Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease

Judes Poirier, Marie Claude Delisle, Rémi Quirion, Isabelle Aubert, Martin Farlow, Debomoy Lahiri, Siu Hui, Philippe Bertrand, Josephine Nalbantoglu, Brian M. Gilfix, Serge Gauthier

Research output: Contribution to journalArticle

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Abstract

Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APOε2, APOε3, and APOε-4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (CHAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that >80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients.

Original languageEnglish
Pages (from-to)12260-12264
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number26
DOIs
StatePublished - Dec 19 1995

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Apolipoprotein E4
Cholinergic Agents
Alzheimer Disease
Alleles
Cholinesterase Inhibitors
Apolipoproteins E
Hippocampus
Tacrine
Choline O-Acetyltransferase
Amyloid Plaques
Brain
Nicotinic Receptors
Temporal Lobe
Age of Onset
Phospholipids
Reference Values
Binding Sites
Cholesterol
Clinical Trials

Keywords

  • choline acetyltransferase
  • muscarinic receptor
  • nicotinic receptor
  • tacrine

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. / Poirier, Judes; Delisle, Marie Claude; Quirion, Rémi; Aubert, Isabelle; Farlow, Martin; Lahiri, Debomoy; Hui, Siu; Bertrand, Philippe; Nalbantoglu, Josephine; Gilfix, Brian M.; Gauthier, Serge.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 26, 19.12.1995, p. 12260-12264.

Research output: Contribution to journalArticle

Poirier, Judes ; Delisle, Marie Claude ; Quirion, Rémi ; Aubert, Isabelle ; Farlow, Martin ; Lahiri, Debomoy ; Hui, Siu ; Bertrand, Philippe ; Nalbantoglu, Josephine ; Gilfix, Brian M. ; Gauthier, Serge. / Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. In: Proceedings of the National Academy of Sciences of the United States of America. 1995 ; Vol. 92, No. 26. pp. 12260-12264.
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AU - Poirier, Judes

AU - Delisle, Marie Claude

AU - Quirion, Rémi

AU - Aubert, Isabelle

AU - Farlow, Martin

AU - Lahiri, Debomoy

AU - Hui, Siu

AU - Bertrand, Philippe

AU - Nalbantoglu, Josephine

AU - Gilfix, Brian M.

AU - Gauthier, Serge

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N2 - Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APOε2, APOε3, and APOε-4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (CHAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that >80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients.

AB - Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APOε2, APOε3, and APOε-4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (CHAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that >80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients.

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