Increased density of senile plaques (SP), but not neurofibrillary tangles (NFT), in non-demented individuals with the apolipoprotein E4 allele: comparison to confirmed Alzheimer's disease patients

Sparks, D. Larry; Liu, Huaichen; Landers, Teresa M.; Danner, Fred; Coyne, Carolyn M.; Hunsaker, John C.

doi:10.1016/0022-510x(96)00008-1

Cited by 42 publications

(20 citation statements)

References 40 publications

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“…43 ⑀4 is associated with a greater ␤-amyloid deposition and neuritic plaque formation in demented and nondemented individuals. 44 In vitro and in vivo data suggest that ␤-amyloid has a vasoconstrictive effect on the cerebral microcirculation. 45,46 This could increase BP levels and exacerbate the insult to the brain created by high SBP.…”

Section: Discussionmentioning

confidence: 99%

Joint Effect of the APOE Gene and Midlife Systolic Blood Pressure on Late-Life Cognitive Impairment

Peila

White²,

Petrovich³

et al. 2001

Stroke

116

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Background and Purpose-The aim of this study was to explore the joint effect of the APOE ⑀4 allele and midlife systolic blood pressure (SBP) on the risk for poor cognitive function in late life. Methods-The study includes 3605 surviving members of the cohort of the Japanese-American men followed prospectively over 26 years (CASI Ͻ74) compared with good cognitive function (CASI Ն82) in never-treated subjects was 1.3 (95% CI 0.9 to 1.9) for the normal SBP/⑀4 category, 2.6 (0.7 to 10.0) for the high SBP/no ⑀4, and 13.0 (1.9 to 83.8) for the high SBP/⑀4. Adjustment for diabetes, prevalent stroke, coronary disease, and ankle-brachial index reduced the RR of poor cognition by 25.5% (RR 13.0 to 10.8) in those with both risk factors. In the treated group, the RR was 1.9 (0.7 to 4.5) for those with both risk factors. Conclusions-The results suggest that midlife high SBP has a stronger adverse effect on cognitive function in persons with higher genetic susceptibility, but this effect may be modified by antihypertensive treatment.

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Section: Discussionmentioning

confidence: 99%

Joint Effect of the APOE Gene and Midlife Systolic Blood Pressure on Late-Life Cognitive Impairment

Peila

White²,

Petrovich³

et al. 2001

Stroke

116

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“…Over the past several years, possession of one or more APOE e4 alleles has emerged as the most important genetic susceptibility factors for AD among older people. Despite intensive investigation, the neurobiological changes responsible for the association of allele status with the occurrence of clinical disease remains controversial, with some data suggesting that its effect is mediated by an increase in the rate of accumulation of AD pathology, [5][6][7] whereas other data suggest that it may be related to other less specific mechanisms such as neural repair or survival. 8 9 33 34 We 21 and others [5][6][7] have reported that allele status is related to AD pathology as identified with routine histopathology.…”

Section: Discussionmentioning

confidence: 99%

“…Despite intensive investigation, the neurobiological changes responsible for the association of allele status with the occurrence of clinical disease remains controversial, with some data suggesting that its effect is mediated by an increase in the rate of accumulation of AD pathology, [5][6][7] whereas other data suggest that it may be related to other less specific mechanisms such as neural repair or survival. 8 9 33 34 We 21 and others [5][6][7] have reported that allele status is related to AD pathology as identified with routine histopathology. Further, several studies have found a relation between the e4 allele and amyloid deposition [10][11][12][13] or both amyloid and tau positive tangles.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4] The neurobiological changes in the brain that account for the association of allele status with disease risk remain poorly understood. Some clinicopathological studies report an association between the e4 allele and neuritic plaques and neurofibrillary tangles, [5][6][7] although other studies did not find this association. 8 9 Several studies also report a relationship between the e4 allele and amyloid deposition, [10][11][12][13][14][15][16] raising the possibility that amyloid deposition accounts for the association of allele status with cognitive function.…”

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confidence: 91%

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Thrombus in transit through a patent foramen ovale: paradoxical embolism

Raaphorst

Wouda²

2005

Journal of Neurology, Neurosurgery & Psychiatry

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Background: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. Objective: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. Methods: There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. Results: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load. Conclusion: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.

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“…However, its association with Alzheimer and vascular neuropathology is controversial. Autopsy-based studies have demonstrated significant correlations between the 4 allele and the density of NPs [37][38][39], NFT [38,[40][41][42] and amyloid deposition [40][41][42][43][44][45], but some studies did not find an association with plaques [46][47][48] or NFT [37,43,46,48,49] Two studies [50,51] reported that the frequency of cerebrovascular lesions was not increased in APOE-4, whereas another group [52] reported that APOE-4 significantly increased the odds of both cortical and subcortical infarctions.…”

Section: Risk Factors For Pathologymentioning

confidence: 99%

The Nun Study: Risk Factors for Pathology and Clinical-Pathologic Correlations

Mortimer

2012

CAR

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The Nun Study was the first cohort study to enroll and follow a large, well-defined population that included demented and non-demented participants, all of whom agreed to donate their brains for research. The inclusion of systematic neuropathologic analysis in this study has resulted in a greater understanding of the role of Alzheimer and vascular pathology in the expression of memory deficits and dementia and has provided data showing that biomarkers for the pathology may be evident many decades earlier in adult life. Findings related to neuropathology in this study have included the following: (1) Although clinical outcomes were strongly correlated with Alzheimer neuropathology, about one-third of the participants fulfilling criteria for neuropathologic Alzheimer's disease (AD) were not demented at the time of death. (2) Brain infarcts by themselves had little effect on cognitive status, but played an important role in increasing the risk of dementia associated with Alzheimer pathology. (3) Hippocampal volume was strongly correlated with Braak neurofibrillary stage even in participants with normal cognitive function. (4) A linguistic characteristic of essays written in early adult life, idea density, had a strong association with not only clinical outcomes in late life, but the severity of Alzheimer neuropathology as well. (5) The effect of apolipoprotein E-e4 on dementia was mediated through Alzheimer, but not vascular pathology.

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Increased density of senile plaques (SP), but not neurofibrillary tangles (NFT), in non-demented individuals with the apolipoprotein E4 allele: comparison to confirmed Alzheimer's disease patients

Cited by 42 publications

References 40 publications

Joint Effect of the APOE Gene and Midlife Systolic Blood Pressure on Late-Life Cognitive Impairment

Joint Effect of the APOE Gene and Midlife Systolic Blood Pressure on Late-Life Cognitive Impairment

Thrombus in transit through a patent foramen ovale: paradoxical embolism

The Nun Study: Risk Factors for Pathology and Clinical-Pathologic Correlations

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