Lower Aβ Research Articles

Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression

To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as “predementia AD with depression”.

Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition.

Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer's disease (AD). The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1-42 (Aβ) deposition and to correlate genetic data with clinical phenotypes. A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects. Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p > 0.05). The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population.

Comparing Pathological Risk Factors for Dementia between Cognitively Normal Japanese and Americans.

The Alzheimer’s Disease Neuroimaging Initiative showed that Japanese had significantly lower brain Aβ burden than Americans among a cognitively normal population. This cross-sectional study aimed to compare vascular disease burden, Aβ burden, and neurodegeneration between cognitively normal elderly Japanese and Americans. Japanese and American participants were matched for age (±4-year-old), sex, and Apolipoprotein E (APOE) genotype. Brain vascular disease burden and brain Aβ burden were measured using white matter lesions (WMLs) and 11C-labeled Pittsburgh Compound B (PiB) retention, respectively. Neurodegeneration was measured using hippocampal volumes and cortical thickness. A total of 95 Japanese and 95 Americans were recruited (50.5% men, mean age = 82). Compared to Americans, Japanese participants had larger WMLs, and a similar global Aβ standardized uptake value ratio (SUVR), cortical thickness and hippocampal volumes. Japanese had significantly lower regional Aβ SUVR in the anterior ventral striatum, posterior cingulate cortex, and precuneus. Cognitively normal elderly Japanese and Americans had different profiles regarding vascular disease and Aβ burden. This suggests that multiple risk factors are likely to be involved in the development of dementia. Additionally, Japanese might have a lower risk of dementia due to lower Aβ burden than Americans. Longitudinal follow-up of these cohorts is warranted to ascertain the predictive accuracy of these findings.

Longitudinal Observation of Early-Onset Alzheimer’s Disease Dementia with Positive CSF Biomarkers/Negative Amyloid-β Positron-Emission Tomography

We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed 18F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

Influence of Physical Activity Levels and Functional Capacity on Brain β-Amyloid Deposition in Older Women.

Physical activity (PA) and Alzheimer's disease are associated. However, how PA influences the cerebral β-amyloid (Aβ) burden remains unclear. The aim of this study was to determine if PA levels and/or functional capacity (FC) are associated with Aβ plaque deposition, and whether these associations differed according to APOE-ε4 genotype. A total of 117 women (69.7 ± 2.6 years; 33.3% APOE-ε4-carriers) from the Women's Healthy Ageing Project cohort (WHAP) were analyzed. PA was measured using the International Physical Activity Questionnaire and, FC was evaluated using the Timed Up and Go test (TUGt). Positron emission tomography with F-18 Florbetaben was carried out to assess cerebral Aβ burden, and quantified using standardized uptake value rations. The sample was split into PA and TUGt tertiles (T1, T2 and T3), and compared according to APOE-ε4 genotype (positive/negative). There were no significant differences in Aβ accumulation according to PA tertiles and APOE-ε4 genotype. Regarding FC, APOE-ε4+ participants in the first TUGt tertile (high performance) obtained significant lower Aβ accumulations compared with the other two tertiles (p < 0.05). Comparing between genotypes, greater Aβ depositions were found between T2 and T3 in APOE-ε4+ compared with those who were APOE-ε4– (p < 0.05). Values of TUGt ≥ 6.5 s (APOE-ε4+) and 8.5 s (APOE-ε4–) were associated with an increased risk of having higher Aβ retention. In conclusion, low performance in TUGt is associated with a negative effect on brain pathology with increasing cerebral Aβ depositions in older women who are APOE-ε4+. In physically active older women (> 600 METs·min/week), higher PA levels are not associated with reduction in Aβ depositions.

In vivo detection of beta-amyloid at the nasal cavity and other skull-base sites: a retrospective evaluation of ADNI1/GO.

Amyloid beta (Aβ) is partially cleared from the CSF via skull base perivascular and perineural lymphatic pathways, particularly at the nasal cavity. In vivo differences in Aβ level at the nasal cavity between patients with Alzheimer's disease (AD), subjects with mild cognitive impairment (MCI) and cognitively normal (CN) individuals have not been previously assessed. This is a retrospective evaluation of subject level data from the ADNI-1/GO database. Standardized uptake value ratio (SUVR) maximum on 11C-Pittsburgh compound-B (PiB)-PET was assessed at the nasal cavity on 223 scans. Exploratory ROI analysis was also performed at other skull base sites. SUVR maximum values and their differences between groups (CN, MCI, AD) were assessed. CSF Aβ levels and CSF Aβ 42/40 ratios were correlated with SUVR maximum values. 103 subjects with 223 PiB-PET scans (47 CN, 32 AD and 144 MCI) were included in the study. The SUVR maxima at the nasal cavity were significantly lower in subjects with AD [1.35 (± 0.31)] compared to CN [1.54 (± 0.30); p = 0.024] and MCI [1.49 (± 0.33); p = 0.049]. At very low CSF Aβ, less than 132pg/ml, there was significant correlation with nasal cavity SUVR maximum. The summed averaged SUVR maximum values were significantly lower in subjects with AD [1.35 (± 0.16)] compared to CN [1.49 (± 0.17); p = 0.003] and MCI [1.40 (± 0.17); p = 0.017]. Patients with AD demonstrate reduced nasal cavity PiB-PET radiotracer uptake compared to MCI and CN, possibly representing reduced Aβ clearance via perineural/perivascular lymphatic pathway. Further work is necessary to elucidate the true nature of this finding.

Biological Features of Reversion from Mild Cognitive Impairment to Normal Cognition: A Study of Cerebrospinal Fluid Markers and Brain Volume.

Background:Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. Although a significant proportion of the population with MCI experience reversion to normal cognition, it is still poorly understood.Objective:This study was designed to extend the present evidence regarding the difference between stable and reverting MCI by including whole brain atrophy measures as possible parameters involved.Methods:405 patients diagnosed with MCI at baseline were selected. After one-year follow-up period, 337 patients (83.2%) were categorized as stable MCI and 68 patients (16.8%) reverted to cognitively normal status (reversion group). Several baseline biomarkers including cerebrospinal fluid (CSF) biomarkers of AD, including Aβ42, t-tau, and p-tau and MRI-based atrophy measurements were compared.Results:Participants with stable MCI demonstrated greater brain atrophy as well as lower Aβ and higher tau proteins in the CSF. The atrophy rate was found to be associated with CSF biomarkers merely in the stable group, after adjustment for confounding variables.Conclusion:These findings provide novel evidence regarding the biological perspective of the reversion phenomenon in individuals with MCI.

Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer\u2019s disease

BackgroundEmerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer’s disease (AD) pathogenesis. Amyloid-beta (Aβ) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low Aβ clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.MethodsRegulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.ResultsIn cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by Aβ while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages.ConclusionsOur data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.

Prognostic Role of CSF β-amyloid 1-42/1-40 Ratio in Patients Affected by Amyotrophic Lateral Sclerosis.

The involvement of β-amyloid (Aβ) in the pathogenesis of amyotrophic lateral sclerosis (ALS) has been widely discussed and its role in the disease is still a matter of debate. Aβ accumulates in the cortex and the anterior horn neurons of ALS patients and seems to affect their survival. To clarify the role of cerebrospinal fluid (CSF) Aβ 1–42 and Aβ 42/40 ratios as a potential prognostic biomarker for ALS, we performed a retrospective observational study on a cohort of ALS patients who underwent a lumbar puncture at the time of the diagnosis. CSF Aβ 1–40 and Aβ 1–42 ratios were detected by chemiluminescence immunoassay and their values were correlated with clinical features. We found a significant correlation of the Aβ 42/40 ratio with age at onset and Mini Mental State Examination (MMSE) scores. No significant correlation of Aβ 1–42 or Aβ 42/40 ratios to the rate of progression of the disease were found. Furthermore, when we stratified patients according to Aβ 1–42 concentration and the Aβ 42/40 ratio, we found that patients with a lower Aβ 42/40 ratio showed a shorter survival. Our results support the hypothesis that Aβ 1–42 could be involved in some pathogenic mechanism of ALS and we suggest the Aβ 42/40 ratio as a potential prognostic biomarker.

Cholesterol in Membranes Facilitates Aggregation of Amyloid β Protein at Physiologically Relevant Concentrations.

The formation of amyloid β (1-42) (Aβ42) oligomers is considered to be a critical step in the development of Alzheimer's disease (AD). However, the mechanism underlying this process at physiologically low concentrations of Aβ42 remains unclear. We have previously shown that oligomers assemble at such low Aβ42 monomer concentrations in vitro on phospholipid membranes. We hypothesized that membrane composition is the factor controlling the aggregation process. Accumulation of cholesterol in membranes is associated with AD development, suggesting that insertion of cholesterol into membranes may initiate the Aβ42 aggregation, regardless of a low monomer concentration. We used atomic force microscopy (AFM) to test the hypothesis and directly visualize the aggregation process of Aβ42 on the surface of a lipid bilayer depending on the cholesterol presence. Time-lapse AFM imaging unambiguously demonstrates that cholesterol in the lipid bilayer significantly enhances the aggregation process of Aβ42 at nanomolar monomer concentration. Quantitative analysis of the AFM data shows that both the number of Aβ42 oligomers and their sizes grow when cholesterol is present. Importantly, the aggregation process is dynamic, so the aggregates assembled on the membrane can dissociate from the bilayer surface into the bulk solution. Computational modeling demonstrated that the lipid bilayer containing cholesterol had an elevated affinity to Aβ42. Moreover, monomers adopted the aggregation-prone conformations present in amyloid fibrils. The results lead to the model for the on-surface aggregation process in which the self-assembly of Aβ oligomers is controlled by the lipid composition of cellular membranes.

Plasma β-Amyloid Levels Associated With Structural Integrity Based on Diffusion Tensor Imaging in Subjective Cognitive Decline: The SILCODE Study.

Background: Accumulating evidence has demonstrated that plasma β-amyloid (Aβ) levels are useful biomarkers to reflect brain amyloidosis and gray matter structure, but little is known about their correlation with subclinical white matter (WM) integrity in individuals at risk of Alzheimer's disease (AD). Here, we investigated the microstructural changes in WM between subjects with low and high plasma Aβ levels among individuals with subjective cognitive decline (SCD).Methods: This study included 142 cognitively normal individuals with SCD who underwent a battery of neuropsychological tests, plasma Aβ measurements, and diffusion tensor imaging (DTI) based on the Sino Longitudinal Study on Cognitive Decline (SILCODE). Using tract-based spatial statistics (TBSS), we compared fractional anisotropy (FA), and mean diffusivity (MD) in WM between subjects with low (N = 71) and high (N = 71) plasma Aβ levels (cut-off: 761.45 pg/ml for Aβ40 and 10.74 pg/ml for Aβ42).Results: We observed significantly decreased FA and increased MD in the high Aβ40 group compared to the low Aβ40 group in various regions, including the body, the genu, and the splenium of the corpus callosum; the superior longitudinal fasciculus; the corona radiata; the thalamic radiation; the external and internal capsules; the inferior fronto-occipital fasciculus; and the sagittal stratum [p < 0.05, familywise error (FWE) corrected]. Average FA values were associated with poor performance on executive and memory assessments. No significant differences were found in either MD or FA between the low and high Aβ42 groups.Conclusion: Our results suggest that a correlation exists between WM integrity and plasma Aβ40 levels in individuals with SCD.

Repeated electromagnetic field stimulation lowers amyloid-\u03b2 peptide levels in primary human mixed brain tissue cultures

Late Onset Alzheimer’s Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted Aβ40 (p = 001) and Aβ42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower Aβ levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in Aβ40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted Aβ precursor protein-α (sAPPα) levels, suggesting the decrease in Aβ did not likely result from redirection toward the α-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate Aβ deposition.

Plasma glial fibrillary acidic protein is elevated in cognitively normal older adults at risk of Alzheimer\u2019s disease

Glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal protein, can be measured in blood samples, and has been associated with Alzheimer’s disease (AD). However, plasma GFAP has not been investigated in cognitively normal older adults at risk of AD, based on brain amyloid-β (Aβ) load. Cross-sectional analyses were carried out for plasma GFAP and plasma Aβ1–42/Aβ1–40 ratio, a blood-based marker associated with brain Aβ load, in participants (65–90 years) categorised into low (Aβ−, n = 63) and high (Aβ+, n = 33) brain Aβ load groups via Aβ positron emission tomography. Plasma GFAP, Aβ1–42, and Aβ1–40 were measured using the Single molecule array (Simoa) platform. Plasma GFAP levels were significantly higher (p < 0.00001), and plasma Aβ1–42/Aβ1–40 ratios were significantly lower (p < 0.005), in Aβ+ participants compared to Aβ− participants, adjusted for covariates age, sex, and apolipoprotein E-ε4 carriage. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished Aβ+ from Aβ− (area under the curve, AUC = 0.78), but was outperformed when plasma GFAP was added to the base model (AUC = 0.91) and further improved with plasma Aβ1–42/Aβ1–40 ratio (AUC = 0.92). The current findings demonstrate that plasma GFAP levels are elevated in cognitively normal older adults at risk of AD. These observations suggest that astrocytic damage or activation begins from the pre-symptomatic stage of AD and is associated with brain Aβ load. Observations from the present study highlight the potential of plasma GFAP to contribute to a diagnostic blood biomarker panel (along with plasma Aβ1–42/Aβ1–40 ratios) for cognitively normal older adults at risk of AD.

Cerebral Amyloid Angiopathy in Amyloid-Positive Patients from a Memory Clinic Cohort.

The overlap between cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is frequent and relevant for patients with cognitive impairment. To assess the role of the diagnosis of CAA on the phenotype of amyloid-β (Aβ) positive patients from a university-hospital memory clinic. Consecutive patients referred for suspected cognitive impairment, screened for Aβ pathological changes in cerebrospinal fluid (CSF), with available MRI and neuropsychological results were included. We determined the association between probable CAA and clinical, neuropsychological (at presentation and after a mean follow-up of 17 months in a sub-sample) and MRI (atrophy, white matter hyperintensities, perivascular spaces) characteristics. Of 218 amyloid-positive patients, 8.3% fulfilled criteria for probable CAA. A multivariable logistic regression showed an independent association of probable CAA with lower Aβ1-42 (adjusted odds ratio [aOR] = 0.94, 95% confidence interval [95% CI] = 0.90-0.98, p = 0.003), and Aβ1-40 (aOR = 0.98, 95% CI=0.97-0.99 p = 0.017) levels in CSF, and presence of severe burden of enlarged perivascular spaces (EPVS) in the centrum semiovale (aOR = 3.67, 95% CI = 1.21-11.15, p = 0.022). Linear mixed-model analysis showed that both groups significantly deteriorated in global clinical severity, executive function and memory. Nevertheless, the presence of probable CAA did not differently affect the rate of cognitive decline. The presence of probable CAA in Aβ positive patients was associated with lower Aβ1-42 and Aβ1-40 CSF levels and increased centrum semiovale EPVS burden, but did not independently influence clinical phenotype nor the rate of cognitive decline within our follow-up time window.

Learning deficit in cognitively normal APOE ε4 carriers with LOW β-amyloid.

IntroductionIn cognitively normal (CN) adults, increased rates of amyloid beta (Aβ) accumulation can be detected in low Aβ (Aβ–) apolipoprotein E (APOE) ε4 carriers. We aimed to determine the effect of ε4 on the ability to benefit from experience (ie, learn) in Aβ– CNs.MethodsAβ– CNs (n = 333) underwent episodic memory assessments every 18 months for 108 months. A subset (n = 48) completed the Online Repeatable Cognitive Assessment‐Language Learning Test (ORCA‐LLT) over 6 days.ResultsAβ– ε4 carriers showed significantly lower rates of improvement on episodic memory over 108 months compared to non‐carriers (d = 0.3). Rates of learning on the ORCA‐LLT were significantly slower in Aβ– ε4 carriers compared to non‐carriers (d = 1.2).DiscussionIn Aβ– CNs, ε4 is associated with a reduced ability to benefit from experience. This manifested as reduced practice effects (small to moderate in magnitude) over 108 months on the episodic memory composite, and a learning deficit (large in magnitude) over 6 days on the ORCA‐LLT. Alzheimer's disease (AD)–related cognitive abnormalities can manifest before preclinical AD thresholds.

Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer's disease-like phenotypes in a preclinical mouse model.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that affects more than 44 million people worldwide. Despite the high disease burden, there is no effective treatment for people suffering from AD. Mesenchymal stem cells (MSCs) are multipotent stromal cells that have been widely studied due to their therapeutic potential. However, administration of cells has been found to have a multitude of limitations. Recently, extracellular vesicles (EVs) derived from MSCs have been studied as a therapeutic candidate, as they exhibit similar immunoprotective and immunomodulatory abilities as the host human MSCs.Methods: To test the potential therapeutic effects of MSC EVs, human bone-marrow derived MSCs were grown in three-dimensional (3D) cell culture, and small EVs were harvested using differential ultracentrifugation. These small EVs were given to non-transgenic (NT) or 5XFAD (5 familial Alzheimer's disease mutations) mice intranasally (IN) every 4 days for 4 months. The mice were then required to perform a variety of behavioral assays to measure changes in learning and memory. Afterwards, immunohistochemistry was performed on brain slices to measure amyloid beta (Aβ) and glial fibrillary acidic protein (GFAP) levels.Results: The data revealed that 5XFAD mice that received hMSC-EV treatment behaved significantly better in cognitive tests than saline treated 5XFAD mice, with no significant change between EV-treated 5XFAD mice and NT mice. Additionally, we found lower Aβ plaque load in the hippocampus of the EV-treated mice. Finally, less colocalization between GFAP and Aβ plaques was found in the brain of EV-treated mice compared to saline.Conclusions: Taken together, these data suggest that IN administration of MSC-derived EVs can slow down AD pathogenesis.

IPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer's Disease.

Neuroinflammation in Alzheimer’s disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aβ), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acetylcholine receptor (α7 nAChR) binds Aβ with high affinity, α7 nAChR may play a role in Aβ-induced neuroinflammation. The conundrum of how α7 nAChR as the mediator of the cholinergic anti-inflammatory response may trigger an inflammatory response has not been resolved. CHRFAM7A, the uniquely human fusion gene between ULK4 and CHRNA7, is a negative regulator of α7 nAChR ionotropic function. To provide the human context, isogenic induced pluripotent stem cell (iPSC) lines were developed from CHRFAM7A null and carrier individuals by genome-editing the null line using TALENs to knock-in CHRFAM7A. In iPSC-derived microglia-like cells, CHRFAM7A mitigated Aβ uptake through the α7 nAChR. Despite the lower Aβ uptake, the presence of CHRFAM7A was associated with an innate immune response that was characterized by NF-κB activation and NF-κB target transcription (TNFA, IL6, and IL1B). LPS, a prototype PAMP, induced a heightened immune response in CHRFAM7A carriers. CHRFAM7A modified the dynamics of NF-κB translocation by prolonging its nuclear presence. CHRFAM7A modified the α7 nAChR metabotropic function, resulting in a human-specific innate immune response. This iPSC model provided an opportunity to elucidate the mechanism and establish high throughput screens.

Metabolic syndrome is associated with plasma β‐amyloid levels in ApoE ε4 non‐carriers

AbstractBackgroundThe relationship between metabolic syndrome (MetS) and Alzheimer’s disease (AD) is not fully understood. As Amyloid‐β (Aβ) deposition in the brain is a main pathophysiology of AD and plasma Aβ is closely related to Aβ deposition in the brain, in present study, we investigated the relationship between plasma Aβ and MetS in community population.MethodThis was a population‐based cross‐sectional study. A total of 1275 participants from a village in the suburbs of Xi’an, China were enrolled from October 2014 to March 2015. Fasting venous blood was taken in the morning and plasma Aβ levels were measured by ELISA. The ApoE genotype was detected using polymerase chain reaction and Sanger sequencing. Metabolic syndrome was diagnosed according to ATP‐III riteria, and MetS severity z scores (MetS‐Z) were calculated from waist circumference, triglycerides, HDL cholesterol, systolic blood pressure, and fasting glucose. Relationships between plasma Aβ and MetS were determined using multiple linear regressions.ResultIn the total population and the ApoE ε4 non‐carriers, MetS was associated with higher plasma Aβ40 level (51.704±8.594 pg/ml vs. 53.536±8.063pg/ml, p=0.002;51.693±8.626 pg/ml vs. 53.593±7.990 pg/ml, p=0.003) and lower Aβ42/ Aβ40 ratio(0.814±0.189 vs 0.784±0.170, p=0.018;0.813±0.189 vs. 0.778±0.172, p=0.011). In the multivariable regression analysis, plasma Aβ40 was associated with MetS in the total population and ApoE ε4 non‐carriers (β=1.711, p=0.008; β=1.661, p=0.019) and Aβ42/ Aβ40 ratio (β=‐0.031, p=0.030; β=‐0.035, p=0.024). Furthermore, plasma Aβ40 correlated positively with MetS‐Z in the total population (r=0.073, p=0.009) and the ApoE ε4 non‐carriers (r=0.074, p=0.015), while Aβ42/Aβ40 ratio was negatively related with MetS (r=‐0.064, p=0.038) in ApoE ε4 non‐carriers, but not in ApoE ε4 carriers. There was no significant correlation between MetS and plasma Aβ42.ConclusionMetabolic syndrome was associated with higher plasma Aβ40 level and lower Aβ42/ Aβ40 ratio in ApoE ε4 non‐carriers, but not in ApoE ε4 carriers. This indicated that the relationships between MetS and plasma Aβ may be confounded by ApoE ε4 status.

Measurement bias in depression assessment according to brain amyloid burden, cognitive function, and sex in the A4 study

AbstractBackgroundWe sought to identify measurement bias (differential item functioning, DIF) in the Geriatric Depression Scale (15 item version) attributable to cerebral amyloid level (Aβ) among cognitively normal older adults. Specifically, we were interested in determining if endorsement of self‐reported memory problems on the GDS‐15 differed by Aβ level. We hypothesized that persons with high Aβ would have a greater probability of endorsing memory problems than those with low Aβ, consistent with the literature showing that subjective cognitive decline in older adults is associated with increased AD risk. We also examined DIF attributable to level of cognitive functioning and sex as positive controls that may account for differences in self‐reported depression.MethodAnalyses were conducted using the pre‐randomization database of the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study (N=3,961). We used the MIMIC (multiple indicators, multiple causes) approach to detect DIF. The MIMIC approach is consistent with item response theory, and allows for the detection of uniform DIF for predictors that are either discretely observed (sex) or continuously observed (Aβ level, cognitive function).ResultWe found DIF with respect to Aβ level, sex, and cognitive functioning. Most DIF detected was of a trivial effect size with some showing small‐to‐moderate effect sizes. Mild DIF, attributable to Aβ level, was shown for the GDS memory item in the hypothesized direction: after adjustment for depressive symptom severity (overall GDS symptoms), persons with high Aβ had a greater probability of endorsing memory problems than those with low Aβ (effect size = 0.22, p &lt;.001). Interestingly, DIF for 2 items assessing hopelessness were also observed according to high Aβ versus low Aβ. Despite these findings we determined that there was negligible impact of DIF attributable to Aβ level on overall depressive symptom level.ConclusionParticipant responses on items of the GDS‐15 are sensitive to Aβ burden, sex, and level of cognitive functioning over and above what would be expected given the effect of those factors on depressive symptom severity overall. However, these direct effects are of small magnitude and do not appreciably impact the validity of inferences based on the GDS‐15.

Differences in structural and functional DMN connectivity in amyloid‐positive AMCI who converted to AD dementia

AbstractBackgroundDefault Mode Network (DMN) has emerged as a potential biomarker of Alzheimer’s disease (AD), but it is not clear if it can differentiate amnestic mild cognitive impairment (aMCI) in the spectrum of AD (with altered amyloid‐ aMCI‐Aβ+) who will evolve to dementia.Methods34 aMCI subjects with evidence of AD pathophysiology (low Aβ42 &lt; 540 pg/mL) were followed for a median of 13 months. All subjects had CDR score of 0.5 (with an obligatory memory score of 0.5), poor performance on RAVLT, considering age and education and Fazekas Scale 0 or 1. White Matter (WM) microstructure was evaluated by diffusion tensor imaging ‐ DTI MultiAtlas; FC by UF2C; HV by Freesurfer softwares. We considered conversion from aMCI to AD dementia if CDR score changed from 0.5 to 1. We performed MANOVAs to differentiate the groups, considering age and time of reevaluation as covariables. Afterwards, we analyzed ROC curves with the variables that were significantly different between the groups.ResultsWe found 8/34 converters (23.5%). Converters were older (p=0.049), but no other differences were found regarding sex, education, time of reevaluation and global cognitive performance in the first evaluation between the groups. aMCI‐Aβ+ converters had higher levels of tau (p=0.035), p‐tau (p=0.011) and a tendency to have smaller right HV (p=0.07). We did not find any significant result concerning DMN FC. However, we found that right cingulum parahippocampal bundle radial diffusivity was higher in aMCI‐Aβ+ converters (p=0.017), indicating myelinic dysfunction. Regarding ROC curve analyses, all significant variables showed moderate diagnostic accuracy: right cingulum parahippocampal bundle (AUC = 0.806), t‐tau (AUC = 0.788) and p‐tau (AUC = 0.706).ConclusionWe found that structural (right parahippocampal cingulum bundle) but not functional DMN connectivity alterations may differentiate aMCI‐Aβ+ subjects who converted to AD dementia.