Association of plasma and cortical amyloid beta is modulated by APOE ε4 status

BackgroundApolipoprotein E (APOE) ε4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Aβ) and fibrillar brain Aβ measured by Pittsburgh compound B positron emission tomography ([¹¹C]PiB PET) has not been assessed.MethodsNinety-six Alzheimer's Disease Neuroimaging Initiative participants with [¹¹C]PiB scans and plasma Aβ_1–40 and Aβ_1–42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [¹¹C]PiB data were used to determine the influence of APOE ε4 allele on association of plasma Aβ_1–40, Aβ_1–42, and Aβ_1–40/Aβ_1–42 with [¹¹C]PiB uptake.ResultsIn APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ_1–40/Aβ_1–42 and [¹¹C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ_1–40/Aβ_1–42 improved the explained variance in [¹¹C]PiB binding compared with using APOE and plasma Aβ_1–40/Aβ_1–42 as separate terms.ConclusionsThe results suggest that plasma Aβ is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.     

CSF Apo-E levels associate with cognitive decline and MRI changes

Apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for Alzheimer’s disease (AD) and it is thought to do so by modulating levels of its product, apolipoprotein E (Apo-E), and regulating amyloid-β (Aβ) clearance. However, information on clinical and biomarker correlates of Apo-E proteins is scarce. We examined the relationship of cerebrospinal fluid (CSF) and plasma Apo-E protein levels, and APOE genotype to cognition and AD biomarker changes in 311 AD neuroimaging initiative subjects with CSF Apo-E measurements and 565 subjects with plasma Apo-E measurements. At baseline, higher CSF Apo-E levels were associated with higher total and phosphorylated CSF tau levels. CSF Apo-E levels were associated with longitudinal cognitive decline, MCI conversion to dementia, and gray matter atrophy rate in total tau/Aβ_1–42 ratio and APOE genotype-adjusted analyses. In analyses stratified by APOE genotype, our results were only significant in the group without the ε4 allele. Baseline CSF Apo-E levels did not predict longitudinal CSF Aβ or tau changes. Plasma Apo-E levels show a mild correlation with CSF Apo-E levels, but were not associated with longitudinal cognitive and MRI changes. Based on our analyses, we speculate that increased CSF Apo-E2 or -E3 levels might represent a protective response to injury in AD and may have neuroprotective effects by decreasing neuronal damage independent of tau and amyloid deposition in addition to its effects on amyloid clearance.     

Subjective cognitive concerns,episodic memory,and the APOE ε4 allele

BackgroundSubjective cognitive concerns may represent a simple method to assess likelihood of memory decline among apolipoprotein E (APOE) ε4 carriers.MethodsWe examined the relationship of self-reported subjective cognitive concerns, using seven specific cognitive concerns, with memory and memory decline over 6 years among APOE ε4 carriers and non-carriers from the Nurses' Health Study.ResultsIn both groups, increasing subjective cognitive concern score predicted worse baseline memory and faster rates of subsequent memory decline, after adjustment for age, education and depression. The relation with baseline memory appeared statistically stronger in APOE ε4 carriers (P-interaction = 0.03). For memory decline, mean differences in slopes of episodic memory (95% CI) for 4 to 7 versus no concern = −0.05 (−0.10, 0.01) standard units in APOE ε4 carriers, and −0.04 (−0.08, −0.01) standard units in non-carriers.ConclusionsAPOE ε4 carriers with self-assessed cognitive concerns appear to have worse memory, and possibly accelerated memory decline.     

High apolipoprotein E in cerebrospinal fluid of patients with Lewy body disorders is associated with dementia

Apolipoprotein E ε4 allele (APOE ε4) increases the apolipoprotein E (apoE) protein levels in Alzheimer’s disease (AD) cerebrospinal fluid (CSF). Thus, we hypothesized that apoE levels were also associated with the APOE genotype, and amyloid-β (Aβ)-associated clinical, functional, and imaging parameters in patients with Lewy body-associated disorders (LBD). Indeed, similar to AD, patients with LBD displayed high CSF apoE levels (greatest in patients with dementia with LBD), and this was linked to APOE ε4. High CSF apoE protein correlated positively with CSF soluble amyloid precursor protein, total tau, and cortical and striatal Pittsburgh compound B retention; and correlated negatively with CSF Aβ₄₂, cognitive tests scores, and glucose uptake ratio in the temporal and parietal cortices. APOE ε4-triggered accumulation of apoE in CSF is related to Aβ-associated clinical and functional imaging parameters in LBD. Accordingly, therapeutic strategies aimed at reducing apoE levels in the brain should be explored not only in AD but also in LBD, particularly when accompanied with dementia.     

Association of peripheral inflammatory markers with connectivity in large-scale functional brain networks of non-demented older adults

BackgroundSystemic inflammation has emerged as a risk factor for cognitive decline and Alzheimer’s disease, but inflammation’s effect on distributed brain networks is unclear. We examined the relationship between peripheral inflammatory markers and subsequent functional connectivity within five large-scale cognitive networks and evaluated the modifying role of cortical amyloid and APOE ε4 status.MethodsBlood levels of soluble tumor necrosis factor-alpha receptor-1 and interleukin 6 were assessed in 176 participants (at baseline mean age: 65 (SD 9) years; 63% women; 85% cognitively normal, 15% mild cognitive impairment (MCI)) and were combined to derive an Inflammatory Index. Approximately six years later, participants underwent resting-state functional magnetic resonance imaging to quantify functional connectivity; a subset of 137 participants also underwent ¹¹C Pittsburgh compound-B (PiB) PET imaging to assess cortical amyloid burden.ResultsUsing linear regression models adjusted for demographic characteristics and cardiovascular risk factors, a higher Inflammatory Index was associated with lower connectivity within the Default Mode (β = −0.013; 95% CI: −0.023, −0.003) and the Dorsal Attention Networks (β = −0.017; 95% CI: −0.028, −0.006). The strength of these associations did not vary by amyloid status (positive/negative). However, there was a significant interaction between Inflammatory Index and APOE ε4 status, whereby ε4-positive participants with a higher Inflammatory Index demonstrated lower connectivity. Inflammatory Index was unrelated to connectivity within other large-scale cognitive networks (Control, Limbic, and Salience/Ventral Attention networks).ConclusionPeripheral pro-inflammatory signaling in older adults without dementia, especially among APOE ε4-positive individuals, is associated with altered connectivity within two large-scale cognitive networks.     

Duration of preclinical,prodromal, and dementia stages of Alzheimer's disease in relation to age,sex, and APOE genotype

IntroductionWe estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration.MethodsWe performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration.ResultsThe overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage.DiscussionEstimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.     

Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls

The apolipoprotein E (ApoE) ε4 allele is the strongest risk factor of sporadic Alzheimer’s disease (AD), however, the fluid concentrations of ApoE and its different isoforms (ApoE2, ApoE3 and ApoE4) in AD patients and among APOE genotypes (APOE ε2, ε3, ε4) remain controversial. Using a novel mass spectrometry-based method, we quantified total ApoE and specific ApoE isoform concentrations and potential associations with age, cognitive status, cholesterol levels and established AD biomarkers in cerebrospinal fluid (CSF) from AD patients versus non-AD individuals with different APOE genotypes. We also investigated plasma total ApoE and ApoE isoform composition in a subset of these individuals. In total n = 43 AD and n = 43 non-AD subjects were included. We found that CSF and plasma total ApoE levels did not correlate with age or cognitive status and did not differ between AD and non-AD subjects deeming ApoE as an unfit diagnostic marker for AD. Also, whereas CSF ApoE levels did not vary between APOE genotypes APOE ε4 carriers exhibited significantly decreased plasma ApoE levels attributed to a specific decrease in the ApoE4 isoform concentrations. CSF total ApoE concentrations were positively associated with CSF, total tau, tau phosphorylated at Thr181 and Aβ1-42 of which the latter association was weaker and only present in APOE ε4 carriers indicating a differential involvement of ApoE in tau versus Aβ-linked neuropathological processes. Future studies need to elucidate whether the observed plasma ApoE4 deficiency is a life-long condition in APOE ?4 carriers and whether this decrease in plasma ApoE predisposes APOE ?4 carriers to AD.     

Fibrillar amyloid correlates of preclinical cognitive decline

BackgroundIt is not known whether preclinical cognitive decline is associated with fibrillar β-amyloid (Aβ) deposition irrespective of apolipoprotein E (APOE) ε4 status.MethodsFrom a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aβ burden.ResultsAt P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners.ConclusionsAsymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.     

The screening of Alzheimer’s patients with CSF biomarkers,modulates the distribution of APOE genotype: impact on clinical trials

Polymorphism of the apolipoprotein E gene (APOE) plays a role in the level of neuropathological lesions and in drug response in Alzheimer’s disease (AD). The aim of this study was to investigate whether the selection of AD patients based on cerebrospinal fluid (CSF) biomarkers assessment may be biased by their APOE distribution. We studied the relationships between APOE genotype and CSF biomarkers levels in a total of 432 patients (AD, n = 244; non-AD, n = 188) explored for cognitive disorders. We studied the distribution of APOE genotypes among AD patient subgroups selected by various cut-offs of CSF biomarkers. Strategies of screening based on CSF Aβ1–42 lead to overselection of ε4/ε4 patients in the AD group. Screening based on tau levels did not change Apoe4 distribution in the AD group. CSF Aβ1–42 discriminated better AD patients with at least one ε4 than AD patients with no ε4. A strong allele-effect relationship was detected between APOE genotype and CSF amyloid-β (Aβ1–42) in AD patients. Selecting AD patients on CSF amyloid levels only may create an overselection of ε4/ε4 carriers, and might potentially bias the population of patients included in clinical trial studies.     

Apolipoprotein E (APOE) ε4 moderates the relationship between c-reactive protein,cognitive functioning,and white matter integrity

Elevated serum C-reactive protein (CRP) and possessing an APOE ε4 allele are two of the most prominent risk factors for cognitive and neurological dysfunction in older adults, but little is known about the unique or cumulative effects of these risk factors in young-to-middle-aged adults. To further characterize these potential relationships, measures of cognition and microstructural white matter integrity were examined using data from a sample of 329 post-9/11 war veterans that was collected as part of a comprehensive evaluation that included assessment of neuropsychological functioning, MRI scanning, psychiatric diagnoses, health screening, markers of inflammation, and APOE genotypes. Hierarchical linear regression analyses revealed the CRP and APOE ε4 interaction was associated with global cognition (β = -0.633), executive functioning (β = -0.566), and global fractional anisotropy (β = -0.470), such that elevated CRP was associated with worse cognition and white matter integrity in APOE ε4 carriers. Diffusion tensor imaging (DTI) was used to determine if CRP × APOE ε4 presence was associated with regionally specific fractional anisotropy in white matter tracts. Tract-based spatial statistics revealed CRP × APOE ε4 presence was associated with fractional anisotropy in the corpus callosum, right superior longitudinal fasciculus, right posterior corona radiata, as well as the bilateral anterior and superior corona radiatas. This suggests that APOE ε4 carriers may be uniquely vulnerable to the potentially negative impact of elevated systematic inflammation to cognition and microstructural white matter integrity.     

Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease

Introduction

Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.

Cognitive correlates of cerebrospinal fluid biomarkers in frontotemporal dementia

ObjectiveIn this study we investigated the relationships between cerebrospinal fluid (CSF) biomarkers (tau and amyloid-β_1-42 [Aβ_1-42]) and cognition or behavior in patients with frontotemporal dementia (the behavioral variant, bvFTD).MethodsWe included 58 patients with bvFTD. All patients underwent a neuropsychological assessment and lumbar puncture. Relationships between CSF biomarkers and cognition or behavior were assessed with linear regression analysis.ResultsAfter correction for age, sex, and education, CSF tau levels were found to be negatively related to the Visual Association Test (standardized β = −0.3, P < .05), whereas CSF Aβ_1-42 levels were found to be positively related to the Mini-Mental State Examination (β = 0.3, P < .05), the frontal assessment battery (β = 0.5, P < .05), and digit span backwards test (β = 0.3, P = .01). We did not find relations between CSF biomarkers and behavior (measured by the neuropsychiatric inventory). After excluding all patients with a CSF biomarker profile often seen in Alzheimer’s disease (high levels of tau and low levels of Aβ_1-42), we still found relations between CSF Aβ_1-42 levels and Visual Association Test object naming (β = 0.4, P < .05), as well as between CSF Aβ_1-42 levels and the frontal assessment battery (β = 0.5, P < .05, but there was no relation between CSF tau and cognition.ConclusionLow CSF Aβ_1-42 levels are associated with worse general cognitive function and worse executive function in patients with bvFTD. Our results provide circumstantial evidence for a pathophysiological role of Aβ_1-42 in bvFTD.     

Apolipoprotein E ε4 genotype and risk of freezing of gait in Parkinson's disease

ObjectiveTo investigate the association between Apolipoprotein E (APOE) genotype and freezing of gait (FOG) in Parkinson's disease (PD).MethodsThis cohort study included 339 early PD patients who were divided into APOE ε4-positive (n = 88) and ε4-negative (n = 251) groups. They were followed-up for up to 6 years to identify the development of FOG. To investigate the influence of CSF β-amyloid 1–42 (Aβ₄₂) on the association between APOE ε4 and FOG, the patients were additionally dichotomized into “high-level” and “low-level” groups using three different cutoff values for the CSF Aβ₄₂ levels.ResultsAt baseline, the APOE ε4-positive group had lower CSF Aβ₄₂ levels than the APOE ε4-negative group. During a median follow-up of 5.0 years, the APOE ε4-positive group had a higher incidence of FOG than the APOE ε4-negative group. In the multivariable Cox model excluding CSF Aβ₄₂, APOE ε4 was a significant predictor of FOG. However, after adding CSF Aβ₄₂ in the model, APOE ε4 did not survive, whereas lower CSF Aβ₄₂ levels were associated with FOG. In the subgroup analyses, the effect of the APOE ε4 allele was not found in the “low-level” group. However, in the “high-level” group, the APOE ε4 allele independently increased the risk of FOG, and this association was stronger than the association with CSF Aβ₄₂.ConclusionThe APOE ε4 allele may be a novel genetic risk factor for FOG in PD. This association seemed to be mainly mediated by Aβ-dependent pathways, but its Aβ-independent effects might also contribute to the development of FOG.     

Amyloid-β₄₂ is associated with cognitive impairment in healthy elderly and subjective cognitive impairment

The aim of this study was to predict cognitive performance on the basis of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau) and amyloid-β?? (Aβ??) in controls and patients at various impairment levels. Previous studies have found an association of CSF T-tau levels with cognitive symptoms, but it has been difficult to relate Aβ to cognition, and it has thus been hypothesized that Aβ reaches a plateau level prior to cognitive symptoms. A comprehensive battery of neuropsychological tests was subjected to factor analysis to yield aggregated cognitive domains. Linear regression models were performed for the total sample of the Gothenburg MCI study (n = 435) and for each level of impairment. Aβ?? and T-tau accounted for a significant proportion of performance in all cognitive domains in the total sample. In controls (n = 60) and patients with subjective cognitive impairment (n = 105), Aβ?? predicted a significant proportion of semantic and working memory performance. For patients with mild cognitive impairment (n = 170), T-tau had the most pronounced impact across cognitive domains, and more specifically on episodic memory, visuospatial, and speed/executive performance. For patients with dementia (n = 100), the most pronounced impacts of Aβ?? were found in episodic memory and visuospatial functioning, while T-tau was substantially associated with episodic memory. Our results suggest that cognition is related to CSF biomarkers regardless of impairment level. Aβ?? is associated with cognitive functions from a potentially early to a later disease phase, and T-tau is more indicative of performance in a later disease phase.     

Aβ amyloid,cognition, and APOE genotype in healthy older adults

BackgroundOnly one study has investigated the relationship between cerebral β-amyloid (Aβ), apolipoprotein E (APOE) ɛ4 genotype, and cognition. Although significant relationships between cerebral Aβ and cognition were observed in ɛ4 carriers but not noncarriers, the magnitude of this relationship was not reported. Further, when demographic variables were controlled, the influence of APOE ɛ4 on the relationship between cerebral Aβ and cognition dissipated.MethodsIn 144 healthy older adults who had undergone amyloid scanning and APOE ɛ4 genotyping in the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Flagship Study of Ageing, correlations were conducted to determine the magnitude of relationship between cerebral Aβ and cognition in ɛ4 carriers and noncarriers. Fisher’s Z was used to compare these correlations and Cohen’s q determined the magnitude of difference between correlations.ResultsCerebral Aβ was significantly associated with tasks of visual and verbal episodic memory in APOE ɛ4 carriers. This association was not observed in ɛ4 noncarriers. The relationship between cerebral Aβ and episodic memory in ɛ4 carriers was significantly different from that in ɛ4 noncarriers, and the magnitude of this difference was small to moderate.ConclusionsIn APOE ɛ4 carriers, there is a moderate negative relationship between cerebral Aβ and episodic memory. This suggests that increased cerebral Aβ may signify the onset of preclinical AD, especially in healthy older adults who are genetically at risk for AD.     

Exercise improves cognition and hippocampal plasticity in APOE ε4 mice

BackgroundHuman studies on exercise, cognition, and apolipoprotein E (APOE) genotype show that ε4 carriers may benefit from regular physical activity.MethodsWe examined voluntary wheel-running, memory, and hippocampal plasticity in APOE ε3 and APOE ε4 transgenic mice at 10–12 months of age.ResultsSedentary ε4 mice exhibited deficits in cognition on the radial-arm water maze (RAWM), a task dependent on the hippocampus. Six weeks of wheel-running in ε4 mice resulted in improvements on the RAWM to the level of ε3 mice. Hippocampal brain-derived neurotrophic factor (BDNF) levels were similar in ε3 and ε4 mice, and after exercise BDNF was similarly increased in both ε3 and ε4 mice. In sedentary ε4 mice, tyrosine kinase B (Trk B) receptors were reduced by 50%. Exercise restored Trk B in ε4 mice to the level of ε3 mice, and in ε4 mice, exercise dramatically increased synaptophysin, a marker of synaptic function.ConclusionsOur results support the hypothesis that exercise can improve cognitive function, particularly in ε4 carriers.     

Neocortical β-amyloid area is associated with dementia and APOE in the oldest-old

ObjectiveApolipoprotein E (APOE) ε2 carriers may be protected from dementia because of reduced levels of cortical β-amyloid. In the oldest-old, however, APOE ε2 carriers have high β-amyloid plaque scores and preserved cognition. We compared different measures of β-amyloid pathology across APOE genotypes in the oldest-old, and their relationship with dementia.MethodsThe study included 96 participants from The 90+ Study. Using all information, dementia diagnoses were made. Neuropathological examination included staging for amyloid plaques and β-amyloid cortical percent area stained by NAB228 antibody.ResultsBoth APOE ε2 and APOE ε4 carriers had high Consortium to Establish a Registry for Alzheimer’s Disease plaque scores. However, APOE ε2 carriers had low cortical β-amyloid percent areas. β-amyloid percent area was associated with dementia across APOE genotypes.ConclusionsLower levels of percent area in APOE ε2 carriers may reflect lower total β-amyloid and may contribute to APOE ε2 carriers’ decreased risk of dementia, despite high β-amyloid plaque scores. The relationship between β-amyloid plaques and dementia in the oldest-old may vary by APOE genotype.     

The neuropsychology of normal aging and preclinical Alzheimer's disease

ObjectiveA National Institute on Aging–sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.MethodsSeventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups.ResultsThere was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups.ConclusionsAlthough cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design.     

Non-neurological surgery and cerebrospinal fluid biomarkers for neuronal and astroglial integrity

Non-neurological surgery has both acute and long-term effects on the brain. Markers for Alzheimer pathology may be used to study surgically induced neurological changes relevant for postoperative confusion, asthenia or cognitive decline. Inflammatory biomarkers, total tau (T-tau) and phosphorylated tau (P-tau) were recently shown to increase progressively in the cerebrospinal fluid (CSF) during surgery for nasal CSF leak, suggesting a neuroinflammatory response with signs of neuronal damage. We used a study group of 35 patients, undergoing knee arthroplasty with a spinal blockade and propofol sedation, to replicate this finding. Five CSF biomarkers were analyzed before, 3 h after and on the morning after the interventions: T-tau and P-tau for cortical axonal integrity and tangle pathology, respectively, the 42 amino acids form of amyloid β (Aβ42) for plaque formation, neurofilament light (NFL) for the integrity of large-caliber myelinated axons and glial fibrillary acidic protein (GFAp) for astroglial cell integrity. CSF T-tau concentrations increased significantly during and after surgery (p = 0.028) and were significantly correlated with the administered doses of bupivacaine. P-tau, Aβ42 and NFL remained unchanged, while the mean GFAp concentration increased with a large standard deviation. CSF T-tau and P-tau correlated significantly with the CSF/serum albumin ratios as an indicator of blood–brain barrier permeability. Findings from earlier studies showing a significant increase in biomarkers for Alzheimer’s pathology during surgery were partly replicated, as neurochemical signs of impaired cortical axonal integrity during non-neurological surgery were detected. Bupivacaine may be involved in these reactions.