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Apolipoprotein E genotype in elderly nondemented subjects without senile changes in the brain.

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ADoliDomotein E
GinotvDe in Elderlv
NondGented Subfects
Without Senile Changes
in the Brain
Masahito Yamada, MD,* Yoshinori Itoh, MD,?
N a o m i Suematsu, MD,f Eiichi O t o m o , MD,t a n d
Masaaki Matsushita, MDS
Only a small minority of elderly subjects can survive with
a brain free of senile changes (senile plaques, neurofibrillary tangles, and amyloid angiopathy) beyond the age of
80 years. We demonstrated that an increase of ~2 allele
frequency and a decrease of ~4 allele frequency of the
apolipoprotein E gene are associated with such brain
aging without senile changes.
Yamada M, Itoh Y, Suematsu N, O t o m o E,
Matsushita M. Apolipoprotein E genotype
in elderly nondemented subjects
without senile changes in the brain.
A n n Neurol 1996;40:243-245
Alzheimer’s disease (AD), the most common dementia
in the elderly, is characterized by severe senile changes
in the brain, including senile plaques (SPs), neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA). Further, nearly all nondemented subjects
older than 80 years of age also present with SPs and
NFTs in the brain, although significantly fewer than
those found in AD. Thus, only a small minority of
elderly people can survive with a brain free of senile
changes beyond the age of 80.
We investigated the influence of the genotype of
apolipoprotein E gene (APOE), a risk factor for AD
[l-51, on brain aging without senile changes.
Materials and Methods
Subjects, age 80 years or older, characterized neuropathologically by the absence or scarcity of senile changes in the brain,
were selected on the basis of the following criteria: (1) no
From the *Department of Neurology, Tokyo Medical and Dental
University, Departments of tInterna1 Medicine and $Pathology,
Yokufukai Geriatric Hospital, and $Department of Psychiatry, University of Tokyo, Tokyo, Japan.
Received Feb 1, 1996, and in revised form Mar 13. Accepted for
publication Mar 13, 1996.
Address correspondence and reprint requests to Dr M. Yamada,
Department of Neurology, Tokyo Medical and Dental University,
1-5-45, Yushima, Bunkyo-ku, Tokyo 1 13, Japan.
0 1996 by the American Neurological Association
APOE Allele Frequencies in Subjects Without Senile Changes
in the Brain (Group A), Subjects Who Had No Alzheimerj
Disease (AD) or Other Neurodegenerative Disease, but Some
Senile Changes in the Brain (Group B), kind Patients with
AD (AD Group)
~ 2 1 ~ 3
~ 3 1 ~ 4
Allele frequency
Group A
(n = 21)
Group B
(n = 4 1 )
3 (14.3‘%,’
17 (81.0%)
I (4.8%)”
1 (2.40/0)
0 (0%)
32 (78.0%) 14 (60.9%)
8 (19.5%)
9 (39.1%)
3 (7.1%)‘
1 (1.2%)
38 (?0.50/0) 73 (89.0‘Yo)
1 (2.4%)d
8 (9.8%)
AD Group
(n = 23)
0 (0%)
37 (80.4(Yo)
9 (19.6Yo)
‘p = 0.045 vs total of the orher groups; hp == 0.007 vs AD group,
p = 0.027 vs total of the other groups; ‘ y =: 0.047 vs total of the
other groups; “ p = 0.01 1 vs AT) group, p =- 0.034 vs total of the
other groups.
SP or fewer than one Sl’lmm’ throughout the brain, (2) no
or scarce NFTs, corresponding to stage 0 or 1 of Alzheimerrelated changes described by Braak and Braak [6], and (3)
no CAA. For detection of senile changes, brain sections including five coronal slices of the cerebral hemisphere were
obtained and examined with conventional (methenamineBodian and Congo red) and imniunohistochemical (amyloid
j3 and 7) stainings.
In a series of 500 elderly Japanese autopsied at a geriatric
hospital, 21 subjects with almost no senile changes in the
brain (group A) (age, 80-99 [mean k: SD, 85.3 2 5.11
years) wcre found. On review of the clinical records, they
had no dementia. Control groups included 41 nondemented
subjects, age 80 years or older, who pathologically showed
no AD or other neurodegenerative disease, but some senile
changes in the brain (group B) (age, 80-99 [88.0 2 5.41
years), and 23 age-matched demented patients with parhologically verified AD [7] (AD group) (age, 77-93 [85.0 2
5.21 years).
For APOE genotyping, DNA was extracted from frozen
brain tissue IS]. Results of the APOE analysis in group A
were compared with those in group R and the AD group.
Statistical analyses were performed by
T h e Table shows APOE genotype distribution and allele frequencies for group A, group B, and the A D
group. Most frequent in group A was € 3 1 ~ 3
(81.0%) and €3 allele (90.5%), as in group B and the
AD group. Frequency of € 2 1 ~ 3genotype (14.3%) or
of € 2 allele (7.1%) in group A was significantly higher
than the total of the other groups. Frequency of €31
€ 4 genotype (4.8%) or of €4 allele (2.4%) in group A
was significantly lower than the total of the other
groups or the AD group. In group A, there was an 82year-old man with the ~ 3 / genotype.
~ 4
244 Annals of Neurology Vol 40 No 2 August 1996
O u r results revealed that an increase of € 2 allele frequency and a decrease of €4 allele frequency were associated with aging brain without senile changes (SPs,
NFTs, and CAA). T h e APOE status appears opposite
to the risk of AD [ 1-41; €4 allele has been consistently
shown to be a risk factor for A D 11-31, although the
association of lowered €2 allele frequency with the risk
of AD [4]was not always found [ 5 ] . Deposition of 0amyloid protein in elderly subjects has been lowest in
those with the € 2 allele and highest in those with the
€4 allele [9]. In addition, an increased € 2 frequency
and a decreased €4 frequency have been associated with
longevity in a population of centenarians [ 101. These
findings suggest that presence of €2 allele and absence
of ~4 allele might be linked to longevity with the brain
aging free of senile changes, and with intact cognitive
It should be noted that the brain of a nondemented
elderly subject carrying one €4 allele could remain
without senile changes. Further, since the majority of
the subjects in group A had only the ~3 allele, genetic
or environmental factor(s) other than the A P O E would
also influence the brain aging without appearance of
senile changes.
This study was supported in part by Healrh Science Research
Grants (Mechanism o f Abnormal Deposition in Dementia Brain)
of rhe Ministry of Health and Welfare of Japan.
1. Strittinatter WJ, Saunders AM, Schmechrl D , er al. Apolipoprotein E: high-avidity binding to (J-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease.
Proc Narl Acad Sci USA 1993;90:1977-1381
2. Saunders AM, Strittmatter WJ, Schrnechel D, er al. Association
of apolipoprotein E allele ~4with late-onser familial and sporadic Alzheimer’s disease. Neurology 199343: 1467-1472
3. Corder EH, Saunders AM, Strittmatrer WJ, et al. Gene dose
of apolipoprotein E rype 4 allele and the risk of Alzheinier’s
disease in late onset families. Science 1393;261:921-923
4. Corder EH, Saunders AM, Kisch NJ, et al. Protective effect
of apolipoprotein E rype 2 allele for late onset Alzheimer disease. Nature Genet 1994;7: 180- 184
5 . Van Duijin CM, de Knijff P, Wehnert A. et al. Tlie apolipoprotein E ~2 allele is associated with an increased risk of earlyonset Alzheimer’s disease and a reduced survival. Ann Neurol
6 . Braak H, Braak E. Neuroparhological staging of Alzheinierrelated changes. Acra Neuropathol 1991;82:233-259
7 . Mirra SS, Heyman A, McKcel D, et al. The consortium to
establish a regisrry foi- Alzheimer’s diseasc (CERAD). Part 11.
Standardization of iieuropathologic assessment of Alzheimer’s
disease. Neurology 1991;41:479-486
8. Itoh Y, Yatnada M , Suematsu N , et al. Influence of apolipoprotein E genotype on cerebral amyloid mgioparhy in rhe elderly. Stroke 1996;27:216-218
9 Polvikoslci T, Sulkava R, Haltia M , er al. Apolipoprorein E,
dementia, and cortical deposition of p-arnyloid protein. N Engl
J Med 1935;333:1242-1247
10. Schachter F, Faure-Delanef I,, Gui-not F, er 21. Genetic associations with human longevity at the APOE and ACE loci. Nature
Gener 1934;6:29-32
Altered Mental Status
in Thrombotic
Purpura Is Secondary to
Nonconvulsive Status
William T. Garrett, MD,* Cherylee W. J. Chang, MD,?
and l h o m a s P. Bleck, MD*
Thrombotic thrombocytopenic purpura (TTP) is a syndrome with numerous neurological manifestations including altered mental status and seizures. At least 10%
of the patients with TTP seen at our institution had nonconvulsive status epilepticus as a cause of or associated
with their altered mental status. We propose that altered
mental status secondary to nonconvulsive status epilepticus requiring electroencephalographic diagnosis and
antiepileptic medication occurs in a substantial proportion of patients with TTP.
Garrett WT, Chang CWJ, Bleck 'IT.
mental status in thrombotic thrombocytopenic
purpura is secondary to nonconvulsive status
epilepticus. Ann Neurol 1996;40:245-246
Patient Histories
Case 1
A 59-year-old woman presented at a community hospital,
complaining of abdominal pain. Her admission physical examination was notable for the presence of guaiac-positive
stools. Significant laboratory findings included a hematocrit
of 23.7%, a platelet count of 49 X 10°L, blood urea nitrogen (BUN) of 36 mgidl, and creatinine of 2.9 mgidl. Schistocytes were noted on her peripheral smear. During transfer
to our institution she had a 3-minute seizure consisting of
lip smacking and left arm tonic extension with secondary
generalization. Neurological examination revealed a diminished mental status with an inability to follow commands.
Cranial nerves were normal. She withdrew all four extremities to painful stimuli. Reflexes were symmetrically hyperactive and Babinski's sign was present bilaterally. A head computed tomographic (CT) scan was normal. Shortly after
admission, she had a second seizure that was similar in duration and character to the first. She was treated with intravenous phenytoin. No further clinical seizures were observed.
Plasmapheresis was initiated and continued daily. After 3
days her mental status had not improved. An electroencephalogram (EEG) revealed conrinuous frontally dominant semirhythmic theta/delta activity with intermixed sharp waves
and occasional spikes. Subtle facial twitches were noted during the recording. Intravenus diazepam attenuated the facial
rwitching and epileptiform activity leaving diffusely distributed 6- to 8-Hz activity; however, the facial twitching and
semirhythmic discharges reoccurred. The patient was treated
with pentobarbital until an EEG burst-suppression pattern
was achieved. Her seizures were controlled with phenytoin
and valproate. She eventually recovered. Neurological examination after discharge was significant only for mild lower
extremity weakness.
Case 2
Thrombotic thrombocytopenic purpura (TTP) is
characterized by microangiopathic hemolytic anemia,
thronibocytopenia, neurological symptoms, renal failure, and fever [I, 21. The neurological manifestations
vary and include altered m e n d status and seizures [351. Signs may be transient or fluctuate; however, permanent deficits do occur [6].
Altered mental status in TTP often resolves with
plasmapheresis [6]. We present 2 patients whose altered mental status did not respond to plasmapheresis
and were subsequently found to be in nonconvulsive
status epilepticus. O n e patient responded to antiepileptic medication and had an excellent outcome.
From the "Department o f Neurology, University of Virginia, Charlotresville, VA; and l-Departnient o f Medicine, University of California, San Diego, La Jolla, CA.
Received Feb 22, 1996. Accepted for publication Mar 18, 1996.
Address correspondence to Dr Garrett, University of Virginia, Department o f Neurology, Box 394, Charlortesville, VA 22908.
A 44-year-old woman presented at a local conmiunity hospital, complaining of abdominal pain. Soon after admission
she developed a fever and had a generalized tonic-clonic
seizure. Her mental status deteriorated and she was transferred to our institution. Neurological examination revealed
a confused female, occasionally responding to questions with
one-word answers. Cranial nerves were normal. She withdrew briskly to painful stimuli in the right upper and lower
extremity, but withdrawal on the left was sluggish, especially
in the arm. Deep tendon reflexes on the left were hyperactive, but both plantar responses were flexor. Significant laboratory findings included a hernarocrit of 23.60/, a platelet
count of 38 X IO'/L, BUN of 101 mg/dl, and creatinine
of 5.4 mgidl. Schistocytes were noted on her peripheral
smear. Head CT was normal. I'lasmapheresis was initiated
and continued daily. After 4 days her mental status had not
improved. An EEG revealed near continuous sharp and slow
wave complexes maximal in the left hemisphere but with
some spread to the right hemisphere. There were no clinical
manifestations. Intravenous diazepam only briefly attenuated
the epileptiform activity. She was treated with phenobarbital
and carbamazipine but continued to deteriorate clinically and
developed multiple organ system failure. An EEG was repeated 3 days later and revealed severe bihemispheric slow-
0 1996 by the American Neurological Association 245
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without, nondemented, change, apolipoprotein, senile, brain, genotypes, subjects, elderly
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