Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation

doi:10.1016/0306-4522(94)00596-W

Neuroscience

Volume 66, Issue 3, June 1995, Pages 583-587

https://doi.org/10.1016/0306-4522(94)00596-W Get rights and content

Abstract

Only recently, evidence was provided that apolipoprotein E allele ε4 located on Chromosome 19 is associated with late onset (i.e. senile) sporadic Alzheimer's disease. Histologically, Alzheimer's disease is associated with intraneuronal neurofibrillary changes and extraneuronal A4/β-amyloid deposition. We set out with a histological staging system which considers the gradual development of Alzheimer's disease-related histological changes over time and correlates highly with the cognitive decline ante mortem. Our analysis revealed that both the mean stage for A4/β-amyloid deposits and the mean stage for neurofibrillary tangles get significantly shifted upwards in ε4-carriers. This represents an earlier onset of the histopathological process of about one decade.

The fact that both types of Alzheimer's disease-related changes correlate positively with the prevalence of the ε4-allele suggests for a causal relationship between the apolipoprotein E polymorphism and the development of Alzheimer's disease.

Reference (21)

BraakH. et al.
Alzheimer's disease: mismatch between amyloid plaques and neuritic plaques
Neurosci. Lett.
(1989)
EmiM. et al.
Genotyping and sequence analysis of apolipoprotein E isoforms
Genomics
(1988)
HixsonJ.E. et al.
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hhal
J. Lipid Res.
(1990)
LannfeltL. et al.
Lack of association between apolipoprotein E allele ε4 and sporadic Alzheimer's disease
Neurosci. Lett.
(1994)
PoirierJ. et al.
Apolipoprotein E polymorphism and Alzheimer's disease
Lancet
(1993)
ArriagadaP.V. et al.
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Neurology
(1992)
BraakH. et al.
Neuropathological stageing of Alzheimer-related changes
Acta Neuropath.
(1991)
BraakH. et al.
CampbellS. et al.
Alzheimer's plaques and tangles: a controlled and enhanced silver staining method
Soc. Neurosci. Abstr.
(1989)
CorderE.H. et al.
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
Science
(1993)

There are more references available in the full text version of this article.

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In the case of this study where Stroop effect on error increased after the exercise intervention for APOE ε4 carriers, we speculate that perhaps neuronal injury in the prefrontal brain region may already be present as a result of possible amyloid-beta (Aβ)- or tau protein accumulation, which is associated with the increased risk of being an ε4 allele carrier. In other words, since neurofibrillary tangles (NFTs) and Aβ plaques are known to accumulate years before symptoms of cognitive decline emerge (Dubois et al., 2016; Jack et al., 2013) and ε4 allele carriers are at a higher risk for this type of neuropathology (Ohm et al., 1995), it is possible that these injuries may further limit benefits from exercise to the prefrontal cortex, a brain region central to response inhibition (Blasi et al., 2006). It should be noted though, that this is a hypothesis which is not currently explored by the literature, and further investigation into this possible mechanism would be of benefit to the field.
Previous research has shown beneficial cognitive changes following exercise training in older adults. However, the work on the potential moderating effects of Apoliprotein E (APOE) ε4 carrier status has been mixed, and the role of exercise intensity remains largely unexplored. The present study sought to examine the influence of APOE ε4 status and exercise intensity on measures of cognitive performance in a group of older adults. Cross-sectional comparisons between a group of younger inactive adults (n = 44, age = 28.86 ± 0.473 SD, 60.5% female) and a group of older inactive adults (n = 142, age = 67.8 ± 5.4, 62.7% female) were made on baseline measurements of APOE ε4 status, VO₂peak, and cognitive performance in the domain of executive functioning. The older adults also participated in a randomized controlled exercise trial, exercising three times per week for 16-weeks in either a low-intensity continuous training (LICT) group or a moderate-intensity continuous training plus interval training (MICT+IT) group at the Center for Health and Neuroscience, Genes, and Environment (CUChange) Exercise Laboratory. Follow-up measurements of VO₂peak and cognitive performance were collected on the older adults after the exercise intervention. Cross-sectional comparisons between the older and younger adults demonstrated significant impairments among older adults in Stroop effect on error and time, Category Switch mixing effects, and Keep Track task. This impairment was not moderated by APOE ε4 carrier status. Improvements from pre- to post-exercise intervention were observed in both exercise groups in Stroop effect on error ([F (1, 256) = 9.381, p < 0.01, η² = 0.031]) and Category Switch switching effect reaction time ([F(1, 274) = 4.442, p < 0.05, η² = 0.020]), with no difference between exercise groups. The moderating effects of APOE ε4 carrier status were mixed. Exercise did not improve the Stroop effect on error among ε4 carriers assigned to MICT+IT when improvements were seen in all other groups. Further research is needed to examine the mechanisms of action by which exercise impacts cognitive task performance, and possible moderators such as genetic variability and exercise intensity.
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CNS inflammation is a key factor in Alzheimer’s Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults.
Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [¹⁸F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [¹⁸F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions.
Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF–Aβ/tau relationships.
Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate.
Apolipoprotein E and Alzheimer's disease: The influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins
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Citation Excerpt :
The strong correlation between APOE genotypes and AD, and the presence of immunoreactive apoE in neurons containing neurofibrillary tangles (27, 28) led to numerous clinical and epidemiological studies on the potential interaction between APOE and Tau, both in the context of AD as well as other tauopathies, including FTD. The majority of clinical studies found an over-representation of the APOE-ε4 allele in both AD and FTD (161–164), while histopathologic examinations revealed a significant positive correlation between APOE genotype and stage of neurofibrillary pathology (165) according to Braak staging (166). In support of these findings, the presence of the APOE-ε4 allele significantly correlates with brain atrophy in disease-specific brain regions in both AD and FTD (154).
Alzheimer's disease (AD) is one of the fastest-growing causes of death and disability in persons 65 years of age or older, affecting more than 5 million Americans alone. Clinical manifestations of AD include progressive decline in memory, executive function, language, and other cognitive domains. Research efforts within the last three decades have identified APOE as the most significant genetic risk factor for late-onset AD, which accounts for >99% of cases. The apoE protein is hypothesized to affect AD pathogenesis through a variety of mechanisms, from its effects on the blood-brain barrier, the innate immune system, and synaptic function to the accumulation of amyloid-β (Aβ). Here, we discuss the role of apoE on the biophysical properties and metabolism of the Aβ peptide, the principal component of amyloid plaques and cerebral amyloid angiopathy (CAA). CAA is characterized by the deposition of amyloid proteins (including Aβ) in the leptomeningeal medium and small arteries, which is found in most AD cases but sometimes occurs as an independent entity. Accumulation of these pathologies in the brain is one of the pathological hallmarks of AD. Beyond Aβ, we will extend the discussion to the potential role of apoE on other amyloidogenic proteins found in AD, and also a number of diverse neurodegenerative diseases.
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2017, Neuroprotection in Alzheimer's Disease
Alzheimer’s disease (AD) is the most common type of dementia. The pathological characterizations of AD are the depositions of a peptide called amyloid beta and of hyper phosphorylated tau protein, gliosis, and neuronal death. While less than 5% of AD cases are caused by genetic mutations, these mutations are the basis for the majority of the animal models of AD. Although not presenting the entire spectrum of AD symptoms, these animal models extend and deepen our understanding on the pathological processes in AD and the possible therapeutic interventions. Nevertheless, many of these therapeutic applications fail later in clinical trials. Understanding the advantages and limitations of AD animal models is crucial for future therapeutic interventions.
Association of APOE with tau-tangle pathology with and without β-amyloid
2016, Neurobiology of Aging
This study tested the hypothesis that the association of apolipoprotein E (APOE) with paired helical filament tau (PHF-tau) tangle pathology differs in brains with and without β-amyloid. Participants were 1056 autopsied individuals from 2 clinical-pathologic cohort studies of aging and Alzheimer's disease (AD), the Religious Orders Study, and the Rush Memory and Aging Project. Neuropathologic measures were obtained using immunohistochemistry targeting β-amyloid and PHF-tau tangles in 8 brain regions. Linear regression was used to compare the relation of APOE ε4 and ε2 to PHF-tau-tangle density in persons with β-amyloid relative to persons without β-amyloid. We found an interaction between APOE ε4 carriers and presence of β-amyloid (β = −0.968, p = 0.013) such that the association of APOE ε4 with PHF-tau tangles was much stronger in brains with β-amyloid. Stratified analysis shows that the association of APOE ε4 with PHF-tau tangles was considerably stronger among those with β-amyloid (β = 0.757, p = 1.1 × 10⁻¹⁵) compared to those without β-amyloid which was not significant (β = −0.201, p = 0.424). Separately, APOE ε2 was associated with fewer tangles in brains with β-amyloid (β = −0.425, p = 7.6 × 10⁻⁴) compared to those without β-amyloid which was not significant (β = −0.102, p = 0.506). Thus, the presence of APOE ε4 and ε2 alleles was not associated with PHF-tau tangles in the absence of β-amyloid. The data provide additional evidence that PHF-tau tangles in the absence of β-amyloid may reflect a pathologic process distinct from Alzheimer's disease.
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Citation Excerpt :
A variety of ad hoc objective approaches have been presented to define an amyloid-positive cutoff using amyloid imaging. These methods include using one or two standard deviations above the mean of the control data (Edison et al., 2008; Kemppainen et al., 2007; Klunk et al., 2004 Okello et al., 2009); inspection of quantitative PET data for natural breakpoints in the distribution of tracer retention in combinations of young controls, elderly controls and/or AD patients (Edison et al., 2008; Gomperts et al., 2008; Hedden et al., 2009; Jack et al., 2008; Maetzler et al., 2009; Mintun et al., 2006; Mormino et al., 2011; Morris et al., 2010; Rowe et al., 2007; Roe et al., 2008); the low end of the range of tracer retention in clinically (Sperling et al.,2009) or pathologically (Fleisher et al., 2011) defined AD patients; receiver operating characteristic (ROC) analyses of PET data from control and AD subjects (Devanand et al., 2007; Mormino et al., 2009; Ng et al., 2007; Pike et al., 2007); visual reads (Engler et al., 2007; Gomperts et al., 2008; Johnson et al., 2007; Ng et al., 2007; Rabinovici et al., 2007; Suotunen et al., 2010; Tolboom et al., 2009); and cluster analysis methods using both PiB(+) and PiB(−) elderly control subjects (Bourgeat et al., 2010). Each approach has advantages and shortcomings.
The development of Aβ-PET imaging agents has allowed for detection of fibrillar Aβ deposition in vivo and marks a major advancement in understanding the role of Aβ in Alzheimer’s disease (AD). Imaging Aβ thus has many potential clinical benefits: early or perhaps preclinical detection of disease and accurately distinguishing AD from dementias of other non-Aβ causes in patients presenting with mild or atypical symptoms or confounding comorbidities (in which the distinction is difficult to make clinically). From a research perspective, imaging Aβ allows us to study relationships between amyloid pathology and changes in cognition, brain structure, and function across the continuum from normal aging to mild cognitive impairment (MCI) to AD; and to monitor the effectiveness of anti-Aβ drugs and relate them to neurodegeneration and clinical symptoms. Here, we will discuss the application of one of the most broadly studied and widely used Aβ imaging agents, Pittsburgh Compound-B (PiB).

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Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation

Abstract

Neurosci. Lett.

Genomics

J. Lipid Res.

Neurosci. Lett.

Lancet

Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease

Neurology

Neuropathological stageing of Alzheimer-related changes

Acta Neuropath.

Alzheimer's plaques and tangles: a controlled and enhanced silver staining method

Soc. Neurosci. Abstr.

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

Science