Lower Cerebrospinal Fluid Aβ42 Research Articles

Association of caffeine consumption with cerebrospinal fluid biomarkers in mild cognitive impairment and Alzheimer's disease: A BALTAZAR cohort study.

We investigated the link between habitual caffeine intake with memory impairments and cerebrospinal fluid (CSF) biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. MCI (N=147) and AD (N=116) patients of the Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk (BALTAZAR) cohort reported their caffeine intake at inclusion using a dedicated survey. Associations of caffeine consumption with memory impairments and CSF biomarkers (tau, p-tau181, amyloid beta 1-42 [Aβ1-42], Aβ1-40) were analyzed using logistic and analysis of covariance models. Adjusted on Apolipoprotein E (APOE ε4), age, sex, education level, and tobacco, lower caffeine consumption was associated with higher risk to be amnestic (OR: 2.49 [95% CI: 1.13 to 5.46]; p=0.023) and lower CSF Aβ1-42 (p=0.047), Aβ1-42/Aβ1-40 (p=0.040), and Aβ1-42/p-tau181 (p=0.020) in the whole cohort. Data support the beneficial effect of caffeine consumption to memory impairments and CSF amyloid markers in MCI and AD patients. We studied the impact of caffeine consumption in the BALTAZAR cohort. Low caffeine intake is associated with higher risk of being amnestic in MCI/AD patients. Caffeine intake is associated with CSF biomarkers in AD patients.

Association of APOE genotype and cerebrospinal fluid Aβ and tau biomarkers with cognitive and motor phenotype in amyotrophic lateral sclerosis.

Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aβ and tau proteins with cognitive and motor phenotype in ALS. APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aβ42, Aβ40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype. APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aβ42 (-0.8 vs. 0.1, log-transformed values) and Aβ42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aβ42 levels, possibly reflecting cerebral Aβ deposition. While lower Aβ42/40 correlated with lower memory score (β = 0.20), Aβ42 positively correlated with both ALS-specific (β = 0.24) and ALS-nonspecific (β = 0.24) scores. Although Aβ42/40 negatively correlated with T-tau (β = -0.29) and P-tau181 (β = -0.33), we found an unexpected positive association of Aβ42 and Aβ40 with both tau proteins. Regarding motor phenotype, lower levels of Aβ species were associated with lower motor neuron (LMN) signs (Aβ40: β = 0.34; Aβ42: β = 0.22). APOE haplotype and CSF Aβ biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.

Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-β42 over Amyloid Positron Emission Tomography.

Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-β42 (Aβ42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. NP with CAA had significantly lower CSF Aβ42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aβ42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CSF Aβ42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.

Impact of self‐reported history of head injury on Alzheimer’s disease biomarker profiles

AbstractBackgroundHead injury (HI) as a risk factor for Alzheimer’s disease (AD) has been attracting increased attention thanks to the discovery that concussion is linked to earlier and more severe development of AD (1). HI is prevalent, and a better understanding of how it contributes to AD risk and prognosis is necessary (2). Previous cross‐sectional studies have provided evidence of differences in biomarker levels between individuals with a history of HI and those without (2); this study investigates the effects of a history of HI on longitudinal patterns of AD biomarkers to better understand how HI affects AD risk.MethodUsing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, we examined longitudinal levels of amyloid β (Aβ), phosphorylated tau (p‐tau), and total tau (t‐tau) in the cerebrospinal fluid (CSF) of 100 individuals with a history of HI and 100 non‐HI controls demographically‐matched on age, sex, race, ethnicity, and years of education. We also analyzed longitudinal levels of blood plasma free plasma (FP) 42, total plasma (TP) 42, pTau181, and NFL.ResultIndividuals with a history of HI had lower CSF Aβ at baseline, lower plasma TP42 at a month 48 follow‐up visit, and lower plasma pTau181 at 72‐ and 96‐month follow‐up visits. There were no differences between the groups on CSF p‐tau or t‐tau levels or plasma FP42 or NFL at any time point.ConclusionLower CSF and plasma amyloid in the HI group may indicate individuals with a history of HI have higher amyloid deposition, given the inverse correlation between CSF/plasma amyloid levels and amyloid deposition on PET (3). The unexpectedly lower plasma pTau in the HI group warrants further analysis. Some of our analyses may be underpowered, as underreporting of HI incidence in ADNI reduces the number of available HI participants. However, despite these limitations, we were able to find significant differences in some biomarkers in individuals with a history of HI. Future studies in expanded samples are needed.1. Fleminger et al. (2003). Journal of Neurology, Neurosurgery & Psychiatry 2. Small et al. (2013). The American Journal of Geriatric Psychiatry 3. Fagan et al. (2006). Annals of Neurology

Cerebrospinal-fluid biomarkers for predicting phenoconversion in patients with isolated rapid-eye movement sleep behavior disorder.

Patients with isolated rapid-eye-movement sleep behavior disorder (iRBD) have an increased risk of developing neurodegenerative diseases. This study assessed cerebrospinal-fluid (CSF) biomarkers of neurodegeneration and blood-brain barrier (BBB) alteration in patients with iRBD compared to controls and ascertain whether these biomarkers may predict phenoconversion to alpha-synucleinopathies (Parkinson's Disease (PD), Dementia with Lewy bodies (DLB), Multiple System Atrophy (MSA)). Patients and controls underwent between 2012 and 2016 a neurological assessment, a lumbar puncture for CSF biomarker analysis (β-amyloid42 - Aβ42; total-tau, and phosphorylated tau), and BBB alteration (CSF/serum albumin ratio). All patients with iRBD were followed until 2021 and then classified into patients who converted to alpha-synucleinopathies (iRBD converters, cRBD) or not (iRBD non-converters, ncRBD). Thirty-four patients with iRBD (mean age 67.12 ± 8.14) and 33 controls (mean age 64.97 ± 8.91) were included. At follow-up (7.63 ± 3.40 years), eight patients were ncRBD and 33 patients were cRBD: eleven converted to PD, 10 to DLB, and two to MSA. Patients with iRBD showed lower CSF Aβ42 levels and higher CSF/serum albumin ratio than controls. Cox regression analysis showed that the phenoconversion rate increases with higher motor impairment (hazard ratio [HR] = 1.23, p = 0.032). CSF Aβ42 levels predicted phenoconversion to DLB (HR = 0.67, p = 0.038) and BBB alteration predicted phenoconversion to PD (HR = 1.20, p = 0.038). This study showed that low CSF Aβ42 levels and high BBB alteration may predict the phenoconversion to DLB and PD in patients with iRBD, respectively. These findings highlight the possibility to discriminate phenoconversion in iRBD patients through CSF biomarkers; however, further studies are needed.

Mediterranean diet is associated with lower white matter lesion volume in Mediterranean cities and lower cerebrospinal fluid Aβ42 in non-Mediterranean cities in the EPAD LCS cohort

The Mediterranean diet (MedDiet) has been associated with better brain health and reduced incidence of dementia. Few studies have compared the effects of the MedDiet in early Alzheimer’s disease or compared the effects of the diet within and outside of the Mediterranean region. The Mediterranean diet adherence screener (MEDAS) and MEDAS continuous scores were calculated at the baseline visit of the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (n = 1625). The scores were included in linear regression models to test for associations with hippocampal volume, log-transformed white matter lesion volume, cerebrospinal fluid pTau18, and Aβ42. Higher MEDAS scores were associated with lower log-transformed white matter lesion volume (β: −0.07, standard error [SE]: 0.02, p < 0.001). This association was only seen in the Mediterranean region (β: −0.12, SE: 0.03, p < 0.001). In the non-Mediterranean region, higher MEDAS continuous scores were associated with lower cerebrospinal fluid Aβ42 (β: −68.30, SE: 14.32, p < 0.001). More research is needed to understand the differences in the associations seen with the MedDiet and Alzheimer’s disease biomarkers in different European regions.

Association Between Cerebrospinal Fluid Biomarkers of Amyloid and Tau and Neuropsychiatric Symptoms Among Participants from the National Alzheimer’s Coordinating Center Uniform Data Set (P10-6.004)

Association Between Cerebrospinal Fluid Biomarkers of Amyloid and Tau and Neuropsychiatric Symptoms Among Participants from the National Alzheimer’s Coordinating Center Uniform Data Set (P10-6.004)

Association of APOE ε4/ε4 with fluid biomarkers in patients from the PUMCH dementia cohort.

Apolipoprotein-E (APOE) ε4 is a major genetic risk factor for Alzheimer's disease (AD). Current studies, which were mainly based on the clinical diagnosis rather than biomarkers, come to inconsistent conclusions regarding the associations of APOE ε4 homozygotes (APOE ε4/ε4) and cerebrospinal fluid (CSF) biomarkers of AD. In addition, few studies have explored the associations of APOE ε4/ε4 with plasma biomarkers. Therefore, we aimed to investigate the associations of APOE ε4/ε4 with fluid biomarkers in dementia and biomarker-diagnosed AD. A total of 297 patients were enrolled. They were classified into Alzheimer's continuum, AD, and non-AD, according to CSF biomarkers and/or β amyloid PET results. AD was a subgroup of the AD continuum. Plasma Amyloid β (Aβ) 40, Aβ42, glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and phosphorylated tau (P-tau)181 were quantified in 144 of the total population using an ultra-sensitive Simoa technology. We analyzed the associations of APOE ε4/ε4 on CSF and plasma biomarkers in dementia and biomarker diagnosed AD. Based on the biomarker diagnostic criteria, 169 participants were diagnosed with Alzheimer's continuum and 128 individuals with non-AD, and among the former, 120 patients with AD. The APOE ε4/ε4 frequencies were 11.8% (20/169), 14.2% (17/120), and 0.8% (1/128) in Alzheimer's continuum, AD and non-AD, respectively. Only CSF Aβ42 was shown to be decreased in APOE ε4/ε4 carriers than in non-carriers for patients with AD (p = 0.024). Furthermore, we did not find any associations of APOE ε4 with plasma biomarkers of AD and non-AD. Interestingly, we found that in non-AD patients, APOE ε4 carriers had lower CSF Aβ42 (p = 0.018) and higher T-tau/Aβ42 ratios (p < 0.001) and P-tau181/Aβ42 ratios (p = 0.002) than non-carriers. Our data confirmed that of the three groups (AD continuum, AD, and non-AD), those with AD had the highest frequency of APOE ɛ4/ɛ4 genotypes. The APOE ɛ4/ɛ4 was associated with CSF levels of Aβ42 but not tau for AD and non-AD, suggesting that APOE ɛ4/ɛ4 affected the Aβ metabolism of both. No associations between APOE ε4/ɛ4 and plasma biomarkers of AD and non-AD were found.

Cerebrospinal Fluid Biomarkers in iNPH: A Narrative Review.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological syndrome characterized by the clinical triad of gait disorder, cognitive impairment and urinary incontinence. It has attracted interest because of the possible reversibility of symptoms, especially with timely treatment. The main pathophysiological theory is based on a vicious circle of disruption in circulation of cerebrospinal fluid (CSF) that leads to the deceleration of its absorption. Data regarding CSF biomarkers in iNPH are contradictory and no definite CSF biomarker profile has been recognized as in Alzheimer's disease (AD), which often co-exists with iNPH. In this narrative review, we investigated the literature regarding CSF biomarkers in iNPH, both the established biomarkers total tau protein (t-tau), phosphorylated tau protein (p-tau) and amyloid peptide with 42 amino acids (Aβ42), and other molecules, which are being investigated as emerging biomarkers. The majority of studies demonstrate differences in CSF concentrations of Aβ42 and tau-proteins (t-tau and p-tau) among iNPH patients, healthy individuals and patients with AD and vascular dementia. iNPH patients present with lower CSF Aβ42 and p-tau concentrations than healthy individuals and lower t-tau and p-tau concentrations than AD patients. This could prove helpful for improving diagnosis, differential diagnosis and possibly prognosis of iNPH patients.

P 25 CSF biomarkers in CAA compared to AD

Background: Both, cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) pathologies coexist on a spectrum, where one end represents parenchymal amyloid deposition causing AD-dementia, and the other end represents vascular amyloid deposition leading to intracerebral hemorrhage and vascular cognitive impairment. CAA is present, to varying degrees, in several AD patients, resulting in a large overlap between the two pathologies in the same brain. Cerebrospinal fluid (CSF) biomarkers could aid in the better discrimination between CAA and AD pathology. Objective: To assess core biomarkers of AD pathology and axonal degeneration in CAA compared to AD and healthy controls. Methods: In a hospital-based setting we recruited 234 patients. N=96 (41%) had probable CAA according to the modified Boston criteria, but did not meet the NIA-AA criteria for AD. N=99 (42%) had AD, and of those n=21 (9%) had AD with CAA, while n=78 (33%) had AD without CAA. N=39 (17%) were considered controls without CAA or AD. CSF measures included β-amyloid (Aβ) 1-40, Aβ 1-42, phosphorylated tau (ptau), total tau (ttau) and neurofilament light chain (NfL). NfL data were missing in n=139 (59%) subjects. Group comparisons were conducted applying ANOVA, adjusted for age and sex, respectively. Bonferroni-adjusted p-values ≤ 0.01 were considered significant. Results: Group differences became obvious for Aβ 1-42, ptau and ttau (Figure). Aβ 1-42 was lower in AD with and without CAA compared to CAA and controls. Ptau was higher in AD with and without CAA compared to CAA and controls. Compared to controls, ttau was higher in AD with and without CAA, and in CAA. There were no group differences for Aβ 1-40 and NfL, albeit there was a clear trend towards higher NfL levels in AD with CAA and CAA compared to AD without CAA and controls (Figure). None of the CSF markers differed between AD with CAA compared to AD without CAA. Conclusion: Lower CSF Aβ 1-42 and higher ptau seem to be specific markers for AD pathology independent of the concurrent occurrence of CAA. They could aid in the discrimination between pure CAA and CAA with AD pathology. Outlook: Upcoming analysis will focus on the correlation between CSF biomarkers and CSVD MRI features according to the STRIVE criteria.

Association between CSF biomarkers of Alzheimer's disease and neuropsychiatric symptoms: Mayo Clinic Study of Aging.

We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults. We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aβ42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Lower CSF Aβ42, and higher t-tau/Aβ42 and p-tau/Aβ42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior. CSF Aβ42, t-tau/Aβ42, and p-tau/Aβ42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers.

Initial biological evaluation of a novel microtubule‐based PET ligand in rodent and NHP models of AD

AbstractBackgroundMicrotubule (MT) integrity is critical for cell function and viability. Abnormal MT stability is commonly attributed to hyperphosphorylation of the MT‐associated protein, tau. However, the time course of MT instability in disease progression remains unknown. In vivo MT imaging offers an opportunity to gain critical information on MT changes in relation to staging of ADRDs. Our lab reported the first brain‐penetrant MT PET ligand, [11C]MPC‐6827 and evaluated in vivo imaging in normal rodents and non‐human primates (NHP). Herein we report its initial biological evaluations in (a) cells, (b) tau knock‐out mice, and (c) aged NHPs (Caribbean‐origin vervets) with changes in AD‐related biomarkers.MethodIn vitro [11C]MPC‐6827 cell uptake assay was performed in patient‐derived SH‐SY5Y cells with different MT destabilizing and stabilizing agents. Radioactive binding was determined as %ID(injected dose)/mg of protein present in each well. Dynamic 0‐60 min brain microPET/CT imaging was performed in tau knock‐out and wild‐type mice (n=4). Four vervets (20‐29y) with different cerebrospinal fluid (CSF) Aβ42 levels (2 high levels‐1461, 1614 and 2 low levels‐579,732) underwent 0‐120 min brain PET/CT imaging with [11C]MPC‐6827. ROIs were drawn on the whole‐brain and SUVR values were calculated from co‐registered PET/MR images.ResultIn vitro cell uptake assays with [11C]MPC‐6827 in SH‐SY5Y cells displayed high uptake with MT destabilizing agents and low uptake with stabilizing agents. MicroPET imaging demonstrated higher radioactive brain uptake in tau knockout over wild‐type mice. Vervets with low CSF Aβ42 levels showed high radioactive brain uptake and the youngest vervet (20y) displayed lowest brain uptake.ConclusionConsistent with our in vitro cell uptake and in vivo rodent imaging experiments, [11C]MPC‐6827 increased with MT destabilizations. Radioactive uptake was inversely related to CSF Aβ levels and directly related to age in a NHP model of AD (Fig 1). Collectively our data suggest that [11C]MPC‐6827 is more selective towards destabilized MTs. On‐going experiments include rigorous PET imaging analyses, determination of metabolic plasma‐blood parameters, and correlations with Aβ42 and tau levels. Nonetheless, our promising results support the high translational utility of [11C]MPC‐6827 to image MTs in ADRDs.

Initial biological evaluations of a novel microtubule‐based PET ligand in Alzheimer’s disease

AbstractBackgroundMicrotubule (MT) integrity is critical for cell function and viability. Abnormal MT‐stability in AD is commonly attributed to hyperphosphorylation of the MT‐associated protein, tau. However, the time course of MT instability in disease progression remains unknown. In vivo MT imaging offers an opportunity to gain critical information on MT changes in relation to staging of ADRDs. Our lab reported the first brain‐penetrant MT PET ligand, [11C]MPC‐6827 and evaluated in vivo imaging in normal rodents and non‐human primates (NHP). Herein we report its initial biological evaluations in (a) neuronal cells, (b) tau knock‐out mice, and (c) aged NHPs (Caribbean‐origin vervets) with changes in AD‐related biomarkers.MethodIn vitro [11C]MPC‐6827 cell uptake assay was performed in patient‐derived SH‐SY5Y cells with different MT destabilizing and stabilizing agents. Radioactive binding efficiency was determined as %ID (injected dose)/mg of protein present in each well. Dynamic 0‐60 min brain microPET/CT imaging was performed in tau knock‐out and wild type mice (n=4). Four vervets (20‐29y) with different cerebrospinal fluid (CSF) Aβ42 levels (2 high levels‐1461, 1614 and 2 low levels‐579,732) underwent 0‐120 min brain PET/CT imaging with [11C]MPC‐6827. ROIs were drawn on the whole‐brain and SUVR values were calculated from co‐registered PET/MR images.ResultIn vitro cell uptake assays with [11C]MPC‐6827 in SH‐SY5Y cells displayed high uptake with MT destabilizing agents and low uptake with stabilizing agents. MicroPET imaging demonstrated higher radioactive brain uptake in tau knockout over wild‐type mice. Vervets with low CSF Aβ42 levels showed high radioactive brain uptake and the youngest vervet (20y) displayed lowest brain uptake.ConclusionConsistent with our in vitro cell uptake and in vivo rodent imaging experiments, [11C]MPC‐6827 increased with MT destabilizations. Radioactive uptake was inversely related to CSF Aβ levels and directly related to age in a NHP model of AD (Fig 1). Collectively our data suggest that [11C]MPC‐6827 is more selective towards destabilized MTs. On‐going experiments include rigorous PET imaging analyses, determination of metabolic plasma‐blood parameters, and correlations with Aβ42 and tau levels. Nonetheless, our promising results support the high translational utility of [11C]MPC‐6827 to image MTs in ADRDs.

Water exchange rate across the blood-brain barrier is associated with CSF amyloid-β 42 in healthy older adults.

IntroductionWe tested if water exchange across the blood‐brain barrier (BBB), estimated with a noninvasive magnetic resonance imaging (MRI) technique, is associated with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and neuropsychological function.MethodsForty cognitively normal older adults (67–86 years old) were scanned with diffusion‐prepared, arterial spin labeling (DP‐ASL), which estimates water exchange rate across the BBB (kw). Participants also underwent CSF draw and neuropsychological testing. Multiple linear regression models were run with kw as a predictor of CSF concentrations and neuropsychological scores.ResultsIn multiple brain regions, BBB kw was positively associated with CSF amyloid beta (Aβ)42 concentration levels. BBB kw was only moderately associated with neuropsychological performance.DiscussionOur results suggest that low water exchange rate across the BBB is associated with low CSF Aβ42 concentration. These findings suggest that kw may be a promising noninvasive indicator of BBB Aβ clearance functions, a possibility which should be further tested in future research.

Effects of amyloid pathology and the APOE ε4 allele on the association between cerebrospinal fluid Aβ38 and Aβ40 and brain morphology in cognitively normal 70-years-olds

The association between cerebrospinal fluid (CSF) amyloid beta (Aβ) Aβ38 or Aβ40 and brain grey- and white matter integrity is poorly understood. We studied this in 213 cognitively normal 70-year-olds, and in subgroups defined by presence/absence of the APOE ε4 allele and Aβ pathology: Aβ−/APOE−, Aβ+/APOE−, Aβ−/APOE+ and Aβ+/APOE+. CSF Aβ was quantified using ELISA and genotyping for APOE was performed. Low CSF Aβ42 defined Aβ plaque pathology. Brain volumes were assessed using Freesurfer-5.3, and white matter integrity using tract-based statistics in FSL. Aβ38 and Aβ40 were positively correlated with cortical thickness, some subcortical volumes and white matter integrity in the total sample, and in 3 of the subgroups: Aβ−/APOE−, Aβ+/APOE− and Aβ−/APOE+. In Aβ+/APOE+ subjects, higher Aβ38 and Aβ40 were linked to reduced cortical thickness and subcortical volumes. We hypothesize that production of all Aβ species decrease in brain regions with atrophy. In Aβ+/APOE+, Aβ-dysregulation may be linked to cortical atrophy in which high Aβ levels is causing pathological changes in the gray matter of the brain.

Distinct patterns of apolipoprotein C-I, C-II, and C-III isoforms are associated with markers of Alzheimer’s disease

Apolipoproteins C-I, C-II, and C-III interact with ApoE to regulate lipoprotein metabolism and contribute to Alzheimer's disease pathophysiology. In plasma, apoC-I and C-II exist as truncated isoforms, while apoC-III exhibits multiple glycoforms. This study aimed to 1) delineate apoC-I, C-II, and C-III isoform profiles in cerebrospinal fluid (CSF) and plasma in a cohort of nondemented older individuals (n = 61), and 2) examine the effect of APOE4 on these isoforms and their correlation with CSF Aβ42, a surrogate of brain amyloid accumulation. The isoforms of the apoCs were immunoaffinity enriched and measured with MALDI-TOF mass spectrometry, revealing a significantly higher percentage of truncated apoC-I and apoC-II in CSF compared with matched plasma, with positive correlation between CSF and plasma. A greater percentage of monosialylated and disialylated apoC-III isoforms was detected in CSF, accompanied by a lower percentage of the two nonsialylated apoC-III isoforms, with significant linear correlations between CSF and plasma. Furthermore, a greater percentage of truncated apoC-I in CSF and apoC-II in plasma and CSF was observed in individuals carrying at least one APOE Ɛ4 allele. Increased apoC-I and apoC-II truncations were associated with lower CSF Aβ42. Finally, monosialylated apoC-III was lower, and disialylated apoC-III greater in the CSF of Ɛ4 carriers. Together, these results reveal distinct patterns of the apoCs isoforms in CSF, implying CSF-specific apoCs processing. These patterns were accentuated in APOE Ɛ4 allele carriers, suggesting an association between APOE4 genotype and Alzheimer's disease pathology with apoCs processing and function in the brain.

Plasma sex hormone-binding globulin predicts neurodegeneration and clinical progression in prodromal Alzheimer's disease.

It was unclear whether sex hormone-binding globulin (SHBG) was a circulating biomarker of Alzheimer’s disease (AD). We tested the cross-sectional relationships between plasma SHBG and cerebrospinal fluid (CSF) AD biomarkers in 707 non-demented adults. Next, the influences of plasma SHBG on dynamic changes of CSF Aβ42, hippocampus volume, brain metabolism, and cognition were explored in 448 non-demented adults from the Alzheimer’s disease Neuroimaging Initiative (ADNI). Finally, the predictive and diagnostic values of plasma SHBG in AD were explored. A positive correlation was found between SHBG levels in plasma and CSF. Individuals with higher plasma SHBG levels had lower CSF Aβ42 (p < 0.005), after adjusting for age, gender, education, APOE4 allele, and cognitive scores. Though no significant difference of plasma SHBG was observed between mild AD dementia and healthy normal, plasma SHBG could contribute to accelerated rates of CSF Aβ42 decrease (p < 0.0005), decline in brain metabolism (p < 0.05), and hippocampus atrophy (p < 0.01), cognitive decline (p < 0.01), as well as higher risk of AD dementia (p < 0.05). These findings indicated plasma SHBG could be a prodromal biomarker to predict disease progression in AD.

Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease.

ObjectiveWe analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.MethodsAmyloid‐β 1 to 42 (Aβ42), total tau (t‐tau) and phosphorylated tau (p‐tau) at the threonine 181 position were measured using the high‐precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear‐mixed effects models.ResultsWe found patients with PD had lower CSF t‐tau (median = 157.7 pg/mL; range = 80.9–467.0); p‐tau (median = 13.4 pg/mL; range = 8.0–40.1), and Aβ42 (median = 846.2 pg/mL; range = 238.8–3,707.0) than HCs at baseline (CSF t‐tau median = 173.5 pg/mL; range = 82.0–580.8; p‐tau median = 15.4 pg/mL; range = 8.1–73.6; and Aβ42 median = 926.5 pg/mL; range = 239.1–3,297.0; p < 0.05–0.001) and a moderate‐to‐strong correlation among these biomarkers in both patients with PD and HCs (Rho = 0.50–0.97; p < 0.001). Of the patients with PD, 31.5% had pathologically low levels of CSF Aβ42 at baseline and these patients with PD had lower p‐tau levels (median = 10.8 pg/mL; range = 8.0–32.8) compared with 27.7% of HCs with pathologically low CSF Aβ42 (CSF p‐tau median = 12.8 pg/mL; range 8.2–73.6; p < 0.03). In longitudinal CSF analysis, we found patients with PD had greater decline in CSF Aβ42 (mean difference = −41.83 pg/mL; p = 0.03) and CSF p‐tau (mean difference = −0.38 pg/mL; p = 0.03) at year 3 compared with HCs. Baseline CSF Aβ42 values predicted small but measurable decline on cognitive, autonomic, and motor function in early PD.InterpretationOur data suggest baseline CSF AD biomarkers may have prognostic value in early PD and that the dynamic change of these markers, although modest over a 3‐year period, suggest biomarker profiles in PD may deviate from healthy aging. ANN NEUROL 2020;88:574–587

CSF amyloid is a consistent predictor of white matter hyperintensities across the disease course from aging to Alzheimer's disease

This study investigated the relationship between white matter hyperintensities (WMH) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Subjects included 180 controls, 107 individuals with a significant memory concern, 320 individuals with early mild cognitive impairment, 171 individuals with late mild cognitive impairment, and 151 individuals with AD, with 3T MRI and CSF Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) data. Multiple linear regression models assessed the relationship between WMH and CSF Aβ1-42, t-tau, and p-tau. Directionally, a higher WMH burden was associated with lower CSF Aβ1-42 within each diagnostic group, with no evidence for a difference in the slope of the association across diagnostic groups (p = 0.4). Pooling all participants, this association was statistically significant after adjustment for t-tau, p-tau, age, diagnostic group, and APOE-ε4 status (p < 0.001). Age was the strongest predictor of WMH (partial R2~16%) compared with CSF Aβ1-42 (partial R2~5%). There was no evidence for an association with WMH and either t-tau or p-tau. These data are supportive of a link between amyloid burden and presumed vascular pathology.

Plasma amyloid is associated with the rate of cognitive decline in cognitively normal elderly: the SCIENCe project

Plasma biomarkers are promising prognostic tools in individuals with subjective cognitive decline (SCD). We aimed to investigate the relationships of baseline plasma amyloid beta (Aβ)42/Aβ40 and total Tau (tTau) with rate of cognitive decline, in comparison to relationships of baseline cerebrospinal fluid (CSF) Aβ42, tTau, and phosphorylated tau181 (pTau181) with rate of cognitive decline. We included 241 subjects with SCD (age = 61 ± 9, 40% female, Mini-Mental State Examination = 28 ± 2) with follow-up (average: 2 ± 2 years, median visits: 3 [range: 1–11]) for re-evaluation of neuropsychological test performance (attention, memory, language, and executive functioning domains). Using age, gender and education-adjusted linear mixed models, we found that lower plasma Aβ42/Aβ40 was associated with steeper rate of decline on tests for attention, memory, and executive functioning, but not language. Lower CSF Aβ42 was associated with steeper decline on tests covering all domains. Associations for plasma amyloid and cognitive decline mirror those of CSF amyloid. Plasma tTau was not associated with rate of cognitive decline, whereas CSF tTau and pTau181 were on multiple tests covering all domains.