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

BMC Neurology volume 24, Article number: 116 (2024) Cite this article

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

Peer Review reports

Background

The cholinergic hypothesis of AD states that selective loss of cholinergic neurons, arising from basal forebrain nuclei, and decreased levels of the neurotransmitter, acetylcholine (ACh), trigger neurodegeneration and cognitive impairment [1]. Corticolimbic cholinergic denervation may be evident at early stages of AD [2, 3]. The failure of this circuitry is inextricably linked with cognitive deficits in memory, learning, attention, and processing speed [4]. Synaptic release of ACh initiates cholinergic neurotransmission and is rapidly terminated by acetylcholinesterase (AChE). The availability of ACh in cholinergic synapses is deficient in AD and can be increased with acetylcholinesterase inhibitors (AChE-Is) [5]. The cholinergic system produces both rapid focal synaptic signaling and slow diffuse extracellular signaling through alpha 7 nicotinic ACh receptors (α7-nAChRs) that act to control glial cell reactivity and functional state [6]. Glial cells provide homeostasis and neuroprotection of the central nervous system (CNS), and if this functionality is deficient, amyloid-β (Aβ) pathology can accumulate [7]. However, tau tangle pathology is more strongly correlated with glial activation than Aβ pathology, and microglial and astrocyte activation may better predict the spatiotemporal spread of tau tangles [8, 9].

The gene apolipoprotein E (APOE) encodes for the protein ApoE, which is the major intercellular lipid carrier in the CNS and is primarily produced by astrocytes, reactive microglia, vascular mural cells, and choroid plexus cells [10, 11]. The APOE4 polymorphism is the major genetic risk factor for sporadic AD [12]. In APOE4 carriers, functional glial responses to clear Aβ are deficient and favor the accumulation of amyloid pathology [7]. Cerebral amyloid accumulation begins earlier in life in APOE4 carriers than in noncarriers [13, 14].

Butyrylcholinesterase (BuChE), along with AChE, is involved in the enzymatic breakdown of both synaptic and extracellular Ach [15, 16]. Astrocytes secrete BuChE and the ACh synthesizing enzyme, choline acetyltransferase (ChAT), to maintain a steady state equilibrium of hydrolysis and synthesis of extracellular ACh [17]. In addition to particular populations of neurons in the amygdala and hippocampus [18], BuChE is localized in glia, myelin, and endothelial cells, and continues to increase in concentration with age, especially in the deep cortex and white matter [19]. Aβ, ApoE, and BuChE are prominent constituents of amyloid plaques and interact with each other to influence the catalytic activity of BuChE [20, 21]. For example, CSF ApoE protein profoundly alters the catalytic functioning and stability of CSF BuChE in patients with mild AD in an ApoE concentration- and polymorphism-dependent manner; this interaction is also Aβ concentration-dependent [20, 22]. BCHE genotype and CSF BuChE activity are also correlated with markers of glial activation in early AD [23, 24]. Lower BuChE activity is associated with higher amyloid accumulation in patients with mild AD [24].

The most common single-nucleotide polymorphism (SNP) of BCHE, the Kalow-variant (BCHE-K; 3q26.1-3q26.2; nucleotide G1615A, codon A539T; rs1803274), is carried by 18–35% of individuals in Western populations [25,26,27,28]. In APOE4 carriers, reduced BuChE activity is more marked in BCHE-K carriers, with a BCHE-K allele dose-dependent reduction in BuChE activity and lowering of glial activation markers [24, 29]. The BCHE-K and APOE4 alleles interact to significantly reduce the age-at-onset of AD [30], and to increase the likelihood of progression from mild cognitive impairment (MCI) to AD [27, 31] and from cognitively unimpaired older individuals to early AD [26]. Carriers of both APOE4 and BCHE-K alleles in the MCI stage of AD have a limbic-amnestic phenotype and progress most rapidly in the mild stage of AD, where they are the only genotype group with a significant response to AChE-I treatment [27, 31,32,33].

The primary objective of this cross-sectional analysis of early AD patients aged less than 75 years was to evaluate BCHE-K effects on age-at-onset of AD in APOE4 carriers. In addition, this study sought to characterize the phenotypic expression of early AD in carriers of APOE4 and BCHE-K relative to other genotype groups with respect to accumulations of amyloid and tau pathology, neurodegeneration, glial activation, hippocampal atrophy, ventricular expansion, and cognitive function.

Methods

This trial (NCT03186989) was conducted in accordance with Good Clinical Practice Guidelines of the International Council for Harmonisation and according to the ethical principles outlined in the Declaration of Helsinki, and reporting adhered to Consolidated Standards of Reporting Trials (CONSORT) guidelines as reported previously [34]. CONSORT guidelines are not applicable in this cross-sectional, baseline analysis. The completed study [34] was approved by relevant ethics committees. Written informed consent was provided by all participants.

Study eligibility criteria

Eligible study participants were between the ages of 50 and 74 years of age; had probable early AD (amnestic or non-amnestic), defined by a Mini-Mental State Examination score (MMSE) of 20–27, inclusive [35], and either a Clinical Dementia Rating Overall Global Score of 1, or a Global Score of 0.5 with a Memory Score of 1 [36]; a CSF pattern of low Aβ1-42 (≤ 1200 pg/ml), elevated total-tau (> 200 pg/ml) and p-tau (> 18 pg/ml), and a total-tau to Aβ1-42 ratio > 0.28 [37]; and a diagnosis of probable AD based on National Institute of Aging-Alzheimer Association (NIA-AA) criteria [38]. Exclusion criteria included any condition preventing participation in writing tasks, MRI or lumbar puncture (LP); significant risk of suicide, major depression, psychosis, confusional state or violent behavior; clinically significant laboratory, vital sign or electrocardiogram finding; and medical history of brain or spinal disease that would be expected to interfere with CSF circulation.

Assessments

CSF from patients was analyzed for markers of amyloid accumulation (inversely indexed by Aβ42), tau pathophysiology (tau phosphorylated at threonine 181 [p-tau181]), neuroaxonal degeneration (neurofilament light chain [NfL]), synaptic injury (neurogranin [Ng]), and glial activation (chitinase-3-like protein 1 [YKL-40]). The CSF analytes and assays are detailed in Table 1. Of 46 patients entering the study, 45 were characterized for common SNPs of APOE (ie, APOE4, APOE3, and APOE2), and BCHE rs1803274 (ie, BCHE-K). Mutations associated with dominantly inherited AD were also assessed (ie, APP, PSEN1, and PSEN2).

Table 1 Methods used to assess CSF biomarkers
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The study required 3-dimensional (3D) T1-weighted structural magnetic resonance imaging (MRI) scans of the head, and volumetric analyses calculated using VivoQuant™, which is comprised of a preprocessing module and a multi-atlas segmentation module, followed by visual inspection and manual editing, if needed [40]. The mean baseline ventricular volume and hippocampal volume were expressed as a percentage of the total intracranial volume (%TIV). Domains of cognitive functioning were assessed using the MMSE and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [41].

Statistical analysis

Patient baseline characteristics were summarized according to genotype and sex (Table 2). Quantitative assessments were summarized using descriptive statistics, including number of patients, mean, and standard deviation. Qualitative assessments were summarized using frequency counts and percentages. The exact test was used to examine the Hardy-Weinberg equilibrium (HWE) of the distribution of APOE and BCHE alleles in the study population. All exact tests were performed using the R package “Hardy Weinberg” [42]. The HWE P value measures the strength of evidence against the null hypothesis that the distribution does not follow Hardy-Weinberg equilibrium. A large P value is consistent with the distribution following HWE.

Table 2 Early AD phenotype across genotype groups defined by APOE4 and BCHE-K carrier status
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An analysis of variance (ANOVA) and an analysis of covariance (ANCOVA) were used to test whether the mean age-at-diagnosis of AD (primary analysis) or the mean age-at-baseline differed across two or more genotype groups, ie, by BCHE-K carrier status in APOE4 carriers, and in APOE4 homozygotes and heterozygotes. When the ANCOVA model was applied, the model included BCHE-K carrier status and sex as factors, and baseline MMSE total score as covariate. Prior to performing ANOVA and ANCOVA, the normality assumption of residuals was tested using the Kolmogorov-Smirnov test. If significant departures from normality were observed, the Wilcoxon Rank Sum test was applied. Both ANOVA and ANCOVA were applied to test baseline CSF Aβ42 across two or more genotype groups. When ANCOVA was applied, age-at-baseline was included as an additional covariate. If the normality assumption was not satisfied, both the ANOVA and ANCOVA models were fitted to the log-transformed data. Box plots were used to visualize data by group.

Relationships between CSF Aβ42, CSF p-tau181, other CSF biomarkers, and brain volumes (as %TIV) were explored in the overall population and in each genotype group in a simple linear correlation analysis with a Pearson correlation coefficient. The squared Pearson correlation coefficient (R2) and P value were provided in the correlation analysis and interpreted by descriptors to indicate the strength of the relationship. Correlation coefficients were defined as: 0.81 ≤ R2 < 1 as strong; 0.49 ≤ R2 < 0.81 as moderately strong; 0.25 ≤ R2 < 0.49 as moderate; 0.09 ≤ R2 < 0.25 as weak; and R2 < 0.09 as negligible. Scatterplots with a simple linear regression line were produced to depict the relationships between two quantitative variables.

Multiple regression analysis was also used to assess the functional relationships between the biomarker of interest and amyloid and tau pathophysiology. A multiple regression model was applied with CSF Aβ42 and CSF p-tau181 as the response variables and APOE4, BCHE-K, age-at-baseline, sex, baseline MMSE total score, and the biomarker of interest (ie, CSF p-tau181, Aβ42, NfL, Ng, YKL-40, total hippocampal volume, and total brain ventricular volume) as independent variables. This determined the strength of association of CSF Aβ42 or CSF p-tau with parameters of interest, in conjunction with the other independent variables included in the model. Cognitive domains were assessed on the MMSE and the RBANS [41].

Results

The study was conducted at 12 centers in Canada, Finland, Germany, the Netherlands, Sweden, and the UK between August 2017 and February 2020. One hundred and two patients were assessed for eligibility. Of these, 56 were excluded based on the eligibility criteria, and one enrolled patient did not provide genetic test results. The study sample comprised 45 patients with a mean age of 65.8 ± 5.8 years and a mean baseline MMSE total score of 23.6 ± 2.3.

The APOE4 allele was present in 73% (N = 33) of the patients: 22% (N = 10) homozygotes and 51% (N = 23) heterozygotes [43]. The BCHE-K allele was present in 36% (N = 16) of patients; 7% (N = 3) homozygotes and 29% (N = 13) heterozygotes (Table S1). Of the 16 BCHE-K carriers, 69% (N = 11) were APOE4 carriers (Table 2). All non-APOE4 alleles were APOE3, except for one patient with an APOE2/3 genotype who also carried one BCHE-K allele. The distribution of APOE genotypes (HWE exact P value = 1) and BCHE genotypes (HWE exact P value = 0.376) were consistent with Hardy-Weinberg equilibrium. One patient had an autosomal dominant PSEN2 mutation, and was heterozygous for APOE4 and BCHE-K.

Age-at-diagnosis of AD in APOE4 carriers was reduced in carriers of BCHE-K

There were no significant APOE4 carrier or allele frequency-associated differences in age-at-diagnosis of AD or in age-at-baseline (i.e., age at the time of this cross-sectional investigation) [43]. In contrast, BCHE-K homozygotes (n = 3) had a lower mean age-at-diagnosis of 59.4 years versus heterozygotes (n = 13) of 62.2 years, versus noncarriers (n = 29) of 66.0 years (Table S1; P = 0.048, ANOVA).

In the primary analysis of this investigation, APOE4 carriers with BCHE-K alleles (n = 11) showed a significantly lower mean age-at-diagnosis (n = 22) (60.6 ± 6.1 versus 67.0 ± 4.0; P < 0.001, ANOVA; P = 0.001, ANCOVA) (Fig. 1A; Table 2), and mean age-at-baseline (62.1 ± 5.9 versus 68.3 ± 4.0; P = 0.001, ANOVA; P = 0.002, ANCOVA) compared to APOE4 carriers without BCHE-K alleles (Fig. 1C). The mean age-at-diagnosis of AD in BCHE-K carriers versus noncarriers was also significantly different from APOE4 heterozygotes (6.7 years; 60.5 versus 67.3 years) and homozygotes (5.7 years; 60.8 versus 66.4 years) (P = 0.013, ANOVA; P = 0.019, ANCOVA) (Fig. 1B). Significant differences were also seen in age-at-baseline (Fig. 1D).

Fig. 1
figure 1

Age-at-diagnosis of AD and age-at-baseline by BCHE-K carrier status in APOE4 carriers, homozygotes, and heterozygotes. A Age-at-diagnosis of AD in APOE4 carriers by BCHE-K carrier status. B Age-at-diagnosis of AD in APOE4 homozygotes and heterozygotes by BCHE-K carrier status. C Age-at-baseline of study in APOE4 carriers by BCHE-K carrier status. D Age-at-baseline of study in APOE4 homozygotes and heterozygotes by BCHE-K carrier status. * P < .001, ANOVA; P = .001, ANCOVA with BCHE-K carrier status and sex as factors and baseline MMSE total score as covariate for mean age-at-diagnosis of AD. **P = .013, ANOVA; P = .019, ANCOVA with APOE4 homozygotes and heterozygotes by BCHE-K carrier status and sex as factors and baseline MMSE total score as covariate for mean age-at-diagnosis of AD. † P = .001, ANOVA; P = .002, ANCOVA with BCHE-K carrier status and sex as factors and baseline MMSE total score as covariate for mean age-at-study-baseline. †† P = .015, ANOVA; P = .025, ANCOVA with APOE4 homozygotes and heterozygotes by BCHE-K carrier status and sex as factors and baseline MMSE total score as covariate for mean age-at-study-baseline

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In APOE4 noncarriers (N = 12), the mean age-at-diagnosis and age-at-baseline of the study were similar between BCHE-K carriers (n = 5) at 63.9. ± 7.6 and 64.8 ± 7.3 years, respectively, and noncarriers (n = 7) at 62.8 ± 7.8 and 64.4 ± 6.6 years, respectively (Table 2).

In patients with both APOE4 and BCHE-K, younger mean age-at-baseline was accompanied by increased amyloid and tau accumulations

Across genotype groups defined by APOE4 and BCHE-K carrier status, the proportion of female patients fell as the burden of APOE4 and BCHE-K alleles diminished (Table 2). Carriers of both alleles had the earliest age-at-diagnosis, greater memory deficits, and the most amyloid accumulation. APOE4 carriers with BCHE-K had slightly higher amyloid and tau accumulations than APOE4 carriers without BCHE-K, despite a mean age-at-baseline that was 6.2 years earlier. In APOE4 carriers, neurodegeneration and glial activation were similar between carriers and noncarriers of BCHE-K (Table 2).

Patients with both APOE4 and BCHE-K had the most amyloid pathology and presented a limbic-amnestic phenotype

Three of four (75%) APOE4 homozygotes with BCHE-K were female. APOE4 carriers exhibited more of a temporo-limbic (hippocampal atrophy > ventricular expansion) and amnestic (memory > visuospatial impairment) phenotype relative to APOE4 noncarriers (Table 2). APOE4 carriers relative to noncarriers had higher levels of amyloid pathology (inversely indexed by the CSF Aβ42 = 664 ± 175 versus 799 ± 180 pg/mL, respectively; P = 0.028 ANOVA, P = 0.028 ANCOVA) (Data not shown [43]). Carriers of both APOE4 and BCHE-K had higher levels of amyloid pathology (CSF Aβ42 = 641 ± 139 pg/mL); amyloid pathology was further increased in APOE4 homozygotes with BCHE-K (CSF Aβ42 = 554 ± 111 pg/mL). The latter subgroup has only the ApoE4 protein, and despite the highest levels of Aβ accumulation, this subgroup had the lowest levels of tau pathophysiology, synaptic injury, neuroaxonal damage, glial activation, and ventricular expansion (Table 2).

Patients without APOE4 and BCHE-K had the least amyloid pathology and an amnestic-sparing phenotype

In marked contrast to carriers of both APOE4 and BCHE-K, noncarriers of these alleles displayed less hippocampal atrophy and an amnestic deficit-sparing phenotype, with the lowest levels of amyloid pathology, the highest levels of neuroaxonal injury, and high levels of ventricular expansion (Table 2). Noncarriers relative to carriers of both APOE4 and BCHE-K had higher CSF indices of tau pathophysiology, synaptic injury, glial activation, and multidomain cognitive deficits, but memory impairments were less severe (Table 2).

More amyloid pathology correlated with less tau pathophysiology, especially in carriers of APOE4 and BCHE-K

Multiple regression analyses indicated that associations with amyloid pathology (inversely indexed by CSF Aβ42) included APOE4 carrier status (P < 0.029), larger total brain ventricle volume (P < 0.021), less synaptic injury (Ng, P < 0.001), less tau (p-tau181, P = 0.005), and showed a trend for an association with less glial activation (YLK-40, P = 0.097). In simple linear correlation analyses in the overall population, amyloid pathology showed significant inverse correlations of weak to moderate strength with tau pathophysiology (P = 0.004), synaptic injury (P < 0.001), and glial activation (P = 0.028) (Figs. 2 and 3). In APOE4 and BCHE-K carriers, inverse correlations were moderate between amyloid pathology and tau pathophysiology (P < 0.022) (Fig. 2) and between amyloid pathology and synaptic injury (P < 0.001) (Fig. 3B). In APOE4 carriers without BCHE-K, inverse correlations between amyloid with tau pathophysiology were weak (Fig. 2; P = 0.042), and between amyloid and synaptic injury or glial activation were moderate (P < 0.001 and P = 0.013, respectively) (Fig. 3B, C).

Fig. 2
figure 2

Correlations of CSF Aβ42 versus CSF p-tau181 in the overall population and in APOE4 and BCHE-K subgroups. Simple linear correlation analyses: R square and P value were obtained by fitting a simple linear regression model

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Fig. 3
figure 3

Correlations of neurodegenerative and glial activation markers with CSF Aβ42 and CSF p-tau181 in the overall study population and in genotype groups. A CSF neurofilament light chain (NfL) (higher levels index more neuroaxonal injury). B CSF neurogranin (Ng) (higher levels index more synaptic injury). C CSF YKL-40 (higher levels index more glial activation). Simple linear correlation analyses: R square and P value were obtained by fitting a simple linear regression model. Only those analytes associated with either CSF Aβ42 or CSF p-tau181 in multiple regression analyses are shown

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Tau pathophysiology correlated with synaptic injury and glial activation, especially in APOE4 and BCHE-K noncarriers

Multiple regression analyses indicated positive associations between tau pathophysiology (CSF p-tau181) and CSF levels of NfL (P = 0.002), Ng (P < 0.001), and YKL-40 (P = 0.01). Thus, more tau pathophysiology associated with increased neuroaxonal damage, synaptic injury, and glial activation. In simple linear regressions in the overall population, tau pathophysiology showed a moderate correlation with neuroaxonal damage (P < 0.001), a moderately strong correlation with synaptic injury (P < 0.001), and a weak correlation with glial activation (P = 0.004) (Fig. 3A-C). In subgroups, correlations of tau pathophysiology with synaptic injury were moderate in APOE4 carriers without BCHE-K (P < 0.001), moderately strong in carriers of both APOE4 and BCHE-K (P < 0.001), and strong in APOE4 noncarriers with (P = 0.001) and without BCHE-K (P = 0.003) (Fig. 3B). The correlation between tau pathophysiology and neuroaxonal damage was moderate in the overall group population, but moderately strong in APOE4 carriers without BCHE-K (P < 0.001) (Fig. 3A), whereas glial activation was weak in the overall population and in APOE4 carriers without BCHE-K (P = 0.043), but was strong in noncarriers of both APOE4 and BCHE-K (P = 0.005) (Fig. 3C). The glial activation marker, YKL-40, has been proposed as an indicator of tau pathology [44], and this may be most applicable in APOE4 and BCHE-K noncarriers. In addition, there was a weak positive correlation between glial activation and synaptic injury in BCHE-K noncarriers, but strong in APOE4 noncarriers without BCHE-K (P = 0.033) and weak in APOE4 carriers without BCHE-K (P = 0.029) (Fig. S1). Correlations were absent in BCHE-K carriers with or without APOE4.

Discussion

In this sample of clinically and pathologically characterized patients with early AD aged less than 75 years, APOE4 carriers with BCHE-K had a mean age-at-diagnosis of AD 6.4 years earlier than in APOE4 carriers without BCHE-K (Fig. 1A). In APOE4 carriers, higher accumulations of amyloid and tau pathophysiology were present in BCHE-K carriers over 6 years earlier than in BCHE-K noncarriers (Table 2). APOE4 allele frequency-dependent effects on the risk-of-onset of AD are highest in the seventh decade, wane over 70 years of age, and are particularly reduced after 80 years of age [45, 46]. Therefore, the magnitude of the observed modifier effect of BCHE-K may be influenced by the younger population age range where the effects of APOE4 on the AD phenotype are maximal and modifiable. The restricted age range for entry into the current study may also have been at least partly responsible for the lack of any significant APOE4 allele frequency-dependent effects on age-at-diagnosis of AD or age-at-baseline.

Amyloid pathology accumulates at an earlier age in carriers of APOE4 and BCHE-K

Amyloid accumulation starts at an earlier age in APOE4/E4 individuals, followed by APOE3/E4, APOE2/E4, APOE3/E3, and APOE2/E3 [13]. The age at which an individual reaches a threshold level of fibrillar Aβ accumulation may correlate with the age of symptom onset [14]. In the current study, amyloid accumulation reached higher levels in genotype groups with lower levels of glial activation, and an inverse correlation was observed between amyloid pathology and glial activation (P = 0.028) (Table 2; Fig. 3C). Levels of amyloid pathology across genotype subgroups are compatible with APOE4 allele frequency-dependent accumulation beginning at an earlier age with the earliest start in APOE4 carriers with BCHE-K alleles, particularly in APOE4 homozygotes with BCHE-K (Table 2).

Aβ, ApoE, and BuChE modulation of cholinergic signaling changes levels of glial activation across the AD severity stage continuum

Optimally, glial activation may balance the need to attenuate amyloid accumulation and limit the spread of tau pathology [47, 48]. This is an important determinant of the pathology mix and clinical features of early AD, including the age-of-onset of AD, and it links amyloid and tau pathology, cholinergic signaling, and glial activation [33].

The key hypothesis underlying the evolution of AD pathology in carriers of APOE4 and BCHE-K is that, in preclinical AD, activation of glia is net hypofunctional and results in the accumulation of amyloid pathology; in early AD, glial activation and tau and neurodegenerative pathology show focal increases in the MTL; and in later stage disease, glial activation accompanied by tau and neurodegenerative pathology spread across the neocortex. The cholinergic system plays a key role in controlling glial reactivity and function through α7-nAChRs with both rapid focal synaptic signaling and slow diffuse extracellular signaling [6]. In the prodromal stages of AD there is minimal loss of cholinergic neurons but cholinergic dysfunction is apparent [49], whereas in the advanced stages of AD, a severe loss of cortical cholinergic innervation is evident [50]. Thus, cholinergic signaling may be a critical contributor to the evolution of AD and especially in carriers of APOE4 and BCHE-K. ApoE forms soluble and highly stable complexes with cholinesterase enzymes and Aβ, that can oscillate between slow and ultrafast ACh hydrolysis, depending on Aβ availability [29]. Reduced cholinesterase activity and decreased glial activation have been observed in APOE4 carriers, particularly in individuals with polymorphic variants of genes encoding cholinesterase enzymes with lower activity, such as BCHE-K [24, 29]. In a concentration- and aggregation-dependent manner, Aβ signals through α7-nAChRs and influences the extracellular fluid equilibrium between the breakdown of ACh via effects on ACh-hydrolyzing capacity of cholinesterase [22] and the synthesis of ACh via effects on choline acetyltransferase (ChAT) activity [51]. In AD, α7-nAChR expression on astrocytes is positively correlated with neuritic plaque burden [52].

Importantly, the combination of APOE4, BCHE-K, and Aβ target the cholinergic system to eventually reduce cholinergic signaling. The decreased cholesterol delivery by ApoE4 to the long and extensively arborized axons of the metabolically taxed cholinergic neurons requires them to expend energy on cholesterol synthesis and to consume acetyl coenzyme A (acetyl-CoA) [53]. Acetyl-CoA is an essential substrate for the synthesis of both ACh and lipids that are required for myelin formation and maintenance of cellular membranes [54]. The ascending white matter projections of the basal forebrain cholinergic system may be particularly vulnerable to the combination of Aβ pathology and ApoE4 [55,56,57]. In both aging and AD, the intraneuronal accumulation of oligomeric assemblies of Aβ42 is a relatively selective trait of basal forebrain cholinergic neurons [58, 59]. Endocytic internalization of Aβ-nAChR complexes may underlie intracellular accumulation of Aβ42 and the neurotoxic consequences, such as tau phosphorylation [60]. In addition, in a concentration- and aggregation-dependent manner, Aβ targets cholinergic synapses [57]. In an amyloid mouse model, loss of α7-nAChRs reduced Aβ42 plaque load, increased soluble Aβ42 oligomers, exacerbated learning and memory deficits, and decreased the functionality of the basal forebrain cholinergic system [61]. Thus, α7-nAChRs may be involved in the formation of Aβ plaque, which may represent a glial strategy to prevent the accumulation of synaptotoxic soluble Aβ [62]. In addition, cholinergic stimulation of α7-nAChRs inhibits high-mobility group box 1 (HMGB1) release and activation of the NF-κB pathway; decreased cholinergic activity is associated with increased HMGB1 levels [63]. Neuronal HMGB1 release may be a key mechanism underlying neuronal APOE4-driven tau pathology and neurodegeneration [64].

Thus, Aβ, ApoE, and BuChE have physiological and disease roles in both the tuning of cholinergic activity and in the vulnerability of the basal forebrain cholinergic system towards degeneration; these actions influence the functional status of cholinoceptive neuronal and non-excitable cells [17]. Initially, increased cholinergic signaling and hypofunctional glia contribute to the accumulation of amyloid pathology and may be net neuroprotective, but later in the disease, deficient cholinergic signaling and overactivated glia contribute to the spread of tau and synaptic pathology. Moreover, there is reduced cholinergic synaptic and extracellular signaling in both normal and pathological aging that will likely lessen ACh-mediated suppression of glial activation and result in age-related increases in glial activation [65].

An age- and genotype-dependent phenotypic extreme of limbic-amnestic and amyloid-predominant early AD is associated with low levels of glial activation (Figs. 3 and 4; Table 2)

Fig. 4
figure 4

Amyloid pathology facilitating phenotype of early AD exemplified by APOE4 homozygotes with BCHE-K aged < 75 years. In preclinical and prodromal AD, especially in APOE4 homozygote BCHE-K carriers below 75 years of age, lower BuChE activity results in higher extracellular ACh and increased signaling through nAChR on glial cells (1). “Functionally underactive” glia with decreased phagocytic, degradative functions, and homeostatic responsiveness (2), impair Aβ clearance resulting in earlier and greater amyloid accumulation (3). In early AD, limbic cholinergic denervation due to ApoE4, Aβ, and tau-mediated damage to basal forebrain cholinergic neurons that project to corticolimbic regions, removes the cholinergic “brake” on glia to increase glial activation, tau pathology and neurodegeneration in the MTL (4). The spread of this pathology outside of the MTL is initially limited until cholinergic denervation has progressed to include other neocortical areas (5). Thus, high levels of amyloid accumulation develop at a younger age, and basal forebrain cholinergic denervation of MTL structures results in hippocampal atrophy and a rapidly progressing limbic-amnestic presentation in early AD with good response to AChE-Is (6). The progression of corticolimbic cholinergic denervation to neocortical areas beyond the MTL results in the spread of glial activation, tau pathology, and neurodegeneration

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At one end of the age-, genotype-, and disease stage-dependent spectrum of early AD is the limbic-amnestic and amyloid accumulation-predominant phenotype, exemplified by APOE4 homozygotes with BCHE-K alleles who are aged less than 75 years (Table 2). In APOE4 carriers with BCHE-K, greater accumulation of Aβ pathology at younger ages is likely due to greater deficits in glial-mediated clearance mechanisms [7, 66] (Figs. 3C and 4). These functionally underactive glia may produce proinflammatory cytokines and be classified as “inflammatory,” but their endolysosomal and phagocytic functions may be greatly reduced [67]. Putatively lower BuChE activity in BCHE-K carriers with APOE4 alleles results in higher extracellular ACh, further reduces the phagocytic function and responsiveness of glial cells, and further impairs Aβ clearance. While excessive cholinergic signaling encourages high levels of amyloid accumulation, the spread and accumulation of tau pathology are simultaneously kept in check (Figs. 2 and 4). However, in early AD, APOE4 is associated with rapidly increasing tau pathology as the combination of ApoE4 and Aβ pathology induces sufficient degeneration of basal forebrain corticolimbic cholinergic neurons to release the cholinergic “brake” on glial activation in the medial temporal lobe (MTL) and eventually in other cortical regions (Fig. 4). Cholinergic denervation and tau pathology accumulating in the MTL result in a rapidly progressing limbic-amnestic presentation with a response to AChE-I that is apparent in the early stages of AD [32, 33]. The focal MTL/limbic denervation is indexed by a more limbic-amnestic presentation (memory > visuospatial impairment, and hippocampal atrophy > ventricular expansion) (Table 2). Although pre-synaptic cholinergic denervation of the MTL induces glial activation, the consequent focal pathology in this region is not fully reflected in CSF measures of glial activation, tau, and neurodegenerative pathology as CSF assessments summarize pathology across the brain. However, these CSF indices will likely show rapid increases as AD progresses and these pathologies spread across the neocortex.

In the limbic-amnestic phenotype, higher amyloid accumulation and lower levels of glial activation were more prominent in APOE4 carriers (Fig. 2). The limbic-amnestic deficits are likely caused by greater and earlier degeneration of the basal forebrain corticolimbic cholinergic projection system that is the result of deficient glial clearance of Aβ. In early-stage AD, APOE4 homozygotes with BCHE-K had the lowest levels of glial activation, neurodegeneration, and tau pathophysiology (Table 2), whereas indices of these pathologies were presumably higher in APOEɛ4 heterozygotes with BCHE-K. In APOEɛ4 heterozygotes the presence of an APOE3 allele (or a rare APOE2 allele) allows for higher levels of glial activation and spread of tau and neurodegenerative pathology. In APOE4 noncarriers without BCHE-K there is less restraint on glial activation exhibited by a strong correlation between glial activation and tau pathophysiology (R2 = 0.825, P = 0.005).

Thus, in APOE4 homozygotes with BCHE-K with mild AD below the age of 75 years, increases in tau pathology first appear in the MTL and these increases are dependent on removal or denervation of the corticolimbic cholinergic “brake” on glial activation. In early AD, APOE4 homozygotes with BCHE-K still have the lowest levels of tau and neurodegenerative pathology, and are on a slightly different journey to end-stage disease than APOE4 heterozygotes with BCHE-K. APOE4 homozygotes with BCHE-K evolve a rapidly increasing burden of tau and neurodegenerative pathology as they progress along the severity continuum toward end-stage disease, where they will have similar levels of pathology to other genotype groups [12].

Hypofunctional glial-mediated clearance of Aβ likely underlies the amyloid accumulation in carriers of APOE4 and BCHE-K aged < 75 years

Balanced glil activation may be needed to stimulate Aβ clearance and avoid the two extremes of “hypofunctional” glia that promote amyloid accumulation and “hyperactivated” glia that facilitate the dissemination of tau [47, 48, 68]. In amyloid mouse models, inhibition of reactive astrogliosis increases Aβ42 plaque burden [69], whereas shifting microglia to an interferon-responsive state boosts ApoE expression, phagocytosis, containment of plaques, and lessens damage to nearby neurons and synapses [70]. However, further shifting of microglia to an overactivated state may increase synaptic engulfment and accelerate the dissemination of tau pathology [71]. Mouse models indicate that ApoE controls glial activation, but ApoE4 locks microglia in a homeostatic state, decreasing in phagocytic capacity, and resulting in a failure to clear pathological debris [7, 66, 72]. Therefore, microglial and astrocyte coverage of plaques is likely protective for surrounding neurons, and ApoE4 is associated with decreased coverage and more neuronal dystrophy [73,74,75].

BCHE-K carriers, who have lower levels of glial activation markers and higher levels of proinflammatory cytokines [24, 29], may exhibit deficient glial responses to neurodegeneration. Rapid and appropriately tuned changes in the catalytic activity of BuChE, and the necessary adaptive changes in cholinoceptive non-excitable cells, may be more difficult to achieve with BuChE-K, particularly in APOE4 carriers. Carriers of APOE4 and BCHE-K may have highly senescent microglia that are associated with blocked endolysosomal processing, impaired phagocytosis, and accelerated Aβ42 pathology [76]. YKL-40 is a context-dependent indicator of glial phagocytic activity in both mice and humans [77]. In the current study, APOE4 noncarriers had higher mean levels of CSF YKL-40 (318 ± 162 ng/mL), relative to APOE4 carriers (247 ± 106 ng/mL; (data not shown, [43]). Mean levels were further reduced in APOE4 homozygotes (202 ± 64 ng/mL) and in APOE4 homozygotes with BCHE-K alleles (190 ± 86 ng/mL; Table 2). This likely explains the inverse correlations observed between amyloid pathology and YKL-40, and between amyloid pathology and synaptic injury in the overall population and in APOE4 carriers; these correlations were absent in APOE4 non-carriers (Fig. 3B and C).

Examination at younger ages may elucidate hypofunctional glial-mediated clearance of Aβ in carriers of APOE4 and BCHE-K

Increases in functional glial activation with age might explain why there is a decreased APOE4-associated risk for AD from of 70–80 years, and why progression to dementia in carriers of both APOE4 and BCHE-K is at least 2-fold greater below 75 years of age compared to older carriers [33]. In a longitudinal study of prodromal AD, 39% of APOE4 and BCHE-K carriers aged less than 75 years progressed to AD over 3–4 years, while 18% of patients aged 75 years or more progressed to AD over 3–4 years [33]. This contrasted with the overall study population, where progression to AD was greater in older patients (29%), compared to those aged less than 75 years (13%). Younger APOE4 carriers have accelerated progression of hippocampal atrophy in prodromal and early-stage AD, but in individuals who are more advanced in age or progression of disease, the influence of APOE4 on hippocampal atrophy is lost [78]. Conversely, global cerebral atrophy in AD patients with a mean age of 70 years was reduced in an APOE4 allele frequency-dependent manner [79], whereas in older patients, with a mean age of 80 years, atrophy was not different by genotype [78, 80]. Thus, the findings in the current study are likely age-dependent and should not be extrapolated to early AD patients aged over 75 years.

The “amyloid accumulating and initially tau spread limiting” phenotype does not contradict the amyloid cascade hypothesis

In a previous study, carriers of APOE4 and BCHE-K with prodromal AD exhibited disease progression rates inversely correlated with age and hippocampal volume, and showed the greatest decline in short- and long-term retrieval from verbal memory and in overall cognitive impairment [27, 33]. Likewise, in the current study of patients with early AD, APOE4 carriers had greater memory deficits, hippocampal atrophy, and amyloid accumulation relative to noncarriers. Additionally, these pathologies occurred ~ 6 years earlier in APOE4 carriers with BCHE-K compared to APOE4 carriers without BCHE-K (Fig. 1C, Table 2). The amyloid cascade hypothesis of AD implies that reaching the threshold for parenchymal amyloid positivity at an earlier age should drive secondary effector tau pathology, with an earlier age-at-onset of AD [81]. Support for this hypothesis comes from slower progression of tau tangle accumulation and slower cognitive decline following antibody-induced removal of amyloid plaque to below key thresholds in patients with early AD [82, 83]. However, in the current study, correlations of amyloid pathology with tau pathophysiology in APOE4 carriers were negative, particularly in carriers of both APOE4 and BCHE-K (Fig. 2). Across groups defined by APOE4 and BCHE-K carrier status, carriers of both alleles had the highest amyloid pathology (Table 2). Amyloid pathology was further increased in APOE4 homozygotes with BCHE-K, and accompanied by the lowest levels of tau and neurodegenerative pathology (Table 2).

The inverse correlations of amyloid pathology with tau pathophysiology and synaptic injury may be a consequence of tau and neurodegenerative pathology localized to the MTL (which includes the entorhinal cortex, amygdala, and hippocampus). This MTL tau and neurodegenerative pathology may be responsible for transitioning APOE4 and BCHE-K carriers into AD at an earlier age with less global tau and neurodegenerative pathology (Table 2; Fig. 4) [84, 85]. Such neuroanatomical distinctions are not discernible from CSF assessments that summarize pathology changes across the brain. Spatial resolution requires tau tangle-ligand positron-emission tomography (tau-PET) neuroimaging. In the presence of global amyloid pathology in APOE4 carriers, tau-PET indicates that tau pathology is more severe with a focal MTL distribution [85, 86]. Furthermore, younger age is associated with a PET-tau signal in the MTL of early AD APOE4 carriers, but this is not seen in APOE4 noncarriers [85]. Across the aging and AD spectrum, APOE4 carriers present with increased microglial activation relative to noncarriers in early Braak stage regions within the MTL. This microglial activation mediates Aβ-independent effects of APOE4 on tau accumulation that are further associated with neurodegeneration and clinical impairment [87].

Degeneration of basal forebrain cholinergic neurons that project to the MTL and other cortical structures precedes and predicts longitudinal entorhinal/MTL degeneration [88, 89]. Notably, preclinical APOE4 carriers exhibit the greatest loss of basal forebrain volume [90]. The ascending corticolimbic neuronal projections of the basal forebrain cholinergic system may be particularly vulnerable to the combination of ApoE4-mediated glial hypofunction and impaired lipid dynamics, and high levels of Aβ and pathological tau [55,56,57]. The impact of focal basal forebrain pathology is magnified as it causes widespread presynaptic cholinergic corticolimbic denervation. Both amyloid and tau pathologies may be required for substantial impairment of cholinergic synaptic plasticity and memory, and for continuous destruction of the projecting branches of the cholinergic nuclei in the basal forebrain [91, 92].

Implications for future clinical research and development of therapeutics

Findings in the current study, if confirmed, could have implications for the conceptualization of Alzheimer pathological cascades, identification of therapeutic targets, and usage of existing and future treatments. The genetic architecture of prognosis in AD is fundamental for proper medical care and in the design and interpretation of clinical trials. Despite its importance, the genetic architecture of prognosis is less established than the genetics of susceptibility. BCHE-K may join APOE4 allele frequency, age, and sex as a foundational component of predictive modeling for early AD phenotypes [93, 94]. Moreover, the cholinergic hypothesis appears seamlessly interlinked with the amyloid cascade hypothesis. APOE and BCHE genotypes appear to exert a critical influence on the functional activation of glia as indexed by the microglial and astrocyte activation CSF marker, YKL-40. The level of extracellular cholinergic signaling to cholinoceptive cells, including glia, depends on the enzymatic activity of BuChE, which is dependent on BuChE levels, BCHE polymorphic variation, ApoE levels, APOE polymorphic variation, and soluble Aβ levels. The health of cholinergic neurotransmission and extracellular signaling systems may be crucial to healthy brain aging [95].

The quantitative removal of amyloid pathology with anti-amyloid antibodies is dependent on Fc receptor-mediated phagocytosis and clearance of Aβ [82, 83]. Response to this targeted immune-activating therapeutic approach may vary depending on the individual’s predominant microglial state. While some beneficial effects might be caused by antibody-mediated stimulation of glia with improved performance of homeostatic functions [96], stimulating the clearance of Aβ prior to substantial levels of corticolimbic cholinergic denervation and spread of tau pathology may produce the best outcomes in APOE4 carriers below the age of 75 years. However, this may require intervention in asymptomatic individuals. In addition, longer treatment durations may be necessary in substantial amyloid accumulators, such as APOE4 homozygotes with BCHE-K alleles, to push amyloid levels below the threshold and to prevent or slow further corticolimbic cholinergic denervation and tau pathology.

While a retuning of innate immune responses may be required to harness protective and beneficial effects and to attenuate negative effects, the required changes will differ across a genotype, age, and the disease stage continuum. Tuning in the wrong direction will simply make matters worse. Considerations may be further complicated by the nuances and complexity of glial cell phenotypes across different brain regions, between adjacent glia, and in different disease contexts [97]. The challenge in the development of potential amyloid pathology limiting therapeutics may not lie in simply upregulating the activation state of glia.

Limitations

Strengths of the study include the well-characterized sample of individuals aged less than 75 years with CSF biomarkers and standardized clinical assessments in expert clinical settings. The limitations of this investigation include its small size, cross-sectional design, and the possibly unrepresentative nature of those enrolled in an interventional clinical trial. Moreover, inferences from the data were based on associations at a particular point in time (baseline) that cannot evidence causal effects, and many correlations involved small sample sizes. Evaluation of the age-at-diagnosis of AD might have benefited from the use of standardized prospective assessments of diagnosis and of onset-age across study sites. Nonetheless, similar genotype group relationships were also demonstrated on the age-at-baseline of study, i.e., at the time this cross-sectional investigation was conducted. Prospective longitudinal assessment in larger samples is necessary to better evaluate phenotypic evolution along the AD continuum and to confirm and develop these findings.

Additionally, more extensive mapping of inflammatory mediators, complement and myelin markers, and CSF ApoE and BChE levels and activity may be illuminating. The primary biomarker used in this study to index tau pathophysiology (CSF p-tau181) may reflect a mix of amyloid and tau pathological changes in the brain [98], and is therefore not a “pure” marker of tau tangle load in the brain. Glia were simplistically ascribed activated or hypofunctional phenotypes, and as facilitating or limiting amyloid accumulation or tau spread. The association of levels of the astrocyte and microglial activation marker, CSF YKL-40, with transcriptional, morphological, and functional states of glia are not clear, and large multiomic datasets and machine learning may be required to elucidate them.

The majority of study participants were of European ancestry; heterogeneity in the genetic neighborhood of these genes and local APOE and BCHE haplotypes may be of importance when interpreting these results [99]. In addition, other genetic variants of BCHE were not assessed in the current study [100], and some have been shown to unequivocally impact the amyloid cascade [101]. Lastly, discerning clinical phenotypes in different genotype subgroups on a variable background of ChE-I therapy and medications with potential anticholinergic properties may be problematic, as ChE-I therapy can influence phenotypic expression. For example, APOE4 carriers—especially those with concomitant BCHE-K alleles—are particularly responsive to AChE-I treatment in the mild stage of AD, and the magnitude of attention, processing speed, and amnestic deficits in these individuals may have been partly obscured [32].

Conclusion

Below the age of 75 years, AD may be more monocausal, without substantial contributions from other age-related pathologies, and the influence of modifying genetic variation on the phenotype of early AD may be more apparent. In APOE4 carriers, the presence versus the absence of BCHE-K alleles associated with a significantly earlier mean age-at-diagnosis of AD of 6.4 years, a more limbic-amnestic phenotype, and similar accumulations of amyloid and tau pathology but more than 6 years earlier. Thus, in APOE4 carriers below the age of 75 years, a major contribution to earlier age-at-diagnosis of AD may be concomitant BCHE-K alleles. In APOE4 carriers, BCHE-K further reduces the functional activation of glia by increasing cholinergic synaptic signaling from basal forebrain corticolimbic cholinergic neuronal projections and extracellular cholinergic signaling through cell surface α7-nAChRs. However, the further lowering of glial activation results in earlier amyloid pathology accumulation that, in combination with ApoE4, is particularly damaging to basal forebrain corticolimbic cholinergic neurons. The spread of tau and synaptic pathology from the MTL to other cortical areas parallels the denervation of corticolimbic cholinergic projections, removal of the cholinergic “brake” on cortical glial activation, and the onset and progression of symptoms. The functional activation of glia, the amyloid cascade hypothesis, and the cholinergic hypothesis of AD are interwoven. In this early AD population, the concept has the potential to explain much of the phenotypic heterogeneity and to enable more appropriate use of existing, emerging, and future therapies. Confirmation of these post hoc findings in larger, prospective, and longitudinal studies is required.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Acknowledgements

We thank the patients and their companions who participated in the study; the sites, and study team from Ionis for executing the study; Michael Moore (Moore Editing, San Diego, CA, USA), who copyedited and styled the manuscript per journal requirements; and Gwendolyn Kaeser (GKaeser Medical Writing, Bend, OR, USA) who edited the manuscript after review.

Funding

The clinical study was funded by Biogen and designed and executed by Ionis. This posthoc assessment was funded by Ionis.

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Authors and Affiliations

  1. Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA, 92010, USA

    Roger M. Lane, Candice Junge, Dan Li, Qingqing Yang & Katrina Moore

  2. Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatric, Karolinska Institutet, Stockholm, Sweden

    Taher Darreh-Shori

  3. Biogen, Cambridge, MA, USA

    Amanda L. Edwards & Danielle L. Graham

  4. Dementia Research Centre, Institute of Neurology, London, UK

    Catherine J. Mummery

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  1. Roger M. Lane
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Contributions

RML was responsible for study design, statistical analysis plan design, and data interpretation, and wrote the initial draft of the manuscript. TD-S critically reviewed, styled, and gave input into the manuscript. CJ oversaw data collection, data analysis, and review of the manuscript. DL and QY advised on statistical analysis plan, performed data analysis, data interpretation, and critical review of the manuscript. KM performed clinical operations and data collection. ALE and DLG designed and conducted biomarker analyses and performed data interpretation and critical review of the manuscript. CJM was the lead investigator and performed data collection, data interpretation, participant recruitment, and critical review of the manuscript. All authors reviewed and provided feedback on the manuscript. The authors had full editorial control of the manuscript and provided their final approval of all content.

Corresponding author

Correspondence to Roger M. Lane.

Ethics declarations

Ethics approval and consent to participate

The trial (NCT03186989) was conducted in accordance with Good Clinical Practice Guidelines of the International Council for Harmonisation, and according to the ethical principles outlined in the Declaration of Helsinki.

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; see supplementary materials (Additional file 2).

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Not applicable.

Competing interests

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.

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Supplementary Information

Additional file 1:

Raw data (including Mean [SD, SEM], Median [P25, P75], and Min/Max). Table S1. Early AD phenotype across genotype groups defined by BCHE-K allele frequency. Table S2. Early AD phenotype across genotype groups defined by APOE4 and BCHE-K carrier status.

Additional file 2.

Ethics committees approving clinical study.

Additional file 3: Figure S1.

Correlations in the overall population and in APOE4 and BCHE-K subgroups of Ng versus YKL-40.

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Lane, R.M., Darreh-Shori, T., Junge, C. et al. Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers. BMC Neurol 24, 116 (2024). https://doi.org/10.1186/s12883-024-03611-5

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BMC Neurology

ISSN: 1471-2377

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