APOE Ε4 Allele Research Articles

The Effects of Hypertension on White Matter Microstructural and Vascular Imaging Metrics

AbstractBackgroundHypertension is one of the key vascular risk factors of AD and related dementia. Cerebral blood flow (CBF) and white matter (WM) integrity may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated if hypertension is related to WM microstructural and vascular imaging metrics in WM.MethodFour‐hundred‐seven subjects (age: 69.7±8.1 years) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core underwent MRI, including neurite orientation dispersion and density imaging (NODDI) and eight‐phase pseudo‐continuous ASL (PCASL). The subjects included 158 MCI, 111 APOE e4 allele carriers, 224 with hypertension, and 249 with impaired glycemic status which includes type 2 diabetes and prediabetics. Hypertension status was defined as SBP≥130mmHG and DBP≥80mmHG. The microstructural imaging metrics including intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI) were obtained from NODDI. The vascular imaging metric included CBF. CBF was obtained from PCASL sequence. Voxel‐wise linear regression analyses were performed to examine if CBF, ICVF, ISOVF, or ODI were related to hypertension adjusting for cognitive status, glycemic status, APOE e4 allele, age, sex, and years of education. All images were normalized into standard space. Tract‐based spatial statistics (TBSS) were used to normalize NODDI images. The false positive cluster thresholding was applied.ResultHypertensive subjects showed impairments in both microstructural and vascular imaging metrics. Based on Figures 1‐(A), 2‐(A) and 3‐(A), there are overlapping brain image voxels between the microstructural and vascular imaging metrics. Additionally, the hypertensive subjects showed significantly lower CBF, higher ISOVF, and higher ODI than normal subjects within the voxel clusters (Figures 1‐(B), 2‐(B), and 3‐(B)). Note that APOE e4 allele, glycemic status, and cognitive status also showed statistical significance in the NODDI parameters, but there was no association in CBF.ConclusionHypertension showed the potential association between the microstructural and vascular impairments in the WM. Each risk factor and cognitive status differently affected WM microstructural and vascular dynamic imaging parameters. These findings warrant further investigations of contributions of hypertension to the microstructural and vascular abnormalities in dementia.

The Effects of Hypertension on White Matter Microstructural and Vascular Imaging Metrics

AbstractBackgroundHypertension is one of the key vascular risk factors of AD and related dementia. Cerebral blood flow (CBF) and white matter (WM) integrity may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated if hypertension is related to WM microstructural and vascular imaging metrics in WM.MethodFour‐hundred‐seven subjects (age: 69.7±8.1 years) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core underwent MRI, including neurite orientation dispersion and density imaging (NODDI) and eight‐phase pseudo‐continuous ASL (PCASL). The subjects included 158 MCI, 111 APOE e4 allele carriers, 224 with hypertension, and 249 with impaired glycemic status which includes type 2 diabetes and prediabetics. Hypertension status was defined as SBP = 130mmHG and DBP = 80mmHG. The microstructural imaging metrics including intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI) were obtained from NODDI. The vascular imaging metric included CBF. CBF was obtained from PCASL sequence. Voxel‐wise linear regression analyses were performed to examine if CBF, ICVF, ISOVF, or ODI were related to hypertension adjusting for cognitive status, glycemic status, APOE e4 allele, age, sex, and years of education. All images were normalized into standard space. Tract‐based spatial statistics (TBSS) were used to normalize NODDI images. The false positive cluster thresholding was applied.ResultHypertensive subjects showed impairments in both microstructural and vascular imaging metrics. Based on Figures 1‐(A), 2‐(A) and 3‐(A), there are overlapping brain image voxels between the microstructural and vascular imaging metrics. Additionally, the hypertensive subjects showed significantly lower CBF, higher ISOVF, and higher ODI than normal subjects within the voxel clusters (Figures 1‐(B), 2‐(B), and 3‐(B)). Note that APOE e4 allele, glycemic status, and cognitive status also showed statistical significance in the NODDI parameters, but there was no association in CBF.ConclusionHypertension showed the potential association between the microstructural and vascular impairments in the WM. Each risk factor and cognitive status differently affected WM microstructural and vascular dynamic imaging parameters. These findings warrant further investigations of contributions of hypertension to the microstructural and vascular abnormalities in dementia.

Visit‐to‐visit blood pressure variability and medial temporal perfusion in APOE e4 homozygotes

AbstractBackgroundBlood pressure variability (BPV), independent of traditionally studied/targeted average blood pressure levels, is an emerging risk factor for cognitive impairment and Alzheimer’s dementia, possibly through links with cerebrovascular disease. Recent studies suggest vulnerability of the medial temporal lobes to tau accumulation and atrophy among individuals with elevated BPV, especially older APOE e4 carriers. Increased BPV has also been linked with lower cerebral blood flow (CBF) and perfusion decline in medial temporal regions, but it remains unclear how BPV and APOE e4 may interact to influence CBF. The aim of the current study was to determine whether the relationship between BPV and medial temporal lobe CBF varies by APOE e4 dose in older adults without dementia.Method105 older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent 3‐4 blood pressure measurements between study baseline and 12‐months follow‐up and arterial spin labeling (ASL)‐MRI at 12‐months follow‐up or later (range: 0 – 84 months). Visit‐to‐visit BPV was calculated as variability independent of mean. CBF was determined for medial temporal regions (residualized by precentral [reference region] CBF), including hippocampus, parahippocampal gyrus, and entorhinal cortex. Venipuncture determined APOE e4 allele count (0 alleles: n = 71; 1 allele: n = 28; 2 alleles: n = 6). Multiple linear regression examined the interaction of BPV x APOE e4 dose on medial temporal CBF, controlling for age, sex, race/ethnicity, antihypertensive use, mean blood pressure, and cerebral metabolism (FDG‐PET).ResultElevated BPV was associated with lower CBF in entorhinal cortex (ß = ‐.96 [‐1.62, ‐.31]; p = .005) and parahippocampal gyrus (ß = ‐.63 [‐1.26, ‐.0002]; p = .049) in individuals with 2 APOE e4 alleles, whereas BPV was not significantly associated with CBF in these regions in individuals with 0 or 1 APOE e4 alleles (p’s > = .08). There was no significant interaction of BPV x APOE e4 dose on hippocampal CBF.ConclusionHigher BPV is associated with lower medial temporal CBF in APOE e4/e4 carriers, suggesting BPV may be an understudied vascular risk factor for those at greatest genetic risk for Alzheimer’s disease, with potential therapeutic implications.

A novel analytic approach to examine the relationship between APOE4 allele status and CSF complement‐related proteins and signaling pathways

AbstractBackgroundThe mechanisms by which the APOE4 allele contributes to AD risk are unclear. Here, we tested the hypothesis that in cognitively normal adults, APOE4 allele is associated with a decrease in complement‐related proteins and downregulation of complement‐related pathways.MethodUntargeted LC‐MS/MS proteomics was conducted on CSF samples (n = 118) from APOE3/3, APOE3/4 and APOE4/4 individuals over age 60, with groups matched on age and sex. We developed a novel analytic approach (which we term “up/down analysis”) based on the directional consistency of the β‐coefficients from a linear model for the intensities of peptides mapping to a given protein with respect to APOE4 carrier status (APOE4‐/ APOE4+). The analysis involves two steps: 1) The direction of the beta‐coefficient (positive/up or negative/down) for the level of each peptide (the outcome variable) due to APOE4 carrier status was derived from linear regression models adjusting for age, sex, and study. 2) These β‐coefficients were tallied for all peptides from a given protein (i.e. number of positive/up versus negative/down β‐coefficients). We then tested the probability under a binomial distribution that the distribution of up versus down peptides from each protein would be as, or more extreme than what we found, with a = 0.05. Pathway enrichment analysis (using p‐values from binomial tests) was conducted using GAGE and functional annotations based on KEGG. We used Benjamini‐Hochberg for multiple comparison correction.ResultWe found 158 proteins for which the direction of peptide intensity was consistently up (+β‐coefficient) or down (‐β‐coefficient) with respect to APOE4 status beyond what would be expected by chance. Of these 158 proteins, 37 were from the complement pathway. Pathway enrichment analysis further supports the role of the complement system; as the top differentially expressed pathway (FDR <0.05) was related to complement signaling.ConclusionOur results suggest that APOE4 carriers have lower CSF levels of key complement cascade proteins, which has previously been viewed as an indicator of complement activation. These results may provide insights into the mechanisms by which APOE4 and associated complement‐related proteins and signaling pathways ultimately contribute to increased AD risk.

Modifiable dementia risk factor associations with AT(N) biomarkers: Findings from the European Prevention of Alzheimer’s Dementia study

AbstractBackgroundThere is strong evidence that targeting modifiable risk factors can maintain and improve cognitive function, as well as reducing risk for Alzheimer’s disease (AD) and other forms of dementia. Further, a discrete AT(N) profile exists for hallmark biomarkers: amyloid β (A), p‐tau (T) and neurodegeneration (N), to discriminate between AD and non‐AD pathological changes. Despite evidence of a biologically defined AD continuum and modifiable risk amelioration, there is a paucity of studies investigating modifiable risk factors with respect to AT(N) biomarkers. The aim of this study was to investigate how modifiable risk factors relate to the three hallmark AT(N) biomarkers of AD.MethodParticipants were drawn from the European Prevention of Alzheimer’s Disease (EPAD): a prospective, multicentre, pan‐European cohort study. Eligible participants underwent clinical and neurological assessments, brain magnetic resonance imaging, cerebrospinal fluid (CSF) collection, neuropsychological assessment and completed a variety of demographic, clinical, medical history and lifestyle surveys for 10 binary modifiable risk variables. Data were analysed via the NeuroToolKit Application (NTKApp, BetaVersion, 2022). Generalized additive models with penalized regression splines were used to model the associations between modifiable risk factor adherence and AT(N) biological criterion: A (CSF amyloid‐β 42 [Aβ42 pg/mL]); T (CSF phosphorylated‐tau 181 [p‐tau 181 pg/mL]); N (total hippocampal volume [mm3]).ResultOf the 2737 participants included, 56% were female (n = 1526), 39% had at least one APOE ε4 allele (n = 1598), with an average age of 66.0 years and 14.4 years of education. Adjusting for age, sex and APOE carrier status: age, APOE and traumatic brain injury (TBI) were significantly associated with CSF Aβ42; age, APOE, body mass index (BMI) and exercise were significantly associated with CSF p‐tau181; and age, sex and education were significantly associated with total hippocampal volume.ConclusionModifiable risk factors of less education, less exercise, TBI and higher BMI were all significantly associated with increased AD biomarker burden. Our results support previous studies identifying associations between modifiable risk factors and AD and suggest that early intervention strategies focused on education and lifestyle factors and improvements in prevention and treatment of TBI may modify risk profiles associated with cognitive decline.

Neurofibrillary tangle distribution in posterior cortical atrophy and early‐onset Alzheimer disease

AbstractBackgroundEarly onset sporadic Alzheimer’s disease (AD) sometimes presents with non‐memory symptoms attributed to relatively greater neocortical than hippocampal tau neurofibrillary tangle (NFT) density. Posterior cortical atrophy (PCA) is a variant of AD presenting with visuospatial deficits and atrophy of the occipital cortex, yet the pathologic underpinning is poorly understood.MethodWe examined brains of 50 patients with early onset (age<65 y.), autopsy‐confirmed AD from the UCSD Alzheimer’s Disease Research Center, 12 of whom were clinically diagnosed with PCA. Immunohistochemistry for tau was performed in the hippocampus (HP), midfrontal cortex (MF), and occipital cortex (OC), and the density of NFTs was measured.ResultPCA and non‐PCA patients did not significantly differ in age (63.35±4.59 y. at death) or sex (40% female). The APOE ε4 allele was much less frequent in PCA (p = 0.002). While the PCA group was less impaired on the MMSE (p = 0.01), they performed comparably on the CDR sum‐of‐boxes. The OC NFT density did not differ between the groups; however, the OC/HP (p = 0.04) and OC/MF (p = 0.008) ratios demonstrate that PCA cases had relatively greater OC pathology than non‐PCA patients. Across the groups, age at symptom onset was inversely associated with OC NFT density (p = 0.01) and the OC/HP NFT ratio (p = 0.008), such that earlier onset was associated with greater OC NFT burden. Visuospatial performance, measured by the Block Design test, was associated with the OC NFT density (p = 0.006), as well as the OC/HP (p = 0.007) and OC/MF NFT ratios (p = 0.03), with the effects remaining significant when restricting to non‐PCA participants. In contrast, memory performance measured by the Logical Memory Immediate Recall measure was only associated with HP NFT density (p = 0.02).ConclusionDespite differences in the predominance of early visuospatial symptoms, PCA and non‐PCA patients did not differ in OC tangle density, with some of the highest densities in non‐PCA patients. However, the degree of visuospatial impairment was associated with the OC/HP NFT ratio across both groups. Results suggest that greater memory impairment in the non‐PCA patients associated with a higher HP tangle density may moderate the predominance of visuospatial impairment so that they do not receive a formal PCA diagnosis.

APOE ε4 is associated with reduced myelin and thus faster rate of tau PET accumulation

AbstractBackgroundMyelin is the cholesterol‐rich layer ensheathing axons in the white matter (WM). The APOE ε4 allele has been associated with both reduced cholesterol transport to myelin layers in mice and with faster tau progression in individuals with AD. Here we asked the questions whether 1) APOE ε4 is associated with lower myelin and 2) any myelin decreases mediate the association between APOE ε4 and the rate of tau‐PET accumulation in Aβ+ individuals. To assess myelin, we repurposed florbetapir‐PET tracer binding, previously shown to be sensitive to myelin binding protein in the WM (Stankow et al. Annals Neurol 2011).MethodWe included 43 Aβ‐ cognitively normal (CN, global florbetapir SUVR < 1.11) and AD‐spectrum participants (56 CN Aβ+, 32 MCI Aβ+, and 20 AD Aβ+) from ADNI. To extract individual myelin levels, we averaged each participant’s florbetapir SUVR within individual T1‐MRI based WM masks (global myelin) or 58 fiber‐tracts generated from multishell DTI (fiber‐tract myelin). To control for a putative influence by grey‐matter florbetapir levels, we adjusted the individual WM‐florbetapir SUVRs for grey‐matter florbetapir SUVR via linear regression analysis and computed z‐scores of the adjusted WM‐florbetapir SUVRs across all participants (Moscoso et al. EJNNMI, 2022). For tau‐PET, flortaucipir SUVRs were extracted in Braak‐stage GM ROIs or in the tracts’ cortical projection zones, and mixed effect linear regression was used to estimate the rate of regional flortaucipir change.ResultHigher APOE ε4 score was associated with both lower WM‐florbetapir z‐score (β = ‐0.329, p<0.001) and faster tau‐PET increase in Braak stage 3+4 ROIs (β = 0.224, p = 0.01) in Aβ+ participants (Fig. 1A&B). Using bootstrapped mediation analysis, we found that the WM‐florbetapir z‐score mediated the effect of APOE dosage on the rate of tau‐PET accumulation in Braak 3+4 (b = 2´10‐4 [95% CI: 2´10‐5, 3´10‐4], p = 0.02, Fig 1C). At the fiber‐tract level, APOE ε4 dosage exacerbated the association between decreased fiber‐tract florbetapir and faster tau‐PET increase in the tracts’ projection zones (p<0.001).ConclusionAPOE ε4 may contribute to the accumulation of tau pathology in a myelin dependent manner. Myelin impairment is treatable by several known drugs and therefore an attractive therapeutic target in AD.

PSP/DEGESCO: A Progressive Supranuclear Palsy Genome‐Wide Association Study in the Spanish Population

AbstractBackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy. We genotyped all the available histopatologically confirmed PSP cases from the Spanish National Biobank Network and patients with a probable PSP diagnosis recruited from research groups linked to the Dementia Genetics Spanish Consortium (DEGESCO). Here, we present the results of the genome‐wide association study (GWAS) performed after the first stage of this project.MethodDNA samples were genotyped by the Centro Nacional de Genotipado (Santiago de Compostela, Spain) using the Affymetrix Axiom 815K Spanish biobank array. After quality control, we kept 156 histopathological (discovery) and 197 clinical (validation) PSP samples. Then, we selected 650 and 800 sex‐matched controls from GR@ACE/DEGESCO for stratified genome‐wide association of the discovery and validation sets, respectively (Table 1). We ran PC1‐4 adjusted logistic regressions with plink v2.00 and meta‐analyzed the discovery and validation sets using METAL. Finally, we meta‐analyzed our results with 36 previously reported SNPs1 reaching the largest PSP sample size to date (N = 3053).ResultWe found a strong genome‐wide significant (GWS) signal associated to the MAPT H1/H2 haplotype (rs8070723 G: OR = 3.40; 95%CI = 2.64‐4.39; p = 2.60·10−20, Figure 1) and identified a previously unreported signal in chromosome 7p13 (rs76827509 T: OR = 0.45; 95%CI = 0.35‐0.58; p = 3.09·10−10). We replicated, with nominal significance, 5 GWS SNPs reported in previous GWAS (Table 2) and found significant effects for NFASC and TOMM40. Because APOE and TOMM40 are in strong linkage disequilibrium, we also checked the effect of APOE variants. We found a protective effect (OR = 0.66; 95%CI = 0.48‐0.90; p = 9.75·10−3) of the rs429358 C allele (APOE ε4) in our dataset.ConclusionThe strong GWS signal of the H1 haplotype confirms the validity of our GWAS results2. We were able to replicate several PSP loci (Table 1). The NFASC variant reached borderline GWS significance after meta‐analysis and is a good PSP risk factor candidate. Finally, the APOE ε4 allele was protective for PSP in our cohort. The second stage of PSP/DEGESCO genotyped 218 additional PSP samples. 1 Sanchez‐Contreras, M. Y. et al. Mol. Neurodegener. (2018) 2 Höglinger, G. U. et al. in Nature Genetics (2011)

P173: Structural Changes in the Hippocampal Subfields in Early-Onset Mild Cognitive Impairment

Objective:The aim of this study was to examine the structural change in the hippocampal subfields in early-onset (EO) mild cognitive impairment (MCI) patients associated with the APOE ε4 carrier state.Methods:This study had 50 subjects aged 55-63 years, all of whom were diagnosed with amnestic MCI at baseline via the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K). The EO-MCI patients were divided into the MCI continued (MCIcont) and Alzheimer’s disease (AD) converted (ADconv) groups 2 years later. The volumes of hippocampal subfields were measured for all the subjects. The calculations were based on the change of the volumes between the 2-year-interval brain Magnetic resonance image (MRI) scans between MCIcont and ADconv groups according to the Apolipoprotein ε4 (APOE ε4) carrier state.Results:There was a significant correlation between APOE ε4 allele and structural changes in several hippocampal subfields. The volume reduction in cornus ammonis 1 (CA1) field and subiculum, especially in the APOE ε4 carriers. The significance was more prominent in ADconv group.Conclusion:These results suggest that the possession of APOE ε4 allele may lead to significantly greater predilection for the structural changes in hippocampal subfields, showing significant changes, especially in the ADconv patients compared with MCIcont patients.

Characterization of an African ancestry‐specific protective allele of the APOE ε4 allele for Alzheimer’s disease risk

AbstractBackgroundWe recently identified a protective interaction between the APOE ε4 allele and an African ancestry‐specific allele (rs10423769_A) significantly reducing the odds ratio for Alzheimer’s disease by 75% in APOE ε4 homozygous carriers. rs10423769 is located approximately 2 mB upstream of APOE in a large area of segmental duplication, within a cluster of pregnancy specific beta‐1 glycoproteins (PSG) genes and a long noncoding RNA, lncRNA (ENSG00000282943). Hi‐C analysis in multiple brain cell types showed no direct chromatin interactions between APOE and the rs10423769 region. rs10423769 has been reported to be a splicing quantitative trait locus for the transmembrane protein 145 gene (TMEM145), which has the highest expression in cerebellum.MethodsSince this interaction region is enriched for segmental duplications, long‐read whole genome sequencing was performed on 16 individuals (nine heterozygous and seven homozygous rs10423769_A carriers) using the Oxford Nanopore PromethION24 to more precisely map this variant. Expression of PSG genes (2, 4, 5 and 11), ENSG00000282943, and TMEM145 isoforms were analyzed by qPCR in cerebellum and frontal cortex of carriers and non‐carriers of rs10423769_A. Hi‐C analysis was conducted in these brain samples as well.ResultsNanopore long‐read sequencing showed that rs10423769 is present as a single copy on chromosome 19. In the frontal cortex, preliminary Hi‐C results supported the presence of transcriptionally active chromatin over the PSG region in some individuals but not in others. Both PSG genes and the lncRNA had low expression in the frontal cortex and cerebellum. We observed higher TMEM145 expression in the cerebellum compared to frontal cortex and detected alternative splicing forms of TMEM145. There was a trend of increased expression of TMEM145 in rs10423769_A carriers, which was not statistically significant likely due to sample size.ConclusionWe established that only one copy of rs10423769 exists in the modifying region, which will facilitate future haplotype analysis. The Hi‐C analysis suggested inter‐individual variations on chromatin structure over PSG genes in frontal cortex, although no expression of these genes was detected. Further analysis of regulatory activity of the region is ongoing. This modifier locus appears to represent a novel protective mechanism for APOE ε4.

Clinical Manifestations.

In Alzheimer's disease (AD), a long preclinical and prodromal period precedes dementia onset in which cognition declines slowly, but at variable rates for different domains. Positive AD biomarkers, (e.g., amyloid, Tau, or APOE ε4 carriage), increase rates of cognitive decline and transition to dementia. However, the extent to which cognitive decline, identified in some older adults, reflects neurodegenerative disease or normal aging in the absence of knowledge about biomarkers or genes is not well understood. We applied a novel approach to classify cognitive decline in individuals using six cognitive composite scores (AIBL Pre-clinical Alzheimer's Cognitive Composite (AIBL-PACC), episodic recall, attention, executive function, language and recognition). We examine group-wise differences across cognitive composite scores and assessed frequencies for AD biomarker positivity amongst the novel groups. Prospective data from 1,389 Cognitively unimpaired (CU) participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing were analysed using an unsupervised multivariate mixture modelling framework, accounting for age, gender and APOE ε4 allele status. Participants cognitive status was classified for their final visit. The cognitive profile and biomarker characteristics of adults with abnormal cognitive decline was compared. Differences in composite score values between cognitive decline and no decline groups were strongest for episodic recall (Cohen's d = 1.49) and the AIBL-PACC score (Cohen's d = 1.45, Table 1, Figure 1A). By comparison, differences in composite scores between Aβ-PET groups, or APOE ε4 allele carriers/non-carriers were of less magnitude (Table 1, Figure 1). Participants with cognitive decline were more likely to be amyloid positive, (decline: 42% vs no decline: 28%, p<0.0001), but not ε4 allele carriers (decline: 28% VS no decline: 27%, p>0.05). A measure of objective cognitive decline, created using flexible mixture models with six cognitive composite scores from AIBL, has utility for discerning participants with early changes in cognition. Based upon using the cognitive data alone, this method was able to detect amyloid positivity in those CU participants with cognitive decline.

The Role of Apolipoprotein E4 Allele in the Gut Microbiome of Puerto Ricans with Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) causes dementia, a debilitating disorder that gradually declines mental function and ends with death. Evidence suggests that the apolipoprotein E (ApoE) gene influences Alzheimer’s risk. Allele E2 is neuroprotective, E3 is neutral, and E4 is associated with a higher genetic risk for AD. Our main goal was to study the gut microbiome of Puerto Ricans with AD compared to unimpaired cognitive controls and its association with ApoE allele variants. We hypothesized that people with AD and does with less protective alleles have reduced microbial diversity.MethodsWe present the preliminary results of forty eight participants (n = 48), 24 with AD and 24 controls, with clinical and cognitive assessments. Fecal samples were collected for genomic DNA extractions followed by 16S rRNA genes (V4 region) amplification and ApoE genotyping was done at the PR‐INBRE CRI genomics core, using real‐time PCR TaqMan‐BHQ probes.ResultsControls, even with a single E4 allele, showed higher abundance of Ruminococcus bicirculans, absent in AD patients. Clostridium leptum was in higher abundance in controls with neuroprotective alleles E2E3 and in considerably reduced abundance in AD patient with E3E4 phenotype. Methanobrevibacter was in higher abundance in participants with any E4 allele than those with either E2 or E3 alleles. Faecalibacterium and Bacteroides were in higher abundance in controls compared to AD patients. Faecalibacterium, Ruminococcus, Clostridium and Bacteroides are anti‐inflammatory taxa and butyrate producers. Methanobrevibacter could favor metabolizing acetate to methane and thus antagonize the health‐directed butyrate benefits.ConclusionParticipants with any ApoE E4 allele have decreasing butyrate‐producing gut bacteria. This developing study area may open the possibility for preventive microbiome‐based therapies that could result in a clinical benefit for patients with and without AD.

Alzheimer’s disease plasma markers and depressive symptoms: an IPD meta‐analysis

AbstractBackgroundDepression has been associated with an increased risk of Alzheimer’s disease (AD), but the biological mechanisms are still not fully understood. Plasma biomarkers, such as amyloid‐beta, tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL), have been associated with AD pathophysiology. However, the relationship with depression is unclear. Assessing these biomarkers in the blood allows for the opportunity to assess if AD pathology is related to depressive symptoms on a large‐scale. We hypothesized if depression is part of the AD process, then these markers will be associated with depressive symptoms.MethodA two‐stage IPD meta‐analysis was performed based on eight cohorts of individuals without dementia as part of the Netherlands Consortium of Dementia Cohorts (NCDC). We examined the cross‐sectional association between each plasma marker for AD (amyloid‐beta42/40 ratio, p‐tau181, NfL, and GFAP) with depressive symptoms (the GDS‐15, PHQ‐9, CES‐D, and SF‐36). Plasma markers were assessed using Single Molecular Array (Simoa; Quanterix) assays. Both plasma markers and depressive symptoms were standardized. We estimated the effect per plasma marker with depressive symptoms using linear regressions, correcting for age, sex, education, and APOE e4 allele presence, in each cohort. The effect estimates were entered into a random‐effects meta‐analysis. We also performed subgroup analyses assessing sex differences and between those with and without an APOE e4 allele.ResultThis study involved 7210 participants with an age range of 38 to 102 years. Based on clinical cut‐offs per questionnaire, high depressive symptomology ranged from one to 22% per cohort. None of the plasma markers were associated with depressive symptoms in the meta‐analysis. However, subgroup analyses found an association with NfL and depressive symptoms in women (beta 0.07; 95% CI: 0.03‐0.10, p &lt; 0.001) and in those with an APOE e4 allele (beta 0.11; 95% CI: 0.05‐0.17, p = 0.001).ConclusionAD pathology did not show an overall relationship with depressive symptoms. However, in women and in those with a genetic risk for AD, NfL showed an association. As NfL is a marker of overall neurodegeneration, this pathology in plasma may be specific to depressive symptoms in certain subgroups.

The moderating effect of APOE E4 on the association of plasma biomarkers with markers of cognition and brain health in Alzheimer’s disease

AbstractBackgroundDue to low success rates in clinical trials for Alzheimer’s disease (AD), there is a need to apply precision medicine approaches, such as stratifying based on APOE genotype, in order to assess its effects on outcome measures. Herein, we aim to better understand how plasma biomarkers of AD and neurodegenerative pathology are associated with cognition and neurodegeneration in APOE E4 carriers compared to non‐carriers.MethodPatients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) diagnosed with AD were included (n = 126, age = 71.0±8.2, 55%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using Simoa assays. Composite cognitive domain scores (attention &amp; working memory, executive function, language, memory, and visuospatial function) were computed from a comprehensive neuropsychological assessment. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted from 3T structural MRI sequences using the SABRE pipeline. Linear regression models with an interaction term, controlling for age, sex and education were used to test the moderating effect of the APOE E4 allele on the association of plasma biomarkers with cognitive and MRI variables. When interaction effects were significant, post‐hoc models stratified by APOE E4 carrier status and controlling for age, sex and education were assessed.ResultThe APOE E4 allele moderated the association of GFAP, NfL and p‐tau181 with memory. Further stratification revealed that higher levels of GFAP, NfL and p‐tau181 were all associated with worse memory only in APOE E4 carriers. APOE E4 was also found to moderate the association of GFAP and p‐tau181 with many imaging markers. Further stratification revealed that higher levels of GFAP were associated with increased white matter hyperintensities, ventricular expansion and grey matter atrophy (temporal lobe, occipital lobe, hippocampus, basal ganglia and thalamus) only in APOE E4 carriers. Higher levels of p‐tau181 were also associated with increased temporal, parietal, and hippocampal atrophy only in APOE E4 carriers.ConclusionPlasma biomarkers, especially GFAP and p‐tau181, appear to be significantly more predictive of memory deficits and brain neurodegeneration in APOE E4 carriers compared to non‐carriers in AD.

Lifelong cognitive reserve mitigates the genetic risk of APOE and TOMM40 variants for dementia in Chinese older adults: a cohort study

AbstractBackgroundEvidence has emerged that cognitive reserve (CR) could mitigate the genetic risk of APOE ε4 allele for dementia and Alzheimer’s disease (AD) in Caucasian and Black populations. Whether CR counteracts dementia risk attributable to TOMM40 variants is unknown. We examined whether lifelong CR might modify the risk of dementia and AD from APOE and TOMM40 variants among Chinese older adults.MethodThis population‐based cohort study included 2052 dementia‐free participants from the Shandong Yanggu Study of Aging and Dementia, who were free of dementia at baseline (2014‐2015) and underwent follow‐up examinations in March‐September 2018. APOE (rs429358 and rs7412) and TOMM40 (rs2075650) were defined using multiple polymerase chain reaction amplification. A lifelong composite CR score was generated from six lifespan intellectual factors and then dichotomized into high and low levels according to the median CR score. Dementia and AD were clinically diagnosed following the international criteria. Data were analyzed using Cox proportional‐hazards models. The interaction between CR and APOE or TOMM40 variants was assessed on multiplicative and additive scales.ResultDuring an average of 3.72 years (range, 2.98‐4.46) of follow‐up, dementia was diagnosed in 94 persons, including 70 with AD. Overall, carrying APOE e4 allele (vs. non‐carriers) was associated with multivariable‐adjusted hazard ratio of 1.50 (95%CI: 0.91‐2.50) for dementia and 1.71 (0.97‐3.01) for AD; the corresponding figures were 1.76 (1.09‐2.85) and 1.81 (1.04‐3.15) for carrying TOMM40 G allele (vs. AA), and 0.47 (0.27‐0.80) and 0.52 (0.27‐0.996) for high CR, respectively. There was a significant additive interaction of APOE or TOMM40 variants with CR on risks of dementia and AD. Compared to low CR, having high lifelong CR was associated with a lower risk of developing dementia and AD in APOE e4 carriers, with multivariable‐adjusted hazard ratios being 0.17 (95%CI: 0.04‐0.73) and 0.13 (0.02‐1.02); the corresponding figures were 0.23 (0.07‐0.81) and 0.13 (0.02‐1.02) in TOMM40 G carriers, and 0.22(0.06‐0.74) and 0.12(0.02‐0.91) in APOE‐e4 or TOMM40 G carriers, respectively.ConclusionCarrying TOMM40 G or APOE e4 allele is associated with increased risks of dementia and AD in Chinese older adults, and the genetic risk could be counteracted by high lifelong CR capacity.

Association of plasma biomarkers with cognitive domains across three neurodegenerative diseases and cerebrovascular disease

AbstractBackgroundIt is critical to better understand the value of plasma biomarkers in predicting cognitive deficits before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of neurodegenerative disease progression in trials. Herein, we investigate their association with five cognitive domains across three common neurodegenerative diseases and cerebrovascular disease.MethodPatients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer’s disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia spectrum disorders (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson’s disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Scores from a 26‐test comprehensive neuropsychological assessment were used to compute composite z‐scores for five cognitive domains: attention &amp; working memory, executive function, language, memory, and visuospatial function. Linear regression models controlling for age, sex, education and APOE E4 allele were used to test the association between plasma biomarkers and cognitive domains in each group separately.ResultIn AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with worse attention &amp; working memory, executive function, and memory. In PD, higher levels of NfL were associated with worse attention &amp; working memory, executive function, and visuospatial function; higher levels of GFAP were also associated with worse executive function. In CVD, higher levels of GFAP were associated with worse executive function, memory and visuospatial function; higher levels of p‐tau181 were also associated with worse memory. In FTD, no associations were found.ConclusionPlasma biomarkers indicative of neuronal and glial pathology are useful to predict the severity of widespread cognitive deficits in AD/MCI, PD, and CVD. Interestingly, p‐tau181 predicted memory deficits in both AD/MCI and CVD, suggesting potential mixed disease or pathological overlap. Plasma Aβ42/40 does not appear to predict any cognitive deficits in any of the neurodegenerative diseases studied. As FTD is highly heterogeneous and had the least number of patients, we are possibly lacking power to detect effects in this group.

Vascular contribution to the relationship between cerebrovascular reactivity and cognition

AbstractBackgroundBrain vascular health is closely related to cognitive performance, and cerebrovascular reactivity (CVR), an indicator of cerebral blood flow (CBF) compensatory capacity in response to vasoactive stimuli, may help elucidate this relationship. Arterial spin labeling (ASL) and blood‐oxygen‐level‐dependent (BOLD) are two representative methods for measuring CVR, although BOLD is a complex combination of CBF, cerebral volume, and cerebral metabolic rate of oxygen. This study aimed to investigate the relationship between cognition and two different CVR methods.MethodSeventy‐nine subjects (age: 68.7±7.2 years) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core underwent MRI, including both dynamic pseudo‐continuous ASL (PCASL) under a hypercapnic respiratory challenge and multi‐TI PCASL for resting CBF and ATT mapping. The dynamic PCASL with a longer TE (20ms) provided simultaneous acquisition of ASL and BOLD. CVR was obtained by calculating CBF or BOLD signal changes during a hypercapnic period. Voxel‐wise multiple linear regression analyses were performed to examine the relationship between CVR and mild cognitive impairment (MCI), adjusting for age, sex, glycemic status, APOE e4 allele, hypertensive status, and years of education. False positive cluster thresholding was applied for each modality. Additional statistical analyses were conducted to investigate differences in baseline CBF and ATT between cognitively healthy and MCI groups within the voxel clusters that showed significantly different CVR values.ResultIn the BOLD‐based CVR analysis, two voxel clusters in the white matter (WM) of superior temporal and parietal lobes showed lower CVR in the MCI group compared to the cognitively healthy group (Figure 1). Additionally, reduced CBF and prolonged ATT were observed within the clusters (Figure 2 and 3).ConclusionSubjects with MCI exhibited lower BOLD‐based CVR in WM, while no association was found between ASL‐based CVR and MCI. BOLD‐based CVR may be a more sensitive measure than ASL‐based CVR in association with cognition, particularly in WM where optimization of ASL acquisition is challenging. The impaired CVR in the MCI group may be due to cerebrovascular impairments, such as reduced CBF and prolonged ATT.

The effects of ApoE e4 genotype on plasma p‐tau181 concentrations on clinically diagnosed Alzheimer’s disease (AD) compared to controls

AbstractBackgroundThe association between ApoE e4, a powerful genetic risk factor for AD, and beta‐amyloid (Aβ) pathology has been reported, but the evidence for the correlation with tau pathology is not as clear. The current study examined the relationship between ApoE e4 allele and plasma concentrations of p‐tau181 in patients with clinically diagnosed AD compared with an age‐matched controls with normal cognitive function.MethodWe examined 302 EDTA plasma samples of patients assessed at the UBC Hospital Clinic for Alzheimer’s disease. The cohort was clinically characterized as controls (n = 59) if no significant cognitive impairment was found, and AD (n = 243) if they fulfilled the NIA‐AA criteria (McKhann 2011). The plasma ptau‐181 levels were measured using an ADx‐developed p‐tau181‐specific Simoa assay. ApoE genotyping was performed on extracted DNA from blood samples. We examined the association of presence of ApoE e4 allele and plasma p‐tau181 concentrations using two‐by‐two ANOVA using SPSS 29.ResultThe plasma concentrations of p‐tau181 in AD who are ApoE e4 carriers (75.4 pg/ml) were slightly higher than but not significantly different from in AD non‐ ApoE4 carriers (70.1 pg/ml) (p = 0.64). The plasma levels of ptau‐181 in control cases with and without the ApoE allele were 24.8 and 24 pg/ml respectively (p = 1.000). There was no statistical significant interaction between the effects of AD and ApoE e4 carrier status on plasma p‐tau181 (F (1, 298) = 0.21, p = 0.65, ηp2 = 0.001).ConclusionWhile the plasma p‐tau181 concentrations were significantly higher in AD groups compared to controls (p&lt;0.001) it was no significant effect of ApoE e4 genotype on the levels of plasma p‐tau181 in the control or AD groups (p = 0.94, p = 0.21). This suggests that the ApoE e4 carrier status does not affect plasma p‐tau181 concentrations significantly, independent of the AD clinical status.

Sex‐ and APOE‐Specific Transcriptomic Signatures in Alzheimer’s Disease: An AZ‐ADRC‐Research Education Scholars Team Science Project

AbstractBackgroundAge, female sex and APOEε4 allele are among the top risk factors for developing late‐onset Alzheimer’s disease (LOAD). To enable Precision medicine for AD drug development, it is crucial targeting specific biological pathways driving AD pathology. While individual effects of sex or APOE have been studied, genes and biological pathways commonly or uniquely altered by these two factors are less understood.MethodROSMAP RNA‐Seq data were obtained from AMP‐AD including 369 frontal cortex samples from APOEε3/ε3 and APOEε3/ε4 individuals. Of these, 209 had an AD diagnosis and 160 were controls. Differentially expressed genes (DEGs, pvalue&lt;.05) between LOAD and cognitively normal individuals were identified using a generalized linear regression model. Gene Set Enrichment Analysis (GSEA) was performed using Gene Ontology Biological Processes (GOBP). Redundant GOBP enriched terms were removed computing semantic similarity measures (adjusted pvalue&lt;.05). Comparison analyses were conducted to identify common and unique DEGs and enriched GOBPs across sex‐genotype conditions.ResultAPOEε3/ε3 female brains exhibited the greatest DEG number (n = 11,851) while APOEε3/ε3 males exhibited the least (n = 714). Nine DEGs were shared across all comparisons, which were involved in metabolic processes, synaptic function, myelination, and GPCR signaling. GSEA revealed comparable numbers of LOAD‐enriched pathways in all female groups and male APOEε3/ε4s (n = 144‐155 GOBP terms), whereas APOEε3/ε3 males exhibited the fewest enriched terms (n = 13). Identified GOBP terms included pathways related to metabolism, cellular responses and regulation, and immune response regulation. However, there were no common GOBP terms across all sex‐genotype conditions.ConclusionOur analyses provide evidence of sex‐ and APOE‐ specific transcriptomic signatures and biological processes altered in LOAD brains. The findings suggest significantly greater transcriptomic dysregulation in female APOEε3/ε3 brains despite the similar extent of affected biological pathways as other sex‐APOE conditions. In contrast, a significantly smaller number of affected biological processes were identified in male APOEε3/ε3s despite having comparable transcriptomic dysregulation as the male APOε4 carriers but less than the female groups. These analyses provide rationale to develop risk factor‐specific therapeutics for the prevention and treatment of LOAD by considering the interaction between biological sex and APOE genotype.

APOEε4 potentiates the effects of Aβ pathology on the deposition of neurofibrillary tangles via tau phosphorylation

AbstractBackgroundThe mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOEε4 carriership and amyloid‐β (Aβ) burden with longitudinal tau pathology progression.MethodWe studied 104 individuals across the aging and AD clinical spectrum from the McGill TRIAD cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as an additional follow‐up tau‐PET scan (mean follow‐up, 2.4 years). We further assessed longitudinal changes in tau phosphorylation (plasma phosphorylated tau at threonine 217 [p‐tau217+]), brain atrophy (gray matter density), and clinical function (clinical dementia rating scale sum of boxes).ResultWe found that APOEε4 carriership potentiates Aβ effects on longitudinal tau tangle accumulation over two years (Figure 1). Interestingly, the APOEε4‐potentiated Aβ effects on tangles were mediated by longitudinal plasma p‐tau217+ increase (Figure 2). In addition, this longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline during the follow‐up period (Figure 3).ConclusionOur results support a model in which the APOEε4 allele plays a key role in Aβ downstream effects on the aggregation of phosphorylated tau in the form of neurofibrillary tangles in the living human brain, which is a key factor in the development of dementia. These observations have important implications for the design of future trials by suggesting that the combination of therapies targeting both ApoeE4 and Aβ pathology might have the potential to synergistically halt tau progression in AD.