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

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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