APOE4 STATUS AND COGNITIVE FUNCTION
IN MIDDLE-AGED AND ELDERLY PEOPLE
Pavel N.A.1, Paun M.R.2, Matei P.V.1,2, Dutu I.1, Tudose C.1,2
*Corresponding Author: Valentin P. Matei, Associate Proffesor, MD, PhD. 2nd Ward of “Prof. Dr. Alexandru
Obregia” Hospital, Berceni Street no 10, Bucharest, Romania. E-mail: valipmatei@yahoo.com
page: 6
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DISCUSSION
The goal of our study was to analyze the impact of
ApoE4 status on various cognitive domains in 51 individuals
that did not screen positive for cognitive impairment on
the MMSE test or clinical evaluation. The prevalence of
ApoE4 in our cohort was 21.5%, which is higher than the
14% generally estimated in the Caucasian population [2].
Our main result was that ApoE4 positive (ApoE4+)
group scored significantly worse than the ApoE4 negative
(ApoE4-) group in the Rey Visuospatial Memory Test. Secondly,
ApoE4+ individuals exhibited a negative trend in
all other cognitive tests, most notably in the RAVLT Trial
5 and RAVLT Recognition tests, in which the difference
was just short of statistical significance.
This corroborates with previous data that associate
ApoE4 with lower-than-expected performance in general
memory and attention driven tasks, even in middle-aged
individuals [18]. Additionally, deficits in spatial cognition
were identified in ApoE4 positive mice from a young age
[19]. Impairments in visuospatial memory are often present
during the early stages of AD or in Mild Cognitive Impairment (MCI), signaling a high-risk of progression
to dementia in the latter case [20]. However, the negative
impact of ApoE4 on cognitive function is not inextricable
from its association with AD; ApoE4 may also exacerbate
the impact of other psychiatric and non-psychiatric illnesses
on cognition, most notably depression [21] and
multiple sclerosis [22].
There was also a noticeable trend towards poorer performance
in verbal memory among ApoE4+ individuals,
reflected particularly in the RAVLT Trial 5 and RAVLT
Recognition tests. Considering its detrimental effects on
memory and attention even in individuals without objective
cognitive decline, it seems probable that a study with a
larger number of participants could detect a significant difference
between ApoE4+ and ApoE4- individuals. There is
also data that is not entirely congruent with our previous
conclusions, most notably a 2020 systematic review which
concluded that ApoE4+ AD patients predominantly exhibit
memory-related symptoms, while ApoE4- patients suffer
greater impairments in executive function, language and
visuospatial memory [6].
We hypothesize that the lower scores obtained by
ApoE4+ individuals in cognitive tests are an early sign
of neurodegenerative processes, which are not yet severe
enough to register on the less sensitive MMSE test used
for screening prior to inclusion in the study. This would be
in line with the plethora of evidence that ApoE4 is associated
with increased risk of developing AD, more severe
disease phenotypes, and earlier onset of symptoms [4], [5].
The probable mechanism is that of ApoE4 precipitating
“pathological” aging phenomena in the brain [23], resulting
in a negative impact on cognition that may manifest
as early as middle age. However, this is not to imply that
all subjects with ApoE4 will invariably develop dementia,
merely that they possess the most significant risk factor in
the summation of factors that contribute to neurodegenerative
disorders. In this sense, our study is a snapshot of a
moment in time in which the pathological threshold has
not yet been reached, but in which individuals that carry
the ApoE4 gene variant are beginning to exhibit slight but
quantifiable cognitive impairment.
The main limitation of our study is the small number
of patients enrolled, possibly preventing us from adequately
quantifying a number of smaller effects that ApoE4 may
have on cognition. The principal strength of our study
is that our two cohorts are perfectly matched by socioeconomic
status, psychiatric and somatic comorbidities.
In conclusion, ApoE4 positive individuals performed
slightly worse than controls on cognitive evaluations and
the difference was most obvious regarding visual memory.
It is possible that the effects of the ApoE4 genotype on
cognition could be visible even in middle-aged persons,
long before any significant changes would appear on a
widely used cognitive test such as MMSE.
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