Ε4 Genotype Research Articles

Onset of Preclinical Alzheimer Disease in Monozygotic Twins.

ObjectiveThe present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins.MethodsWe studied in 96 monozygotic twin‐pairs relationships between amyloid‐beta (Aβ) aggregation as measured by the Aβ1–42/1–40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aβ production (beta‐secretase 1, Aβ1–40, and Aβ1–38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes.ResultsTwenty‐seven individuals (14%) had an abnormal amyloid PET, and 14 twin‐pairs (15%) showed discordant amyloid PET scans. Within twin‐pairs, Aβ production markers and total‐tau (t‐tau) levels strongly correlated (r range = 0.73–0.86, all p < 0.0001), and Aβ aggregation markers and 181‐phosphorylated‐tau (p‐tau) levels correlated moderately strongly (r range = 0.50–0.64, all p < 0.0001). Cross‐twin cross‐trait analysis showed that Aβ1–38 in one twin correlated with Aβ1–42/1–40 ratios, and t‐tau and p‐tau levels in their cotwins (r range = −0.28 to 0.58, all p < .007). Within‐pair differences in Aβ production markers related to differences in tau levels (r range = 0.49–0.61, all p < 0.0001). Twin discordance analyses suggest that Aβ production and tau levels show coordinated increases in very early AD.InterpretationOur results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021;89:987–1000

Reversal of apolipoprotein E4-dependent or chemical-induced accumulation of APP degradation products by vitamin C-induced release of heparan sulfate from glypican-1

The Apolipoprotein E4 (ApoE4) genotype is the most influential risk factor for sporadic Alzheimer's disease. It appears to be associated with retarded endosome-to-autophagosome trafficking. The amyloid precursor protein (APP) and the heparan sulfate (HS)-containing proteoglycan glypican-1 (Gpc-1) are both processed in endosomes, and mutually regulated by the APP degradation products and the released HS. We have investigated APP and Gpc-1 processing in ApoE3 and ApoE4 expressing human fibroblasts, in human neural stem cells (NSC) exposed to the cholesterol transport inhibitor U18666A and in induced neurons obtained by reprogramming of ApoE fibroblasts (ApoE-iN). We have used immunofluorescence microscopy, flow cytometry, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis western blotting with antibodies recognizing the released HS, APP, amyloid β(Aβ), late endosomes (Rab7), autophagosomes (LC3) and neurons (Tuj1). We found that the capacity to release HS was not fully utilized in ApoE4 expressing fibroblasts and that HS-Aβ complexes accumulated in the nuclei. In ApoE3 fibroblasts, the β-cleaved APP C-terminal fragment (β-CTF) and Aβ were primarily present in late endosomes and autophagosomes. When HS release from Gpc-1 was enhanced by ascorbate in ApoE4/4 fibroblasts, there was efficient transfer of Aβ and HS from the nuclei to autophagosomes. In U18666A-treated NSC as well as in ApoE4/4-iN we repeatedly found accumulation of APP degradation products (β-CTF/Aβ). This was reversed by subsequent exposure to ascorbate or dehydroascorbic acid.

Impact of APOE \u03b54 genotype on initial cognitive symptoms differs for Alzheimer\u2019s and Lewy body neuropathology

BackgroundAPOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer’s pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ε4 genotype on initial cognitive symptoms among those with Alzheimer’s disease pathology (ADP) and Lewy-related pathology (LRP).MethodsA retrospective cohort study of 2288 participants with neuropathology confirmed ADP or LRP in the National Alzheimer’s Coordinating Center database, who had initial cognitive symptoms documented and had a Clinical Dementia Rating-Global (CDR-G) score ≤ 1 (cognitively normal, MCI, or early dementia). Unadjusted and adjusted logistic regression models taking into account age at evaluation, sex, and education examined the relationship between APOE ε4 genotype and initial symptoms (memory, executive, language visuospatial) among ADP with LRP and ADP-LRP groups.ResultsOne thousand three hundred three participants met criteria for ADP alone, 90 for LRP alone, and 895 for co-existing ADP and LRP (ADP-LRP). Younger age increased odds of non-amnestic symptoms across all three groups. In the adjusted model among ADP, APOE ε4 carriers had higher odds of amnestic initial symptoms 1.5 [95% CI, 1.7–2.14, p = 0.003] and lower odds of initial language symptoms 0.67 [95% CI, 0.47–0.96, p = 0.03] than non-carriers. The odds for these two symptoms were not different between ADP and mixed ADP-LRP groups. Female sex and higher education increased odds of initial language symptoms in the ADP group in the adjusted model. In the unadjusted model, APOE ε4 carriers with LRP had a higher odds of visuospatial initial symptoms 21.96 [95% CI, 4.02–110.62, p < 0.0001], while no difference was noted for initial executive/attention symptoms. Among LRP, the odds of APOE ε4 on amnestic symptom was not significant; however, the interaction effect evaluating the difference in odds ratios of amnestic symptom between ADP and LRP groups also did not reach statistical significance.ConclusionsThe odds of specific initial cognitive symptoms differed between ADP and LRP among APOE ε4 carriers compared to non-carriers. The odds of initial amnestic symptom was higher among ADP APOE ε4 carriers and the odds of visuospatial initial symptom was higher with LRP APOE ε4 carriers. This supports the hypothesis that APOE ε4 differentially impacts initial cognitive symptoms together with underlying neuropathology.

Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion.

Early appearance of neutralizing antibodies during acute hepatitis C virus (HCV) infection is associated with spontaneous viral clearance. However, the longitudinal changes in antigen-specific memory B cell (MBCs) associated with divergent HCV infection outcomes remain undefined. We characterized longitudinal changes in E2 glycoprotein-specific MBCs from subjects who either spontaneously resolved acute HCV infection or progressed to chronic infection, using single-cell RNA-seq and functional assays. HCV-specific antibodies in plasma from chronically infected subjects recognized multiple E2 genotypes, while those from spontaneous resolvers exhibited variable cross-reactivity to heterotypic E2. E2-specific MBCs from spontaneous resolvers peaked early after infection (4-6 months), following expansion of activated circulating T follicular helper cells (cTfh) expressing interleukin 21. In contrast, E2-specific MBCs from chronically infected subjects, enriched in VH1-69, expanded during persistent infection (> 1 year), in the absence of significantly activated cTfh expansion. Early E2-specific MBCs from spontaneous resolvers produced monoclonal antibodies (mAbs) with fewer somatic hypermutations and lower E2 binding but similar neutralization as mAbs from late E2-specific MBCs of chronically infected subjects. These findings indicate that early cTfh activity accelerates expansion of E2-specific MBCs during acute infection, which might contribute to spontaneous clearance of HCV.

Evaluation of APOE polymorphisms and the risk for age-related macular degeneration in a Southeastern Brazilian population.

This study aimed to evaluate the role of APOE polymorphisms (rs429358 and rs7412) in the risk of age-related macular degeneration in a sample of the Southeastern Brazilian population. Seven hundred and five unrelated individuals were analyzed, 334 with age-related macular degeneration (case group), and 371 without the disease (control group). In the case group, patients were further stratified according to disease phenotypes, divided into dry and wet age-related macular degeneration, and non-advanced and advanced age-related macular degeneration. APOE polymorphisms (rs429358 and rs7412) were evaluated through polymerase chain reaction and direct sequencing. In the comparison of cases vs. controls, none of the associations reached statistical significance, considering the Bonferroni-adjusted P-value, although there was a suggestive protection for the E3/E4 genotype (OR = 0.626; P-value = 0.037) and E4 carriers (OR = 0.6515; P-value = 0.047). Statistically significant protection for both the E3/E4 genotype and E4 carriers was observed in the comparisons: advanced age-related macular degeneration vs. controls (OR = 0.3665, P-value = 0.491 × 10-3 and OR = 0.4031, P-value = 0.814 × 10-3, respectively), advanced age-related macular degeneration vs. non-advanced age-related macular degeneration (OR = 0.2529, P-value = 0.659 × 10-4 and OR = 0.2692, P-value = 0.631 × 10-4, respectively). In the comparison of wet age-related macular degeneration vs. control, protection was statistically significant only for E3/E4 (OR = 0.4052, P-value = 0.001). None of the comparisons demonstrated any significant association for E2 genotypes or E2 carriers in age-related macular degeneration risk in this study. Findings suggest a protective role of the E4 haplotype in the APOE gene in the risk for advanced and wet forms of age-related macular degeneration, in a sample of the Brazilian population. To our knowledge, this is the first Brazilian study to show the association between APOE polymorphisms and age-related macular degeneration.

Semantic intrusion errors as a function of age, amyloid, and volumetric loss: a confirmatory path analysis.

To examine the direct and indirect effects of age, APOE ϵ4 genotype, amyloid positivity, and volumetric reductions in AD-prone brain regions as it relates to semantic intrusion errors reflecting proactive semantic interference (PSI) and the failure to recover from proactive semantic interference (frPSI) on the Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L), a cognitive stress test that has been consistently more predictive of preclinical and prodromal Alzheimer's disease (AD) than traditional list-learning tests. Cross-sectional study. 1Florida Alzheimer's Disease Research Center baseline study. Two-hundred and twelve participants with Mini-Mental State Examination (MMSE) score above 16 and a broad array of cognitive diagnoses ranging from cognitively normal (CN) to dementia, of whom 58% were female, mean age of 72.1 (SD 7.9). Participants underwent extensive clinical and neuropsychological evaluations, MR and amyloid Positron Emission Tomography/Computer/Computer Tomography (PET/CT) imaging, and analyses of APOE ϵ4 genotype. Confirmatory path analyses were conducted in the structural equation modeling framework that estimated multiple equations simultaneously while controlling for important covariates such as sex, education, language of evaluation, and global cognitive impairment. Both amyloid positivity and decreased brain volumes in AD-prone regions were directly related to LASSI-L Cued B1 and Cued B2 intrusions (sensitive to PSI and frPSI effects) even after controlling for covariates. APOE ϵ4 status did not evidence direct effects on these LASSI-L cognitive markers, but rather exerted their effects on amyloid positivity, which in turn related to PSI and frPSI. Similarly, age did not have a direct relationship with LASSI-L scores, but exerted its effects indirectly through amyloid positivity and volumes of AD-prone brain regions. Our study provides insight into the relationships among age, APOE ϵ4, amyloid, and brain volumetric reductions as it relates to semantic intrusion errors. The investigation expands our understanding of the underpinnings of PSI and frPSI intrusions in a large cohort.

Plasma antioxidants and risk of dementia in older adults.

IntroductionPlant‐based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained.MethodsWe measured antioxidants in a case‐cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer's disease (AD) during a median of 5.9 years of follow‐up. We measured baseline plasma levels of retinol, α‐, and γ‐tocopherol; zeaxanthin and lutein (combined); beta‐cryptoxanthin; cis‐lycopene; trans‐lycopene; α‐carotene; and trans‐β‐carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist‐adjudicated risks of all‐cause dementia and AD.ResultsPlasma retinol, α‐, and γ‐tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β‐carotene, or vitamin E supplements. Higher trans‐β‐carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans‐β‐carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α‐carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α‐carotene: 1.15; 95% CI: 1.02, 1.29).DiscussionPlasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.

GenoRisk: A polygenic risk score for Alzheimer's disease.

IntroductionRecent clinical trials are considering inclusion of more than just apolipoprotein E (APOE) ε4 genotype as a way of reducing variability in analysis of outcomes.MethodsCase‐control data were used to compare the capacity of age, sex, and 58 Alzheimer's disease (AD)–associated single nucleotide polymorphisms (SNPs) to predict AD status using several statistical models. Model performance was assessed with Brier scores and tenfold cross‐validation. Genotype and sex × age estimates from the best performing model were combined with age and intercept estimates from the general population to develop a personalized genetic risk score, termed age, and sex‐adjusted GenoRisk.ResultsThe elastic net model that included age, age x sex interaction, allelic APOE terms, and 29 additional SNPs performed the best. This model explained an additional 19% of the heritable risk compared to APOE genotype alone and achieved an area under the curve of 0.747.DiscussionGenoRisk could improve the risk assessment of individuals identified for prevention studies.

BIN1 rs744373 SNP and COVID-19 mortality.

Apolipoprotein E (APOE) e4 genotype, which increases the risk of Alzheimer’s disease (AD), predicted severe COVID-19 infection in one UK Biobank (UKB) cohort. Single nucleotide polymorphisms (SNPs) in the bridging integrator 1 (BIN1) gene indicate the second highest odds-ratios for sporadic AD, exceeded only by APOE variants. The objective of the present study was to evaluate the effects of BIN1 and the SNP rs744373 on COVID-19-relaetd survival using UKB-derived data. In addition, the interaction and alignment of BIN1 and SARS-Cov-2 were evaluated. For this purpose, the major (non-Alzheimer’s) BIN1 allele was designated as BIN and the SNP rs744373 minor (Alzheimer’s) allele as RS7. To evaluate the interaction and alignment of BIN1 and SARS-Cov-2, Protein Data Bank (pdb) entries were searched on the RCSB Protein Data Bank. The results revealed that the BIN RS7 heterozygote was associated with the lowest mortality rate (11.7%), followed by the BIN BIN homozygote (17.2%). The RS7 RS7 homozygote was associated with the highest mortality rate (28.1%). Logistic regression analysis was also performed using survival or mortality as the dependent variable, and sex, age, genotype, AD and coronary heart disease (CHD) as independent variables. The effects of sex, age and genotype were significant at the 95% level. The male sex and older-aged subjects were more likely to succumb to test-confirmed COVID-19 than females and younger subjects. The effects of AD and CHD were insignificant. Protein molecule alignment analyses suggested that the BIN allele may interfere with the replication of the SARs-Cov2 virus. The findings of the present study demonstrate that the risks for COVID-19 mortality are not simply related to an advanced chronological age or the comorbidities commonly observed in aged subjects, such as CHD and AD, but also with AD genes.

Sex-related differences in cognitive trajectories in older individuals with type 2 diabetes and overweight or obesity.

IntroductionIt is unknown whether rates of cognitive decline differ between older women and men with type 2 diabetes (T2D) and overweight or obesity.MethodsTwo to four cognitive assessments were obtained across up to 10 years from 2799 adults (mean age 68 years; 62% women) with T2D who had been enrolled in a clinical trial of weight loss intervention. Sex‐related differences in means and rates of decline of cognitive scores were assessed.ResultsWomen outperformed men in verbal learning and processing speed (P < 0.001), but not executive function (P = 0.22). The rates of decline over time for women and men were similar (P ≥ 0.10); however women, but not men, with apolipoprotein E (APOE) ε4 alleles had steeper declines in verbal learning (P = 0.02) and processing speed (P = 0.007) than those without these alleles.DiscussionCognitive advantages for women with T2D and overweight/obesity over men are preserved as they age; however, these are eroded by the APOE ε4 genotype.

Relation of apolipoprotein E gene polymorphism with the severity of coronary artery disease in patients with stable ischemic heart disease

Aim: Atherosclerosis begins from an early age and manifests in later years as Coronary artery disease (CAD). This inflammatory process is aggravated by age, smoking, hypercholesterolemia, hypertension, diabetes mellitus, and genetic factors. We aimed to investigate which isoform of APOE is related to extensive coronary lesions in patients with stable coronary heart disease.Materials and Methods: This study was carried on single center. One hundred and ten patients diagnosed with stable coronary artery disease by coronary angiogram were enrolled consecutively. Syntax score was calculated by a tool of website calculator (www.syntax.com). According to the Syntax score, patients were split into three groups. APOE genotyping was performed through blood samples. Patients split into three groups according to the APOE genotypes: E4 (3/4 and 4/4 genotypes), E3(3/3 genotype), E2 (2/2 and 2/3 genotypes). APOE groups were compared according to baseline characteristics and syntax scores.Results: Coronary angiography and APOE genotypes of 98 patients were analyzed. 81 of patients (%82.6) had E3E3 allele; 6 of patients (%6.1) had E2E3 allele; 10 patients (%10.2) had E3E4 allele and 1 patient (%1) had E2E4 allele. Due to the contrast effect of E2 and E4 on CAD, we excluded patients with E2E4 allele from the study. Firstly, we assessed distribution of APOE genotype E2 (E2E3), E3 (E3E3 and E3E4), E4 (E3E4) within 3 groups of syntax scores. Total of 6 patients of E2 allele was at low syntax score group. 83 patients of E3 allele were at the low-risk group of syntax score. 10 patients of E3 allele were at the mid group and 4 patients were at the high-risk group of syntax score. 7 patients of E4 allele subjects were at the low-risk and 1 patient was at the high-risk group of syntax score. Compared to syntax score groups and APOE genotypes, E2 alleles were in lower syntax score group versus E3 (P=0.046) and E4 (P=0.003) alleles. However E4 alleles were in higher syntax score group versus E3 alleles (P= 0.034). The Syntax score was seemed to be lower in the E2 allele group versus E4 and E2 groups (P=0.013).Conclusion: we reported the first study that E2 allele was related with less and E4 allele was more extensity and severity of CAD in patients with stable ischemic coronary disease.

Assessment of Plasma Amyloid-β42/40 and Cognitive Decline Among Community-Dwelling Older Adults

Plasma measurement of amyloid-β (Aβ) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce. To investigate the associations between plasma Aβ42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns. This multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020. Plasma Aβ42 and Aβ40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aβ assessment was defined as the baseline for this study. Cognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed. A total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aβ42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aβ42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aβ42/40 ratio greater than 0.107. In this study, low plasma Aβ42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aβ42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.

Sex-specific BDNF and APOE ε4 genotype interactions on white matter hyperintensity volume

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). One variant of the brain-derived neurotrophic factor (BDNF) gene also confers higher risk of AD. APOE and BDNF genotypes may have interactive effects on AD pathology. The aim of this study was to determine whether APOE and BDNF genotype differentially impact white matter hyperintensity volume (WMHV). We used data from 212 cognitively unimpaired individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) We used generalized linear models to predict WMHV from BDNF genotype and an interaction with APOE. Sex, age, education, vascular risk, and imaging-based amyloid load (Florbetapir SUVR) were used as covariates. . WMHV was derived by using the Lesion Segmentation Toolbox (LST) in SPM12 with a threshold of k = 0.15. We used the Hachinski Ischemic Scale to measure for vascular risk. We found no significant interaction of BDNF-APOE on WMHV (β = 0.40, 95% CI: (-0.39, 1.20), p = 0.32). In sex-stratified analyses the BNDF-APOE interaction was significantly associated with WMHV in males (β = 1.14, 95% CI:(0.17, 2.11), p = 0.02), but not in females (β = -0.37, 95% CI: (-1.47, 0.76), p = 0.50). For males, carriers of both BDNF Met and APOE ε4 alleles had the highest WMHV. Sex-specific differences in BDNF expression may be related to hormonal differences, and BDNF genotype might underlie these differences. Given the continued interest in using BDNF as a treatment target for AD, understanding complex genotype interactions may aid in future therapeutic studies.

APOE ε4 genotype, lifestyle profiles, and cognitive function among Chinese oldest old

AbstractBackground APOE ε4 is the single most important genetic risk factor for cognitive impairment and Alzheimer disease. While its interaction with lifestyle profile on cognition has been controversial and a recent study indicated that healthy lifestyle profiles only showed its benefits among APOE ε4 non‐carriers among those elderly aged over 65 years old. Accordingly, we examined the association between the APOE genotype and cognitive impairment and its interaction with lifestyle profiles among Chinese oldest old (aged over 80 years old).Method APOE ε4 is the single most important genetic risk factor for cognitive impairment and Alzheimer disease. While its interaction with lifestyle profile on cognition has been controversial and a recent study indicated that healthy lifestyle profiles only showed its benefits among APOE ε4 non‐carriers among those elderly aged over 65 years old. Accordingly, we examined the association between the APOE genotype and cognitive impairment and its interaction with lifestyle profiles among Chinese oldest old (aged over 80 years old).ResultAmong the 6,160 participants, 57.6% were women and 17.5% were APOE ε4 carriers, with a mean age of 90.1 (SD 7.2) years. The mean MMSE score was 23.3 (SD: 0.4) and 18.2% of the participants had cognitive impairment at baseline. Carrying APOE e4 allele was associated with 22% higher odds (95% CI: 1.02‐1.46) of cognitive impairment. Compared with those with unhealthy lifestyle score, participants with healthy lifestyle score were associated with a 38% (95% CI: 23% ‐ 50%) lower odds of cognitive impairment. No significant interaction between APOE genotype and lifestyle profiles was observed. The association between lifestyle profiles and cognitive function did not vary by APOE genotype.Conclusion APOE genotype and lifestyle profiles were associated with cognitive function among Chinese oldest old, respectively and healthier lifestyle is associated with lower odds of cognitive impairment regardless of APOE genotype.

Association of Alzheimer’s disease progression with baseline clinical and genetic characteristics

AbstractBackgroundMitochondrial genetics are important in the etiology of Alzheimer’s disease (AD). Based on the polymorphisms in mitochondrial DNA (mtDNA) the population can be classified into subgroups called the haplogroups. Previous studies have explored the association of haplogroups and genetic variants in APOE ε4 with AD but the results are inconsistent. Also, patients with mild cognitive impairment (MCI) at baseline often progress differently over several years of follow up.MethodWe carried out a cross‐sectional study to examine the association of the rate of incidence of AD with APOE ε4 genotype and haplogroups. The data collected at the University of Kansas AD Center (KU ADC) consisting of 146 AD and 265 normal subjects, and the data collected by AD Neuroimaging Initiative (ADNI) consisting of 244 AD and 242 normal subjects were used for these analyses. Logistic regression and Fisher Exact tests were used to explore the associations. We also carried out the association analyses of the differences in the disease progression rates from MCI to AD among the haplogroups using both datasets.ResultRates of incidence of AD were statistically significantly different among the haplogroups (2.2 × 10−8), with differing strengths of association across haplogroups. APOE ε4 was significantly associated with AD overall (p‐value = 1.9 × 10−11) and the association further varied by haplogroups. The results of the KU ADC population were consistent with those of the ADNI data. Out of 112 MCI subjects at baseline in KU ADC, 26 progressed to AD and 20 reverted back to normal at the last clinical visit. In ADNI, 172 progressed to AD and 42 reverted back out of 482 MCI at baseline. For both datasets, the proportion of subjects who progressed to AD differed by haplogroups. APOE ε4 genotype was significantly associated with increased risk of progression from MCI to AD (p‐value = 8.6 × 10−7 KUADC and p‐value = 1.33 × 10−9 ADNI).ConclusionThe rate of incidence of AD differed by mtDNA haplogroup and the strength of association further differed by APOE ε4 genotype. The rates of progression of MCI subjects to AD also differed by haplogroups and APOE ε4 genotype.

The accumulation rate of tau aggregates is higher in females and younger amyloid-positive subjects.

The development of tau-PET allows paired helical filament tau pathology to be visualized in vivo. Increased knowledge about conditions affecting the rate of tau accumulation could guide the development of therapies halting the progression of Alzheimer's disease. However, the factors modifying the rate of tau accumulation over time in Alzheimer's disease are still largely unknown. Large-scale longitudinal cohort studies, adjusting for baseline tau load, are needed to establish such risk factors. In the present longitudinal study, 419 participants from four cohorts in the USA (Avid 05e, n = 157; Expedition-3, n = 82; ADNI, n = 123) and Sweden (BioFINDER, n = 57) were scanned repeatedly with tau-PET. The study participants were cognitively unimpaired (n = 153), or patients with mild cognitive impairment (n = 139) or Alzheimer's disease dementia (n = 127). Participants underwent two to four tau-PET (18F-flortaucipir) scans with a mean (± standard deviation) of 537 (±163) days between the first and last scan. The change in tau-PET signal was estimated in temporal meta- and neocortical regions of interest. Subject specific tau-PET slopes were predicted simultaneously by age, sex, amyloid status (determined by amyloid-β PET), APOE ε4 genotype, study cohort, diagnosis and baseline tau load. We found that accelerated increase in tau-PET signal was observed in amyloid-β-positive mild cognitive impairment (3.0 ± 5.3%) and Alzheimer's disease dementia (2.9 ± 5.7%), respectively, when compared to either amyloid-β-negative cognitively unimpaired (0.4 ± 2.7%), amyloid-β-negative mild cognitive impairment (-0.4 ± 2.3%) or amyloid-β-positive cognitively unimpaired (1.2 ± 2.8%). Tau-PET uptake was accelerated in females (temporal region of interest: t = 2.86, P = 0.005; neocortical region of interest: t = 2.90, P = 0.004), younger individuals (temporal region of interest: t = -2.49, P = 0.013), and individuals with higher baseline tau-PET signal (temporal region of interest: t = 3.83, P < 0.001; neocortical region of interest: t = 5.01, P < 0.001). Tau-PET slopes decreased with age in amyloid-β-positive subjects, but were stable by age in amyloid-β-negative subjects (age × amyloid-β status interaction: t = -2.39, P = 0.018). There were no effects of study cohort or APOE ε4 positivity. In a similar analysis on longitudinal amyloid-β-PET (in ADNI subjects only, n = 639), we found significant associations between the rate of amyloid-β accumulation and APOE ε4 positivity, older age and baseline amyloid-β positivity, but no effect of sex. In conclusion, in this longitudinal PET study comprising four cohorts, we found that the tau accumulation rate is greater in females and younger amyloid-β-positive individuals, while amyloid-β accumulation is greater in APOE ε4 carriers and older individuals. These findings are important considerations for the design of clinical trials, and might improve our understanding of factors associated with faster tau aggregation and spread.

Association of APOE genotype and lipid lowering with cognitive function in a randomized placebo‐controlled trial of Evolocumab

AbstractBackgroundAPOE encodes a cholesterol transporter, and the ε4 allele is associated with higher cholesterol levels, ß‐amyloid burden, and risk of Alzheimer’s disease (AD). A recent pooled re‐analysis of clinical trials (Geifman et al., 2017) found that long‐term use of cholesterol‐lowering medications may lower rates of cognitive decline in patients with mild to moderate AD, with potentially greater therapeutic efficacy for ε4/ε4 carriers. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. The purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab, LDL cholesterol level, and cognitive function.MethodOf 16,174 APOE‐genotyped patients (25.8% with one ε4 allele; 2.3% with two ε4 alleles) from FOURIER, a randomized, placebo‐controlled trial of evolocumab added to statin therapy, 13,481 completed the Everyday Cognition Scale (ECog) to report subjective cognitive changes from the end of the trial compared to its beginning (scores ≥2 reflect subjective decline). A subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial.ResultThere was a dose‐dependent relationship between APOE ε4 genotype and subjective memory decline on the ECog in the placebo arm (p = .009; ε4/ε4 carriers vs. non‐carriers: OR = 1.38, 95% CI [.98,1.95]) but not the evolocumab arm (p = .77, OR = 1.14, 95% CI [.81,1.60]). However, the genotype x treatment interactions were not significant, likely due to a limited number of ε4/ε4 carriers. After adjustment for demographic and medical covariates, APOE genotype did not significantly moderate the relationships between treatment arm or post‐baseline LDL cholesterol level on CANTAB performance (p’s&gt;.05) in the subset examined.ConclusionAPOE genotype did not significantly moderate the relationship between evolocumab treatment and cognitive function, although analyses were limited by the low population frequency of the ε4/ε4 genotype. This supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol‐lowering medications in people at genetic risk for Alzheimer’s disease.

Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex

AbstractBackgroundHigher intake of vitamin E has been associated with a lower risk of Alzheimer’s disease (AD), however the underlying mechanisms are unclear. One explanation might be that anti‐inflammatory properties of tocopherols prevent microglia activation. In this study we investigated the association of brain tocopherol levels with microglia activation in elderly humans.MethodWe included 113 deceased participants (88.5±6 years, 60% female) from the prospective Memory and Aging Project. Brain levels of α‐ and γ‐tocopherol were measured by HPLC coupled to electrochemical detection. Microglia presence was assessed in three stages of activation, based on morphology; i.e. I – not activated, II – activated, III – most activated. Microglia densities and tocopherol levels were log‐transformed when not normally distributed, standardized and averaged across two cortical and two subcortical brain regions. Linear regression analyses examined associations between tocopherol levels and microglia densities (outcome) in two models; a model adjusted for age, sex, education, APOE ε4 genotype and post mortem time interval (model 1), and a model additionally adjusted for total amyloid load and neurofibrillary tangles severity (model 2).ResultTotal microglia density (stage I‐III) was lower in cortical versus subcortical brain regions (153.2 (111.2‐194.0); 209.2 (175.8‐224.1), p&lt;0.001). Levels of α‐ and γ‐tocopherol and activated microglia (II/III or III only) density did not differ between brain regions. Higher α‐ and γ‐tocopherol levels were associated with lower total and activated microglia densities in cortical (range (B(SE) ‐0.25,‐0.19 (0.09,0.10) p&lt;0.05) but not in subcortical brain regions (range B(SE) ‐0.01, 0.12 (0.09,0.10) p&gt;0.05). When we additionally adjusted for AD neuropathology effect estimates diminished and lost significance except for the association between α‐tocopherol and total microglia density in cortical brain regions (B(SE) ‐0.20 (0.09), p=0.03).ConclusionThese results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.

APOE genotype, brain imaging, and neuropsychological testing markers of Alzheimer’s disease: Data from the Strong Heart Study

AbstractBackgroundCarrying an APOE ε4 allele increases risk for Alzheimer’s disease and related dementias. However, risk effects and prevalence of risk alleles are not consistent across races/ethnicities. Prevalence of cognitive impairment or dementia and attributable risk from APOE ε4 genotype are unknown in American Indians (AI). This project evaluated associations of APOE genotype with cranial imaging and cognitive testing markers of vascular and Alzheimer’s dementias in a large, prospective, population‐based cohort of AI.MethodThe Strong Heart Study recruited 4,549 AI aged 45‐75 from 13 tribal communities across 3 major geographic regions in 1989‐1991. In 2010‐2013, all eligible surviving participants, then aged 65‐95, underwent cognitive examination including 3MS, WAIS, COWA, and CVLT‐II long delay free recall and cranial magnetic resonance imaging (MRI). APOE was genotyped from blood using ABI PRISM Linkage Mapping and DNA sequencing.ResultMost participants carried either 3.3 (73%) or 4.3 genotypes (23%). Clinical risk factors for dementia were prevalent, including high body mass index (mean&gt;30), hypertension (80%), diabetes (48%), high LDL (39‐44%), chronic kidney disease (27%), and prior stroke (8‐9%). APOE ε4 carriers did not differ from non‐carriers in clinical factors, with the exception of serum LDL (103.9 mg/dL vs 96.7 mg/dL, P=0.015). Findings from MRI were also similar between genotypes, including presence of infarcts or hemorrhages, brain volume, and grade (0‐9) for white matter hyperintensities, sulcal widening, and ventricle enlargement. APOE ε4 carriers had marginally more WMH volume than non‐carriers. Cognitive examination scores were also similar, including Modified Mini Mental Status Examination (3MSE), Weschler Adult Intelligence Scale coding test (WAIS), Controlled Oral Word Association test (COWA), California Verbal Learning Test long delay free recall (CVLT).ConclusionDespite evidence for higher risk of Alzheimer’s and related dementias from presence of APOE ε4 allele among individuals from other populations, our study found little evidence of such an effect in elderly AIs. These findings raise intriguing questions about the presence of as‐yet‐unknown protective factors. Limitations of this study include cross‐sectional analyses and possibility of selective survival before the MRI examination. Future research should directly examine whether longitudinal changes in cognition and brain structure are associated with APOE genotype.

A polygenic risk score for Alzheimer’s disease determines the risk of incident dementia in APOE ɛ4 negative individuals over the age of 95: A population‐based cohort study

AbstractBackgroundThe combined effect of common genetic variants (SNPs) into polygenic risk scores (AD‐PRS) have been shown to have a strong influence on incident AD between ages 60 and 95 years, especially in carriers of the APOE ϵ4 genotype. However, few studies have investigated the effect of AD‐PRS on incident dementia in the general population and among the oldest old (≥ 95 years).MethodA population‐based sample of 2053 participants aged 70‐108 years, from the Gothenburg H70 Birth Cohort Studies, Sweden, was followed for incident dementia. An AD‐PRS (39 SNPs) were constructed using effect sizes from large genome‐wide association studies. Dementia was diagnosed according to DSM‐III‐R based on information from neuropsychiatric examinations and close informant interviews. Cox regression models adjusted for sex, birth year, age at blood sampling, and APOE ϵ4 status, were used to analyse the associations between AD‐PRS and incident dementia in the total sample and in the oldest old (n = 338). Additionally, we stratified the analysis by APOE ϵ4 carriership and tertiles of the AD‐PRS.ResultDuring mean follow‐up of 7.19 years (SD 4.68; 14,775.25 person‐years), 607 participants developed dementia (220 over the age of 95 years). In the total sample, AD‐PRS was associated with incident dementia (HR per increased point of the score 1.38; 95%CI 1.12‐1.73, p = 0.003), especially among APOE ϵ4 non‐carriers (HR 1.72; 95%CI 1.33‐2.23, p &lt; 0.0001). Among the oldest old, AD‐PRS was associated with incident dementia in APOE ϵ4 non‐carriers only (HR 1.80; 95%CI 1.20‐2.69, p = 0.004). Further, in this age group, APOE ϵ4 carriership was associated with increased risk of dementia only among those in the low‐risk tertile of AD‐PRS (HR 1.84; 95%CI 1.08‐3.12, p = 0.004).ConclusionWe found an association between AD‐PRS and dementia in the general population up to very old ages, especially among APOE ϵ4 non‐carriers. In the oldest old, an effect of APOE ϵ4 carriership on dementia risk was observed among individuals in the low‐risk tertile of the AD‐PRS. These results could provide additional information to identify individuals at risk for dementia.