Effect Of E4 Research Articles

Synergistic Effect between the APOE ε4 Allele with Genetic Variants of GSK3B and MAPT: Differential Profile between Refractory Epilepsy and Alzheimer Disease.

Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder characterized by recurrent focal seizures originating in the temporal lobe. Despite the variety of antiseizure drugs currently available to treat TLE, about 30% of cases continue to have seizures. The etiology of TLE is complex and multifactorial. Increasing evidence indicates that Alzheimer's disease (AD) and drug-resistant TLE present common pathological features that may induce hyperexcitability, especially aberrant hyperphosphorylation of tau protein. Genetic polymorphic variants located in genes of the microtubule-associated protein tau (MAPT) and glycogen synthase kinase-3β (GSK3B) have been associated with the risk of developing AD. The APOE ε4 allele is a major genetic risk factor for AD. Likewise, a gene-dose-dependent effect of ε4 seems to influence TLE. The present study aimed to investigate whether the APOE ɛ4 allele and genetic variants located in the MAPT and GSK3B genes are associated with the risk of developing AD and drug-resistant TLE in a cohort of the Mexican population. A significant association with the APOE ε4 allele was observed in patients with AD and TLE. Additional genetic interactions were identified between this allele and variants of the MAPT and GSK3B genes.

Protein intake and episodic memory: the moderating role of the apolipoprotein E ε4 status

BackgroundThis study investigated the correlation between protein intake and Alzheimer’s disease (AD)-related cognitive decline, particularly in episodic memory, among older adults without dementia. Furthermore, we assessed the moderating effect of apolipoprotein ε4 (APOE4) on this association and analyzed its influence on other cognitive functions beyond memory.MethodsThe study involved 196 participants who underwent assessments for protein intake, cognitive performance, APOE4 genotyping, and nutritional biomarkers. Protein intake was categorized into low, medium, and high based on the consumption of dairy, legumes, eggs, meat, and fish.ResultsHigh protein intake was significantly associated with better episodic memory and overall cognition. Moreover, a significant interaction was found between high protein intake and APOE4, indicating that APOE4 moderates the association between high protein intake level and episodic memory. Sensitivity analysis confirmed these results among participants with stable food intake.ConclusionsOur study results demonstrated that high protein intake is associated with better episodic memory among older adults without dementia. Furthermore, the findings highlight the significant role of APOE4 status in moderating the relationship between protein consumption and episodic memory. These results suggest that dietary interventions focusing on protein intake could be beneficial for cognitive health, particularly in individuals with a genetic predisposition to AD.

Interplay of Large Neutral Amino Acids, Metabolic Syndrome, and Apolipoprotein E ε4 on Brain Integrity at Midlife.

Large neutral amino acids (LNAAs) tryptophan and phenylalanine have been implicated in the pathogenesis of neurodegenerative diseases. Given limited research on the effects of LNAA on brain health across different life stages, vascular risk, and genetic backgrounds, our study aimed to explore the interaction of LNAA levels, metabolic syndrome (MetS), and the presence of the apolipoprotein E ε4 (ApoE ε4) allele brain integrity at midlife. Sixty-eight adults aged 40-61 underwent a health assessment to calculate the number of MetS components, quantify LNAA, measure white matter hyperintensity (WMH) volume, and genotype ApoE ε4. Multivariate linear regression analyses were performed to test the joint effect of LNAA, MetS, and ApoE ε4 on WMH while adjusting for sex, age, and education. Significant 3-way interactions were observed between serum tryptophan (β = 0.042, SE = 0.018, p < 0.05) and phenylalanine (β = 0.044, SE = 0.013, p < 0.01) levels, number of MetS components, and ApoE ε4 alleles status on WMH volume. Neither individual LNAA levels nor MetS components alone predicted WMH volume. The study highlights significant 3-way interactions between LNAA, MetS, and genetic risk factors in the pathology of WMH, particularly in individuals genetically predisposed to Alzheimer's disease. These interactions suggest differential impacts of LNAA on WMH volume dependent on both genetic and metabolic factors. Results emphasize the need for personalized metabolic and genetic profile assessments in neurodegenerative disease management.

Effect of apolipoprotein E ε4 and its modification by sociodemographic characteristics on cognitive measures in South Asians from LASI-DAD.

We investigated the effects of apolipoprotein E (APOE) ε4 and its interactions with sociodemographic characteristics on cognitive measures in South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD). Linear regression was used to assess the association between APOE ε4 and global- and domain-specific cognitive function in 2563 participants (mean age 69.6±7.3 years; 53% female). Effect modification by age, sex, and education were explored using interaction terms and subgroup analyses. APOE ε4 was inversely associated with most cognitive measures (p<0.05). This association was stronger with advancing age for the Hindi Mental State Examination (HMSE) score (βε4×age=-0.44, p=0.03), orientation (βε4×age=-0.07, p=0.01), and language/fluency (βε4×age=-0.07, p=0.01), as well as in females for memory (βε4×male=0.17, p=0.02) and language/fluency (βε4×male=0.12, p=0.03). APOEε4 is associated with lower cognitive function in South Asians from India, with a more pronounced impact observed in females and older individuals. APOEε4 carriers had lower global and domain-specific cognitive performance. Females and older individuals may be more susceptible to ε4 effects. For most cognitive measures, there was no interaction between ε4 and education.

APOE ε4 Allele Frequency Among Cognitively Healthy Members of an Ojibwe Tribal Nation.

APOE ε4 frequency varies by geography and ancestry. We provide data regarding the frequency of this allele in the Ojibwe people, the fifth largest Indigenous people in the United States. Population study including 33 cognitively normal older individuals of an Ojibwe Tribal Nation (total population: 984; all with ≥25% Ojibwe ancestry). APOE ε4 allele frequency was 19.7%, which is comparable with other cognitively normal American Indian, Alaskan Native, and non-Hispanic White populations of the United States and Europe, with the exception of a lower frequency among Choctaw Nation of Oklahoma participants with >50% American Indian ancestry. While some global populations have very low APOE ε4 prevalence, this allele appears common among American Indian Tribal Nations included thus far in the United States. Because APOE ε4 is a cornerstone for novel diagnostics and therapeutics for Alzheimer disease (AD), future study is warranted to understand ancestry-dependent effects of APOE ε4 on AD risk and biology.

APOE ε4 is associated with decreased synaptic density in cognitively impaired participants.

We aimed to investigate the effect of apolipoprotein E4 (APOE) ε4 on synaptic density in cognitively impaired (CI) participants. One hundred ten CI participants underwent amyloid positron emission tomography (PET) with 18F-florbetapir and synaptic density PET with 18F-SynVesT-1. We evaluated the influence of APOE ε4allele on synaptic density and investigated the effects of ε4 genotype on the associations of synaptic density with Alzheimer's disease (AD) biomarkers. The mediation effects of AD biomarkers on ε4-associated synaptic density loss were analyzed. Compared with non-carriers, APOE ε4 allele carriers exhibited significant synaptic loss in the medial temporal lobe. Amyloid beta (Aβ) and tau pathology mediated the effects of APOE ε4 on synaptic density to different extents. The associations between synaptic density and tau pathology were regulated by the APOE ε4 genotype. The APOE ε4 allele was associated with decreased synaptic density in CI individuals and may be driven by AD biomarkers.

Life course plasma metabolomic signatures of genetic liability to Alzheimer’s disease

Mechanisms through which most known Alzheimer’s disease (AD) loci operate to increase AD risk remain unclear. Although Apolipoprotein E (APOE) is known to regulate lipid homeostasis, the effects of broader AD genetic liability on non-lipid metabolites remain unknown, and the earliest ages at which metabolic perturbations occur and how these change over time are yet to be elucidated. We examined the effects of AD genetic liability on the plasma metabolome across the life course. Using a reverse Mendelian randomization framework in two population-based cohorts [Avon Longitudinal Study of Parents and Children (ALSPAC, n = 5648) and UK Biobank (n ≤ 118,466)], we estimated the effects of genetic liability to AD on 229 plasma metabolites, at seven different life stages, spanning 8 to 73 years. We also compared the specific effects of APOE ε4 and APOE ε2 carriage on metabolites. In ALSPAC, AD genetic liability demonstrated the strongest positive associations with cholesterol-related traits, with similar magnitudes of association observed across all age groups including in childhood. In UK Biobank, the effect of AD liability on several lipid traits decreased with age. Fatty acid metabolites demonstrated positive associations with AD liability in both cohorts, though with smaller magnitudes than lipid traits. Sensitivity analyses indicated that observed effects are largely driven by the strongest AD instrument, APOE, with many contrasting effects observed on lipids and fatty acids for both ε4 and ε2 carriage. Our findings indicate pronounced effects of the ε4 and ε2 genetic variants on both pro- and anti-atherogenic lipid traits and sphingomyelins, which begin in childhood and either persist into later life or appear to change dynamically.

Effects of APOE ε4 and Neuropathological Diagnoses on Neuropsychiatric Symptoms: Mediation Analyses and Likely Causation in an Integrated National Alzheimer’s Coordinating Center Database

BackgroundIn this study, we sought to identify paths from APOE ε4 to neurobehaviors itemized on a neuropsychiatric inventory (Neuropsychiatric Inventory–Questionnaire [NPI-Q]) that involved neuropathologies associated with APOE ε4 (amyloid, tau, cerebral amyloid angiopathy, and Lewy bodies) or cognition mediators (memory or global cognitive status) as well as direct paths from APOE ε4 to neurobehaviors. MethodsA total of 1199 cases with available neurobehavioral, cognition, and neuropathological data were included. We conducted a series of causal mediation analyses in which APOE ε4 always served as the independent variable, and NPI-Q neurobehavioral items, when included in the mediation analysis, served as the outcome. Neuropathologies or cognition served as mediators. ResultsMultiple significant indirect paths from APOE ε4 through neuropathologies to neurobehaviors were identified. More refined analyses indicated that neuritic plaques and Braak stage drove the findings. A significant direct effect of APOE ε4 on memory was also identified. Additionally, Lewy body disease, when treated as an exposure, had a direct effect on hallucinations consistent with features of the disease. ConclusionsWe found strong evidence for partial mediation of NPI-Q symptoms by cognition, suggesting that cognitive limitations may have promoted maladaptive behavior. In addition, neuritic amyloid plaque levels and Braak stage, but not diffuse amyloid plaque extent, were key in NPI-Q–mediated associations, suggesting the possibility that synaptic failure plays an important role in multiple neurobehavioral symptoms in dementia, including psychosis. Finally, we found strong evidence that APOE ε4 may have direct effects on cognition when we used verbal episodic memory but not global cognitive status as an outcome.

Examining the relationship between anxiety and regional brain volumes in the National Alzheimer's Coordinating Center uniform, imaging, and biomarker datasets

Anxiety has been associated with a greater risk of Alzheimer's disease (AD). Existing research has identified structural differences in regional brain tissue in participants with anxiety, but results have been inconsistent. We sought to determine the association between anxiety and regional brain volumes, and the moderation effect of APOE ε4. Using data from participants in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set, with complete imaging (MRI) and biomarker data (n = 1533), multiple linear regression estimated the adjusted effect of anxiety on 30 structural MRI regions. The moderation effect of APOE ε4 on the relation between structural MRI regions and anxiety was assessed as was the moderation effect of cognitive status. False discovery rate was used to adjust for multiple comparisons. After controlling for intracranial volume, age, sex, years of education, race, Hispanic ethnicity, and cognitive status, seven MRI regions demonstrated lower volumes among participants with anxiety: total cerebrum gray matter volume, right hippocampus volume, hippocampal volume (total), right and left frontal lobe cortical gray matter volume, and right and total temporal lobe cortical gray matter volume. Findings suggest that anxiety is associated with significant atrophy in multiple brain regions, with corresponding ventricular enlargement. Future research should investigate if anxiety-related changes to brain morphology contribute to greater AD risk.

Gene-dose effects of APOE ε4 on age-dependent increases in Peak Width of Skeletonised Mean Diffusivity during midlife

Gene-dose effects of APOE ε4 on age-dependent increases in Peak Width of Skeletonised Mean Diffusivity during midlife

THE ASSOCIATION BETWEEN APOE Ε4 AND EPISODIC MEMORY IN MIDLIFE: TESTING THE COGNITIVE PHENOTYPE HYPOTHESIS

Abstract Carrying at least one ε4 allele of Apolipoprotein E (APOE ε4) is a strong genetic risk factor for Alzheimer’s disease (AD). It is contentious whether the effect of APOE ε4 on memory decline is because of cognitive phenotype or prodromal AD cases. Inconsistent findings on this topic could be due to the presence of AD pathology in older ages and the lack of sensitivity of memory measures. To exclude potential prodromal AD cases, we tested the association between APOE ε4 and episodic memory among cognitively unimpaired adults in midlife. Data from a subset of 103 participants (Mage=57±6 years; 87.4% females) from an ongoing clinical trial (NIH R01AG058919) were analyzed. APOE genotype was assessed from passive drool saliva samples, and participants completed memory assessments. Analyses of covariance compared 39 carriers of APOE ε4 versus 64 non-carriers of APOE ε4 for their performance of mnemonic discrimination, auditory-verbal and visuospatial short- and long-term memory, paired associative memory, and verbal logical memory, while controlling relevant covariates (e.g., age, education, sex, and physical activity level). After covariate adjustments, significant negative relationships between APOE ε4 and mnemonic discrimination were observed while nearly significant negative relationships were observed for auditory-verbal long-term memory. These findings imply that APOE ε4 could be associated with a cognitive phenotype of decline in mnemonic discrimination and auditory-verbal long-term memory, and the phenotype effects on memory decline could start in midlife. This suggests the importance of early lifestyle interventions for cognitive health in midlife, especially in people at genetic risk for AD.

Effect of APOE ε4 and its modification by sociodemographic characteristics on cognitive measures in South Asians from LASI‐DAD

AbstractBackgroundThe ε4 allele of the apolipoprotein E (APOE) gene is the most significant genetic risk factor for dementia in nearly all human populations. However, the effects of APOE ε4 on late‐life cognitive function and its potential modification by sociodemographic factors have not been extensively studied in South Asians. We investigated the effects of APOE ε4 and its interaction with sociodemographic characteristics on cognitive measures in 2,607 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI‐DAD).MethodWe determined APOE ε4 carrier status from rs429358 and rs7412 genotypes in whole genome sequencing data. We first examined the main effects of APOE ε4 on seven cognitive measures, including five broad cognitive domain scores, a general cognitive function summary score, and the Hindi Mental State Examination (HMSE) score using linear regression models. Model 1 adjusted for age, sex, state of residence, and the first 10 genetic principal components (PCs). Model 2 additionally adjusted for education level, literacy, and urban/rural residence. We then tested for interaction between APOE ε4 and sociodemographic factors (age, sex, and education) through cross‐product terms, and further evaluated significant interactions (p&lt;0.05) using stratified analysis.ResultAPOE ε4 was inversely associated with all cognitive measures except visuospatial function in the full sample in Model 1 after Bonferroni correction (p&lt;0.007), all of which remained nominally significant in Model 2 (p&lt;0.05). For example, APOE ε4 carrier status was associated with a decrease in the HMSE score of 0.77 points (p = 1.6×10−4) and a decrease in general cognitive function score of 0.09 standard deviations (p = 0.001) in Model 2. Furthermore, interaction tests showed that the effect of APOE ε4 was stronger in females than males for memory (ßAPOE ε4_male = ‐0.121, βAPOE ε4_female = ‐0.177) and language/fluency (βAPOE ε4_male = 0.075, βAPOE ε4_female = ‐0.125), and stratified analysis indicated that the APOE ε4 effects were significant only in females (p&lt;0.05).ConclusionAPOE ε4 is associated with lower cognitive function in older South Asians from India. For memory and language/fluency, this association is stronger in females than males.

Apoe ε4 exacerbates age‐dependent decline of cortical microstructural changes in cognitively normal midlife individuals: the PREVENT‐Dementia and ALFA studies

AbstractBackgroundThe APOE ε4 allele is the primary genetic risk factor for the sporadic type of Alzheimer’s disease (AD). However, the mechanisms by which APOE ε4 is associated with neurodegeneration are still poorly understood. Here, we applied the NODDI to characterise the effects of APOE ε4 and its interactions with age and education on cortical microstructure in cognitively normal individuals.MethodData from 1954 participants were included from the PREVENT‐Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non‐carriers, 757 APOE ε4 carriers). T1 MRIs were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index (ODI) maps from diffusion MRI. Primary analyses were focused on the (a) main effects of APOE ε4, and the (b) interactions of APOE ε4 with age and education on lobar and vertex‐wise ODI and implemented using Permutation Analysis of Linear Models.ResultAPOE ε4 carriers and non‐carriers did not differ in terms of lobar ODI. However, there were APOE ε4 × age interactions in the temporo‐parietal and frontal lobes (TFCE p FWE &lt; 0.05), indicating steeper age‐dependent ODI changes in APOE ε4 (Figure 1). Lobar analyses revealed decreased temporal ODI in APOE ε4 carriers after age = 60 (Figure 2). There was a three‐way interaction of APOE ε4 x age x education; steeper age‐related ODI declines among APOE ε4 carriers with lower years of education (Figure 3, TFCE p FWE &lt; 0.05). There were no significant main effects or interactions of APOE ε4 on cortical thickness.ConclusionWe found novel evidence that APOE ε4 worsened age‐related ODI decreases in brain regions typically associated with atrophy patterns of AD. This finding also suggests that APOE ε4 may hasten the onset age of dementia by accelerating age‐dependent reductions in cortical ODI, although additional studies are needed to verify this hypothesis. These findings were independent of cortical thickness. While conclusions are limited due to the cross‐sectional design, our findings imply that APOE ε4 related changes in ODI may precede macroscopically visible changes in cortical atrophy and may be a more sensitive marker of incipient AD.

Influence of APOE on the Alzheimer’s disease polygenic risk scores based on hippocampal subfield volumes

AbstractBackgroundNumerous studies have shown the association between Alzheimer’s disease, hippocampal subfield volume atrophy, and the role of APOE. In our previous study, we showed the differential atrophy in the hippocampal subfield volumes (HSV) identified using Alzheimer’s disease polygenic risk scores (AD PGRS). Here, we evaluate the influence of the APOE 𝛆4 on the AD PGRS of the HSV.MethodWe calculated the AD PGRS for HSV atrophy in 1,086 individuals (319 cognitively normal (CN), 591 mild cognitively impaired (MCI), and 176 Alzheimer’s disease dementia (ADD)). We then stratified the samples based on the APOE 𝛆4 carriers and non‐carriers. We studied the AD PGRS for the HSV for the left‐right hemispheres.ResultThe analysis was performed for the left and right hemispheres separately. The effects of APOE 𝛆4 were larger on the left hemisphere than on the right hemisphere. The effects of the APOE 𝛆4 were severe on most of the subfield volumes. Although, certain subfield volumes showed larger effects for 𝛆4 non‐carriers and certain subfield volumes showed no effect between 𝛆4 carriers and non‐carriers.ConclusionThe APOE 𝛆4 carriers showed a higher AD PGRS for hippocampal subfield volume atrophy than the APOE 𝛆4 non‐carriers. The AD PGRS and the APOE 𝛆4 showed the differential risk for the subfield volumes bilaterally. These risk scores can be used in preclinical Alzheimer’s risk modeling. We also hypothesize that hippocampal subfield volume atrophy occurs in both normal and pathological aging. However, atrophy is intense in pathological aging due to the underlying processes and the functioning of the risk genes. A clear understanding of this will enhance the specificity and sensitivity for the early diagnosis of Alzheimer’s disease.

Different astrocyte phenotypes mediate the pathological cascade early in the Alzheimer’s disease continuum

AbstractBackgroundGlial fibrillary acidic protein (GFAP) and chitinase‐3‐like protein 1 (YKL‐40) are biomarkers of different astrocyte phenotypes, both of which are elevated in the dementia phase of Alzheimer’s disease (AD). However, the specific contribution of these astrocyte phenotypes early in the AD continuum is not fully understood. Here, we studied how these two astrocyte phenotypes mediate the early pathogenic cascade in the preclinical stage of AD.MethodWe assessed 384 cognitively unimpaired individuals from the ALFA+ study with amyloid‐β (Aβ)42/40, phosphorylated tau (p‐tau181), neurofilament light (NfL) and YKL‐40 measured in cerebrospinal fluid (CSF) and GFAP measured in plasma, as well as [18F]flutemetamol positron emission tomography (PET) and neuropsychological testing (Annual change in the Preclinical Alzheimer’s Cognitive Composite [PACC]). Path analysis using structural equation modelling was used to quantify the relationships between biomarkers of reactive astrogliosis and Amyloid‐Tau‐Neurodegeneration biomarkers, while incorporating age, sex, and apolipoprotein E (APOE) ε4 effects. Direct effects with FDR‐corrected p‐values below .05 were considered significant.ResultCSF Aβ42/40 was associated with Aβ aggregation as measured by PET and with CSF p‐tau181, respectively. The latter was associated with CSF NfL, but no associations were found between any biomarkers and PACC changes in this early sample (Figure 1; Table 1). Plasma GFAP mediated the association between CSF Aβ42/40 and Aβ‐PET. Additionally, CSF YKL‐40 mediated the association between Aβ‐PET and p‐tau181 and between p‐tau181 and NfL. APOE ε4 had a direct association with CSF Aβ42/40 only, whereas age had independent associations with CSF Aβ42/40, NfL, GFAP and YKL‐40. Male sex was associated with higher CSF NfL levels, independently of other variables tested.ConclusionOur results suggest that astrocyte phenotypes that release GFAP into the blood influence the aggregation of soluble Aβ into fibrillary plaques. On the other hand, those releasing YKL‐40 into the CSF appear to play a role later in the pathological cascade, mediating downstream tau pathology and neuronal damage. These results indicate that different astrocyte phenotypes are specifically involved in distinct stages of the early pathological cascade in preclinical AD. Interventions targeting astrocyte dysfunction in preclinical stages may prevent or delay the onset of AD dementia.

A genome‐wide association study of LATE‐NC (limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change) reveals a distinct genetic architecture

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is the third leading cause of late‐life dementia. However, its pathophysiology remains largely unknown, and the relationship of LATE‐NC with Alzheimer’s disease (AD) pathology and frontotemporal lobar degeneration‐TDP (FTLD‐TDP) remains unclear. To address this knowledge gap, we performed a genome‐wide association study (GWAS) of LATE‐NC.MethodDeceased participants of European ancestry from the Religious Orders Study, the Rush Memory and Aging Project (ROSMAP, n = 1,379), and the Adult Changes in Thought study (ACT, n = 459) were included in our study. The primary phenotypes were LATE‐NC burden (a multi‐regional semi‐quantitative TDP‐43 composite, continuous) in ROSMAP, and the presence/absence of LATE‐NC (binary) in ACT, assessed with post‐mortem TDP‐43 immunohistochemistry. Quantitative amyloid‐β (Aβ) and paired helical filament tau (PHFtau) burden were also examined in ROSMAP. GWAS was performed using linear (ROSMAP) or logistic (ACT) additive models. We controlled age, sex, genotyping platforms, and the first three genotype principal components. Sample size‐weighted GWAS meta‐analysis (total n = 1,838) was performed by combining p‐values considering the direction of the association. Confounding and moderating effects of AD pathology on LATE‐NC risk variants were examined in ROSMAP.ResultWe observed two genome‐wide significant risk loci (p&lt;5.0×10−8) in APOE (ε4) and SHANK2 (s146617441G, allele frequency 0.021). In ROSMAP, APOE ε4 was associated with higher LATE‐NC burden after controlling for quantitative Aβ and PHFtau (beta = 0.27, p = 7.3×10−6), and the APOE ε4 – LATE‐NC association was present in the subgroup without detectable Aβ (n = 170, beta = 0.50, p = 0.025). rs146617441G was not directly associated with quantitative Aβ or tau. Instead, rs146617441G×Aβ interaction term was associated with higher LATE‐NC burden (beta = 0.25, p = 0.032), suggesting the synergy between Aβ‐dependent and LATE‐NC‐specific pathways in LATE‐NC pathogenesis. Three additional loci reached a pre‐specified suggestive p‐value threshold (p&lt;1.0×10−6; CMTM7 [rs56284874G], RNF145 [rs111653954T], and CACNA2D3 [rs71303704C]). A previously reported FTLD‐TDP risk locus in TMEM106B (rs1990622A) showed a weaker positive association with LATE‐NC (meta‐analysis p = 9.6×10−4).ConclusionOur GWAS revealed LATE‐NC‐specific risk loci (SHANK2 and other suggestive loci). The unique genetic architecture of LATE‐NC further supports the distinction between LATE‐NC and FTLD‐TDP, and the AD‐independent effect of APOE ε4 on LATE‐NC highlights the pleiotropic role of APOE in neurodegeneration.

Associations of APOE4 and Alzheimer’s disease biomarkers with cortical reinstatement and episodic memory in clinically unimpaired older adults

AbstractBackgroundCortical reinstatement is a key neural correlate of episodic remembering across the lifespan and explains significant variability in memory performance among older adults. We assessed whether Alzheimer’s disease (AD) risk factors – cerebrospinal fluid (CSF) Aβ42/Aβ40, CSF pTau181, plasma pTau181, and APOE genotype – impact cortical reinstatement in clinically unimpaired older adults.MethodParticipants were 150 clinically unimpaired older adults enrolled in the Stanford Aging and Memory Study (SAMS). APOE genotype was determined from whole‐genome sequencing and participants were classified as ε4 carriers (N = 38) or non‐carriers (N = 112). CSF Aβ42/Aβ40 and pTau181 and plasma pTau181 were quantified using the automated Lumipulse G system. Cortical reinstatement was quantified during successful retrieval of word‐picture associations using fMRI multivoxel pattern analysis (MVPA) in five regions of interest, including parahippocampal gyrus (PHG), ventral temporal cortex (VTC), middle temporal gyrus (MTG), angular gyrus (ANG), and posterior medial cortex (PMC). Regression analyses examined cross‐sectional relationships between regional cortical reinstatement and a) APOE genotype (N = 150), b) CSF Aβ42/Aβ40 and pTau181 (N = 113), and (c) plasma pTau181 (N = 140), as well as associations of these variables with associative memory discrimination (d’). All models included age, sex, and regional MVPA classifier accuracy during memory encoding.ResultAPOE ε4 genotype was negatively associated with reinstatement strength in VTC (β = ‐0.54, p &lt; .005), MTG (β = ‐0.32, p &lt; .05), and ANG (β = ‐0.32, p &lt; .05) and CSF Aβ42/Aβ40 burden was linked to weaker reinstatement in ANG (β = 0.16, p &lt; .05). In VTC, the effect of APOE ε4 on reinstatement remained significant after controlling for CSF Aβ42/Aβ40 (β = ‐0.47, p &lt; .05); a similar pattern was observed in MTG and ANG. Although CSF pTau181 was unrelated to reinstatement strength, both pTau181 and cortical reinstatement explained unique variance in memory performance (pTau181: β = ‐0.26, p &lt; .005, reinstVTC: β = 0.39, p &lt; .001). Analogous findings were observed with plasma pTau181.ConclusionThese results suggest that APOE ε4 impacts cortical reinstatement, and that this effect may be independent of amyloid burden. These effects of APOE ε4 may be distinct from tau‐mediated effects on episodic memory in human aging.

Naturalistic Assessment of Reaction Time Variability in Older Adults at Risk for Alzheimer’s Disease

AbstractBackgroundBreakdowns in attentional control may underscore cognitive changes seen in the earliest stages of Alzheimer’s disease (AD). One way to measure these changes is to assess variability in cognitive performance. Variability in cognition may be most evident when repeatedly sampled over hours or days and in different environmental contexts or at different times of day. We analyzed data from an ongoing smartphone‐based study of cognition in AD which utilizes extremely brief cognitive tests taken remotely over several days in natural environments.MethodOlder adults (N = 319, aged 75 +/‐ 5 years) completed repeated cognitive testing on the Ambulatory Research in Cognition (ARC) platform and had CSF or PET amyloid biomarkers and APOE genotype available. RTSD was assessed in a brief processing speed task by taking the SD of correct RTs. All models adjusted for baseline age, education, and gender.ResultAveraging across sessions, symptomatic participants (indicated by Clinical Dementia Rating® (CDR®) &gt; 0) showed more variability than asymptomatic (CDR 0) participants (p = 0.009). APOE ε4 carriers showed more variability than non‐carriers, although this was not significant (p = 0.067). More fine‐grained models considered RTSD within each session (e.g. from trial‐to‐trial) using mixed effects models. Symptomatic participants exhibited greater trial‐to‐trial RTSD compared to asymptomatic participants (p = 0.001). APOE ε4 carriers also exhibited greater trial‐to‐trial RTSD compared to non‐carriers (p = 0.004). When limiting the sample to asymptomatic participants to determine if there were changes in the preclinical stage of AD, there remained a strong APOE ε4 effect, with carriers exhibiting greater trial‐to‐trial RTSD than non‐carriers (p = 0.005). Interestingly, amyloid was not significant in any models.ConclusionOlder adults at risk for AD show increased RTSD even in brief assessments. These subtle fluctuations in attention were most evident in APOE e4 carriers at very short time intervals, and less so when averaged across trials and sessions. Overall, these findings suggest that fluctuations in attention in preclinical AD are most evident from moment to moment, highlighting the need for fine‐grained and repeated assessment of attentional control.

APOE ε4-Allele in Middle-Aged and Older Autistic Adults: Associations with Verbal Learning and Memory.

Autism spectrum disorder (ASD) is a neurodevelopmental disability and recent evidence suggests that autistic adults are more likely to develop Alzheimer's disease (Alz) and other dementias compared to neurotypical (NT) adults. The ε4-allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alz and negatively impacts cognition in middle-aged and older (MA+) adults. This study aimed to determine the impact of the APOE ε4-allele on verbal learning and memory in MA+ autistic adults (ages 40-71 years) compared to matched NT adults. Using the Auditory Verbal Learning Test (AVLT), we found that ε4 carriers performed worse on short-term memory and verbal learning across diagnosis groups, but there was no interaction with diagnosis. In exploratory analyses within sex and diagnosis groups, only autistic men carrying APOE ε4 showed worse verbal learning (p = 0.02), compared to autistic men who were not carriers. Finally, the APOE ε4-allele did not significantly affect long-term memory in this sample. These findings replicate previous work indicating that the APOE ε4-allele negatively impacts short-term memory and verbal learning in MA+ adults and presents new preliminary findings that MA+ autistic men may be vulnerable to the effects of APOE ε4 on verbal learning. Future work with a larger sample is needed to determine if autistic women may also be vulnerable.

Detrimental Effects of ApoE ε4 on Blood-Brain Barrier Integrity and Their Potential Implications on the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease representing the most common type of dementia in older adults. The major risk factors include increased age, genetic predisposition and socioeconomic factors. Among the genetic factors, the apolipoprotein E (ApoE) ε4 allele poses the greatest risk. Growing evidence suggests that cerebrovascular dysfunctions, including blood-brain barrier (BBB) leakage, are also linked to AD pathology. Within the scope of this paper, we, therefore, look upon the relationship between ApoE, BBB integrity and AD. In doing so, both brain-derived and peripheral ApoE will be considered. Despite the considerable evidence for the involvement of brain-derived ApoE ε4 in AD, information about the effect of peripheral ApoE ε4 on the central nervous system is scarce. However, a recent study demonstrated that peripheral ApoE ε4 might be sufficient to impair brain functions and aggravate amyloid-beta pathogenesis independent from brain-based ApoE ε4 expression. Building upon recent literature, we provide an insight into the latest research that has enhanced the understanding of how ApoE ε4, secreted either in the brain or the periphery, influences BBB integrity and consequently affects AD pathogenesis. Subsequently, we propose a pathway model based on current literature and discuss future research perspectives.