APOE ε4 Genotype and Longitudinal Changes in Cerebral Blood Flow in Normal Aging

Thambisetty, Madhav; Beason‐Held, Lori L.; An, Yang; Kraut, Michael A.; Resnick, Susan M.

doi:10.1001/archneurol.2009.913

Cited by 187 publications

(177 citation statements)

References 28 publications

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“…Moreover a genedose effect was reported in each of these brain regions in late-middle-age individuals, with greater decrease in individuals with two APOE4 alleles compared to those with only one . Accelerated rates of decline in resting-state cerebral blood flow in frontal, parietal and temporal cortices have also been reported in one previous study using H 2 O-PET (Thambisetty et al, 2010).…”

Section: Apoe4 and Fdg-pet / Hypometabolismsupporting

confidence: 75%

Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers

Chételat

Fouquet

2013

Revue Neurologique

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Abstract:Introduction. The E4 allele of the apolipoprotein E (APOE4) is the major known genetic risk factor for AD, with a dramatic increase in the risk of developing AD as the number of APOE4 alleles increases from 0 to 2. For this reason, asymptomatic APOE4 carriers as a group offer a great opportunity to seek for the presence of early biomarkers for AD. The present article reviews neuroimaging studies on APOE4 carriers, focusing on cognitively normal individuals and on the main neuroimaging biomarkers for AD, i.e. atrophy with structural MRI, hypometabolism with FDG-PET, and amyloid deposition with amyloid-PET imaging.State of art. There is a great number of studies on the effect of APOE4 on brain structures, and they tend to show significant atrophy in APOE4 carriers compared to non carriers especially in regions susceptible to AD pathology such as the hippocampus. However, results are rather discrepant which suggests that the effect of APOE4 on brain structure is subtle. As for FDG-PET metabolism, the few studies show decreased metabolism, again especially in AD-sensitive regions such as posterior associative parietal areas, with a dose-dependent effect (i.e. worsening as the number of APOE4 alleles increases). Finally, there is a unanimous and major effect of APOE4 on amyloid deposition with an increase in Aβ load as the number of APOE4 alleles increases and a decrease in the age of predicted amyloid-positivity in APOE4 carriers. This graded effect of APOE4 on atrophy, hypometabolism, and amyloid deposition is consistent with multimodal neuroimaging studies suggestive of a predominant effect of APOE4 on amyloid rather than tau-related injury and on brain metabolism rather than brain structure. Neuroimaging studies also suggest that APOE4 effects may be mediated by both Aβ-dependent and Aβ-independent pathological processes. This contradicts the view that Aβ pathology is a necessary upstream event to neuronal injury in AD. Perspectives and conclusion. Future studies would tell whether the mechanisms and sequences evidenced in carriers is comparable to those found in non carriers, but it is likely that APOE4 not only influences the risk for AD, but also modulates the physiopathological cascade. Altogether, APOE4 carriers offer a great opportunity to investigate brain changes in the asymptomatic stages of AD and to further our understanding of the physiopathology of the disease, although precaution is needed for interpretation in AD at large. Etat des connaissances. De très nombreuses études ont évalué les effets de l'APOE4 sur la structure cérébrale. Les résultats sont très divergents, même s'ils suggèrent dans l'ensemble un effet subtile dans le sens d'une diminution de volume dans les régions les plus sensibles à la MA telles que l'hippocampe. Les rares études en TEP-FDG indiquent une baisse du métabolisme là encore dans les régions altérées précocement dans la MA comme le cortex associatif pariétal postérieur, avec un effet dose-dépendant (i.e. fonction du nombre d'allèles APOE4). Enfin, l'effet sur les d...

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Section: Apoe4 and Fdg-pet / Hypometabolismsupporting

confidence: 75%

Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers

Chételat

Fouquet

2013

Revue Neurologique

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“…Although cross-sectional studies are easier to carry out, and have contributed most of what we know to date about aging of the brain, they are vulnerable to cohort effects, and longitudinal studies are necessary for identifying the effects of aging within individuals. There have been a few longitudinal studies of brain function in older adults, which have shown decreased task-related activity over time 193 , both decreases and increases, depending on the specific brain region and cognitive demands 194,195 , and a greater decline of activity in older individuals with risk factors for AD 196 . With so few data points it is difficult to come to any strong conclusions about change over time, highlighting the need for these kinds of studies.…”

Section: Discussionmentioning

confidence: 99%

The cognitive neuroscience of ageing

2012

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PrefaceThe availability of neuroimaging technology has spurred a marked increase in the human cognitive neuroscience literature, including the study of cognitive aging. Although there is a growing consensus that the aging brain retains considerable plasticity of function, currently measured primarily by means of functional magnetic resonance imaging, it is less clear how age differences in brain activity relate to cognitive performance. The field also is hampered by the complexity of the aging process itself and the large number of factors that are influenced by age. In this review, current trends and unresolved issues in the cognitive neuroscience of aging are discussed.

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“…5,6 Indeed, APOE E4 carrier status has been related to increased hippocampal atrophy 38 and a greater decline in cerebral blood flow in frontal, temporal and parietal areas. 39 As the frontal and parietal areas in the brain have been implicated in abstract reasoning, 40 and reduced hippocampal volumes have been associated with memory decline in the ageing population, 41,42 it may not be unreasonable to assume that the lower performance on memory and reasoning tests observed in APOE E4 carriers might be accounted for by changes in brain morphology. Furthermore, the putative role of APOE E4 in neuronal damage and atherosclerosis might offer a suitable explanation for the finding that APOE E4 carrier status is associated with cognitive performance in old age, but not in childhood 10,11 or in adults before age 50, 9 as neurodegenerative processes might not take place until later in life.…”

Section: Discussionmentioning

confidence: 99%

APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921

et al. 2011

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Carriers of the APOE E4 allele have an increased risk of developing Alzheimer's disease. However, it is less clear whether APOE E4 status may also be involved in non-pathological cognitive ageing. The present study investigated the associations between APOE genotypes and cognitive change over 8 years in older community-dwelling individuals. APOE genotype was determined in 501 participants of the Lothian Birth Cohort 1921, whose intelligence had been measured in childhood in the Scottish Mental Survey 1932. A polymorphic variant of TOMM40 (rs10524523) was included to differentiate between the effects of the APOE E3 and E4 allelic variants. Cognitive performance on the domains of verbal memory, abstract reasoning and verbal fluency was assessed at mean age 79 years (n = 501), and again at mean ages of 83 (n = 284) and 87 (n = 187). Using linear mixed models adjusted for demographic variables, vascular risk factors and IQ at age 11 years, possession of the APOE E4 allele was associated with a higher relative rate of cognitive decline over the subsequent 8 years for verbal memory and abstract reasoning. Individuals with the long allelic variant of TOMM40, which is linked to APOE E4, showed similar results. Verbal fluency was not affected by APOE E4 status. APOE E2 status was not associated with change in cognitive performance over 8 years. In nondemented older individuals, possession of the APOE E4 allele predicted a higher rate of cognitive decline on tests of verbal memory and abstract reasoning between 79 and 87 years. Thus, possession of the APOE E4 allele may not only predispose to Alzheimer's disease, but also appears to be a risk factor for non-pathological decline in verbal memory and abstract reasoning in the ninth decade of life.

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APOE ε4 Genotype and Longitudinal Changes in Cerebral Blood Flow in Normal Aging

Cited by 187 publications

References 28 publications

Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers

Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers

The cognitive neuroscience of ageing

APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921

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