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Clinical correlates of apolipoprotein E in Alzheimer's disease.

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Clinical Correlates of Apolipoprotein E in
Alzheimer’s Disease
G. B. Frisoni, MD, A. Bianchetti, MD, S. Govoni, PhD,
and M. Trabucchi, MD
We read with interest the study by Gomez-Isla and colleagues [ l ] on the clinical correlates of apolipoprotein E
(apoE) in Alzheimer’s disease (AD). The authors state that
AD starts earlier and the disease ha3 a longer duration (presumably from onset to first observation, although this is not
explicitly stated in the article) in €4 carriers, but from the
time of first observation onward, disease progression curiously seems to be similar in carriers and noncarriers. As highlighted by Gomez-Isla and colleagues [I], we have recently
reported on slower disease progression in ~4 carriers [2].
Here, we try to clarify our findings with the apparently contrasting findings of Gomez-Isla and colleagues [ I].
Disease progression in AD is defined as the ratio between
cognitive performance change and time during which the
change is occurring. Progression of AD over the whole course
is probably not linear for biological reasons and for the ceiling and floor effects common to all measurement scales [3].
Therefore, cognitive status at the beginning and at the end
of the observation period and duration of observation must
all be known, to compare progression rates. In our study [2],
we retrospectively computed cognitive status at disease onset
on the basis of epidemiological data on the Mini-Mental
State Examination (MMSE) in the general population, and
calculated progression rate as the ratio between cognitive decline (MMSE at disease onset minus MMSE at observation)
and disease duration. In the figure, based on our data [2],
the slopes of the lines joining cognitive status at disease onset
(time 0 ) and at observation indicate rate of progression (gray
lines). Since intermediate assessments were not available, we
cannot claim that the slopes had been constant over the
whole disease duration for all three genotypes, but at least
that those computed are the mean slopes until observation.
Had prospective measures been raken starting from observation (black lines), a floor effect on disease progression might
3 ) sehave occurred on the group (in this case, ~ 3 / ~most
verely impaired at the beginning of the prospective observation period, and thus the progression for this group might
have a slope similar to that of the least impaired group ( ~ 4 /
Moreover, since family history and age at onset are important modifiers of the effect of apoE, in our study [2] we
chose to focus the analysis on the most prevalent stratum of
the AD population, ie, sporadic late-onset (more than 70
years) AD. Gomez-Isla and colleagues [I] do not provide
data on cognitive status at the beginning and at the end of
the observation period and on duration of observation across
€4 genotypes. Furthermore, they do not stratify by age at
onset and family history. It would be interesting if the au-
Time from disease onset (months)
Abbeimer > disease progression across apoE genoiypes. Grey lines represent our retrospective data [2]. Black lines represent bypotbetical prospective findings.
688 Copyright 0 1936 by the American Neurological Association
thors would try to fit their data into the framework that we
have outlined.
Alzheimer j. Disease Unit
Ospedale S.Cuore-FBF
Via Pilastroni 4, and
Geriatric Research Group
Via Romanino I
Brescia, Italy
1 . Gomez-Isla T, West HL, Rebeck GW, et al. Clinical and pathological correlates of apolipoprotein E ~4 in Alzheimer’s disease.
Ann Neurol 1996;39:62-70
2. Frisoni GB, Calabresi L, Geroldi C, et al. Gene dose of the
~4 allele of apolipoprotein E and gender in sporadic late-onset
Alzheimer’s disease. Ann Neurol 1995;37:596-604
3. Yesavage JA, Brooks JO. O n the importance of longitudinal
research in Alzheimer’s disease. J Am Geriarr Soc 1992;39:942944
Bradley T . Hyman, MD, PhD, Teresa Gomez-Isla, MD,
PhD, and John H. Growdon, MD
We appreciate the comments of Frisoni and associates [l],
regarding our study of the clinical and pathological correlates
of apolipoprotein E (APOE) genotype in Alzheimer’s disease
121. We agree that whether inheritance of APOE ~4 influences the clinical rate of progression in Alzheimer’s disease
is an important although complicated issue. Our data suggest
that APOE t 4 influences the average age of onset of dementia but does not alter the course of the illness thereafter. This
result was derived from a serial evaluation of 153 patients
for an average of 31.8
18.7 months [ 2 ] ,during the middle
stages of Alzheimer dementia, when the patients were living
at home and attending the outpatient neurology clinic. In
this phase of the illness, decline on the Blessed Dementia
Scale and on the Activity of Daily Living scales is linear, and
free from floor effects 131. Covarying gender, age of onset,
and initial degree of impairment did not alter this outcome.
In a subsequent more detailed study, we found that rate of
decline on a broad range of neuropsychometric tests were
not influenced by APOE genotype [4].Conclusions similar
to our report of finding no influence of APOE ~4o n rate
of progression of dementia have been found in several other
large series where rate of progression was assessed prospectively by serial examinations. For example, Dal Forno and
colleagues [5] followed 101 patients for more than 10 years
(average of 3.5 years) and concluded that APOE ~4 did not
consistently alter rate of change on cognitive scores. Waring
and collaborators [6] came to a similar conclusion based on
the Mayo Clinic experience of 132 Alzheimer‘s disease patients followed over 2.7 years.
It is uncertain how APOE t 4 can influence the pathophysiology of the disease, to change the age at onset but not to
worsen the progression thereafter. Our studies of pathological correlations suggest that the major influence of APOE
t 4 is on AP deposition. We detected no difference in neurofibrillary tangle number according to genotype if duration of
illness was covaried. This is concordant with our previous
observations that amyloid burden does not correlate with
severity or duration of illness [7,81, but neurofibrillary tangle
number does parallel severity of disease [8]. These clinicalpathological correlations may help generate and test hypotheses about the pathophysiologic basis of APOE genotype’s influence in Alzheimer‘s disease.
a Service
Massachusetts General Hospital
Boston, MA 02114
1 . Frisoni G, Bianchetti A, Govoni S,Trabucchi M. Clinical Correlates of Apolipoprotein E in Alzheimer’s Disease. Ann Neurol
1996;40:688-689 (Letter)
2. Gomez-Isla T, West H, Rebeck G, et al. Clinical and pathological correlates of apolipoprotein E e4 in Alzheimer’s disease. Ann
Neurol 1996;39:62-70
3. Locasio J , Growdon J, Corkin S. Cognitive test performance in
detecting, staging, and tracking Alzheimer’s disease. Arch Neurol
1995f2: 1087-1099
4. Growdon J H , Locascio JJ, Corkin S, et al. Apolipoprotein E
genotype does not influence rates of cognitive decline in Alzheimer‘s disease. Neurology. 1996;47:444-448
5. Dal Forno G, Rasrnusson X, Brandt J , et al. Apolipoprotein E
genotype and rate of decline in probable Alzheimer’s disease.
Arch Neurol 1996;53:345-350
6. Waring SC, Rocca WA, Smith GE, et al. Apolipoprotein E and
rate of clinical progression in Alzheimer’s disease. Neurology
1996;46:A348 (Abstract)
7. Hyman BT, Marzloff K, Arriagada PV. The lack of accumulation of senile plaques or ainyloid burden in Alzheimer’s disease
suggests a dynamic balance between amyloid deposition and resolution. J Neuropathol Exp Neurol 1993;52:594-600
8. Arriagada PV, Growdon J H , Hedley-Whyte ET, Hyman BT.
Neurofibrillary tangles but not senile plaques parallel duration
and severity of Alzheimer’s disease. Neurology 1992;42:631639
CNS Distribution of Free-Radical Inactivating
Enzymes in Amyotrophic Lateral Sclerosis
J. D. Mitchell, P. S. Fitzmaurice, J. M. Knight,
and I. C. Shaw
We read with interest the report of Przedborski and colleagues [l] and feel their work emphasizes the importance
of specifying the exact nature of the tissue used to make such
measurements and ensuring that this material is as representative of the pathological process as possible. Further insights
into discrepancies between the results of other workers in
this important area might be gained from consideration of
these issues.
Przedborski and colleagues [ 11 refer to the lack of evidence
of reduced central nervous system (CNS) selenium levels in
amyotrophic lateral sclerosis (ALS). The evidence is indeed
otherwise. The finding of increased levels of selenium and
manganese [2] in spinal cord from patients who had died of
ALS leads to early suggestions that free radical mechanisms
were important in ALS pathogenesis [3]. Most of this work
was done on whole cord sections. Increased spinal cord selenium levels have also been subsequently reported using material obtained from the lumbar enlargement, presumably us-
Annals of Neurology
Vol 40
No 4
October 1996 689
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clinical, correlates, apolipoprotein, disease, alzheimers
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