APOE Status Research Articles

Predicting the apolipoprotein E ε4 allele carrier status based on gray matter volumes and cognitive function.

Apolipoprotein E (ApoE) ε4 carriers have a higher risk of developing Alzheimer's disease (AD) and show brain atrophy and cognitive decline even before diagnosis. To predict ApoE ε4 status using gray matter volume (GMV) obtained from magnetic resonance imaging images and demographic data with machine learning (ML) methods. We recruited 74 participants (25 probable AD, 24 amnestic mild cognitive impairment, and 25 cognitively normalolder people) with known ApoE genotype (22 ApoE ε4 carriers and 52 noncarriers) and scanned them with three-dimensional (3D) T1-weighted (T1W) and 3D double inversion recovery (DIR) sequences. We extracted GMV from regions of interestrelated to AD pathology and used them as features along with age and mini-mental state examination (MMSE) scores to train different ML models. We performed both receiver operating characteristiccurve analysis and the prediction analysis of the ApoE ε4 carrier with different ML models. The best model of ML analyses was a cubic support vector machine (SVM3) that used age, the MMSE score, and DIR GMVs at the amygdala, hippocampus, and precuneus as features (AUC=.88). This model outperformed models using T1W GMV or demographic data alone. Our results suggest that brain atrophy with DIR GMV and cognitive decline with aging can be useful biomarkers for predicting ApoE ε4 status and identifying individuals at risk of AD progression.

MARKERS OF GLUCOSE METABOLISM ARE ASSOCIATED WITHCCOGNITIVE DECLINE AMONG FAMILIES WITH EXCEPTIONAL SURVIVAL

Abstract Although the connection between type 2 diabetes (T2D) and dementia is known, it is less clear whether this relationship extends to cognitive decline. Our aim was to examine whether baseline fasting plasma glucose, insulin, HOMA-IR, and HbA1c, and T2D status predict cognitive decline in a multicenter cohort study of families with a clustering of exceptional survival. We analyzed change across five cognitive tests collected over 7.9 years: Mini-Mental State Examination, Digit Span, Logical Memory, Animal Fluency and Digit Symbol Substitution. Among 2,175 family members (mean age 63±11 years (range 32-100); 54% women), 39.8% had prediabetes and 6.8% had T2D. Multiple linear mixed models were adjusted for age, sex, field center, education, APOEε4 status, BMI and family relatedness. A trend was observed for immediate (p=0.047) and delayed (p=0.037) memory, with normal glucose tolerance (NGT) predicting increased scores, prediabetes showing no change, and T2D predicting decreased scores. Among those without T2D (N=2,026), each standard deviation (SD) higher glucose (11.5 mg/dl) was related to a greater decline in delayed memory (-0.34±0.16mg/dl; p=0.032), each SD higher HbA1c (0.32%) was related to a greater decline in immediate (-0.36±0.15 mg/dl; p=0.016) and delayed (-0.31±0.16 %; p=0.05) memory, while each SD higher HOMA-IR (1.5) was related to a greater decline in Digit Span Backwards (-0.13±0.06; p=0.047). Findings suggest that among individuals with a clustering of exceptional survival, T2D, glucose, and HbA1c may predict greater decline in episodic memory, an ability typically affected early in Alzheimer dementia. The possible mechanisms, including genetic and metabolic mediators, warrant further investigation.

ASSOCIATIONS BETWEEN CLINICAL FUNCTIONING AND AD BIOMARKERS AMONG HISPANIC AND WHITE NON-HISPANIC OLDER ADULTS

Abstract Objectives Hispanics are 1.5x more likely to develop Alzheimer’s disease (AD) when compared to White non-Hispanics (WNHs). There is also evidence to support that cognitive performance disproportionately reflects neuropathology among Hispanics and that functional decline is concurrent with the accumulation of AD biomarkers. The current study aimed to examine relationships between AD biomarkers and a functional measure among Hispanic and WNH older adults. It was hypothesized that the functional measure would be strongly related to AD biomarkers among Hispanics. Methods The modified clinical dementia rating scale (mCDR) was administered in the participants primary language (English or Spanish) to WNH (n=203) and Hispanic (n=258) older adults who were cognitive normal or diagnosed with Mild Cognitive Impairment (MCI) or dementia. Invariance SEM models were used to compare the pattern of relationships between the mCDR and neurocognitive test performance, MRI volumes, and amyloid load adjusting for age, education, ApoE4 status, and intracranial volume. Results Model fit was good and not significantly worsened by imposing strict structural invariance. Nested model comparisons indicated that regression weights and correlations among measures differed by group, suggestive of moderation by Hispanic status. Among Hispanic participants, sex (♌=-0.17, p<.05) and Amyloid load (♌=0.25, p<.001) significantly predicted mCDR scores. MRI volumes significantly predicted MCDR scores among both Hispanic (♌=-0.51, p<.001) and WNH participants (♌= -0.42, p<.001). Conclusions Functional measures like the mCDR may better correlate with Amyloid load among Hispanic older adults than among WNHs, while the correlation with MRI volumes may be comparable in both groups.

SOCIAL SUPPORT BUFFERS THE EFFECT OF APOE4 GENE ON COGNITION

Abstract APOE4 allele is one of the most robust genetic risks for Alzheimer’s Disease (AD). It is associated with an earlier onset and conversion from Mild Cognitive Impairment (MCI) to AD dementia. Several studies have shown epigenetic interactions between the social context and the APOE4 allele’s relationship with cognition. Still, explorations of social risk factors for AD in genetically vulnerable populations are limited. This study explored whether the positive effects of social support (SS) on cognition are affected by APOE status in a sample of 115 older adults (n = 72.25, SD = 8.29). SS was measured using the Multidimensional Scale of Perceived Social Support (MSPSS), the preclinical Alzheimer’s Cognitive Composite-5 (PACC5) score to assess concurrent cognition, and the APOE polymorphism was determined via genotyping. As hypothesized, SS buffered the effect of APOE4 gene on PACC5 score, F(1, 107)=5.18, p = .02, Δ R2=.02. Specifically, older individuals who were positive for the allele displayed a significant and positive association between SS and mPACC5 (b=.19, p = .03). This relationship was not found for those who were APOE4 negative (b = -.04, p =.49). These results support the need to consider the epigenetic influence of social factors on later-life cognition, especially for those at risk for developing AD.

Predicting Amyloid-β Positivity in Alzheimer’s Disease: Comprehensive Analysis of Feature Selection and Machine Learning Models for Accurate Identification

To accurately identify individuals at risk of Alzheimer’s disease (AD), it is crucial to develop precise tools for predicting amyloid-β (Aβ) positivity in the brain. We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to analyze 1,377 human subjects. These participants were divided into five groups: cognitive normal (CN), subjective memory complaints (SMC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and confirmed AD. Each group was further divided into ten subgroups based on sex, resulting in a comprehensive analysis. The dataset was used to create and evaluate the performance of 15 machine learning (ML) models. A set of 17 potential predictors was generated by combining variables from different categories, including six demographic factors (such as age), ten measurements (such as ADAS13), and APOE4 status. Through ML-based predictive modeling, several cognitive assessment measures, including ADAS13, demonstrate significant importance in multiple ML models. The highest accuracies in the 10 subgroups were 0.875, 0.892, 0.778, 0.850, 0.771, 0.739, 0.781, 0.791, 0.879, and 0.903, respectively. The collection of ML models consists of practical and valuable risk feature scores that can significantly enhance the identification of individuals who are likely to test positive for Aβ.

Tau PET burden in Brodmann areas 35 and 36 is associated with individual differences in cognition in non-demented older adults.

The accumulation of neurofibrillary tau tangles, a neuropathological hallmark of Alzheimer's disease (AD), occurs in medial temporal lobe (MTL) regions early in the disease process, with some of the earliest deposits localized to subregions of the entorhinal cortex. Although functional specialization of entorhinal cortex subregions has been reported, few studies have considered functional associations with localized tau accumulation. In this study, stepwise linear regressions were used to examine the contributions of regional tau burden in specific MTL subregions, as measured by 18F-MK6240 PET, to individual variability in cognition. Dependent measures of interest included the Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini Mental State Examination (MMSE), and composite scores of delayed episodic memory and language. Other model variables included age, sex, education, APOE4 status, and global amyloid burden, indexed by 11C-PiB. Tau burden in right Brodmann area 35 (BA35), left and right Brodmann area 36 (BA36), and age each uniquely contributed to the proportion of explained variance in CDR-SB scores, while right BA36 and age were also significant predictors of MMSE scores, and right BA36 was significantly associated with delayed episodic memory performance. Tau burden in both left and right BA36, along with education, uniquely contributed to the proportion of explained variance in language composite scores. Importantly, the addition of more inclusive ROIs, encompassing less granular segmentation of the entorhinal cortex, did not significantly contribute to explained variance in cognition across any of the models. These findings suggest that the ability to quantify tau burden in more refined MTL subregions may better account for individual differences in cognition, which may improve the identification of non-demented older adults who are on a trajectory of decline due to AD.

Predicting clinical progression trajectories of early Alzheimer's disease patients.

Models for forecasting individual clinical progression trajectories in early Alzheimer's disease (AD) are needed for optimizing clinical studies and patient monitoring. Prediction models were constructed using a clinical trial training cohort (TC; n=934) via a gradient boosting algorithm and then evaluated in two validation cohorts (VC 1, n=235; VC 2, n=421). Model inputs included baseline clinical features (cognitive function assessments, APOE ε4 status, and demographics) and brain magnetic resonance imaging (MRI) measures. The model using clinical features achieved R2 of 0.21 and 0.31 for predicting 2-year cognitive decline in VC 1 and VC 2, respectively. Adding MRI features improved the R2 to 0.29 in VC 1, which employed the same preprocessing pipeline as the TC. Utilizing these model-based predictions for clinical trial enrichment reduced the required sample size by 20% to 49%. Our validated prediction models enable baseline prediction of clinical progression trajectories in early AD, benefiting clinical trial enrichment and various applications.

Multimodal Exercise and Cognitive Training Program Improves Cognitive Function in Amnestic Mild Cognitive Impairment

To investigate the preliminary efficacy of a combined physical exercise + cognitive training intervention for older adults with amnestic mild cognitive impairment (aMCI). Randomized clinical trial. Veteran Affairs Hospital, Palo Alto, CA. Sample included 72 community-dwelling volunteers (mean age 72.4 ± 9.5) diagnosed with aMCI. Participants were randomized to either a combined aerobic and resistance exercise + cognitive training (CARE+CT) or stretching exercise + CT (SE+CT). Primary outcomes included intervention specific assessments of word list and name-face recall. Secondary cognitive outcomes included standardized composite scores that reflect cognitive domains (e.g., learning and memory, executive function, processing speed, visuospatial ability, language). Secondary physiological outcomes included VO2 max and functional capacity (e.g., distance walked 6-minute walk test). APOE and BDNF were determined from whole blood samples. Controlling for age and employment status, linear mixed effects models revealed that all participants experienced significant improvement in the delayed recall of word list, learning and memory and executive function. Only the CARE+CT condition had significant improvement in processing speed and functional capacity. APOE4 status impacted cognitive benefits of those in the SE+CT condition. Results provide preliminary support for combined exercise and cognitive training interventions for older adults with aMCI. Further research is needed to understand the mechanisms involved as well as the impact of these interventions in diverse samples. ClinicalTrials.gov Identifier: NCT01962038.

Effect of Interaction between APOE genotype and Type 2 diabetes on Cognitive and Neuropathology features

AbstractBackgroundType 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are common diseases in aging populations. Multiple large epidemiological studies suggest that T2DM is strongly associated with cognitive impairment and dementia. Prior studies suggest T2DM may be an important modifier of the relationship between AD and APOE, which is the strongest known genetic risk factor of AD.MethodWe obtained study data from the National Alzheimer’s Coordinating Center (NACC) and included 30,483 participants aged ≥60 years at baseline. T2DM status was determined based on any self‐reported diabetes diagnosis or anti‐diabetes treatment during annual assessments. To facilitate analysis, we created two binary variables to classify participants with regard to T2DM (presence or absence) and APOEε4 (carrier or non‐carrier) status. Cognitive domain scores for memory, attention, language and executive function were standardized using z‐scored neuropsychological tests administered at annual visits. Multivariable linear mixed‐effects models with a cross‐product interaction term between T2DM and APOEε4 status, including main effects, assessed whether the association of APOEε4 with domain‐specific cognitive change was modified by T2DM status. In the subset of participants who underwent autopsy (n = 5,663), we examined whether T2DM modified the association between APOEε4 and neuropathological features using multivariable logistic regression.ResultA significant interaction exists between T2DM and APOE genotype. APOEε4 carriers with T2DM had more rapid declines in attention, language, memory, and executive cognitive scores over time. APOEε4 non‐carriers with T2DM had lesser impairment compared to APOE ε4 carriers without T2DM. Among the autopsied participants, non‐APOE ε4 carriers with T2DM had larger odds of infarcts/lacunes and atherosclerosis. Compared to non‐APOE ε4 carriers without T2DM, APOE ε4 carriers with or without T2DM showed higher odds of AD neuropathological changes (ADNC), but lower odds of ADNC among non‐APOE ε4 carriers with T2DM.ConclusionT2DM modifies the association between APOE ε4 and cognitive decline and AD neuropathological features. T2DM in non‐APOE ε4 carriers increased the risk of infarcts/lacunes but not ADNC.

Associations between Verbal Memory Performance and Regional Brain Volumes Differ by APOE4 Carrier Status in Midlife Women

AbstractBackgroundAPOE4 genotype is a stronger risk factor for Alzheimer’s disease (AD) in women than men, and its influence on memory and AD biomarkers differs by disease stage. Among cognitively normal older APOE4 carriers, APOE4 status influences memory similarly in males and females but adversely influences hippocampal volume in males. The effect of APOE4 status on regional brain volumes earlier in life, and in relation to memory, are less well understood. We examined whether associations between verbal memory performance and regional brain volumes differed by APOE4 status in cognitively normal midlife women. We hypothesized that APOE4 carriers would show weaker associations between memory performance and brain volumes than non‐carriers, particularly in the temporal lobe.MethodParticipants were enrolled in MsBrain, a cohort study of midlife women. Verbal memory was assessed with the California Verbal Learning Test (CVLT‐II). Cortical thickness was measured and segmented by FreeSurfer using individual T1w MPRAGE images. Multiple regressions were conducted to determine associations between memory (learning, free recall) and regional brain volumes by APOE4 status (carriers versus non‐carriers), controlling for age, education, and race.ResultIn 148 cognitively normal postmenopausal women (mean age = 59.17 years, 84.4% white, n = 37 APOE4 carriers), APOE4 status had no main effect on CVLT‐II measures or brain volumes, except the volume of the left supramarginal gyrus. However, APOE4 status modified the magnitude of association between verbal memory and brain volumes, specifically the association between: a) verbal learning and volume in the left caudal middle frontal gyrus (CMFG), left isthmus cingulate gyrus, left parahippocampal gyrus, left insula, right precuneus, right lateral orbitofrontal gyrus (LOG), and right temporal pole (TP); and b) free recall and volume in the left CMFG, right LOG, right posterior cingulate gyrus, and right TP. The direction of the associations between verbal memory and brain volumes was positive in non‐carriers and negative in carriers.ConclusionIn cognitively normal midlife women, APOE4 carrier status may influence the extent to which the hippocampal, temporal, and frontal lobe structures support verbal memory performance. This subtle effect may emerge before the main effect of this genetic risk factor on brain volume and memory.

Synergistic contributions of vascular risk factors and APOE ε4 carriage to cognitive performance in middle‐aged adults enrolled in the Healthy Brain Project

AbstractBackgroundMidlife vascular risk factors (VRFs) and APOE ε4 carriage are individually associated with poor cognitive performance and increased dementia risk. However, the extent to which VRFs interact with APOE ε4 carriage to influence cognition in midlife remains unclear. This study aimed to investigate interactions between VRFs and APOE status on cognitive performance in cognitively normal (CN) middle‐aged adults.MethodCN adults aged 40‐70 enrolled in the Healthy Brain Project with ≥75% complete baseline data on five VRFs and APOE status were included (N = 1610; 546 ε4 carriers). Cardiovascular risk was operationalized by assessing history of hypertension, hypercholesterolemia, diabetes mellitus, body mass index (BMI) ≥25, and current cigarette smoking. Participants were categorized into low (0) or high vascular risk groups (≥1 VRF) determined via median split. Analyses of covariance (ANCOVAs) investigated interactions between VRF group × APOE status on attention and memory composites (derived from the Cogstate Brief Battery), controlling for age, sex, education, ethnicity, and depressive/anxiety symptoms. Linear regression analyses explored contributions of individual VRFs on memory in ε4 carriers and non‐carriers.ResultA significant VRF group × APOE status interaction was observed for memory (p = .04), but attention was lower in those at high vascular risk, regardless of APOE ε4 status (Table 1, Figure 1A and 1B). For memory, APOE ε4 carriers with high vascular risk demonstrated worse performance compared to ε4 carriers and non‐carriers with low vascular risk (Figure 1A and 1B). Linear regression analyses revealed that BMI ≥25 and hypercholesterolemia were significantly associated with worse memory performance in ε4 carriers only (Table 2).ConclusionIn CN middle‐aged adults, vascular risk significantly modified associations between APOE status and memory performance, such that ε4 carriers with high vascular risk demonstrated the lowest memory performance. More specifically, higher BMI and hypercholesterolemia were significantly associated with lower observed memory performance within this group. Results suggest that middle‐aged ε4 carriers with vascular risk factors may be an important sub‐group to target within lifestyle prevention trials to reduce future risk of cognitive impairment and decline.

APOE4 Genotype Relates with Body Mass and Percent Fat Mass in Cognitively Normal Older Adults

AbstractBackgroundLower body mass is related to the progression of Alzheimer’s disease (AD). Carriers of the APOE e4 (APOE4) allele have an increased risk of developing AD, and APOE4 status has been shown to be associated with decreased body mass and fat mass in AD. However, this relationship in cognitively normal older adults is unclear. We investigated whether body mass index (BMI) and body composition are related with APOE4 status in cognitively normal older adults.MethodBaseline data from 211 cognitively normal older adults in an ongoing nutrition intervention RCT (Nutrition Intervention for Cognitive Enhancement; NICE study) were analyzed. Whole blood was attained, and genetic analyses were used to determine APOE genotype. Participants with ≥ 1 APOE4 allele were classified as APOE4 carriers. BMI was calculated from weight and height. Fat mass percentage was measured using dual energy x‐ray absorptiometry. We compared means between APOE4 carriers and non‐carriers for BMI and fat mass percentage using covariate‐adjusted ordinary least squares (OLS) regression models (i.e., ANCOVA), adjusting for age and sex. Statistical analyses were performed using R (v. 4.2.2; R Foundation, Vienna, Austria). Statistical significance was set at p < 0.05.ResultParticipants were 75% female with a mean age of 71.4 ± 4.9 years. 34% of participants were APOE4 carriers. Mean BMI and percent fat mass were 28.4 ± 4.6 kg/m2 and 40% ± 4.6, respectively. ApoE4 carriers had significantly lower BMI (27.5 kg/m2 ± 3.9 vs. 28.9 kg/m2 ± 4.8, p = 0.02) and lower body fat percentage (38% ± 8.0 vs. 42% ± 6.7, p < 0.01) compared to non‐carriers, respectively.ConclusionIn this study, cognitively normal older adult APOE4 carriers had lower BMI and lower body fat percentage compared to non‐carriers. These findings suggest that APOE4 status may influence body weight and body composition, which may represent a way APOE4 increases the risk of symptomatic AD. Future studies are needed to explore the mechanisms underpinning the relationship of APOE4 with decreased body mass and differential body compositions and to determine if these results are consistent in different life stages.

High Precision β‐Amyloid 1‐40, β‐Amyloid 1‐42, and Ptau181 Plasma Assay Performance in NCRAD Biomarker Assay Laboratory

AbstractBackgroundTo achieve the robust and reliable implementation of assays in the National Centralized Repository for Alzheimer’s Disease and related Dementias (NCRAD), new assays and platforms must be assessed for performance characteristics. The goal of this study is to assess the [Fujirebio Lumipulse] G1200 performance in comparison to existing platformsMethodPlasma samples utilized for assay precision measurements were collected from healthy control subjects and patients with Alzheimer’s disease (AD) by the Indiana Biobank. Five samples were chosen to span the assay range and were assayed on two separate days. Clinical utility was assessed with plasma samples (N = 179) collected by the Indiana Alzheimer’s Disease Research Center (IADRC). A subset (N = 92) of these samples were also assayed on the Neurology 4‐Plex E Advantage Kit on the [Quanterix] Simoa‐HDx platform. All samples were assayed on the [Fujirebio Lumipulse] G β‐Amyloid 1‐40, β‐Amyloid 1‐42, and Ptau181 plasma assays.Result[Fujirebio Lumipulse] G β‐Amyloid 1‐40, β‐Amyloid 1‐42, and Ptau181 plasma assays had an average inter‐assay coefficient of variation of 2.6%, 2%, and 2% respectively (Figure 1). In samples with both [Fujirebio Lumipulse] and Simoa‐HDx pTau181 data, linear regression showed an R^2 of 0.80 and slope of 1.67. Bland‐Altman analysis showed a consistent bias of 54%. Once results were standardized by Z‐score, slope was near one, y‐intercept near zero, demonstrating comparability of results. Area Under Receiver Operating Characteristic curve (AUC) for IADRC samples with PET data was 0.84 for Aβ 42/40 ratio alone and 0.87 including age, sex and APOE status. AUC for Ptau181 alone was 0.83 and 0.89 including age, sex and APOE status. Assays were able to detect differences in clinical diagnosis or amyloid status (Figure 2A and B).ConclusionThe [Fujirebio Lumipulse] assays exhibited high precision. When standardized by Z‐score, the [Fujirebio Lumipulse] Ptau181 assay was comparable to the Simoa‐HDx Ptau181v2 assay allowing comparison of data between assay platforms. AUCs for amyloid PET were higher when considering age, sex and APOE status in the model. The assays were able to differentiate between clinical diagnoses and amyloid status suggesting suitability for implementation.

Brain‐age prediction and its associations with glial and synaptic CSF markers

AbstractBackgroundMRI‐derived brain‐age prediction is a promising biomarker of biological brain aging. Accelerated brain aging has been found in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, no previous studies have investigated the relationship between specific pathophysiological pathways in AD and biological brain aging. Here, we studied whether glial activation and synaptic dysfunction are associated with biological brain aging in the earliest stages of the Alzheimer’s continuum.MethodWe included 418 cognitively unimpaired individuals (CU) from the ALFA+ study with available structural MRI, and CSF biomarkers of amyloid‐ß (Aß42/40) and tau pathology (p‐tau181), synaptic dysfunction (neurogranin, GAP43, SYT1, SNAP25), glial activation (sTREM2, YKL40, GFAP, interleukin‐6 and S100b) and a‐synuclein (Table 1). Aß42/40, neurogranin and the glial activation biomarkers were measured using the Roche NeuroToolKit. We computed brain‐age delta as the difference between chronological and predicted brain‐age. The latter was estimated using a previously pretrained machine learning algorithm on cerebral morphological measurements on individuals from the UKBioBank cohort (N = 22.000). General linear modeling was used to test the associations between CSF biomarkers and brain‐age delta, adjusting by p‐tau, age, APOE status and sex. For the biomarkers whose associations were significant, we evaluated the interaction term “biomarker” × AT status while adjusting by age, APOE status and sex. AT staging was performed using pre‐established cut‐off values. We then used hippocampal volume as a marker of AD‐related neurodegeneration and repeated the same association studies with CSF biomarkers, adjusting by p‐tau, age, APOE status, sex and TIV.ResultBrain‐age delta was negatively associated with CSF sTREM2 (Padjusted<0.001), meaning that younger‐appearing brains showed higher levels of this biomarker (Table 1). None of the other biomarkers survived multiple comparisons. Hippocampal volume was not significantly associated with any of the CSF biomarkers (Table 2). There was no significant interaction between AT status and CSF sTREM2 for brain‐age delta, nor for hippocampal volume.ConclusionThese results showed that higher levels of CSF sTREM2 were associated with younger‐appearing brains in CU individuals independently of AT status, which might indicate a protective effect of this microglial phenotype in brain aging. This effect might not be AD‐related.

The potential utility of genetic susceptibility to life course modifiable factors for dementia prevention

AbstractBackgroundPotentially modifiable risk factors for dementia prevention, intervention, and care based on efforts to curb the increasing prevalence of dementia have been presented by the dementia committees. These risk factors for developing dementia need to be managed throughout the life cycle. However, the criteria for prioritizing risk management in subtype dementias caused by various factors are still uncertain in clinical practice. In this study, using a polygenic risk score (PRS) approach, we investigated the association of genetic susceptibility to life‐course modifiable factors in each subtype of dementia, including all‐cause dementia, and evaluated the utility of using it for predicting dementia.MethodWe utilized 5,974 all‐cause dementia cases and propensity‐matched healthy control data from UK Biobank. We generated APOE isoforms and Alzheimer’s disease (AD)‐PRS (excluding APOE regions) derived from the IGAP 2019 genome‐wide association study (GWAS) using genotyped data. Then, we performed a regression analysis to confirm the associations between AD‐PRS, APOE status, and each type of dementia. In addition, to investigate the genetic susceptibility of life‐course modifiable factors, we generated PRSs related to 18 life‐course factors for dementia prevention using independent GWAS summary statistics. Then, using each life‐course factor PRS, multivariate regression analysis was conducted to evaluate whether PRS is associated with each type of dementia independent of age, sex, genetic principal components, APOE status, and AD‐PRS.ResultThe APOE status and AD‐PRS showed significant associations with all‐cause dementia as well as AD dementia (ADD), vascular dementia (VD), and frontotemporal dementia (FTD) (Figure 1). In the multivariate regression analysis, hypertension, and body mass index PRSs showed significant associations with ADD and VD. In addition, vascular risk factors such as type 2 diabetes, high‐density lipoprotein, and systolic blood pressure PRSs showed significant associations with VD. In particular, in FTD, unlike other subtype dementias, only depression genetic susceptibility and relationship were found.ConclusionWe observed that genetically predicted life‐course modifiable factors were associated with risks of several types of dementia independently of the well‐known non‐modifiable risk factors (APOE status and AD‐PRS). Our findings suggest the potential utility of prioritizing candidate modifiable factors that should be primarily managed for dementia prevention in personalized medicine.

Association of plasma biomarkers with cognitive function in persons with dementia and cognitively healthy in the Democratic Republic of Congo

AbstractBackgroundCross‐sectional and longitudinal measurements of plasma biomarkers of Alzheimer’s disease (AD) in Western countries are being applied in clinical practice, whereas their associations with culturally validated cognitive tests in other settings remain unknown. We aim to examine cross‐sectional association of plasma protein biomarker concentrations and APOE proteotype with cognitive function and explore the discriminative role of these AD biomarkers in such an association.MethodThis is a cross‐sectional retrospective study completed from 2018 to 2022 in the Democratic Republic of Congo (DRC). Subjects were recruited from clinics, hospitals, churches, and across DRC. The study started in January 2018 until December 2022. Data were analyzed from May 2022 to December 2022. The DRC Memory clinic team recruited 1430 individuals 65 years and over. Based on Community Screening Instruments for Dementia (CSID), and Alzheimer’s Questionnaire (AQ), and DSM‐5 diagnostic criteria, participants included 44 individuals classified as major neurocognitive disorder (dementia) and 41 as healthy controls (HC). Subjects underwent cognitive assessment with a validated, culturally‐tailored cognitive battery. AD plasma biomarkers (Aβ42, Aβ40, Aβ42/40, p‐tau 181), APS (derived from Aβ42/40, APOE status, and age), and APOE proteotype were utilized to assess for genetic risk.ResultIndividuals with dementia had significantly lower Aβ42/40 levels, higher APS, and higher APOE ε4 prevalence compared to HC. Linear regressions showed significantly associations between Aβ42/40 and APS with ANT, ALMT, and AVMT scores, while APOE ε4 presence was associated with ANT, ALMT, AVMT, and APT scores. APS showed the highest AUC value (AUC = 0.78, 95% CI: 0.68‐0.88) followed by Aβ42/40 (AUC = 0.75, 95% CI: 0.66‐0.86) and APOE ε4 (AUC = 0.69 (CI 0.57‐0.81) in discriminating dementia from HC.ConclusionSelect AD biomarkers were associated with cognition and differentiated dementia from HC, consistent with extant research. These findings may have implications for the assessment of AD biomarkers in DRC.

The relationship between sleep duration and cortical sulcal width in midlife and older adults

AbstractBackgroundEmerging evidence suggests that poor sleep is associated with worse cognitive and structural brain health, and an increased risk of developing dementia (Bubu et al., 2016; Fjell et al., 2022; Tai et al., 2022). The present study investigated the influence of sleep duration on the cognition‐brain relationship in older adults using sulcal width (SW), a reliable measure of changes in the ageing brain (Bertoux et al., 2019). The influence of napping, depression likelihood, and genetic risk for dementia (APOE ε4 status) was also explored.MethodParticipants were 137 cognitively normal adults, aged 46‐72 from the Prospective Imaging Study of Ageing (PISA). Demographic information, sleep duration, and depressive symptoms were collected via online questionnaires. Cognition was assessed using the Cambridge Brain Systems battery. APOE genotype was determined from blood‐extracted DNA. Imaging data was acquired using a 3T Siemens PRISMA scanner. SW was extracted using the Morphologist pipeline (Borne et al., 2020).Canonical Partial Least Squares (PLS) were used to obtain latent variables of cognition and SW. ANCOVAs measured the effect of sleep duration categories (7‐7.5 hours versus {<7 or ≥8 hours}) on the cognitive and SW components, with sex and age as covariates. Status of depression likelihood was added as a covariate of interest. The effect of napping, and APOE ɛ4 allele on these same components were measured by ANCOVAs, with sex and age as covariates.ResultWe observed a significant effect of sleep duration on SW (F(1, 133) = 4.17, p = 0.043, Fig. 1). This effect remained significant (F(1,132) = 4.89, p = 0.029) after including depression likelihood as a covariate, which was also significant in the model (F(1,132) = 4.62, p = 0.034). A significant interaction between APOE ε4 status and age (p = 0.050) on SW was also observed.ConclusionResults add weight to studies suggesting that not too much or too little sleep is needed to maintain brain health in later life (Li et al., 2022; Liang et al., 2019). Depression, a risk factor for dementia (Livingston et al., 2020), was also associated with poorer brain health. Results suggest that at approximately 60 years of age, the influence of a positive APOE ε4 status is associated with increasing age‐related brain atrophy.

Synaptic proteins in pre‐symptomatic Alzheimer’s disease: biomarkers for early detection of Cognitive Decline

AbstractBackgroundSynaptic proteins in the cerebrospinal fluid (CSF) may reveal changes in the pre‐symptomatic stages of Alzheimer’s disease (AD), thus may be candidate biomarkers for early detection of the disease.MethodThe PREVENT‐AD cohort includes symptom‐free (upon enrolment) elderly participants who are at risk of developing AD from their family history. We used enzyme‐linked immunosorbent assay kits to assess CSF samples from 129 such participants for the “classical” AD biomarkers total tau, phosphorylated (181) tau and Aβ42. We also used neuroimaging data (MRI, PET) and neuropsychological assessments (MMSE, RBANS) as potential indicators disease progression. We then used in the CSF samples to measure the soluble synaptic biomarkers ADAM 22 (post‐synaptic), ADAM23 (pre‐synaptic). Immunoprecipitated SYT1 (pre‐synaptic) from CSF were analyyzed using high‐resolution selected ion monitoring analyses on a quadrupole–orbitrap mass spectrometer Q Exactive. Statistical analysis of the association of these markers with evidence of disease in analyses were done included sex and APOE e4 status as covariates.ResultAmong participants who remained cognitively unimpaired, we observed significant correlations between baseline CSF ADAM 22 levels and t‐tau (R2 = 0.22, p < 0.0001), p‐tau (R2 = 0.22, p < 0.0001), and Aβ42 (R2 = 0.06, p = 0.01488). We also found similarly suggestive correlations also between CSF ADAM 23, CSF SYT1 and the same disease markers. Covariate analyses suggested little or no variation in the associations between these synaptic proteins with t‐tau and p‐tau by sex, APOE e4 status, negative PET amyloid positivity (standardized uptake value ratio ≤ 1.37) and negative CSF total tau positivity (≤ 335pg/ul). PET amyloid positivity was significantly associated with ADAM22 and p‐tau interactions whereas SYT1 was significantly associated with t‐tau and p‐tau in CSF tau‐positive participants. In linear regression analyses, baseline CSF ADAM22 levels correlated with the language cognitive performance trajectory slopes estimated over the course of 5 to 8 years on the RBANS (R2 = 0.04, p = 0.03912). We found no significant interaction between other baseline CSF synaptic protein levels and other subscales of the RBANS.ConclusionCSF synaptic protein levels show promising correlation with landmark AD proteins and emerging cognitive deficits.

Are Digital Markers of Everyday Driving Comparable to Fluid Biomarkers in Identifying Preclinical Alzheimer Disease?

AbstractBackgroundPreclinical Alzheimer’s disease (AD) may have a subtle functional signature reflected in changes in everyday driving behaviour. Driving has the potential to serve as a digital marker for AD when captured continuously and characterized accurately. This study directly compares the diagnostic performance of digital markers of everyday driving, cerebrospinal fluid (CSF), and blood biomarkers in detecting amyloid deposition in AD, using amyloid positron emission tomography (PET) as the “gold standard”.MethodParticipants were enrolled in a longitudinal study on driving and preclinical AD biomarkers at Washington University School of Medicine. The Driving Real‐World In‐Vehicle Evaluation System (DRIVES) Project uses in‐vehicle GPS dataloggers to collect daily driving among cognitive normal drivers. This study included 121 drivers (aged 65+) with complete blood, CSF, and PET biomarker data. We employed three artificial neural network (ANN) to examine the relationship between everyday driving and PET‐amyloid status. The first model solely included driving features. The second ANN model (i.e., “non‐intrusive” model) added age and education level as additional features. The third model included all of the previous features plus APOE e4 status. Plasma Aß42/Aß40<0.1013 and CSF Aß42/Aß40<0.0673 were used to detect PET‐amyloid positivity. To compare the performance of the ANN models and the CSF and plasma biomarkers, area under the receiver operating curve (AUC) from 5‐fold cross‐validation were calculated.ResultIndividuals who were PET‐amyloid positive (n = 46) were more likely to be older (p<.05) and carry an APOE e4 allele (p<.0001). The two groups did not differ in sex or education. In predicting PET‐amyloid positivity, the five most important driving features were the number of left turns per mile, 80th percentile of jerk, minimum vehicle speed, speed variability, and the number of speeding incidents. The CSF biomarker achieved the highest performance (AUC = 0.96±0.04), followed by the model with driving, age, education and APOE e4 status (AUC = 0.88±0.05). The model with only driving features achieved lower performance (AUC = 0.74±0.07), while the non‐intrusive ANN model achieved comparable performance to the plasma biomarker (AUC: 0.82±0.11vs.0.83±0.12).ConclusionDigital markers of everyday driving along with age and education level offer a non‐intrusive and scalable diagnostic tool for preclinical AD that provides ongoing assessments.

Inter‐network connectivity of early Aβ and tau‐seeded functional networks is associated with longitudinal tau accumulation in at‐risk cognitively normal older adults

AbstractBackgroundFunctional connectivity (FC) between networks may be related to Aβ and tau interactions in preclinical Alzheimer’s disease (AD). Here, we investigated associations between inter‐network FC of early Aβ and tau‐seeded networks, APOEe4, global Aβ, and longitudinal tau accumulation in cognitively healthy older adults (OA).MethodVoxel‐wise PiB‐PET and FTP‐PET OA images were ordered by increasing pathology burden and iteratively compared to a reference set of young adult (YA) PET images. Peak voxels of the earliest significant differences were matched to Brainnetome ROIs and used to construct separate Aβ and tau‐seeded networks within a group average YA FC matrix (Figure 1). Next, the average inter‐network FC between all node pairs between the networks was calculated in OA (n = 60; aged 77.6±5.5). Longitudinal FTP slopes of the entorhinal cortex (EC) and inferior temporal gyrus (ITG) were estimated using linear mixed effects models. Linear regression was used to assess relationships between baseline inter‐network FC, APOEe4 status, baseline global PiB, and both a prior ROI and voxel‐wise FTP slopes.ResultIn all OA, inter‐network FC was not associated with baseline global PIB (t(58) = ‐0.23, p = 0.82), EC FTP slope (t(58) = 0.49, p = 0.63), or ITG FTP slope (t(58) = ‐1.45, p = 0.15). There was a significant interaction between baseline global PiB status and inter‐network FC where FC was negatively associated with ITG FTP slope in PiB+ participants (t(56) = ‐2.01, p = 0.04; Figure 2A). There was also a significant interaction between APOEe4 status and inter‐network FC in predicting ITG FTP slope with a negative relationship only in e4 carriers (t(56) = ‐3.19, p = 0.003; Figure 2B). Voxel‐wise analyses revealed significant negative relationships between inter‐network FC and FTP slope in the left fusiform gyrus and ITG in PiB+ participants and e4 carriers, respectively (Figure 2C‐D).ConclusionLower baseline inter‐network FC of early Aβ and tau‐seeded networks was associated with greater longitudinal tau accumulation outside of the medial temporal lobe (MTL) in cognitively normal OA with higher AD risk (i.e., elevated Aβ or APOEe4). Our results suggest that this network disruption is associated with faster rates of tau accumulation outside of the MTL, possibly reflecting a later stage in the preclinical progression to AD.