Ε4 Allele Status Research Articles

Biomarker and neuropsychological correlates of the N400 event-related potential in Alzheimer's disease

ObjectiveThe current study sought to characterize the relationship of the N400 (N4) effect event-related potential to Alzheimer's disease (AD) biomarkers and broader cognition in older adults on the late-life cognitive continuum. MethodParticipants who were cognitively intact (n = 43), or had amnestic mild cognitive impairment (MCI; n = 19), or mild AD (n = 12), completed a word-pair judgement task during concurrent EEG recording to elicit the N400. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and biomarker data (PET-imaged beta-amyloid (aβ) deposition, apolipoprotein-E ε4 (APOE4) allele status, hippocampal volumes) were collected as part of a larger study. ResultsThe AD group had slower response times and poorer accuracy on the word-pair judgement task than the intact group. The N4 effect was smaller and occurred later in AD relative to intact participants. MCI participants' values were intermediate. N4 effect amplitudes were not associated with RBANS scores but were positively associated with aβ deposition. Conversely, poorer performance across most RBANS Indexes and the Total score was associated with longer N4 latencies. There was also a negative association between hippocampal volumes and the N4 latency and a positive association between aβ deposition and latency. Finally, the latency of the N4 independently predicted variance in RBANS Total scores, above and beyond aβ deposition, hippocampal volumes, and APOE4 allele status. ConclusionsThese findings support the relevance of the N4 effect in individuals along the late-life cognitive continuum, and motivate future studies into its potential as a longitudinal predictor in AD.

A prediction model of dementia conversion for mild cognitive impairment by combining plasma pTau181 and structural imaging features.

The early stages of Alzheimer's disease (AD) are no longer insurmountable. Therefore, identifying at-risk individuals is of great importance for precise treatment. We developed a model to predict cognitive deterioration in patients with mild cognitive impairment (MCI). Based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we constructed models in a derivation cohort of 761 participants with MCI (138 of whom developed dementia at the 36th month) and verified them in a validation cohort of 353 cognitively normal controls (54 developed MCI and 19 developed dementia at the 36th month). In addition, 1303 participants with available AD cerebrospinal fluid core biomarkers were selected to clarify the ability of the model to predict AD core features. We assessed 32 parameters as candidate predictors, including clinical information, blood biomarkers, and structural imaging features, and used multivariable logistic regression analysis to develop our prediction model. Six independent variables of MCI deterioration were identified: apolipoprotein E ε4 allele status, lower Mini-Mental State Examination scores, higher levels of plasma pTau181, smaller volumes of the left hippocampus and right amygdala, and a thinner right inferior temporal cortex. We established an easy-to-use risk heat map and risk score based on these risk factors. The area under the curve (AUC) for both internal and external validations was close to 0.850. Furthermore, the AUC was above 0.800 in identifying participants with high brain amyloid-β loads. Calibration plots demonstrated good agreement between the predicted probability and actual observations in the internal and external validations. We developed and validated an accurate prediction model for dementia conversion in patients with MCI. Simultaneously, the model predicts AD-specific pathological changes. We hope that this model will contribute to more precise clinical treatment and better healthcare resource allocation.

Fish consumption, cognitive impairment and dementia: an updated dose-response meta-analysis of observational studies

BackgroundCognitive impairment is projected to affect a preponderant proportion of the aging population. Lifelong dietary habits have been hypothesized to play a role in preventing cognitive decline. Among the most studied dietary components, fish consumptionhas been extensively studied for its potential effects on the human brain.AimsTo perform a meta-analysis of observational studies exploring the association between fish intake and cognitive impairment/decline and all types of dementia.MethodsA systematic search of electronic databases was performed to identify observational studies providing quantitative data on fish consumption and outcomes of interest. Random effects models for meta-analyses using only extreme exposure categories, subgroup analyses, and dose-response analyses were performed to estimate cumulative risk ratios (RRs) and 95% confidence intervals (CIs).ResultsThe meta-analysis comprised 35 studies. Individuals reporting the highest vs. the lowest fish consumption were associated with a lower likelihood of cognitive impairment/decline (RR = 0.82, 95% CI: 0.75, 0.90, I2 = 61.1%), dementia (RR = 0.82, 95% CI: 0.73, 0.93, I2 = 38.7%), and Alzheimer’s disease (RR = 0.80, 95% CI: 0.67, 0.96, I2 = 20.3%). The dose-response relation revealed a significantly decreased risk of cognitive impairment/decline and all cognitive outcomes across higher levels of fish intake up to 30% for 150 g/d (RR = 0.70, 95% CI: 0.52, 0.95). The results of this relation based on APOE ε4 allele status was mixed based on the outcome investigated.ConclusionsCurrent findings suggest fish consumption is associated with a lower risk of cognitive impairment/decline in a dose-response manner, while for dementia and Alzheimer’s disease there is a need for further studies to improve the strength of evidence.

Efficacy and Safety of Exogenous Ketones in People with Mild Neurocognitive Disorder and Alzheimer's Disease: A Systematic Literature Review.

Mild neurocognitive disorder (NCD), formally known as mild cognitive impairment, is usually the clinical stage preceding the development of Alzheimer's disease (AD), the most prevalent major NCD, and other causes of dementia. Glucose is a major source of energy for human brain metabolism and the uptake of glucose is reduced in patients with mild NCD, AD, and other NCDs. Unlike glucose, the uptake of ketones remains normal in people with mild NCD and AD, suggesting that the use of ketone bodies may compensate for glucose energy deficiency in patients with mild NCD and AD. The aim of this systematic review was to summarize the efficacy and safety of exogenic ketones, including medium chain triglycerides (MCTs), on cognitive function in patients with mild NCD and AD. The Embase, MEDLINE, MEDLINE In-Process, PubMed Ahead-of-Print, Cochrane Central Register of Controlled Trials, Europe PMC databases were searched from inception to April 2022. Studies reporting cognitive function efficacy and safety outcomes from randomized controlled trials of exogenic ketones in patients with mild NCD and AD were included. Data were extracted by 1 reviewer and checked by a second reviewer. Risk of bias was assessed using the Cochrane risk of bias tool, version 2. This review identified 13 individual trials investigating the efficacy and safety of MCT or coconut oil for patients with mild NCD or with AD. Because of the heterogeneity of the studies, a narrative synthesis was used. Overall, improvements associated with exogenic ketones were observed in multiple aspects of cognitive abilities, although the large heterogeneity between the included studies makes it difficult to draw firm conclusions from the current literature. Although some studies investigated the impact of the apolipoprotein E ε4 allele status on treatment efficacy, the current data are insufficient to conclude whether such an effect is present. PROSPERO registration No. CRD42022336664.

Differences in the Distribution of Aβ in the Brain between U.S. Veterans and Adults aged 62+ and suffering from Alzheimer's Disease.

Elevated concentration of amyloids in the cerebrum results in elevated risks for cerebral hemorrhage and early AD onset following early depression/dementia onset. In this study, we compare patterns of amyloid depositions across eight regions of interest of the human brain between U.S. Veterans and non-Veterans adults aged 62+. Data were taken from the ADNI and DoD-ADNI studies. A pseudo-randomization algorithm was applied to achieve comparability, reduce bias due to age mismatching, and account for non-treatment-related differences between subsamples extracted from DoD-ADNI and ADNI databases. The pool of participants included data about age, race, apolipoprotein ε4 allele (APOE) status, modified Hachinski Ischemic Score, education level, and geriatric depression score, which were used to build a propensity score. Aβ concentration, resulting from the PET image analysis, in key brain regions of interest, and two categorical variables describing the 0.79 and 1.11 cutoffs were used as outcomes, while the Veteran and AD status were used as predictors. To balance subsamples, we applied a pseudo-randomization algorithm, eliminating the observed sources of heterogeneity. We used a generalized linear model for continuous variables and the logistic regression model for binary variables. The pattern of the Aβ distribution in Veteran's brains was found to be different from the classic AD pattern. The amyloid depositions following Veteran status were concentrated in cerebellar gray matter and the cerebellum in general. In contrast, the AD pattern shows more Aβ depositions in the frontal lobe, cingulate cortex, parietal, and temporal lobes, along with higher whole-cerebrum concentration of amyloids. Since Florbetapir PET cannot distinguish between senile plaques and depositions in blood vessels, the elevated concentration of amyloids in a cerebellum for participants with the Veteran status may suppose elevated risks for cerebral hemorrhage and early AD onset following early depression/dementia onset.

Suboptimal self-reported sleep efficiency and duration are associated with faster accumulation of brain amyloid beta in cognitively unimpaired older adults.

This study investigated whether self-reported sleep quality is associated with brain amyloid beta (Aβ) accumulation. Linear mixed effect model analyses were conducted for 189 cognitively unimpaired (CU) older adults (mean±standard deviation 74.0±6.2; 53.2% female), with baseline self-reported sleep data, and positron emission tomography-determined brain Aβ measured over a minimum of three time points (range 33.3-72.7 months). Analyses included random slopes and intercepts, interaction for apolipoprotein E (APOE) ε4 allele status, and time, adjusting for sex and baseline age. Sleep duration<6hours, in APOE ε4 carriers, and sleep efficiency<65%, in the whole sample and APOE ε4 non-carriers, is associated with faster accumulation of brain Aβ. These findings suggest a role for self-reported suboptimal sleep efficiency and duration in the accumulation of Alzheimer's disease (AD) neuropathology in CU individuals. Additionally, poor sleep efficiency represents a potential route via which individuals at lower genetic risk may progress to preclinical AD. In cognitively unimpaired older adults self-report sleep is associated with brain amyloid beta (Aβ) accumulation.Across sleep characteristics, this relationship differs by apolipoprotein E (APOE) genotype.Sleep duration<6hours is associated with faster brain Aβ accumulation in APOE ε4 carriers.Sleep efficiency< 65% is associated with faster brain Aβ accumulation in APOE ε4 non-carriers.Personalized sleep interventions should be studied for potential to slow Aβ accumulation.

Dementia risk and thalamic nuclei volumetry in healthy midlife adults: the PREVENT Dementia study.

A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer's disease, mild cognitive impairment and asymptomatic individuals with risk factors for early-onset Alzheimer's disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition. Seven hundred participants aged 40-59 years were recruited into the PREVENT Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3 T MRI scans using FreeSurfer 7.1.0. Thalamic nuclei were grouped into six regions: (i) anterior, (ii) lateral, (iii) ventral, (iv) intralaminar, (v) medial and (vi) posterior. Cognitive performance was evaluated using the computerized assessment of the information-processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate correction for multiple comparisons. We did not find significant volumetric differences in the thalamus or its subregions, which survived false discovery rate correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without a dementia family history. A larger volume of the mediodorsal medial nucleus (Pfalse discovery rate = 0.019) was associated with a faster processing speed in those without a dementia family history. Larger volumes of the thalamus (P = 0.016) and posterior thalamus (Pfalse discovery rate = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein ε4 allele carriers. We did not find significant volumetric differences in thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without a dementia family history but have little effect on those with a dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein ε4 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis.

APOE ε4 allele status modulates the spatial patterns of progressive atrophy in the temporal lobes after mild traumatic brain injury.

We evaluated how the apolipoprotein E (APOE) ε4 allele modulated the spatial patterns of longitudinal atrophy in the Alzheimer's disease-vulnerable brain areas of patients with mild traumatic brain injury (mTBI) from the acute to chronic phase post injury. Fifty-nine adult patients with acute mTBI and 48 healthy controls with APOE ε4 allele testing underwent T1-weighted magnetic resonance imaging and neuropsychological assessments with 6 to 12 months of follow-up. Progressive brain volume loss was compared voxel-wise in the temporal lobes. Patients with the APOE ε4 allele presented significant longitudinal atrophy in the left superior and middle temporal gyri, where the progressive gray matter volume loss predicted longitudinal impairment in language fluency, whereas mTBI APOE ε4 allele noncarriers showed mainly significant longitudinal atrophy in the medial temporal lobes, without significant neuropsychological relevance. The atrophy progression observed in mTBI patients with the APOE ε4 allele may increase the possibility of developing a specific phenotype of Alzheimer's disease with language dysfunction. The apolipoprotein E (APOE) ε4 allele and mild traumatic brain injury (mTBI) are risk factors for Alzheimer's disease (AD) progression.It is unclear how the interaction of mTBI with the APOE ε4 allele impacts the progressive atrophy topography in AD-vulnerable brain regions.In this study, patients with the APOE ε4 allele showed progressive atrophy patterns similar to the early stage of logopenic variant of primary progressive aphasia (lvPPA) phenotype of AD. APOE ε4 allele carriers with mTBI history may be at the risk of developing a given AD phenotype with language dysfunction.

Sex differences in the associations between the risk for late‐life Alzheimer’s disease, protective lifestyle factors and cognition in mid‐life: The PREVENT Dementia study.

AbstractBackgroundIt is now acknowledged that Alzheimer’s Disease (AD) processes are present decades before the symptoms manifest, but whether lifestyle activities can protect against these early AD processes in mid‐life remains poorly understood. Furthermore, the impact of sex as a biological variable on associations between dementia risk, protective lifestyle activities and cognition is unknown. In this study, we aimed to replicate findings from our two recent studies (Deng et al., 2022; Heneghan et al., 2022) on the contribution of mid‐life modifiable activities to cognition in individuals with dementia risk, in a larger independent cohort (N = 461 vs N = 208 used previously). Second, we investigated associations between biological sex, dementia risk, protective lifestyle activities and cognitive performance.MethodCognitively unimpaired middle‐aged participants (40‐59 years; N = 461) completed cognitive and clinical assessments cross‐sectionally. Risk factors (Apolipoprotein E [APOE] ε4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score [CAIDE]) were assessed and mid‐life activities were measured with the Lifetime of Experiences Questionnaire.ResultReplicating our key previous findings, we found that episodic and relational memory was (a) significantly negatively associated with the CAIDE risk score (Figure 1a), (b) positively associated with stimulating lifestyle activities (Figure 1b), and (c) that females performed significantly better than males in episodic and relational memory (Figure 2a). The key novel finding of this study was that APOE ε4 genotype modulated the association between sex, lifestyle and cognition. Only for APOE ε4+ females, not APOE ε4‐, higher occupational attainment was associated with better episodic and relational memory (Figure 2c, 2d). Conversely, only for APOE ε4+ males, not APOE ε4‐, higher occupational attainment was associated with worse episodic and relational memory (Figure 2c, 2d).ConclusionThese findings suggest that modifiable lifestyle activities offset cognitive decrements due to inherited AD risk in mid‐life and support the targeting of modifiable lifestyle activities for the prevention of AD. Furthermore, these findings suggest an urgent need for targeted research on female‐specific risk factors, to inform personalised strategies for AD prevention and the promotion of female brain health.

Moderation effects of APOE‐ε4 on marine omega‐3 fatty acids and its relation to change in cognitive function among community‐dwelling older adults

AbstractBackgroundIn a recent trial, we observed no effect of omega‐3 fatty acids (omega‐3s) supplementation on cognitive decline. However, brain concentrations and metabolism of lipid molecules in response to omega‐3s may be regulated by apolipoprotein E (APOE)‐ε4 allele status. Further, while APOE‐ε4 is an established risk factor for Alzheimer disease, its association with cognitive decline is uncertain, especially in more diverse samples. The few randomized clinical trials (RCTs) addressing the moderation of effects of omega‐3s on cognitive decline by APOE‐ε4 have yielded inconsistent findings. Thus, we examined moderation by APOE‐ε4 on effects of omega‐3s vs. placebo for global and domain‐specific cognitive change over 2 years in a well‐characterized, diverse sample of older adults.MethodsVITamin D and OmegA‐3 TriaL (VITAL) is a 2×2 factorial RCT of vitamin D3 (2000 IU/day) and/or omega‐3s (1 g/day including 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) for cardiovascular disease and cancer prevention. We included 743 VITAL in‐clinic sub‐cohort participants who completed all cognitive tests at baseline and had APOE genotype data. The primary outcome was change in global cognition (averaging z‐scores of 9 tests) over 2 years; episodic memory and executive function/attention were examined separately. We used multiplicative interaction terms in general linear models of response profiles to examine moderation by APOE‐ε4 carrier status on effects of omega‐3s vs. placebo for cognitive change outcomes over 2 years.ResultsThe mean age (standard deviation) of participants was 67.1 (5.3) years; 50.6% were females; 13.5% were from racial and/or ethnic minority backgrounds; and 24.9% were APOE‐ε4 allele carriers. Over 2 years, compared with APOE‐ε4 non‐carriers, APOE‐ε4 carriers had faster declines in global cognition and episodic memory but not in executive function/attention; e.g., the mean difference in change (95% confidence interval) for episodic memory comparing APOE‐ε4 carriers vs. non‐carriers was ‐0.18 (‐0.33 to ‐0.03). There were no significant interactions between APOE‐ε4 carrier status and randomization status (omega‐3s vs. placebo) on change in global, episodic memory, or executive function/attention scores.ConclusionAPOE‐ε4 significantly predicted cognitive decline but did not modify the effect of omega‐3s on global and domain‐specific cognitive change over 2 years.

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.

Cross‐sectional and longitudinal associations of plasma makers of amyloid and tau pathology and neurodegeneration with gait speed

AbstractBackgroundHigher brain amyloid PET is associated with slower gait speed and has been hypothesized to play a role in age‐related mobility decline. With the development of blood‐based biomarkers of Alzheimer’s disease pathology, we examined whether plasma levels of amyloid‐beta (Aβ)40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated tau 181 (p‐tau181) and 217 (p‐tau217), total tau, and neurofilament light chain (NfL) were associated with gait speed.MethodThis study included 779 cognitively unimpaired participants (median age 75, 54.8% male, median follow‐up 6.8 years) in the Mayo Clinic Study of Aging with concurrent measurement of plasma biomarkers and gait speed. Individuals with chronic kidney disease or a history of stroke were excluded. The plasma markers (pg/mL) were measured on the Quanterix Simoa® HD‐1 analyzer (total tau, Aβ42, Aβ40, NfL) and the Meso Scale Discovery platform (p‐tau181, p‐tau217). Gait speed (m/s) was obtained by timing a self‐paced walk across 25 ft using a stopwatch. Linear mixed effects models, with subject‐specific intercepts and slopes for time since baseline, with z‐scored baseline plasma markers were used to predict cross‐sectional and longitudinal gait speed. All models adjusted for baseline age and sex.ResultAt baseline, higher Aβ42 [Beta = ‐0.019; 95%CI = (‐0.035, ‐0.004)], total‐tau [‐0.026; (‐0.041, ‐0.011)], and p‐tau181 [‐0.021; (‐0.036, ‐0.006)] were associated with slower gait speed. Gait speed decreased, on average, by about 0.015 m/s annually for those in this study. Each one standard deviation (SD) increase in baseline level of plasma Aβ40 [‐0.005; (‐0.007, ‐0.002)], NfL [‐0.006; (‐0.009, ‐0.004)], and p‐tau217 [‐0.004; (‐0.007, ‐0.001)] accelerated this decline over time. In contrast, each one SD increase in Aβ42/Aβ40 ratio [0.003; (0.001, 0.006)] mitigated decline. Additional analyses adjusting for Charlson comorbidity index, Beck Depression Inventory, body mass index, and APOE E4 allele status gave similar results.ConclusionBoth cross‐sectional and longitudinal associations of plasma markers of amyloid and tau pathology and neurodegeneration with gait speed among cognitively unimpaired individuals were present. Therefore, not only are these markers of cognitive changes, they are also related to motor changes such as those affecting gait speed.

Ginseng intake and Alzheimer disease-specific cognition in older adults according to apolipoprotein ε4 allele status.

The probable association among ginseng intake, Alzheimer's disease (AD)-specific cognition, and apolipoprotein ε4 (APOE4) remains poorly investigated. Hence, we examined the association between ginseng intake and AD-specific cognition in older adults under the moderating effect of APOE4 status. This study enrolled 160 adults aged 65-90 years without dementia. All participants underwent comprehensive dietary and clinical assessments including ginseng intake, AD-related cognition (i.e., delayed episodic memory, as the earliest cognitive change in AD), and non-memory cognition for comparative purposes. Ginseng intake was associated with higher delayed episodic memory, but not non-memory cognition, compared to no ginseng intake. The interaction between ginseng intake and APOE4 status had a significant effect on delayed episodic memory. Subgroup analyses showed that ginseng intake was associated with higher delayed episodic memory in the APOE4-negative but not the APOE4-positive subgroup. The benefits of ginseng intake on delayed episodic memory were prominent in the high duration (≥5 years) and midlife onset (<65 years) groups. Our study of older adults with no dementia suggests that ginseng intake (with high duration and midlife onset) had a beneficial effect on AD-specific cognitive decline, i.e., the delayed episodic memory. In addition, APOE4 status moderates the association between ginseng intake status and AD-specific cognitive decline.

Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers

Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression. To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals. This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses. Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort. The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion. Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time. In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.

Effect of a 1-Year Nutritional Blend Supplementation on Plasma p-tau181 and GFAP Levels among Community-Dwelling Older Adults: A Secondary Analysis of the Nolan Trial.

Observational studies and some randomized controlled trials have suggested that nutritional supplementation could be a possible intervention pathway to prevent cognitive decline and Alzheimer's disease (AD). As measuring amyloid-β and tau pathophysiology by positron emission tomography (PET) or cerebrospinal fluid (CSF) analyses may be perceived as complex, plasma versions of such biomarkers have emerged as more accessible alternatives with comparable capacity of predicting cognitive impairment. This study aimed to evaluate the effect of a 1-year intervention with a nutritional blend on plasma p-tau181 and glial fibrillary acidic protein (GFAP) levels in community-dwelling older adults. Effects were further assessed in exploratory analyses within sub-cohorts stratified according to p-tau status (with the third tertile considered as high: ≥15.1 pg/ mL) and to apolipoprotein E (APOE) ε4 allele status. A total of 289 participants ≥70 years (56.4% female, mean age 78.1 years, SD=4.7) of the randomized, double-blind, multicenter, placebo-controlled Nolan trial had their plasma p-tau181 assessed, and daily took either a nutritional blend (composed of thiamin, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folic acid, cobalamin, vitamin E, vitamin C, vitamin D, choline, selenium, citrulline, eicosapentaenoic acid - EPA, and docosahexaenoic acid - DHA) or placebo for 1 year. After 1-year, both groups presented a significant increase in plasma p-tau181 and GFAP values, with no effect of the intervention (p-tau181 between-group difference: 0.27pg/mL, 95%CI: -0.95, 1.48; p=0.665; GFAP between-group difference: -3.28 pg/mL, 95%CI: -17.25, 10.69; p=0.644). P-tau-and APOE ε4-stratified analyses provided similar findings. In community-dwelling older adults, we observed an increase in plasma p-tau181 and GFAP levels that was not different between the supplementation groups after one year.

ABCA7‐reducing mutation carriers have reduced CSF amyloid biomarker levels, suggestive of increased amyloid deposition

AbstractBackgroundThe Alzheimer’s disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower ABCA7 expression and hereby increased risk for AD. However, the exact mechanism‐of‐action remains unclear. By studying CSF biomarkers reflecting different types of AD‐related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers.MethodThe study population consisted of 228 AD patients (27 PTC mutation and 16 pathogenic expansion carriers) for whom CSF was available and ABCA7 sequencing and VNTR genotyping had been performed. CSF levels of amyloid β (Aβ) 40 and 42, sAPP‐α and ‐β, YKL‐40 and hFABP were determined using ELISA and Meso Scale Discovery assays. We compared differences in levels of these biomarkers AD patients with or without an ABCA7 PTC mutation or expansion, and further stratified on APOE e4 status.ResultCarriers of ABCA7 mutations/expansions had significantly lower Aβ42 levels (p= 0.0031) and amyloid ratio (p=0.020) compared to non‐carrier patients, and were threefold more likely to have abnormal Aβ42 values. The effect on amyloid biomarkers remained significant when considering PTC mutations or VNTR expansions separately. APOE e4 carriers had significantly lower Aβ42 (p=0.0013) and amyloid ratio (p&lt;0.001) compared to non‐APOE e4 carriers. When combined, both APOE e4 allele and ABCA7 carrier status influenced amyloid ratio and Aβ42 levels. Remarkably, within non‐APOE e4 carriers, ABCA7 mutation/expansion carriers did have significantly reduced Aβ42 levels (mean=540 pg/mL) compared to ABCA7 non‐carriers (812 pg/mL; p=0.0051), attaining lower levels as e4 carriers (612 pg/mL). Finally, in carriers of the pathogenic expansion we observed lower YKL40 levels (p=0.011), suggesting reduced neuroinflammation.ConclusionOur results highlight that carriers of ABCA7 PTC mutations and repeat expansions show more pronounced abnormalities in CSF amyloid beta markers than non‐carrier patients, especially in non‐APOE e4 carriers. Expansion carriers also had a decrease in neuroinflammation marker YKL40. Our results suggest that reduced ABCA7 expression leads to increase in amyloid pathology and potentially a reduced inflammatory response to damage.

The association between long‐term PM2.5 exposure and late‐life amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study cohort

AbstractBackgroundA number of studies show an association between long‐term exposure to ambient particulate matter ≤ 2.5 um (PM2.5) and late‐life cognitive impairment. Mechanistic models suggest that PM2.5 may influence cognitive health through promotion of Alzheimer’s disease, which is characterized by brain amyloid accumulation. However, the association between long‐term PM2.5 exposure and brain amyloid deposition remains poorly characterized in epidemiological studies.MethodWe used data from the Atherosclerosis Risk in Communities (ARIC) study cohort. We used a chemical transport model with data fusion to estimate mean PM2.5 concentrations (ug/m3) in 36‐, 12‐, 4‐, and 1‐km grid cells in ARIC study areas. We linked the concentrations to geocoded participant addresses and calculated mean PM2.5 concentrations from 2000 to 2007. We estimated amyloid deposition using florbetapir amyloid positron emission tomography (PET) scans in 346 ARIC‐PET participants with normal cognition or mild cognitive impairment in 2011‐2014. We defined amyloid positivity as a global cortical standardized uptake value ratio (SUVR) ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and mean 2000‐2007 PM2.5 concentration after adjusting for potential confounders. We additionally explored effect measure modification by APOE e4 allele status and tested whether effect estimates were consistent using alternate PM2.5 exposure methods.ResultAfter restricting to participants with non‐missing exposure and confounder data and excluding one participant with dementia, the analytic sample included 279 participants. At the time of amyloid‐PET scans, their mean age was 78 years, 56% were female, 42% were Black, and 26% had mild cognitive impairment. After adjusting for age, sex, education, and race‐study center, we found no significant association between brain amyloid positivity and long‐term mean PM2.5 exposure. We also found no evidence of effect measure modification by APOE e4 allele status. Results were consistent when we used alternate PM2.5 estimation methods.ConclusionOur findings suggest that ambient PM2.5 may induce neurotoxic effects through non‐amyloid, potentially vascular pathways, though we note the small sample size may have made us underpowered to detect a significant association.

Different associations of varying types of Vitamin E and cognitive function in older adults with or without APOE Ɛ4 allele

AbstractBackgroundDifferent forms of vitamin E may have a different association with cognitive function, which might vary by the APOE E4 allele status. We aim to examine vitamin E from different sources and in varying forms and their relation to cognitive decline among those with and without the APOE E4 allele.MethodsWe included 2,014 participants from the Chicago Health and Aging Project (62% African Americans, 63% female). Global cognition was assessed using a composite score of episodic memory, perceptual speed, and the MMSE. Diet was assessed by a 139‐item FFQ. APOE genotype was assessed by hME Sequenom mass‐array platform. Mixed models were adjusted for age, sex, education, smoking status, calorie intake, alcohol consumption, use of supplements, time since baseline, and the interaction term of time with each covariate.ResultsA higher dietary vitamin E was associated with slower cognitive decline. Those in the highest quintile of dietary vitamin E intake had 28% slower cognitive decline than the lowest quintile (β = 0.014, p = 0.02). A higher intake of dietary αlpha‐tocopherol was associated with slower cognitive decline in participants with APOE E4 allele, but not among those without. In participants with APOE E4 allele and in the highest quintile of alpha‐tocopherol intake had a 16.4% slower rate of global cognitive decline than those in the lowest quintile (β = 0.015, p = 0.0015). A higher intake of delta‐tocopherol was associated with a slower decline in individuals without the APOE E4 allele only. Among those without the APOE E4 allele and in the highest quintile, the rate of global cognitive decline was slower by 22% than the lowest quintile (β = 0.012, p = 0.0014). We found no significant associations between beta‐ and gamma‐tocopherol intakes and cognitive decline among those with and without the APOE E4 allele.ConclusionOur study found a positive association of alpha‐tocopherol with cognitive decline among those with the APOE E4 allele and delta‐tocopherol with the decline in those without the APOE E4 allele. Our findings suggest that different forms of vitamin E might have a different association with cognitive decline in older adults depending on their APOE E4 allele status.

Choroid Plexus Volume and Permeability at Brain MRI within the Alzheimer Disease Clinical Spectrum.

Background Mounting evidence suggests that the choroid plexus (CP) plays an important role in the pathophysiology of Alzheimer disease (AD), but its imaging profile in cognitive impairment remains unclear. Purpose To evaluate CP volume, permeability, and susceptibility by using MRI in patients at various stages of cognitive impairment. Materials and Methods This retrospective study evaluated patients with cognitive symptoms who underwent 3.0-T MRI of the brain, including dynamic contrast-enhanced (DCE) imaging and quantitative susceptibility mapping (QSM), between January 2013 and May 2020. CP volume was automatically segmented using three-dimensional T1-weighted sequences; the volume transfer constant (ie, Ktrans) and fractional plasma volume (ie, Vp) were determined using DCE MRI, and susceptibility was assessed using QSM. The effects of CP volume, expressed as the ratio to intracranial volume, on cognition were evaluated using multivariable linear regression adjusted for age, sex, education, apolipoprotein E ε4 allele status, and volumetric measures. Results A total of 532 patients with cognitive symptoms (mean age, 72 years ± 9 [SD]; 388 women) were included: 78 with subjective cognitive impairment (SCI), 158 with early mild cognitive impairment (MCI), 149 with late MCI, and 147 with AD. Among these, 132 patients underwent DCE MRI and QSM. CP volume was greater in patients at more severe stages (ratio of intracranial volume × 103: 0.9 ± 0.3 for SCI, 1.0 ± 0.3 for early MCI, 1.1 ± 0.3 for late MCI, and 1.3 ± 0.4 for AD; P < .001). Lower Ktrans (r = -0.19; P = .03) and Vp (r = -0.20; P = .02) were negatively associated with CP volume; susceptibility was not (r = 0.15; P = .10). CP volume was negatively associated with memory (B = -0.67; standard error of the mean [SEM], 0.21; P = .01), executive function (B = -0.90; SEM, 0.31; P = .01), and global cognition (B = -0.82; SEM, 0.32; P = .01). Conclusion Among patients with cognitive symptoms, larger choroid plexus volume was associated with severity of cognitive impairment in the Alzheimer disease spectrum. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Chiang in this issue.

A Conformational Variant of p53 (U-p53AZ) as Blood-Based Biomarker for the Prediction of the Onset of Symptomatic Alzheimer’s Disease

BackgroundOngoing research seeks to identify blood-based biomarkers able to predict onset and progression of Alzheimer’s disease (AD).ObjectiveThe unfolded conformational variant of p53 (U-p53AZ), previously observed in AD individuals, was evaluated in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort for diagnostic and prognostic assessment, validated on a neuropsychological-based diagnosis, over the course of six years.DesignRetrospective Longitudinal Prognostic biomarker study.SettingSingle-center study based on the AIBL cohort.Participants482 participants of the AIBL cohort, aged 60–85 years, without uncontrolled diabetes, vascular disease, severe depression or psychiatric illnesses.MeasurementsThe AlzoSure® Predict test, consisting of immunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS), was performed to quantify the AZ 284® peptide as readout of U-p53AZ and compared with an independent neuropsychological diagnosis. The amyloid load via amyloid β-positron emission tomography (Aβ-PET) and supporting clinical information were included where possible.ResultsU-p53AZ diagnostic and prognostic performance was assessed in both time-independent and time-dependent (36, 72 and 90 months following initial sampling) analyses. Prognostic performance of Aβ-PET and survival analyses with different risk factors (gender, Aβ-PET and APOE ε4 allele status) were also performed. U-p53AZ differentiated neuropsychologically graded AD from non-AD samples, and its detection at intermediate/high levels precisely identified present and future symptomatic AD. In both time-independent and time-dependent prognostic analyses U-p53AZ achieved area under the curve (AUC) >98%, significantly higher than Aβ-PET AUCs (between 84% and 93%, P respectively <0.0001 and <0.001). As single factor, U-p53AZ could clearly determine the risk of AD neuropsychological diagnosis over time (low versus intermediate/high U-p53AZ hazard ratio=2.99). Proportional hazards regression analysis identified U-p53AZ levels as a major independent predictor of AD onset.ConclusionsThese findings support use of U-p53AZ as blood-based biomarker predicting whether individuals would reach neuropsychologically-defined AD within six years prior to AD diagnosis. Integration of U-p53AZ in screening processes could support refined participant stratification for interventional studies.