Moderating effect of APOE ε4 on the association of sleep disturbance and amyloid-β pathology among cognitively normal older adults

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

Lack of association between bridging integrator 1 (BIN1) rs744373 polymorphism and tau-PET load in cognitively intact older adults.

High levels of β-amyloid (Aβ) in the brain and carriage of the APOE ε4 allele have each been linked to cognitive impairment in cognitively normal (CN) older adults. However, the relationship between these two biomarkers and cognitive decline is unclear. The aim of this study was to investigate the relationship between cerebral Aβ level, APOE ε4 carrier status, and cognitive decline over 18 months, in 317 cognitively healthy (CN) older adults (47.6% males, 52.4% females) aged between 60 and 89 years (Mean = 69.9, SD = 6.8). Cognition was assessed using the Cogstate Brief Battery (CBB) and the California Verbal Learning Test, Second Edition (CVLT-II). Planned comparisons indicated that CN older adults with high Aβ who were also APOE ε4 carriers demonstrated the most pronounced decline in learning and working memory. In CN older adults who were APOE ε4 non-carriers, high Aβ was unrelated to cognitive decline in learning and working memory. Carriage of APOE ε4 in CN older adults with low Aβ was associated with a significantly increased rate of decline in learning and unexpectedly, improved cognitive performance on measures of verbal episodic memory over 18 months. These results suggest that Aβ and APOE ε4 interact to increase the rate of cognitive decline in CN older adults and provide further support for the use of Aβ and APOE ε4 as biomarkers of early Alzheimer’s disease.

A challenge in developing informative neuroimaging biomarkers for early diagnosis of Alzheimer's disease is the need to identify biomarkers that are evident before the onset of clinical symptoms, and which have sufficient sensitivity and specificity on an individual patient basis. Recent literature suggests that spatial patterns of brain atrophy discriminate amongst Alzheimer's disease, mild cognitive impairment (MCI) and cognitively normal (CN) older adults with high accuracy on an individual basis, thereby offering promise that subtle brain changes can be detected during prodromal Alzheimer's disease stages. Here, we investigate whether these spatial patterns of brain atrophy can be detected in CN and MCI individuals and whether they are associated with cognitive decline. Images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to construct a pattern classifier that recognizes spatial patterns of brain atrophy which best distinguish Alzheimer's disease patients from CN on an individual person basis. This classifier was subsequently applied to longitudinal magnetic resonance imaging scans of CN and MCI participants in the Baltimore Longitudinal Study of Aging (BLSA) neuroimaging study. The degree to which Alzheimer's disease-like patterns were present in CN and MCI subjects was evaluated longitudinally in relation to cognitive performance. The oldest BLSA CN individuals showed progressively increasing Alzheimer's disease-like patterns of atrophy, and individuals with these patterns had reduced cognitive performance. MCI was associated with steeper longitudinal increases of Alzheimer's disease-like patterns of atrophy, which separated them from CN (receiver operating characteristic area under the curve equal to 0.89). Our results suggest that imaging-based spatial patterns of brain atrophy of Alzheimer's disease, evaluated with sophisticated pattern analysis and recognition methods, may be useful in discriminating among CN individuals who are likely to be stable versus those who will show cognitive decline. Future prospective studies will elucidate the temporal dynamics of spatial atrophy patterns and the emergence of clinical symptoms.

CSF α-synuclein aggregation is associated with APOE ε4 and progressive cognitive decline in Alzheimer's disease.

With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC). PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype. An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

Histopathologic studies have demonstrated differential amyloid-β (Aβ) burden between cortical sulci and gyri in Alzheimer's disease (AD), with sulci having a greater Aβ burden. To characterize Aβ deposition in the sulci and gyri of the cerebral cortex in vivo among subjects with normal cognition (NC), mild cognitive impairment (MCI), and AD, and to evaluate if these differences could improve discrimination between diagnostic groups. T1-weighted 3T MR and florbetapir (amyloid) positron emission tomography (PET) data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). T1 images were segmented and the cortex was separated into sulci/gyri based on pial surface curvature measurements. T1 images were registered to PET images and regional standardized uptake value ratios (SUVr) were calculated. A linear mixed effects model was used to analyze the relationship between clinical variables and amyloid PET SUVr measurements in the sulci/gyri. Receiver operating characteristic (ROC) analysis was performed to define amyloid positivity. Logistic models were used to evaluate predictive performance of clinical diagnosis using amyloid PET SUVr measurements in sulci/gyri. 719 subjects were included: 272 NC, 315 MCI, and 132 AD. Gyral and sulcal Aβ increased with worsening cognition, however there was a greater increase in gyral Aβ. Females had a greater gyral and sulcal Aβ burden. Focusing on sulcal and gyral Aβ did not improve predictive power for diagnostic groups. While there were significant differences in Aβ deposition in cerebral sulci and gyri across the AD spectrum, these differences did not translate into improved prediction of diagnosis. Females were found to have greater gyral and sulcal Aβ burden.

INTRODUCTIONHearing loss is identified as one of the largest modifiable risk factors for cognitive impairment and dementia. Studies evaluating this relationship have yielded mixed results.METHODSWe investigated the longitudinal relationship between self‐reported hearing loss and cognitive/functional performance in 695 cognitively normal (CN) and 941 participants with mild cognitive impairment (MCI) enrolled in the Alzheimer's Disease Neuroimaging Initiative.RESULTSWithin CN participants with hearing loss, there was a significantly greater rate of cognitive decline per modified preclinical Alzheimer's cognitive composite. Within both CN and MCI participants with hearing loss, there was a significantly greater rate of functional decline per the functional activities questionnaire (FAQ). In CN and MCI participants, hearing loss did not significantly contribute to the risk of progression to a more impaired diagnosis.DISCUSSIONThese results confirm previous studies demonstrating a significant longitudinal association between self‐reported hearing loss and cognition/function but do not demonstrate an increased risk of conversion to a more impaired diagnosis.CLINICAL TRIAL REGISTRATION INFORMATIONNCT00106899 (ADNI: Alzheimer's Disease Neuroimaging Initiative, clinicaltrials.gov), NCT01078636 (ADNI‐GO: Alzheimer's Disease Neuroimaging Initiative Grand Opportunity, clinicaltrials.gov), NCT01231971 (ADNI2: Alzheimer's Disease Neuroimaging Initiative 2, clinicaltrials.gov), NCT02854033 (ADNI3: Alzheimer's Disease Neuroimaging Initiative 3, clinicaltrials.gov).HighlightsHearing loss is a potential modifiable risk factor for dementia.We assessed the effect of self‐reported hearing loss on cognition and function in the ADNI cohort.Hearing loss contributes to significantly faster cognitive and functional decline.Hearing loss was not associated with conversion to a more impaired diagnosis.

Longitudinal Evolution of Financial Capacity and Cerebral Tau and Amyloid Burden in Older Adults with Normal Cognition or Mild Cognitive Impairment

Association of Circulating Caprylic Acid with Risk of Mild Cognitive Impairment and Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Cohort.

Tau pathology mediated the plasma biomarkers and cognitive function in patients with mild cognitive impairment

A neuroinflammatory reaction in Alzheimer disease (AD) brains involves reactive astrocytes that overexpress monoamine oxidase-B (MAO-B). 18F-(S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (18F-SMBT-1) is a novel 18F PET tracer highly selective for MAO-B. We characterized the clinical performance of 18F-SMBT-1 PET across the AD continuum as a potential surrogate marker of reactive astrogliosis. Methods: We assessed 18F-SMBT-1 PET regional binding in 77 volunteers (76 ± 5.5 y old; 41 women, 36 men) across the AD continuum: 57 who were cognitively normal (CN) (44 amyloid-β [Aβ]-negative [Aβ-] and 13 Aβ-positive [Aβ+]), 12 who had mild cognitive impairment (9 Aβ- and 3 Aβ+), and 8 who had AD dementia (6 Aβ+ and 2 Aβ-). All participants also underwent Aβ and tau PET imaging, 3-T MRI, and neuropsychologic evaluation. Tau imaging results were expressed in SUV ratios using the cerebellar cortex as a reference region, whereas Aβ burden was expressed in centiloids. 18F-SMBT-1 outcomes were expressed as SUV ratio using the subcortical white matter as a reference region. Results: 18F-SMBT-1 yielded high-contrast images at steady state (60-80 min after injection). When compared with the Aβ- CN group, there were no significant differences in 18F-SMBT-1 binding in the group with Aβ- mild cognitive impairment. Conversely, 18F-SMBT-1 binding was significantly higher in several cortical regions in the Aβ+ AD group but also was significantly lower in the mesial temporal lobe and basal ganglia. Most importantly, 18F-SMBT-1 binding was significantly higher in the same regions in the Aβ+ CN group as in the Aβ- CN group. When all clinical groups were considered together, 18F-SMBT-1 correlated strongly with Aβ burden and much less with tau burden. Although in most cortical regions 18F-SMBT-1 did not correlate with brain volumetrics, regions known for high MAO-B concentrations presented a direct association with hippocampal and gray matter volumes, whereas the occipital lobe was directly associated with white matter hyperintensity. 18F-SMBT-1 binding was inversely correlated with Mini Mental State Examination and the Australian Imaging Biomarkers and Lifestyle's Preclinical Alzheimer Cognitive Composite in some neocortical regions such as the frontal cortex, lateral temporal lobe, and supramarginal gyrus. Conclusion: Cross-sectional human PET studies with 18F-SMBT-1 showed that Aβ+ AD patients, but most importantly, Aβ+ CN individuals, had significantly higher regional 18F-SMBT-1 binding than Aβ- CN individuals. Moreover, in several regions in the brain, 18F-SMBT-1 retention was highly associated with Aβ load. These findings suggest that increased 18F-SMBT-1 binding is detectable at the preclinical stages of Aβ accumulation, providing strong support for its use as a surrogate marker of astrogliosis in the AD continuum.

Retinal biomarkers reflecting in vivo brain Alzheimer disease (AD) pathologic abnormalities could be a useful tool for screening cognitively normal (CN) individuals at the preclinical stage of AD. To investigate the association of both functional and structural alterations of the retina with in vivo AD pathologic abnormalities in CN older adults and model a screening tool for detection of preclinical AD. This cross-sectional study included a total of 49 CN individuals, and all assessment was done at the Seoul National University Hospital, Seoul, South Korea. All participants underwent complete ophthalmic examination, including swept-source optical coherence tomography (SS-OCT) and multifocal electroretinogram as well as amyloid-β (Aβ) positron emission tomography and magnetic resonance imaging. Data were collected from January 1, 2016, through October 31, 2017, and analyzed from February 1, 2018, through June 30, 2020. For structural parameters of the retina, the thickness of the macula and layer-specific thicknesses, including peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer measured by SS-OCT, were used for analysis. For functional parameters of the retina, implicit time and amplitude of rings 1 to 6 measured by multifocal electroretinogram were used. Of the 49 participants, 25 were women (51.0%); mean (SD) age was 70.6 (9.4) years. Compared with 33 CN individuals without Aβ deposition (Aβ-CN), the 16 participants with Aβ (Aβ+CN) showed reduced inner nasal macular thickness (mean [SD], 308.9 [18.4] vs 286.1 [22.5] μm; P = .007) and retinal nerve fiber layer thickness, particularly in the inferior quadrant (133.8 [17.9] vs 103.8 [43.5] μm; P = .003). In addition, the Aβ+CN group showed prolonged implicit time compared with the Aβ-CN group, particularly in ring 5 (41.3 [4.0] vs 38.2 [1.3] milliseconds; P = .002). AD-related neurodegeneration was correlated with the thickness of the ganglion cell-inner plexiform layer only (r = 0.41, P = .005). The model to differentiate the Aβ+CN vs Aβ-CN groups derived from the results showed 90% accuracy. The findings of this study showing both functional as well as structural changes of retina measured by multifocal electroretinogram and SS-OCT in preclinical AD suggest the potential use of retinal biomarkers as a tool for early detection of in vivo AD pathologic abnormalities in CN older adults.

ObjectiveTo investigate the associations between cerebral microhemorrhages (CMH) and cognitive decline across the Alzheimer’s dementia continuum.MethodsUsing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, we studied 619 participants, categorized into 221 cognitively normal (CN) participants, 281 patients with mild cognitive impairment (MCI), and 117 patients with Alzheimer’s disease (AD). CMH prevalence and distribution were determined using T2-weighted magnetic resonance imaging (MRI), focusing on the frontal, occipital, and parietal subcortical regions of interest (ROIs).Clinical dementia rating scale sum of boxes (CDR-SB) and mini-mental state examination (MMSE) were used for diagnosis and composite cognitive scores regarding visuospatial abilities, language, memory, and executive functions were used as outcome variables. Age, gender, and APOE ε4 positivity status were used as covariates.ResultsThe AD group displayed significantly elevated tau and P-tau levels compared to MCI and CN groups (p < 0.001). APOE ε4 positivity was 67.5% in the AD group, surpassing the 50.2% in MCI and 29% in CN individuals (p < 0.001). Cognitive assessments revealed that the AD group’s CDR-SB score and MMSE both significantly differed from these scores in the MCI and CN groups (p < 0.001). Overall, CMH prevalence was 27.7%, with a predominant distribution in the frontal subcortical ROIs. MCI subjects with CMH showed notably diminished ADNI Visuospatial Composite Scores compared to those without CMH. Age significantly predicted CMH in CN and MCI (p < 0.05). In AD participants, APOE ε4 heterozygotes (p = 0.02) and homozygotes (p = 0.01) hadincreased CMH likelihood.ConclusionCMHs are significantly associated with cognitive decline in patients with MCI. This association is more prominent in regard to the decline in visuospatial abilities.

BackgroundIdentifying biomarkers associated with Alzheimer’s disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome‐wide association studies (EWAS) have revealed correlations between DNA methylation level at cytosine‐phosphate‐guanine (CpG) sites and AD pathology in the brain or diagnosis in peripheral blood.MethodWe performed cross‐sectional analysis of DNA methylation in peripheral blood as a predictor of AD progression in participants in the Alzheimer’s Disease Neuroimaging Initiative cohort.ResultThe rate of cognitive decline in participants from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigit and mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. Two differentially methylated positions were identified (P &lt; 5.79 × 10−8 [Bonferroni correction threshold]): cg00386386 was associated with the slope of mPACCdigit in CN participants, and cg09422696 annotated to RP11‐661A12.5 was associated with the slope of CDR‐SB in MCI participants. No CpG sites significantly associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 70, 76, and 102 differentially methylated regions (DMRs) with Sidak‐corrected P &lt; 0.05 were identified as associated with the slopes of mPACCtrailsB, mPACCdigit in CN participants, and CDR‐SB in MCI participants, respectively; these included DMRs annotated to HOXA4, HOXB6, and HOXB9. Overall, 75 and 123 DMRs were associated with conversion status in participants with CN and with MCI, respectively. The most significant DMR was annotated to an AD‐associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak‐corrected P = 7.74 × 10−24), which was associated with both the slope of CDR‐SB and the MCI conversion status. The identified DMRs were enriched in CpG islands, promoter, and exons, including 5’ untranslated region and protein coding, whereas intergenic region, short and long interspersed nuclear element repeats, and introns were depleted.ConclusionCandidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in CN and MCI participants, respectively, in the longitudinal ADNI cohort.