APOE related alterations in cerebral activation even at college age

Scarmeas, Nikolaos; Habeck, Christian; Hilton, John; Anderson, Karen E.; Flynn, Joseph; Park, Aileen; Stern, Yaakov

doi:10.1136/jnnp.2004.053645

Cited by 89 publications

(75 citation statements)

References 34 publications

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“…Task-associated, perspective dependent and performance correlated BOLD signal changes in the MTLs were all different on average in APOE*4 carriers and non-carriers. Reports of altered visuospatial abilities in cognitively normal middle-aged APOE*4 carriers (24) and brain metabolic changes in young APOE*4 carriers (47,53) raise the possibility that neurophysiologic alterations seen in APOE*4 carriers could reflect a "trait" rather than a "state". This raises the question of whether altered BOLD responses in these older APOE*4+ subjects represents a pre-dementia state or reflects a life-long difference in neuronal activation or neurovascular coupling.…”

Section: Discussionmentioning

confidence: 99%

“…In MCI, carriers of the APOE*4 allele reduced metabolism in the parietal-temporal regions and medial parietal lobe, including the posterior cingulate and retrosplenial area (40), perhaps reflecting greater pathologic burden and worse prognosis for these patients (for review see (10,41)). PET and SPECT metabolic studies also reveal hypometabolism in younger (47,53) and older (48,52,59) cognitively unimpaired APOE*4+ subjects. Studies with fMRI have been less consistent; both increased (3,19,26,62,71), decreased (36,61) and unchanged (1) BOLD responses have been reported in APOE*4+ subjects and no clear anatomic region is reliably affected.…”

Section: Introductionmentioning

confidence: 88%

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Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers

Borghesani¹,

Johnson²,

Shelton³

et al. 2008

Neurobiology of Aging

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The apolipoprotein ε4 allele (APOE*4) is a major genetic risk factor for Alzheimer's disease (AD) and has been associated with altered cortical activation as assessed by functional neuroimaging in cognitively normal younger and older carriers. We chose to evaluate medial temporal lobe (MTL) activation during encoding and recognition using a perspective dependent (route or survey) visuospatial memory task by monitoring the blood-oxygen-level-dependent (BOLD) fMRI response in older, non-demented APOE*4 carriers (APOE*4+) and non-carriers (APOE*4−). During encoding, the APOE*4− group had greater average task-associated BOLD responses in ventral visual pathways, including the MTLs, as compared to the APOE*4+ group. Furthermore, MTL activation was greater during route encoding than survey encoding on average in APOE*4−, but not APOE*4 +, subjects. During recognition, both groups performed similarly and no BOLD signal differences were found. Finally, within-group analysis revealed MTL activation during encoding was correlated with recognition performance in APOE*4−, but not APOE*4+ subjects. Reduced task-associated MTL activation that does not correlate with either visuospatial perspective or task performance suggests that MTL dysregulation occurs prior to clinical symptoms of dementia in APOE*4 carriers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers

Borghesani¹,

Johnson²,

Shelton³

et al. 2008

Neurobiology of Aging

View full text Add to dashboard Cite

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“…However, there have been as yet no data suggesting a direct genetic link between miRNAs or miRNA recognition elements and neurodegenerative disease. Together, these observations may indicate that neurodegenerative diseases like AD, which takes place over multiple decades rather than just years (Scarmeas et al, 2005), tend to reflect a "downward spiral" effect of multiple processes, and miRNAs may play a contributory role. (A, B) and protein (C, D) levels, decreased miR-107 levels correlate with increased BACE1 levels in AD pathological progression.…”

Section: Non-demented-case1mentioning

confidence: 99%

The Expression of MicroRNA miR-107 Decreases Early in Alzheimer's Disease and May Accelerate Disease Progression through Regulation of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1

Wang¹,

Rajeev²,

Stromberg³

et al. 2008

J. Neurosci.

751

605

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MicroRNAs (miRNAs) are small regulatory RNAs that participate in posttranscriptional gene regulation in a sequence-specific manner. However, little is understood about the role(s) of miRNAs in Alzheimer's disease (AD). We used miRNA expression microarrays on RNA extracted from human brain tissue from the University of Kentucky Alzheimer's Disease Center Brain Bank with near-optimal clinicopathological correlation. Cases were separated into four groups: elderly nondemented with negligible AD-type pathology, nondemented with incipient AD pathology, mild cognitive impairment (MCI) with moderate AD pathology, and AD. Among the AD-related miRNA expression changes, miR-107 was exceptional because miR-107 levels decreased significantly even in patients with the earliest stages of pathology. In situ hybridization with cross-comparison to neuropathology demonstrated that particular cerebral cortical laminas involved by AD pathology exhibit diminished neuronal miR-107 expression. Computational analysis predicted that the 3Ј-untranslated region (UTR) of ␤-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA is targeted multiply by miR-107. From the same RNA material analyzed on miRNA microarrays, mRNA expression profiling was performed using Affymetrix Exon Array microarrays on nondemented, MCI, and AD patients. BACE1 mRNA levels tended to increase as miR-107 levels decreased in the progression of AD. Cell culture reporter assays performed with a subset of the predicted miR-107 binding sites indicate the presence of at least one physiological miR-107 miRNA recognition sequence in the 3Ј-UTR of BACE1 mRNA. Together, the coordinated application of miRNA profiling, Affymetrix microarrays, new bioinformatics predictions, in situ hybridization, and biochemical validation indicate that miR-107 may be involved in accelerated disease progression through regulation of BACE1.

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“…Thus far, reports of structural and functional effects of the APOE 4 allele in young adults are limited (17)(18)(19)(20). Only 2 small fMRI studies have tested for early life associations of the APOE polymorphism with changes in brain function.…”

mentioning

confidence: 99%

Distinct patterns of brain activity in young carriers of the APOE -ε4 allele

Filippini

MacIntosh

Hough

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

1,519

1,180

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The APOE 4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE 4-carriers and 18 matched noncarriers (age range: 20 -35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased ''default mode network'' (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in 4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in 4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE 4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.hippocampus ͉ memory ͉ neuroimaging ͉ resting connectivity A polipoprotein E (apoE, protein; APOE, gene) is a very-lowdensity lipoprotein that removes cholesterol from the blood and carries it to the liver for processing (1). In the central nervous system, apoE has a key role in coordinating the mobilization and redistribution of cholesterol, phospholipids, and fatty acids, and it is implicated in mechanisms such as neuronal development, brain plasticity, and repair functions (2). The human APOE gene, which is encoded on chromosome 19, has 3 allelic variants ( 2, 3, and 4). The 4 allele has been associated with a higher risk of cardiovascular disease (3), both early-onset (4) and late-onset (5) Alzheimer's disease (AD), poor outcome from traumatic brain injury (6), and age-related cognitive impairment (7).Neuroimaging studies of the APOE polymorphism in healthy subjects have largely focused on gray matter (GM) alterations in middle or late life, particularly in brain regions associated with the greatest AD pathological findings. Even in asymptomatic subjects, hippocampal and frontotemporal GM reduction has been observed in APOE 4-carriers relative to noncarriers (8). Moreover, a reduction of resting glucose metabolism was reported in young and middle-aged cognitively normal APOE 4-carriers in brain regions known to be affected by AD, including the posterior cingulate, parietal, temporal, and prefrontal cortices (9-11). fMRI task-based studies (mainly investigating memory processes) have shown greater activation in middle-aged and elderly APOE 4-carriers relative to noncarriers (12-16). Although these studies suggest an influence of the APOE 4 allele on brain structure and metabolism, they do not make clear at what age these influences initially manifest. Furthermore, although differences in structure, resting metabolism, and function have each been reported in 4-carriers relative to noncarriers, it remains to be established to what extent these characteristics interact.Thus far, reports of structural and functional eff...

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APOE related alterations in cerebral activation even at college age

Cited by 89 publications

References 34 publications

Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers

Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers

The Expression of MicroRNA miR-107 Decreases Early in Alzheimer's Disease and May Accelerate Disease Progression through Regulation of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1

Distinct patterns of brain activity in young carriers of the APOE -ε4 allele

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