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

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

doi:10.1186/s12883-024-03611-5

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

BMC Neurol. 2024 Apr 9;24(1):116. doi: 10.1186/s12883-024-03611-5.

Authors

Roger M Lane¹, Taher Darreh-Shori², Candice Junge³, Dan Li³, Qingqing Yang³, Amanda L Edwards⁴, Danielle L Graham⁴, Katrina Moore³, Catherine J Mummery⁵

Affiliations

¹ Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA, 92010, USA. rlane@ionisph.com.
² Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatric, Karolinska Institutet, Stockholm, Sweden.
³ Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
⁴ Biogen, Cambridge, MA, USA.
⁵ Dementia Research Centre, Institute of Neurology, London, UK.

Abstract

Background: The authors sought 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.

Methods: Patients aged 50-74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study.

Results: In APOE4 carriers (N = 33), the 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 observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an 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 pathophysiology (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).

Conclusion: These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD 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. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype.

Trial registration: NCT03186989 since June 14, 2017.

Keywords: Amyloid; Apolipoprotein E; Butyrylcholinesterase; Cholinergic; Glial activation; Innate immune; Sex differences; Tau.

MeSH terms

Alzheimer Disease* / cerebrospinal fluid
Amyloid beta-Peptides
Apolipoprotein E4 / genetics
Apolipoproteins E / genetics
Butyrylcholinesterase / genetics
Child
Humans
Phenotype

Substances

Amyloid beta-Peptides
Apolipoprotein E4
Apolipoproteins E
Butyrylcholinesterase
BCHE protein, human
ApoE protein, human

Associated data

ClinicalTrials.gov/NCT03186989