White matter hyperintensities in cholinergic pathways are associated with dementia severity in e4 carriers but not in non-carriers

Yu, Ming-Chun; Chuang, Yi‐Fang; Wu, Shu-Ching; Ho, Cheng-Feng; Liu, Yi‐Chien; Chou, Chia-Ju

doi:10.3389/fneur.2023.1100322

Cited by 7 publications

(8 citation statements)

References 52 publications

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“…Degeneration of basal forebrain cholinergic neurons that project to the MTL and other cortical structures, precedes and predicts longitudinal MTL degeneration (65). The ascending neuronal projections of the basal forebrain cholinergic system may be particularly vulnerable to the combination of apoE4-mediated glial hypofunction and deficient lipid delivery with high levels of Aβ and tau pathology (66)(67)(68). Corticolimbic cholinergic denervation may be evident at early stages of AD (69), and failure of this circuitry is inextricably linked with amnestic deficits (70).…”

Section: Discussionmentioning

confidence: 99%

Glial activation mediates phenotypic effects ofAPOEε4and sex in Alzheimer’s disease

Lane,

Li,

Darreh-Shori

2024

Preprint

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INTRODUCTION: This study examined the impact of apolipoprotein e4 (APOEe4) allele frequency and sex on the phenotype of Alzheimer disease (AD). METHODS: The baseline characteristics, CSF, and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50-74 years with confirmed mild AD from clinical trialNCT03186989were evaluated in a post-hoc study. RESULTS: A phenotypic spectrum was observed from a predominant amyloid and limbic-amnestic phenotype in male APOEe4 homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in female APOEe4 noncarriers. Amyloid pathology inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest correlations observed in male APOEe4 carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in female APOEe4 noncarriers. DISCUSSION: Glial activation is influenced by apoE isoform and sex, which explains much of the phenotypic heterogeneity in mild AD below age 75 years.

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Section: Discussionmentioning

confidence: 99%

Glial activation mediates phenotypic effects ofAPOEε4and sex in Alzheimer’s disease

Lane,

Li,

Darreh-Shori

2024

Preprint

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“…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 – 57 ]. In both aging and AD, the intraneuronal accumulation of oligomeric assemblies of Aβ 42 is a relatively selective trait of basal forebrain cholinergic neurons [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…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 – 57 ]. The impact of focal basal forebrain pathology is magnified as it causes widespread presynaptic cholinergic corticolimbic denervation.…”

Section: Discussionmentioning

confidence: 99%

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

Lane,

Darreh-Shori,

Junge

et al. 2024

BMC Neurol

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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

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“…Acetyl-CoA is an essential substrate for the synthesis of both ACh and lipids essential for myelin formation and maintenance of cellular membranes (50). The ascending white matter projections of the basal forebrain cholinergic system may be particularly vulnerable to the combination of Aβ pathology and ApoE4 (51)(52)(53).…”

Section: Both Aβ and Apoe Modulate The Cholinergic Systemmentioning

confidence: 99%

“…Degeneration of basal forebrain cholinergic neurons, that project to the MTL and other cortical structures, precedes and predicts longitudinal entorhinal/MTL degeneration (81,82) and preclinical APOE4 carriers exhibit the greatest loss of basal forebrain volume (83). The ascending neuronal projections of the basal forebrain cholinergic system may be particularly vulnerable to the combination of ApoE4mediated glial hypofunction, high levels of Aβ, and tau pathologies (51)(52)(53). The impact of focal basal forebrain pathology is magnified as it causes widespread presynaptic cholinergic corticolimbic denervation.…”

Section: Both Aβ and Apoe Modulate The Cholinergic Systemmentioning

confidence: 99%

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

Lane,

Darreh-Shori,

Junge

et al. 2024

Preprint

View full text Add to dashboard Cite

BackgroundWe 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.

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White matter hyperintensities in cholinergic pathways are associated with dementia severity in e4 carriers but not in non-carriers

Cited by 7 publications

References 52 publications

Glial activation mediates phenotypic effects ofAPOEε4and sex in Alzheimer’s disease

Glial activation mediates phenotypic effects ofAPOEε4and sex in Alzheimer’s disease

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

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

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