects of APOE4 and BCHE-K on the phenotype of early AD. Competing Interest Statement RML, CJ, DL, QY, KM: Employees of, and holders of stock/stock options in, Ionis. TDS:No conflicts of interest. ALE, DLG: Employees of, and holders of stock/stock options in, Biogen. CJM: Supported by the NIHR Biomedical Research Centre at UCLH; received honoraria for patient and clinician educational activities related to AD from Biogen, Lilly, and Peerview; received institutional consulting/advisory board fees from Biogen, Roche, Eli Lilly, Prevail, Alnylam, Alector, Eisai, WAVE, and Ionis; served as a site investigator for several clinical trials sponsored by Ionis and Biogen. Funding Statement Biogen (Cambridge, Boston) sponsored the study in which the data for this cross-sectional baseline investigation was collected. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Patients provided written, informed consent at the time of recruitment. The study was approved by the institutional review board or independent ethics committee at each investigational site (specified as Principal Investigator; IRB/Ethic Committee; Reference number) Dr Albert Ludolph; Ethikkommission der Universitat Ulm; 412/16 Dr Siegfried Muhlack; Ethik-Kommission der Ruhr-Universitat Bochum; 16-5929 Dr Catherine Mummery; London-Central Research Ethics Committee Manchester HRA Centre; 17/LO/0440 Dr Simon Ducharme; MUHC Neurosciences Research Ethics Board; 2017-3206 Dr Juha Rinne; National Committee on Medical Research Ethics; 73/06.00.01/2017 Dr Ralf Bodenschatz; Ethikkommission der Sachsischen Landesarztekammer; EK-AMG-MCB-155/16-1 Dr Peter Paul de Deyn; Central Committee on Research Involving Human Subjects; NL60032.000.16 Dr Anne Borjesson Hansen; Regionala etikprovningsnamnden i Stockholm Karolinska Institutet i Solna; 2017/300-31 Dr Michael Jonsson; Regionala etikprovningsnamnden i Stockholm Karolinska Institutet i Solna; 2017/300-31 Dr Daniel Blackburn; London-Central Research Ethics Committee Manchester HRA Centre; 17/LO/0440 Dr Anja Schneider; Ethikkommission an der Medizinischen Fakultat der Rheinischen Friedrich-Wilhelms-Universitat Bonn; 035/18-AMG Dr Phillipus Scheltens; Central Committee on Research Involving Human Subjects; NL60032.000.16 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript and suppplementary materials (and in addition are available upon reasonable request to the corresponding author)