Resting state brain signal complexity of young healthy adults reflects genetic risk for developing Alzheimer’s Disease

AbstractThe e4 allele of the APOE gene is strongly associated with impaired brain functionality and cognitive decline in humans at older age. It is controversial whether and how the APOE e4 allele is affecting brain activity among young healthy individuals and how such effects may contribute to individual differences in cognitive performance. Signal complexity is a critical aspect of brain activity that has been shown to be associated with brain function. In this study, we analyzed multiscale entropy (MSE) of EEG signals among young healthy adults as an indicator of brain signal complexity and investigated how MSE is predicted by APOE genotype groups. Furthermore, by means of structural equation modeling, we investigated whether MSE predicts fluid intelligence. Results indicate larger MSE in young healthy e4 carriers across all time scales. Moreover, better fluid intelligence (gf) is associated with smaller MSE at low time scales and larger MSE at higher scales. However, MSE does not account for better cognitive performance among APOE e4 carriers by mediating the APOE genotype effect on fluid intelligence. The present results shed further light on the neural mechanisms underlying gene-behavior association relevant for Alzheimer’s Disease risk.

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Association between polygenic risk for Alzheimer’s disease, brain structure and cognitive abilities in UK Biobank.

10.31234/osf.io/cr69u ◽

2021 ◽

Author(s):

Rachana Tank ◽

Joey Ward ◽

Kristin E. Flegal ◽

Daniel Smith ◽

Mark E.S. Bailey ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fluid Intelligence ◽

Late Onset ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Healthy Adults ◽

Uk Biobank ◽

Polygenic Risk ◽

Structural Brain

Background and purpose: Previous studies testing associations between polygenic risk for late-onset Alzheimer’s disease (LOAD-PGR) and brain magnetic resonance imaging (MRI) measures have been limited by small samples and inconsistent consideration of potential confounders. This study investigates whether higher LOAD-PGR is associated with differences in structural brain imaging and cognitive values in a relatively large sample of non-demented, generally healthy adults (UK Biobank). Method: Summary statistics were used to create PGR scores for n=32,790 participants using LDpred. Outcomes included 12 structural MRI volumes and 6 concurrent cognitive measures. Models were adjusted for age, sex, body mass index, genotyping chip, 8 principal components, lifetime smoking, apolipoprotein (APOE) e4 genotype and socioeconomic deprivation. We tested for statistical interactions between APOE e4 allele dose and LOAD-PGR vs. all outcomes. Results: In fully adjusted models, LOAD-PGR was associated with worse fluid intelligence (standardised beta [β] = -0.080 per LOAD-PGR standard deviation, p = 0.002), matrix completion (β = -0.102, p = 0.003), smaller left hippocampal total (β = -0.118, p = 0.002) and body (β = -0.069, p = 0.002) volumes, but not other hippocampal subdivisions. There were no significant APOE x LOAD-PGR score interactions for any outcomes in fully adjusted models. Discussion: This is the largest study to date investigating LOAD-PGR and non-demented structural brain MRI and cognition phenotypes. LOAD-PGR was associated with smaller hippocampal volumes and aspects of cognitive ability in healthy adults, and could supplement APOE status in risk stratification of cognitive impairment/LOAD.

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Inflammation in Alzheimer’s Disease: Do Sex and APOE Matter?

Journal of Alzheimer s Disease ◽

10.3233/jad-200982 ◽

2020 ◽

Vol 78 (2) ◽

pp. 627-641 ◽

Cited By ~ 1

Author(s):

Paula Duarte-Guterman ◽

Arianne Y. Albert ◽

Amy M. Inkster ◽

Cindy K. Barha ◽

Liisa A.M. Galea ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Differences ◽

Age Groups ◽

Apoe Genotype ◽

Physiological Changes ◽

Opposite Pattern ◽

Cognitively Normal ◽

E4 Allele ◽

Tissue Origin

Background: Alzheimer’s disease (AD) disproportionately affects females with steeper cognitive decline and more neuropathology compared to males, which is exacerbated in females carrying the APOE ɛ4 allele. The risk of developing AD is also higher in female APOE ɛ4 carriers in earlier age groups (aged 65–75), and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be influenced by sex. Inflammation is observed in AD and is related to aging, stress, and neuroplasticity, and although studies are scarce, sex differences are noted in inflammation. Objective: The objective of this study was to investigate underlying physiological inflammatory mechanisms that may help explain why there are sex differences in AD and APOE ɛ4 carriers. Methods: We investigated, using the ADNI database, the effect of sex and APOE genotype (non-carriers or carriers of 1 and 2 APOE ɛ4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on CSF (N = 279) and plasma (N = 527) markers of stress and inflammation. Results: We found CSF IL-16 and IL-8 levels differed by sex and APOE genotype, as IL-16 was higher in female APOE ɛ4 carriers compared to non-carriers, while the opposite pattern was observed in males with IL-8. Furthermore, females had on average higher levels of plasma CRP and ICAM1 but lower levels of CSF ICAM1, IL-8, IL-16, and IgA than males. Carrying APOE ɛ4 alleles and diagnosis (MCI and AD) decreased plasma CRP in both sexes. Conclusion: Sex and APOE genotype differences in CSF and plasma inflammatory biomarkers support that the underlying physiological changes during aging differ by sex and tissue origin.

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ACE I/D polymorphism in Alzheimer’s disease

Open Life Sciences ◽

10.2478/s11535-007-0051-9 ◽

2008 ◽

Vol 3 (1) ◽

pp. 49-54

Author(s):

Marianna Trebunova ◽

Eva Slaba ◽

Viera Habalova ◽

Zuzana Gdovinova

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Interaction Analysis ◽

Neurological Diseases ◽

Apoe Genotype ◽

Gene Interaction ◽

Genotype Distribution ◽

Ace Gene ◽

Increased Risk ◽

E4 Allele

AbstractAngiotensin-converting enzyme (ACE) has been reported to show altered activity in patients with neurological diseases. The recent studies found that a 287 bp insertion/deletion (I/D) polymorphism of the ACE gene may be associated with susceptibility to Alzheimer’s disease (AD) but the results have been heterogenous between studies in Europe. In the present study we examined for the first time the association of ACE I/D polymorphism along with APOE genotype in 70 sporadic AD and 126 control subjects in Slovak Caucasians (Central Europe). An increased risk for AD was observed in subjects with at least one APOE*E4 allele (OR=3.99, 95% CI=1.97–8.08). No significant differences for the genotype distribution or the allele frequency were revealed comparing controls and patients for ACE gene. Gene-gene interaction analysis showed increase of the risk to develop AD in subjects carrying both the ACE DD genotype and the APOE*E4 allele (OR=10.32, 95% C.I. 2.67–39.81).

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[P3-550]: INTERACTION BETWEEN AGE AND APOE GENOTYPE ON THE COGNITIVE PERFORMANCE OF HEALTHY INDIVIDUALS AT RISK FOR ALZHEIMER's DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1770 ◽

2017 ◽

Vol 13 (7S_Part_24) ◽

pp. P1189-P1189

Author(s):

Marta Crous-Bou ◽

Gonzalo Sánchez-Benavides ◽

Raffaele Cacciaglia ◽

Nina Gramunt ◽

Carolina Minguillon ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

At Risk ◽

Cognitive Performance ◽

Apoe Genotype ◽

Healthy Individuals

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Segmented Linear Mixed Model Analysis Reveals Association of the APOE ɛ4 Allele with Faster Rate of Alzheimer’s Disease Dementia Progression

Journal of Alzheimer s Disease ◽

10.3233/jad-210434 ◽

2021 ◽

pp. 1-17

Author(s):

X. Richard Chen ◽

Yongzhao Shao ◽

Martin J. Sadowski ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mixed Model ◽

Linear Mixed Model ◽

Late Onset ◽

Apoe Genotype ◽

Middle Temporal Gyrus ◽

Mixed Model Analysis ◽

Increased Risk ◽

E4 Allele

Background: APOE ɛ4 allele carriers present with increased risk for late-onset Alzheimer’s disease (AD), show cognitive symptoms at earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the ɛ4 allele controls the rate of disease progression. Objective: To determine effects of the ɛ4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD. Methods: A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of 73 ɛ3/ɛ3, 99 ɛ3/ɛ4, and 39 ɛ4/ɛ4 Alzheimer’s Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia. Results: ɛ4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant ɛ4 allele-dose effects after dementia transition but not during MCI. The ɛ4 effect was more prevalent in younger participants and in females. ɛ4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI. Conclusion: Possession of the ɛ4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design.

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The Association of Essential Metals with APOE Genotype in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210158 ◽

2021 ◽

pp. 1-12

Author(s):

Mirjana Babić Leko ◽

Jasna Jurasović ◽

Matea Nikolac Perković ◽

Ena Španić ◽

Ankica Sekovanić ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Plasma Levels ◽

Late Onset ◽

Apoe Genotype ◽

Plasma Sodium ◽

Essential Metals ◽

E4 Allele

Background: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. Objective: To test the association of essential metals with APOE genotype. Methods: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype. Results: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. Conclusion: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

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Association between polygenic risk for Alzheimer’s disease, brain structure and cognitive abilities in UK Biobank

Neuropsychopharmacology ◽

10.1038/s41386-021-01190-4 ◽

2021 ◽

Author(s):

Rachana Tank ◽

Joey Ward ◽

Kristin E. Flegal ◽

Daniel J. Smith ◽

Mark E. S. Bailey ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fluid Intelligence ◽

Late Onset ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Healthy Adults ◽

Uk Biobank ◽

Polygenic Risk ◽

Structural Brain

AbstractPrevious studies testing associations between polygenic risk for late-onset Alzheimer’s disease (LOAD-PGR) and brain magnetic resonance imaging (MRI) measures have been limited by small samples and inconsistent consideration of potential confounders. This study investigates whether higher LOAD-PGR is associated with differences in structural brain imaging and cognitive values in a relatively large sample of non-demented, generally healthy adults (UK Biobank). Summary statistics were used to create PGR scores for n = 32,790 participants using LDpred. Outcomes included 12 structural MRI volumes and 6 concurrent cognitive measures. Models were adjusted for age, sex, body mass index, genotyping chip, 8 genetic principal components, lifetime smoking, apolipoprotein (APOE) e4 genotype and socioeconomic deprivation. We tested for statistical interactions between APOE e4 allele dose and LOAD-PGR vs. all outcomes. In fully adjusted models, LOAD-PGR was associated with worse fluid intelligence (standardised beta [β] = −0.080 per LOAD-PGR standard deviation, p = 0.002), matrix completion (β = −0.102, p = 0.003), smaller left hippocampal total (β = −0.118, p = 0.002) and body (β = −0.069, p = 0.002) volumes, but not other hippocampal subdivisions. There were no significant APOE x LOAD-PGR score interactions for any outcomes in fully adjusted models. This is the largest study to date investigating LOAD-PGR and non-demented structural brain MRI and cognition phenotypes. LOAD-PGR was associated with smaller hippocampal volumes and aspects of cognitive ability in healthy adults and could supplement APOE status in risk stratification of cognitive impairment/LOAD.

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Total Cholesterol and APOE-Related Risk for Alzheimer’s Disease in the Alzheimer’s Disease Neuroimaging Initiative

Journal of Alzheimer s Disease ◽

10.3233/jad-215091 ◽

2021 ◽

pp. 1-10

Author(s):

Michelle M. Dunk ◽

Ira Driscoll ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Total Cholesterol ◽

Cholesterol Metabolism ◽

Apoe Genotype ◽

Control Group ◽

Cholesterol Levels ◽

Related Risk ◽

E4 Allele

Background: APOE ɛ4 allele confers greatest genetic risk for Alzheimer’s disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE, and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk. Objective: To investigate the relationship between total cholesterol and APOE-related AD risk in the Alzheimer’s Disease Neuroimaging Initiative. Methods: Participants (N = 1,534) were classified as controls (cognitively normal; N = 404), early mild cognitive impairment (MCI; N = 294), late MCI (N = 539), or AD (N = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument. Results: Total cholesterol was higher in APOE4+ compared to APOE3 and APOE2+ (ps < 0.04) carriers. Those with AD and late MCI (ps < 0.001) had higher total cholesterol than the control group. Comparing APOE4+ to APOE3 carriers, the predicted odds ratios per mg/dL greater total cholesterol were 1.11 for MCI (95% confidence interval, 1.04–7.32), 1.05 for early MCI (1.01–3.22), 1.13 for late MCI (1.05–11.70), 1.21 for AD (1.09–54.05), and 1.13 for composite dementia (MCI or AD; 1.06–11.59) (ps < 0.05, F-statistics>10). Conclusion: Higher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels.

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APOE ɛ4-TOMM40L Haplotype Increases the Risk of Mild Cognitive Impairment Conversion to Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-200556 ◽

2020 ◽

Vol 78 (2) ◽

pp. 587-601

Author(s):

Remy Cardoso ◽

Carolina Lemos ◽

Bárbara Oliveiros ◽

Maria Rosário Almeida ◽

Inês Baldeiras ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Apoe Genotype ◽

Csf Biomarkers ◽

Cognitively Normal ◽

Conversion Time ◽

E4 Allele ◽

Normal Controls

Background: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer’s disease (AD) conversion remain controversial. Objective: Evaluate whether TOMM40 poly-T (TOMM40′ 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype. Methods: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group of those that remained stable (MCI-S). Results: TOMM40′ 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p < 0.001, 95% CI: 2.830 to 24.617). However, when adjusted for the presence of APOE ɛ4 allele, both the L allele and ɛ4 allele lost significance in the model (p > 0.05). We then analyzed the APOE ɛ4-TOMM40′ 523 L haplotype and observed that patients carrying this haplotype had significantly higher risk (OR = 5.83; 95% CI = 2.30–14.83) and mean lower times of conversion to AD (p = 0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p = 0.007). Conclusion: This study shows that the APOE ɛ4-TOMM40′ 523 L haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction.

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Associations of APOE e2 genotype with cerebrovascular pathology: a postmortem study of 1275 brains

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-323746 ◽

2020 ◽

Vol 92 (1) ◽

pp. 7-11 ◽

Cited By ~ 1

Author(s):

Terry E Goldberg ◽

Edward D Huey ◽

Davangere P Devanand

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Variant ◽

Apoe Genotype ◽

Amyloid Plaques ◽

Amyloid Angiopathy ◽

Protective Effects ◽

Comprehensive Investigation ◽

Increased Risk ◽

E4 Allele

ObjectiveWe assessed the association of apolipoprotein E (APOE) genotype with cerebrovascular disease (CVD) in a large neuropathological database maintained by the National Alzheimer’s Coordinating Center (NACC). Such a comprehensive investigation of APOE and CVD pathology has not heretofore been conducted. We focused on APOE e2, an established neuroprotective genetic variant against Alzheimer’s disease.MethodsTo implement these objectives APOE associations in the NACC database of 1275 brains with 11 CVD pathologies, including old and recent infarcts, haemorrhages, cerebral amyloid angiopathy (CAA) and arteriosclerosis, were examined. These pathologies were uniformly and semiquantitatively measured across 39 Alzheimer’s Disease Center sites. We used χ2 statistics and ordinal regression to assess the significance of associations and Bonferroni corrected for multiple comparisons.ResultsOf the cases, 98 were e2/e3 or e2/e2 genotypes (‘e2’ carriers), 621 were e3 homozygotes (‘e3’ group), and 556 were e4/e3 (442) or e4/e4 (114) genotypes (‘e4’ group). Results indicated that the APOE e4 allele significantly increased risk for CAA. After stratification by CAA presence/absence, we found that in those cases in which CAA was present, APOE e2 significantly increased risk for gross haemorrhage. All other associations were negative.ConclusionsIn this, the largest study of APOE e2 effects on pathologically verified CVD, e2 was not protective against any CVD pathology compared with e3 homozygotes, including CAA. Regarding the latter pathology, e4 was associated with increases in its severity. Furthermore, and perhaps unexpectedly, e2 significantly increased risk of acute/subacute gross haemorrhage in the presence of CAA. Thus, there were limits to e2 neuroprotection against amyloidosis, despite its known and large protective effects against diffuse and neuritic amyloid plaques compared with e3/e3 and e4 carriers in this very collection.

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