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Apolipoprotein E-4 allele doses in late-onset Alzheimer's disease.

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zymes in the reported biopsies, sufficient evidence indicates
that such a dysfunction exists and probably plays a major role
in the patients’ symptomatology. The earliest sign in patients
with AZT myopathy who have normal strength is muscle
fatigue 13). These patients have focal depletion of cytochrome oxidase [4] and, even in the absence of light microscopic abnormalities, they have by electronmicroscopy subsarcolemmal accumulations of abnormal mitochondria and
increased lipid droplets 131. Focal depletion of cytochrome
oxidase was also noted in those muscle biopsies we have
examined. Further, by 31P-magnetic resonance spectroscopy
during a steady-state exercise, we have demonstrated depletion of phosphocreatine and delayed recovery, consistent
with early defects in oxidative phosphorylation {51. In addition, normal human myotubes and normal rats treated with
AZT demonstrate reduction in the cytochrome mRNA {GI.
Whether muscle carnitine levels in patients with AZT myopathy correlate more closely with the level of the respiratory
chain enzymes rather than lipid droplets is currently unknown.
The correlation with the plasma carnitine level that
Campos and colleagues also raised is more complex in patients with acquired immunodeficiency syndrome (AIDS)
who have a multisystem disease in which dietary factors, deficiency states, cachexia, or kidney dysfunction may influence
the level of plasma carnitine. Plasma carnitine level has been
reportedly reduced in AZT-treated patients with AIDS 171,
and it was reduced in the plasma of some of the patients
we examined. The long-chain or short-chain acetylcarnitine
levels, however, have not been measured. The hypothesis
proposed by Campos and colleagues that the muscle mitochondrial dysfunction leads sequentially to accumulation of
coenzyme A esters, formation of acetylcarnitine, and finally,
depletion of the carnitine pool is attractive if the aforementioned factors are also taken into consideration.
Regardless of the mechanism involved, we agree with
Campos and colleagues that the laboratory evidence from the
present study along with the fundamental observation that
AZT causes muscle mitochondriotoxicity [1) are sufficient
to justify a controlled therapeutic treatment trial with Lcarnitine. We already have evidence that L-carnitine in vitro
can prevent and improve the mitochondrial abnormalities
and the lipid accumulation induced by AZT in normal human
muscle in tissue culture IS].
Neuromuscular Diseases Section
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, M D 20892
1. Dalakas MC, Illa I, Pezeshkpour GH, et al. Mitochondrial myopathy caused by long-term zidovudine (AZT) therapy. N Engl J
Med 1990;322:1098-1105
2. Arnaudo E, Dalakas M, DiMauro S, Schon EA. Depletion of
muscle mitochondrial DNA in AIDS patients with zodovudineinduced myopathies. Lancet 1991;337:508-5 10
3. Cupler EJ, Danon M, Jay CA, et al. The early histological abnormalities of subclinical AZT-myopathy (AZT-MY). Neurology
4. Chariot P, Monnet I, Gherardi R. Cytochrome c oxidase reaction
improves histopathological assessment of zidovudine myopathy.
Ann Neurol 1993;34:561-565
Souiedan S, Sinnwell T, Jay C, et al. Impaired muscle energy
metabolism in patients with AZT-myopathy: a blinded comparative study of exercise 31P magnetic resonance spectroscopy
(MRS) with muscle biopsy. Neurology 1992;42(S):146
Lewis W, Gonzalez 3,Chomyn A, Papoian T. Zidovudine induces molecular, biochemical, and ultrastructural changes in rat
skeletal muscle mitochondria. J Clin Invest 1992;89:1345-1 360
DeSimone C, Tzantzoglou S,Jirillo E, et al. L-Carnitine deficiency
in AIDS patients. AIDS 1992;6:203-205
Semino-Mora C, Leon-Monzon ME, Dalakas MC. The effect of
L-carnitine on the AZT-induced destruction of human myotubes.
Part I: L-Carnirine prevents the myotoxicity of AZT in vitro. Lab
Invest 1994;71:102-112
Apolipoprotein E-€4 Allele
Doses in Late-Onset
Alzheimer’s Disease
GCrard Lucotte, PhD,’ Jean-Claude Turpin, MD,?
and Paul Landais, MD$
The frequency of the allele for apolipoprotein E4 (ApoE+4)
is increased in late-onset familial Alzheimer’s disease (AD)
[1, 2). There is also a significant association between €4 and
sporadic A D [3], and analysis of €4 allele frequency as a
function of age in sporadic cases revealed a bimodal distribution with peaks at 65 and 75 years I4). Corder and coworkers [2] showed that the age at onset in familial A D is
lower for individuals homozygous for ApoE-~4compared
with heterozygotes and those with other genotypes. They
indicate also that ApoE-~4gene dose is related to survival
in familial A D (survival distributions were constructed from
information on age at death in subjects known to be deceased
and from age when last examined in other subjects, regardless of disease status).
W e have found that the cumulative probability of remaining unaffected over time decreases for each dose of
ApoE-~4in sporadic, late-onset AD. In a retrospective study
of consecutive cases of AD, recruited from our local psychogeriatric service over 5 years, in 132 unrelated French patients (40 males and 92 females), most met criteria of the
National Institute for Neurological and Communicative Disorders (NINCDS) for probable AD. Four are now possible
cases, and 7 are autopsy confirmed; in 10 we have since
obtained evidence of familial A D (1 demented patient in
second-degree relatives). For the present study, late-onset
was defined as age at onset >60 years. Age at onset was
defined as the age at which family members considered an
individual to be first definitely affected by the disease.
Genomic D N A was prepared from peripheral blood leucocytes and amplification of D N A by the polymerase chain
reaction using primers described in {5}; restriction isotyping
of the ApoE gene sequence was done by an already published
method [33. Four genotypes were observed (homozygotes
E414 and E313, and heterozygotes E4/3 and E3/2) and 17
patients were E414 homozygotes (ApoE-~4gene dosage was
Annals of Neurology
Vol 36 No 4 October 1994 681
with two ApoE-c4 alleles. T h e effect of genotypes o n age at
onset of A D was analyzed using the product-limit method
to compare unaffected groups using the log-rank test. E414
genotype was associated with a younger age at disease occurrence than E4I3 o r non-E4 genotypes ( p < 0.0001); the
log-rank test used is also significant, but at a lesser degree, for
comparisons between E413 and all non-orher €4genotypes.
*Laboratory of Neurogenetics and
?Department of Neurology
Maison Blanche Hospital
Reims , France
$Labovatoy of Biostatistics and
Medical Informatics
Paris, France
85 Age at onset
Age at onset for subjects with 0 (circles), 1 (triangles), and 2
(squares) apolipoprotein E-€4 alleles. Onset curoes were estimated by Kaplan-Meier product-limit distributions.
as follows: 2 doses for E414 genotype; 1 dose for E413 genotype; 0 doses for E313 and E312 genotypes).
The figure shows that the probability of remaining unaffected over time is decreased for each dose of Apo E -~ 4 .
For example, at age 7 1 an estimated 1% of subjects without
A poE-~4were diagnosed with AD, compared with 30% of
subjects with one A p o E - ~ 4allele, and almost 9292 of subjects
682 Annals of Neurology Vol 36 No 4
October 1974
1. Strittmatter WJ, Saunders AM, Schmeckel D, et al. Apolipopro-
rein E: high-avidity binding to P-amyloid and increased frequency
of type €4 allele in late-onset familial Alzheimer's disease. Proc
Natl Acad Sci USA 1993;90:1977-1981
Corder EH, Saunders AM, Strittmatrer WJ, er al. Gene dose of
apolipoprotein E type €4 allele and the risk of Alzheimer's disease
in late-onset families. Science 1993;261:921-923
Lucotte G, David F, Visvikis S, et al. Apolipoprotein E-€4 allele
and Alzheimer's disease. Lancet 1993;34?:1309
Poirier J, Davignon J, Bouthillier D, et al. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 1993;342:697-699
Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid
Res 1990;31:545-548
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allele, dose, apolipoprotein, latex, disease, alzheimers, onset
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