Structural and resting‐state MRI detects regional brain differences in young and mid‐age healthy APOE‐e4 carriers compared with non‐APOE‐e4 carriers

Dowell, Nicholas G.; Evans, Susan E.; Tofts, Paul S.; King, Sarah L.; Tabet, Naji; Rusted, Jennifer

doi:10.1002/nbm.3502

Cited by 46 publications

(37 citation statements)

References 85 publications

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“…This finding may relate to subthreshold pathologic aggregation 25,26 or to the association of APOE -ε4 genotype with non–amyloid-dependent processes in the brain that are associated with cognitive functioning. 27 …”

Section: Discussionmentioning

confidence: 99%

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia

et al. 2018

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IMPORTANCE Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. OBJECTIVE To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. MAIN OUTCOMES AND MEASURES Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤−1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. RESULTS Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%–7%] at 72 years and 21% [95% CI, 10%–33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, −1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%–20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%–17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. CONCLUSIONS AND RELEVANCE Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.

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Section: Discussionmentioning

confidence: 99%

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia

et al. 2018

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“…There is some support in the literature for an age x APOE interaction, with several studies identifying the end of the 5 th decade as a point when detrimental performance effects of APOE e4 emerge (Caselli et al, 2009;Jochemsen, Muller, van der Graaf, & Geerlings, 2012;Marioni et al, 2015;Shin et al, 2014). It would seem behavioural performance is preserved in e4 carriers up until 5 th decade despite evidence for structural and functional changes prior to this (e.g Dowell et al 2016;Trachtenberg et al, 2012a;2012b). Given the reported attentional detriments in a late-mid age sample (Greenwood et al, 2000;2005a;2005b), research probing additional factors that may mediate the emergence of decline in this genotype, is important.…”

Section: Discussionmentioning

confidence: 99%

Putting attention in the spotlight: The influence of APOE genotype on visual search in mid adulthood

Lancaster

Forster

Tabet

et al. 2017

Behavioural Brain Research

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The Apolipoprotein E e4 allele is associated with greater cognitive decline with age, yet effects of this gene are also observed earlier in the lifespan. This research explores genotype differences (e2, e3, e4) in the allocation of visuospatial attention in mid-adulthood. Sixty-six volunteers, aged 45-55 years, completed two paradigms probing the active selection of information at the focus of attention (a dynamic scaling task) and perceptual capacity differences. Two methods of statistical comparison (parametric statistics, Bayesian inference) found no significant difference between e4 carriers and the homozygous e3 group on either the dynamic scaling or perceptual load task. E2 carriers, however, demonstrated less efficient visual search performance on the dynamic scaling task. The lack of an e4 difference in visuospatial attention, despite previous suggestion in the literature of genotype effects, indicates that select attentional processes are intact in e4 carriers in mid-adulthood. The association of e2 genotype with slower visual search performance complicates the premised protective effects of this allele in cognitive ageing.

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“…A young group (average age 21) and a mid-age group (average age 50), of right-handed males and females with 21 4 carriers in the young group and 17 in the mid-age group (N = 17) was investigated by Dowell et al [103]. They found no detectable genotype-dependent differences in hippocampal volume for either the young or mid-aged adults.…”

Section: Brain Structure-function Differences In Young Apolipoproteinmentioning

confidence: 99%

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

Smith

Ashford

Perfetti³

2019

JAD

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Inheritance of a single copy of the apolipoprotein E (APOE) 4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to 3 allele homozygosity. There is a decreased risk associated with the APOE 2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous 4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on 4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the 4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral 4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing 3 allele, at the expense of decreased fitness in old age, which is substantially improved by the 3 allele. However, possession of the 4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion. conceptualization of AD pathology dates from 1968 when Blessed et al. showed in elderly individuals that the NFTs correlated with the severity of the dementia, though the neuritic plaques, which contain cerebral amyloid-␤ (A␤), did not [2]. A major advance in understanding AD pathology was the demonstration that AD pathology predominantly affects the posterior-temporal, inferior parietal, posterior cingulate, and medial temporal region [3], with a characteristic pattern of progression beginning in the entorhinal cortex involving neurofibrillary (NF)

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Structural and resting‐state MRI detects regional brain differences in young and mid‐age healthy APOE‐e4 carriers compared with non‐APOE‐e4 carriers

Cited by 46 publications

References 85 publications

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia

Putting attention in the spotlight: The influence of APOE genotype on visual search in mid adulthood

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

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