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

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, APOc2, APOr3, and APOE4. 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.Apolipoprotein E (apoE), a 34-kDa protein, mediates the binding of lipoproteins to the low density lipoprotein receptor. It functions as a ligand in receptor-mediated internalization of lipid-rich lipoproteins and is also involved in reverse lipid transport (1). In the central nervous system (CNS), apoE plays a key role in mobilization and redistribution of cholesterol and phospholipid during membrane remodeling associated with synaptic plasticity (2-4). The importance of apoE to brain lipid transport is underscored further by the absence of other key plasma apolipoproteins such as apoAl and apoB (5) in this tissue. ApoE mRNA (3) and protein (6) are found predominantly in astrocytes within the CNS. The apoE gene on chromosome 19 has three common alleles (APOs2, -s3, and -£4), which encode three major apoE isoforms. Recently, the frequency of the apoE4 allele was shown to be markedly increased in sporadic (7-9) and late-onset familial Alzheimer disease (AD) (10, 11). Most interestingly, a gene dosage effect was observed in both familial (10) and sporadic (7) casesThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.namely, as age of onset increases, APOE4 allele copy number decreas...

Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease

“…15,23,24,26,28 Explanations for these inconsistent findings include aspects of study design, such as small sample size, single versus multiple drug dosing, lack of randomization, variable outcome measures used, variable follow-up periods and variable definitions of response to ChEI treatment; pharmacokinetic and pharmacodynamic characteristics of the different ChEIs used; and genetic heterogeneity in the trial populations. Earlier work had suggested that the greater cholinergic deficit 11 and rate of cognitive decline 12 associated with the carriage of APOE e4 might result in a poorer response to ChEI treatment. However, our finding of an improved response to ChEI treatment with APOE e4 carriage is plausible and consistent with other subsequent treatment studies.…”

“…9 The major genetic risk factor for late-onset (non-familial) AD is carriage of the apolipoprotein E e4 allele (APOE e4). 10 The presence of APOE e4 is associated with a greater cholinergic deficit 11 and rate of cognitive decline 12 than in non-carriers of APOE e4, suggesting a likelihood of poorer clinical response to ChEI treatment. Gender may interact with APOE genotype in cognitive decline and, therefore, may also be a predictor of response.…”

“…Results have been inconsistent. Initial reports suggested a better response to tacrine in individuals who were noncarriers of APOE e4, 11,14 particularly in women. 15 However, other researchers have reported that the presence of APOE e4 is associated with improved outcome with ChEI therapy.…”

Apolipoprotein E ɛ4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

“…Although the e4 allele has been shown to promote the neuropathological features of AD, including b-amyloid (Ab) deposition Nagy et al, 1995;Norrman et al, 1995;GomezIsla et al, 1996) and neurofibrillary tangle formation Nagy et al, 1995;Norrman et al, 1995;Gomez-Isla et al, 1996), attempts to relate these features to psychotic symptoms in AD have yielded conflicting results (Zubenko et al, 1991;Förstl et al, 1994;Mukaetova-Ladinska et al, 1995;Sweet et al, 2000). Additionally, ApoE e4 has been linked with more profound cholinergic loss in the frontal cortex (Soininen et al, 1995) and medial temporal lobe (Poirier et al, 1995), and acetylcholine levels have in turn been implicated in psychotic disturbances in AD (Cummings and Kaufer, 1996). Neuroimaging studies may shed additional light on the association between ApoE e4 and psychotic manifestations of AD.…”

“…Among the three major isoforms of ApoE (e2, e3, and e4), the e4 allele has been reported to increase an individual's risk of developing AD, and decrease age of disease onset, in proportion to the number of e4 alleles present (Corder et al, 1993;Farrer et al, 1997). The search for phenotypic correlates of e4 has included neuropathological studies of the rate of b-amyloid (Ab) deposition Nagy et al, 1995;Norrman et al, 1995;Gomez-Isla et al, 1996), neurofibrillary tangle formation Nagy et al, 1995;Norrman et al, 1995;Gomez-Isla et al, 1996), cholinergic markers (Poirier et al, 1995;Soininen et al, 1995), and medial temporal lobe atrophy (Lehtovirta et al, 1996b;Hashimoto et al, 2001;Basso et al, in press).…”