ApoE Research Articles

Education or Socioeconomic Status: which proxy of cognitive reserve associates better with cognitive function and amyloid imaging results?

AbstractBackgroundCognitive reserve (CR) is partially responsible for inter‐individual differences in developing dementia due to Alzheimer’s disease (AD). However, education years, as the primary proxy of CR, does not capture various life experiences, vocational background, and resources available to those who did not have an opportunity to complete formal education. We compared education years against Hollingshead Four‐Factor Index of Socioeconomic Status (SES‐Adults) to examine the latter’s utility as a better proxy of cognitive reserve. The SES‐Adults is a survey collecting information on marital status, retired/employed status, educational attainment, and occupational prestige for participants and their partners. The survey results are then converted into one of the 5 social class categories including low, working, middle, upper‐middle, and upper socioeconomic status.MethodA cross‐sectional study was conducted on a cohort of adults and older adults (n = 264) with mean age of 67.96 years. Participants were recruited from a longitudinal study investigating neuropsychological and biological correlates of dementia, namely the Western Australian Memory Study (WAMS). We examined the relationships between education years and the SES‐Adults scores, with cognitive function and amyloid load while controlling for age, gender (male/female), and APOE ε4 carriage. Amyloid load was measured using 18F‐NAV‐469 tracer.ResultThe cohort included 190 females and 74 males with 80 APOE ε4 carriers (available genotyped individuals = 203). Linear regression results showed education years was significantly correlated with both general cognitive function (MoCA) and amyloid load (R2 = 0.2935, Adjusted‐R2 = 0.2513; p<0.026) while controlling for the effects of age, gender, and APOE ε4 carriage. The SES‐Adults was not significantly related to cognition or amyloid load (p = .914). When SES was included in regression model, the relationships between education years and outcome measures turned non‐significant.ConclusionWe found education years to be significantly related to both cognition and amyloid load. However, no significant results was noted for the SES‐Adults. This cross‐sectional study showed that education is a reliable CR proxy as compared to a comprehensive measure of socioeconomic status(SES‐ Adults) .

Cortical microinfarcts along the Alzheimer’s disease continuum in adults with Down syndrome ‐ an update

AbstractBackgroundCortical microinfarcts (CMI) are emerging biomarkers of vascular damage associated with cognitive decline and are frequent in sporadic AD (sAD) patients. However, no study assessed CMI in Down syndrome (DS), a genetically determined form of AD. Therefore, we aimed to assess CMI’s frequency in adults with DS, sAD, and cognitively unimpaired euploid controls and its relationship with age, sex, clinical status, and APOE ε4 carriership.MethodCross‐sectional study. We included 175 participants with 3T‐MRI: 64 with DS (39 asymptomatic [aDS], 11 prodromal AD [pDS], and 14 AD‐dementia [dDS]), 62 with sAD (41 prodromal AD, 21 AD dementia), and 49 controls. A neuroradiologist blind to participants’ data visually analyzed the 3T‐MRI images following a validated protocol to detect CMI (Figure 1). We compared CMI’s prevalence in the different clinical groups along the AD continuum in DS and sAD, in APOE ε4 carriers vs. non‐carriers, and males vs. females using Chi‐square, Mann‐Whitney, or Kruskal‐Wallis tests when appropriate.ResultCMI’s prevalence was 7.8% in DS (5.1% in aDS, 21.4% in pDS, and 0% in dDS [p = 0.085]), 17.7% in sAD (22.0% in prodromal AD and 9.5% in AD dementia [p = 0.389]), and 10.2% in controls (p = 0.207). CMI frequency increased with age in DS, sAD, and controls (Table 1). Regarding sex, CMI’s frequency was 10% in men and 5.9% in women with DS (p = 0.884), and 27.3% in men and 12.5% in women with sAD (p = 0.267). In controls, CMIs’ frequency was 10% in men and 10.3% in women (p = 1.000). Regarding APOEε4 carriership, CMI’s prevalence was 21.4% in APOEε4 carriers and 9.1% in non‐carriers in sAD (p = 0.428), 8.7% in carriers and 6.0% in non‐carriers in DS (p = 1.000), and 8.3% in carriers and 8.6% in non‐carriers controls (p = 1.000) (Table 2).ConclusionCMI’s prevalence increased with age, but was not different in DS, sporadic AD, and controls. Also, sex and APOEε4 carriership did not impact the prevalence of CMI in the three study groups.

Clinical Manifestations.

Olfactory dysfunction has been reported for its association with cognitive impairment and incident dementia. However, the underlying role of neurodegeneration in this relationship is not fully understood. This prospective cohort study included participants from the Shanghai Aging Study (SAS) who were 60 years or older and diagnosed as dementia-free at baseline and completed at least one follow-up interview between 2010 and 2022. At baseline, olfactory identification function was assessed by the 12-item Sniffin' Sticks Smell test (SSST-12). Olfactory dysfunction was defined as SSST-12 < 7, 6, and 5 in three age groups of participants with (age < 70, 70 ≤ age < 80, and age ≥ 80), respectively, according to previously reported normative data of olfaction in the SAS. Baseline blood Neurofilament Light Chain (NfL) was quantified using the ultra-sensitive Single Molecular Array technology (Quanterix), and dichotomized into low and high levels according to the median concentration. Multiple cognitive function assessments were administered by the Mini-mental State Examination (MMSE) at baseline and follow-ups. We used the linear mixed-effect model to fit the MMSE trajectories in participants with and without olfactory dysfunction adjusting for baseline age, sex, education year, smoking, and APOE ε4, with person-specific MMSE intercept and slope. Stratified analysis was conducted in participants with low and high NfL. Among 1125 participants included in this study, 296 were defined as having olfactory dysfunction at baseline. Less education, higher proportion of APOE ε4 allele, and lower baseline and follow-up MMSE scores were observed in participants with olfactory dysfunction (Table 1). During the median 9.4 years follow-up, participants with olfactory dysfunction at baseline evidenced a faster MMSE decline compared with those without olfactory dysfunction (b [95% CI]: -0.08 [-0.15, -0.02], P = 0.02) (Figure 1). Such association remained statistically significant (-0.18 [-0.31, -0.06], P = 0.005) in the subgroup with high NfL, but not in the subgroup with low NfL (0.004 [-0.07, 0.07], P = 0.92) (Figure 2). Blood NfL may modify the association of olfactory dysfunction with long-term cognitive decline in community-dwelling older adults. In individuals with high potential neurodegeneration, olfactory dysfunction may be an independent indicator of future cognitive deterioration.

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)

Association between cardiovascular health and brain age: a large population‐based study in the UK Biobank

AbstractBackgroundCardiovascular health (CVH) has been associated with cognitive decline and dementia, but the extent to which CVH impact brain age remains unclear. We aimed to investigate the association of CVH assessed by Life’s Essential 8 (LE8) score with neuroimaging‐based brain age and brain predicted age difference (PAD).MethodThe study included a total of 34098 participants (mean age 54.82±7.50 years; 53.21% female) from the UK Biobank, who underwent brain magnetic resonance imaging (MRI) scans 9 years after baseline. A brain age prediction model with the best prediction performance was trained from 9 candidate models (Lasso, support vector regression, and XGBoost, with or without the addition of 2 variable selection methods, respectively) based on T1‐weighted MRI, T2‐FLAIR, T2∗, diffusion‐MRI, task fMRI, and resting‐state fMRI in 4355 healthy participants. Using the model, we calculated brain age and brain PAD (predicted age‐chronological age). Baseline LE8 score was calculated by the mean score of 8 metrics (diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure) and tertiled as low, moderate, and high CVH. Data were analyzed using linear regression models.ResultAt baseline, LE8 score was ranged from 15.00 to 100.00. In linear regression adjusted for age, sex and education, better CVH was associated with younger brain age (β [95% CI]: ‐0.029 [‐0.032, ‐0.026]) and smaller brain PAD (β [95% CI]: ‐0.033 [‐0.035, ‐0.030]). Compared to moderate CVH, low CVH was associated with older brain age (β [95% CI]: 0.444 [0.345, 0.543]) and bigger brain PAD (β [95% CI]: 0.513 [0.422, 0.604]), whereas high CVH was associated with younger brain age (β [95% CI]: ‐0.360 [‐0.459, ‐0.261]) and smaller brain PAD (β [95% CI]: ‐0.398 [‐0.489, ‐0.307]). The additional adjustment did not alter the relationships observed. After stratification by age, cardiovascular disease (CVD), or APOE ε4, the association remained significant among adults aged 40‐60 years and 60+ years, among CVD and non‐CVD, as well as among APOE ε4 carriers and non‐ carriers.ConclusionBetter cardiovascular health is associated with younger brain age and reduced brain PAD. This association is significant even in middle‐aged, non‐CVD and non‐carriers adults.

APOE ε4 and cognitive networks: Centrality of episodic memory nodes in patients with mild cognitive impairment

AbstractBackgroundThe literature based on univariate models does not lead to unequivocal conclusions on the effects of APOE variability on cognition. We thus hypothesised that the impact of APOE‐ε4 on cognitive functioning can be reliably captured by graph‐theory.MethodCognitive datasets were extracted from the National Alzheimer’s Coordinating Center’s database. After the application of stringent exclusion criteria, 16,173 participants with a known APOE ε3ε3/ε4ε3/ε4ε4 genotype were retained: 8,118 controls, 3,482 MCI patients and 4,573 AD‐dementia patients. ε3ε3 individuals were classified as “non‐carriers”, while ε4ε3/ε4ε4 individuals were tagged as “carriers”. Two independent sub‐cohorts were defined based on the version of the battery used to characterise cognitive profiles. Pairwise Markov random‐field models of cognitive functioning were constructed in “R” using the “qgraph” package, following published methodological guidelines. Nine cognitive nodes were established, and partial correlations were run to calculate the statistical strength of all node‐to‐node edges. This was regularised via the LASSO penalty‐imposing method, to control graph sparsity. Differences in global and nodal metrics between ε4 carriers and non‐carriers were tested via permutation‐based Network Invariance Tests. These analyses were run separately in each sub‐cohort and within each diagnostic status. “Expected Influence” was analysed as the centrality metric of interest, to assess how influential each node is within its network.ResultA significant APOE‐dependant effect emerged from the analysis of the Logical‐Memory nodes in MCI patients in both sub‐cohorts. While non‐carriers showed equal centrality in immediate and delayed recall, the latter was significantly less central among carriers. These findings were replicated in the sub‐groups of sole amnestic‐MCI patients (n = 2,971), were independent of differences in network communities, clinical severity or other demographic factors. No effects were found in the other diagnostic groups or in global network metrics.ConclusionAPOE‐ε4 influences nodal properties of cognitive networks when patients are clinically classified as MCI. Our findings expand this area of knowledge by characterising the statistical effect of the ε4 allele in terms of its differential impact on immediate and delayed recall, and how this results in specific network effects. The study of the wider cognitive network can complement univariate approaches in characterising the effects of risk factors.

Racial and Ethnic Differences in Plasma Biomarker Eligibility in a Preclinical Alzheimer’s Disease Trial

AbstractBackgroundIn Alzheimer’s disease (AD) trials, differential screen failure due to cognitive and biomarker requirements may contribute to underrepresentation of racially and ethnically minoritized groups. The AHEAD 3‐45 Study (NCT04468659) is an ongoing program testing lecanemab at the stage of preclinical AD that utilizes plasma biomarker prescreening, acquired before cognitive, clinical, and medical history eligibility assessments, to enrich for participants likely to qualify based on amyloid PET eligibility criteria.MethodsWe examined the frequency of plasma amyloid biomarker eligibility among racial and ethnic groups in the AHEAD Study. We assigned participants ages 55‐80 to mutually exclusive groups: Hispanic Black (HB), Hispanic White (HW), Non‐Hispanic Asian (NHA), Non‐Hispanic Black (NHB), and Non‐Hispanic White (NHW). We used univariate logistic regression models to explore group differences in screen failure rates as determined by an algorithm that includes the plasma Aβ 42/40 ratio, age, and APOE status. The algorithm indicates an adequately high probability of elevated brain amyloid (&gt;20 centiloids). We further explored whether APOE ε4 status (carrier vs non‐carrier) contributed to group differences.ResultsAmong 4274 participants undergoing plasma screening, 59 (1.4%) were HB, 622 (14.6%) were HW, 74 (1.73%) were NHA, 329 (7.7%) were NHB, and 3190 (74.6%) were NHW. Screen failure rates were 86% for HB, 76% for HW; 80% for NHA; 77% for NHB, and 62% for NHW. Using NHW participants as a reference group, we observed increased odds of screen failure among all other groups (HB OR = 4.0 95% CI 2.0, 9.1; HW OR = 2.0 95% CI 1.6, 2.4; NHA OR = 2.5 95% CI 1.4, 4.5; NHB OR = 2.1, 95% CI 1.6, 2.7). Observed differences were consistent across APOE ε4 carriers and non‐carriers.ConclusionDifferential rates of amyloid eligibility were observed despite the lack of systematic sample bias due to clinical or cognitive requirements observed in previous studies. Potential explanations for these observations include differences in clinical trial access, incidences of elevated amyloid, needed cutoffs for biomarker assays, and confounding due to comorbidities or other unmeasured covariates.This work is supported by a public‐private partnership between Alzheimer’s Clinical Trial Consortium (U24 AG057437) and Eisai.

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.

Electrical field strength from anodal prefrontal tDCS determines degree of white matter integrity changes in amnestic MCI patients

AbstractBackgroundAn electrical field (EF) strength induced by tDCS affects a therapeutic effect. Additionally, sequential tDCS has improved white matter integrity in cognitively impaired patients. However, researchers have not evaluated the impact of EF strength on white matter integrity in the prodromal stage of dementia. This study aimed to elucidate the effect of EF strength from prefrontal anodal tDCS on white matter integrity change and the modulating role of relevant genetic and pathologic factors in this effect in amnestic mild cognitive impairment (MCI) patients.MethodIn 55 amnestic MCI patients, we delivered anodal‐tDCS (2 mA/day, five times/week, for two weeks) over the left dorsolateral prefrontal cortex (DLPFC), calculated the EF strength for the left inferior frontal gyrus and DLPFC through the stimulation navigation program analysis. Additionally, we assessed the white matter integrity by diffusion tensor imaging before and after two weeks of stimulation; finally, we evaluated the modulating factors: amyloid‐beta (Aβ) deposition, APOE ε4‐allele status, and BDNF polymorphism.ResultAs the EF intensity in the left inferior frontal gyrus increased, the range of changes in white matter integrity significantly increased in left anterior thalamic radiation, corticospinal tract, inferior fronto‐occipital fasciculus, and inferior longitudinal fasciculus. Additionally, we found that greater change in white matter integrity was observed with higher regional EF strength in the APOE ε4 non‐carriers and BDNF MET non‐carrier, which could be attributed to an interaction between these modulating factors and EF intensity in the left anterior thalamic radiation and right uncinate fasciculus.ConclusionThese findings provide evidence for the precision‐medicine‐based application of tDCS in the prodromal stage of dementia, inducing the optimized therapeutic effect.

Neuropsychological assessment as a predictor of dementia conversion in Alzheimer’s disease

AbstractBackgroundProgressive cognitive decline is a characteristic of Alzheimer’s disease (AD). Identifying reliable predictors of conversion to dementia in older adults, particularly those with mild cognitive impairment (MCI), is critical for clinicians, patients, and patient families.Method1083 adult participants (Age: M = 73.20, SD = 6.92) were included in this study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The average follow up was over 5 years (M = 65.25, SD = 40.16). Cox proportional hazards regression models were implemented to estimate the risk of dementia. Models were built sequentially to examine changes in predictive contributions when including biomarkers and cognitive predictors.Result57% of participants were classified as MCI and 43% as cognitively normal (CN). By the end of study, there is an overall conversion rate of 24% from the participants with cognitive normal and MCI to dementia. Participants with MCI demonstrated significantly higher rates of conversion than those with CN (F(1,258) = 92.51, p &lt; .001, η2 = .26). The initial model indicated greater age (HR = 1.03, p = .004), fewer years of education (HR = 0.95, p &lt; .027), the presence of at least one APOE ε4 gene (HR = 3.23, p &lt; .001), and higher levels of neurofilament light chain (NFL) (HR = 1.28, p &lt; .001) predicted conversion to dementia. A second model indicated higher levels of Ab42 was predictive of lower risk (HR = 0.41, p &lt; .001), whereas higher levels of P‐tau was predictive of greater risk (HR = 1.48, p &lt; .001). APOE ε4 presence and NfL levels remained significant predictors. Finally, composites of memory and executive scores were added. Memory performance at baseline was highly associated with dementia risk (HR = 0.26, p &lt; .001), with poorer performance at baseline predicting greater likelihood of conversion. Similarly, poorer performance on executive functioning tasks was predictive of dementia risk (HR = 0.57, p &lt; .001).ConclusionComposite scores of memory and executive functions are strong predictors of conversion to dementia. Such composites are approximately as predictive as Ab42, and more predictive than demographics, APOE ε4 presence, baseline P‐tau and NFL.

Predicting cognitive decline in amyloid‐positive patients with mild cognitive impairment or mild dementia

AbstractBackgroundCognitive decline rates in Alzheimer’s disease (AD) vary greatly. Disease‐modifying treatments (DMT) may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid‐positive patients with mild cognitive impairment (MCI) or mild dementia.MethodsFrom the Amsterdam Dementia Cohort, we selected amyloid‐positive participants with MCI (n = 317, 66±7yrs, 45%Female, baseline MMSE 26±2) or mild dementia (n = 666, 65±7yrs, 49%Female, MMSE 22±4) and ≥2 annual MMSEs. Follow‐up was 3±2yrs with 4±2 MMSEs. Amyloid positivity was based on cerebrospinal fluid (CSF) AD biomarker concentrations or amyloid PET. We used linear mixed modelling to predict MMSE over time. First, decline trajectories were described with cubic time curves (S‐shaped). Then, we backwards selected predictors from baseline MMSE, age, sex, APOE ε4 dose, magnetic resonance imaging (MRI; visual scores: medial temporal lobe [MTA], global atrophy), CSF concentrations (phosphorylated tau [pTau], Aβ1‐42), and their interactions with linear time. MCI and mild dementia were modelled separately as stratification increased log‐likelihood.ResultsFor MCI and mild dementia, rates of cognitive decline increased over time. In MCI, average MMSE declined from 26.4(95%CI:26.2‐26.7) to 25.8(25.5‐26.1) after 18 months, to 24.2(23.7‐24.6) after three years, and to 21.0(20.1‐21.7) after five years. In mild dementia, MMSE declined from 22.4(95%CI:22.0‐22.6) to 19.8(19.4‐20.2), 15.3(14.6‐15.9), and 7.8(6.7‐8.9). For MCI, selected predictors of future MMSE were baseline MMSE, and interactions of time with age, MTA and pTau (table 1). For mild dementia, additional selected interactions with time were baseline MMSE, Aβ1‐42, and APOE ε4. Figure 1 shows the predicted decline distribution. As an example; predicted MMSE after three years for a 65yrs female MCI patient with baseline MMSE 27, would be 26.3 with MTA 0 and pTau 20pg/ml, compared to 23.8 with MTA 1 and pTau 40pg/ml (figure 2a;2b). In the latter case, 27% slower decline would lengthen follow‐up to a predicted MMSE of twenty by fourteen months.ConclusionWe constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and aid in conversations about DMT initiation and the evaluation of their potential effect.

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.

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.

Native Hawaiians and Pacific Islanders: Is APOE a Biomarker of Disease?

AbstractBackgroundNative Hawaiians and Pacific Islanders (NHPI) are among the least represented racial groups in Alzheimer’s disease (AD) research (for example, there are only 18 samples in the NACC). The prevalence of AD is unknown in NHPIs. Likewise, no large studies have reported disease biomarkers, including assessing APOE genotypes for correlation with AD. In one small study in Guam natives, APOE ε4 was not correlated with AD. We have enrolled 648 NHPIs in our cohort with AD8 and CDR scores, and results of their performance on the NACC neuropsychological battery. We collected APOE genotypes for 234 individuals.MethodBrain health events were held to recruit study participants. Biological samples (saliva or blood) were collected at these events then transported to our lab where DNA was extracted and analyzed to determine APOE genotypes.ResultTable 1 summarizes the cognitive assessments and APOE genotypes for 234 individuals. APOE allele frequencies vary widely based on race. However, in our dataset, the ε4 frequency in NHPI females and males is the same and higher than reported in other races.We are underpowered to detect significant trends in subjects with and without dementia (Table 2). Our preliminary data reveal ε4 allele frequencies in subjects with and without dementia. No trend towards ε4 differences in impaired versus normal subjects.ConclusionWe are augmenting and refining the existing cohort. We are genotyping APOE in 414 additional NHPIs and formally diagnosing each subject. We will have sufficient samples to determine whether or not APOE correlates with AD status. If APOE is not a biomarker of AD in NHPIs, this suggests that the genetic architecture of AD in NHPIs is unique and demonstrates the importance of prioritizing NHPIs in future AD research.

Blood‐based quantification of Aβ oligomers indicates impaired clearance from brain in ApoE ε4 positive subjects

AbstractBackgroundQuantification of Aβ oligomers in plasma may be useful not only for early diagnosis of Alzheimer’s disease (AD), but particularly to improve our understanding of underlying pathologies. However, quantification necessitates an extremely sensitive and selective technology due to very low concentrations and possible interferences of matrix components. Owing to their central role in AD pathology, oligomers are an attractive therapeutic target to ultimately halt disease progression or even to cure AD.MethodIn the present study, we developed and validated the surface‐based intensity‐distribution analysis (sFIDA) assay for quantification of Aβ oligomers in plasma. sFIDA is single particle sensitive and completely insensitive to Aβ monomers.ResultThe blood‐based sFIDA assay delivered a sensitivity of 1.8 fM, an inter‐ and intra‐assay variation below 20% for silica‐nanoparticles (SiNaPs) as calibration standard, and no interference with matrix components. Quantification of Aβ oligomers in 366 plasma samples from the DELCODE cohort, revealed decreased oligomer concentrations in subjective cognitive decline and AD patients compared to healthy controls. Correlation analysis between CSF and plasma oligomer concentrations suggest an impaired clearance of Aβ oligomers depending on ApoE ε4 status.ConclusionsFIDA is able to quantitate Aβ oligomers in plasma samples down to the low fM range. Aβ oligomers in plasma may reveal clearance mechanisms from the brain into blood, and how they are impaired during disease progression.

Predictive value of BMI in Cognitive Outcome in Mild Cognitive Impairment

AbstractBackgroundThis study aimed to determine the association between neuropsychological performance and body mass index (BMI) in patients with mild cognitive impairment (MCI). In addition, this study investigated the effects of the APOE genotype and sex in the relationship between the BMI and cognition in MCI.MethodsA total of 3,038 subjects with MCI aged 65‐90 were enrolled from the Clinical Research Center for Dementia of South Korea (CREDOS) cohort and a dementia cohort of the Ewha Womans University Mokdong Hospital (EUMC). MCI patients were classified into three subgroups (normal‐weight, overweight and obesity) according to the Asian standard of BMI. Cognitive performances between groups were compared by one way analysis of variance. To investigate the effects of the age, education, APOE genotype and sex, multivariate linear regression models after adjusting for possible confounders were used.ResultsEven‐though normal BMI groups were younger, had more males and less comorbidities, higher BMI groups (Overweigh and Obese) were associated with better performance in cognitive functions, scores of all neurocognitive tests were significantly increased (RCFT copy, p = 0.047; animal fluency, p = 0.039; phonemic fluency, p = 0.013; SVLT delay recall, p = 0.005; RCFT delay recall, K‐MMSE, p = 0.001; K‐BNT and Stroop test, p&lt;0.001), and CDR‐SB (p = 0.001) was decreased. The APOE ε4 carriers showed positive relationship between the BMI and the memory tasks: SVLT delay recall (p = 0.017) and RCFT delay recall (p = 0.002). And comparing between APOE ε4 carrier gender groups, significant positive relationship was shown only with visual memory task as BMI increases.ConclusionsOur findings suggested that higher BMI in patients with MCI were associated with better cognitive performance. The effects of the APOE genotype and sex in the associations between BMI and cognition were distinguishing. Therefore, according to physical status, APOE ε4 genotype, and sex‐specific strategies in the assessments and treatments may be necessary in elderly patients with MCI.

The Effects of Sex and APOE4 Genotype on Longitudinal Changes in White Matter Integrity Differ by Diagnostic Group Along the Spectrum of Alzheimer’s Disease

AbstractBackgroundSex and APOE ε4 (APOE4) are well‐established risk factors for Alzheimer’s disease (AD), with female ε4‐carriers at greatest risk. Uncovering the neurobiological substrates of sex and genetic effects in AD is critical to improve prevention, intervention, and treatment monitoring. While changes to white matter (WM) integrity are commonly noted in the progression of AD, it is unclear if these changes are further modulated by sex and APOE4 status. In the current study, we examined the effects of sex and APOE4 carrier status on WM integrity, both cross‐sectionally and longitudinally, across the AD continuum.MethodA total of 457 participants (233 cognitively normal (CN), 167 mild cognitive impairment (MCI), and 57 AD; 223 females; 187 APOE ε4‐carriers) was selected from the ADNI database, based on the availability two diffusion MRI (dMRI) sessions. The dMRI data were processed using FSL’s TBSS pipeline to quantify the degree of fractional anisotropy (FA). Annualized FA change maps were created to measure voxel‐wise WM change over time. The effect of sex, APOE4‐carrier status, diagnosis, and their interactions, on cross‐sectional and longitudinal WM integrity were assessed by FSL’s randomise and cluster‐level correction, controlling for age.ResultAt baseline, females exhibited greater FA than males in the fornix, right inferior fronto‐occipital fasciculus, left inferior and superior longitudinal fasciculus, while males showed greater FA in the left corticospinal tract. Additionally, there were widespread differences across the skeleton by diagnosis, with FA decreasing stepwise across the continuum (CN&gt;MCI&gt;AD). There were no APOE4‐related differences in baseline WM integrity. Longitudinally, a three‐way interaction between diagnosis, APOE4, and sex emerged within the corpus collasum, left anterior thalamic radiation, left corticospinal tract, left uncinate fasciculus, and left inferior and superior longitudinal fasciculus. Posthoc analyses revealed that within the AD group, but not CN or MCI groups, females underwent greater WM degeneration than males among nonε4‐carriers, while males showed greater WM degeneration than females among ε4‐carriers.ConclusionThese findings suggest that increased risk associated with sex and APOE4 genotype may change and interact with the progression of AD. Future studies are warranted to examine the contribution of cerebrovascular risk factors to AD progression in male ε4‐carriers.

Clinical Manifestations.

Alzheimer's disease (AD) is characterised biologically by beta-amyloid (Aβ) plaques and tau tangles, but autopsy studies reveal that most older adults also present with cerebrovascular disease (CVD) markers. Effects of biological AD on cognition in the context of concurrent CVD remain unclear. In older adults with CVD pathology, this study sought to determine ante-mortem cognitive trajectories associated with Aβ/tau positivity or negativity (+/-) at autopsy. Participants aged 65-95 classified as cognitively unimpaired at baseline from the National Alzheimer's Coordinating Center database, with ≥1 follow-up between 2005-2015, and available autopsy/APOE data were included (N = 924). Autopsy indicated that all participants had at least one of six CVD pathology markers. Participants were classified into four groups (A-T-, A+T-, A-T+, A+T+) based on semiquantitative Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque staging and Braak staging. Linear mixed models including group × time interactions assessed rate of change in Preclinical Alzheimer's Cognitive Composite scores, episodic memory, and executive function. Interactions between age, sex, APOE ε4 × time and the interval between death/the final study visit were included as covariates. A+T+ adults demonstrated significantly faster cognitive decline on all outcomes in the ∼10 years preceding death compared to A-T-, A+T-, and A-T+ adults (Table 1, Figure 1, d = 0.15 - 0.39). At final visit prior to death, a greater proportion of A+T+ adults (36%) received a dementia diagnosis compared to A-T+ (14%) or A+T- (15%) (p <.001). When analyses were restricted to exclude dementia diagnoses, significantly faster decline on all outcomes (p's <.001, d = 0.06 - 0.36) was similarly observed in A+T+ adults compared to A-T-, A+T- and A-T+ adults (Figure 2). Cognitive trajectories were equivalent between A-T- and A+T- for all outcomes (p's >.55). ln older adults with CVD pathology, A+T+ at autopsy was associated with greater cognitive decline over 10 years preceding death compared to A+T-, A-T+, and A-T- older adults. Faster cognitive decline in this group in the context of low final visit dementia diagnoses may suggest that post-mortem A+T+ is associated with a steep trajectory of cognitive decline ante-mortem, but that dementia progression is not inevitable.

Developing Topics.

A previous comparative analysis of plasma Aβ42/40 immunoassays and mass spectrometry-based assays conducted in 2021 found that several assays had strong performance in predicting amyloid PET status (Zicha et al., 2022). In the spirit of enabling the National Institute on Aging and the Alzheimer's Association framework for classifying Alzheimer's disease (AD) utilizing measures of pathology for amyloid, tau, and neurodegeneration (ATN), we have added to this comparative analysis a newly developed immunoassay on an automated, scalable platform. Robustly validated plasma Aβ assays represent a non-invasive and cost-effective alternative to CSF or neuroimaging for early detection of Alzheimer's disease pathology and screening participants for enrollment into clinical trials. The project team consists of pharmaceutical industry, patient advocacy, governmental, and academic representatives. The current study utilized an additional aliquot of the same 130 plasma samples provided by ADNI that were previously tested on three immunoassays and three mass spectrometry-based assays. The statistical analysis plan was performed as published previously to determine if the measurement of plasma Aβ with age and APOE ε4 status performs better than age and APOE ε4 status alone in determining amyloid PET status. In this sample cohort, the new automated immunoassay with age and APOE genotype had similar prediction of amyloid status compared to mass spectrometry-based assays, with an ROC AUC of 85.7 (95% CI: 79.1 - 92.4) for the immunoassay and 84.2 (95% CI: 77.0 - 91.3) for the best- performing mass spectrometry-based assay. The Spearman correlation of plasma Aβ42/40 with amyloid PET (florbetapir standardized uptake value ratio) for the new immunoassay was -0.567 (p < 0.001) compared to -0.536 (p < 0.001) for the best performing mass spectrometry-based assay. The new immunoassay significantly improved the prediction of amyloid positivity beyond age and APOE ε4 genotype (p = 0.003). Results from this comparative analysis together with the continued advancement in plasma assay technology identify a potential use for plasma Aβ42/40 measurement in addressing the amyloid component of the ATN framework. Further evaluation of plasma Aβ42/40 in addition to p-tau in plasma is planned using longitudinal samples to determine the ability of plasma biomarkers to detect amyloidosis.

Incidence and symptomatology of ARIA

AbstractBackgroundTo summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti–β‐amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment.MethodA literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence‐Based Medicine.ResultTwenty‐two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid‐attenuated inversion recovery and T2‐weighted sequences were termed ARIA‐E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA‐H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA‐E incidence was further associated with treatment dose, affecting the 55%of ApoE ε4 carriers in the high‐dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3%of ARIA‐E cases at higher treatment doses across RCTs, whereas ARIA‐H cases were generally asymptomatic. Most ARIA‐E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA‐E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6%across RCTs.ConclusionEvidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid‐modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real‐world clinical settings.