Audrey Gabelle

Interest in plasma biomarkers for neurodegenerative disorders is growing, but their reliance on glomerular filtration makes kidney function a key potential confounder. This study assesses the effect of kidney function (eGFR) on plasma biomarkers of neurodegeneration and on their accuracy for detecting cerebral amyloidosis. This observational study aims at studying the effect of kidney function on blood biomarkers through simultaneous measurements of creatinine, plasma, and CSF biomarkers (Aβ42, Aβ40, p-tau181, p-tau217, neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP], and brain-derived tau [BD-tau]), as well as plasma biomarker ratios (Aβ42/Aβ40, p-tau217/Aβ42, NfL/p-tau217, and p-tau181/Aβ42), in the ALZAN cohort of patients. This prospective multicenter cohort (#NCT05427448), recruited across Montpellier, Nîmes, and Perpignan hospitals, included patients from November 2022 to July 2024 who met the following criteria: age ≥18 years, informed consent, and concomitant CSF and blood sampling. To determine the association between plasma biomarkers and kidney function, we performed univariable linear regression analyses. A total of 420 patients were included (mean age: 71.1 years, %female: 53.2) and subdivided into 3 groups according to eGFR value (ml/minute/1.73 m²): 90 (n = 190). All mean plasma biomarker levels were significantly higher in the eGFR < 60 group. Except for p-tau217, a statistically significant inverse correlation was observed between eGFR and individual plasma biomarkers. Furthermore, age-adjusted univariable linear regression analysis revealed an association between eGFR and all plasma biomarkers. Kidney dysfunction significantly impaired the specificity of several biomarkers (p-tau181, GFAP, NfL, and BD-tau; p < 0.001) for detecting cerebral amyloidosis (CSF Aβ42/Aβ40 < 7%), whereas p-tau217 was unaffected. It is important to note that ratio-based plasma biomarkers were not influenced by reduced kidney function. Impaired kidney function was linked to increased plasma cerebral amyloidosis biomarkers, but ratio-based measures (especially p-tau217/Aβ42) showed stable sensitivity and specificity for detecting cerebral amyloidosis across all eGFR groups. Additional studies including more patients with lower eGFR values in diverse diagnostic settings are needed to clarify the influence of kidney function on these biomarkers. This Class II evidence shows that kidney function influences individual blood biomarkers used for cerebral amyloidosis detection, but not their ratios. NCT05427448.

IMPORTANCE There are no approved oral disease-modifying treatments for Alzheimer’s disease (AD) with the ability to prolong time in a stable disease state and with clinically meaningful outcomes clear to patients and caregivers. DESIGN The Phase IIb/III ANAVEX2-73-AD-004 study was a randomized, double-blind, placebo-controlled, 48-week trial with prespecified gene or GWAS identified genetic variant populations related to the mechanism of the pharmacological intervention. OBJECTIVE Providing evidence of improved Precision Medicine neurology clinical treatment responses with optimal blarcamesine dose for up to ∼70% of AD patients within prespecified SIGMAR1 (ABCLEAR1) and GWAS identified COL24A1 (ABCLEAR2) and SIGMAR1/COL24A1 (ABCLEAR3) non-missense gene populations. Describing once-daily, oral therapeutic intervention of blarcamesine in early AD, with a differentiated upstream and constitutional mechanism of action by enhancing autophagy through SIGMAR1 activation and restoration of cellular homeostasis. SETTING Multicenter - 52 medical research centers/hospitals in 5 countries. INTERVENTION 508 participants with Early AD (Stage 3) were randomized to receive blarcamesine (n = 338) oral capsules once daily either in medium dose group (30 mg) or in high dose group (50 mg) or placebo (n = 170) for 48 weeks. An open-label-extension study ATTENTION-AD, continued for up to 192 weeks. MAIN OUTCOME AND MEASURES Further improved clinical and biomarker outcomes of the ABCLEAR2 and ABCLEAR3 populations were accretive to the previously reported intent-to-treat (ITT) and prespecified ABCLEAR1 populations. The co-primary cognitive and functional outcomes were assessed as changes in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB as well as patient assessed clinical outcomes CGI-I, NPI-Q and QoL-AD (Quality of Life AD Patient) as well as biomarkers global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), and volumetric MRI scans were analyzed by general linear model. RESULTS The ITT population (mean age, 73.7 years; 225 [48.7%] women), consisted of 462 randomized participants, with ABCLEAR1 population comprising of 300 participants, ABCLEAR2 population of 336 participants and ABCLEAR3 of 222 participants. In both the ABCLEAR2 and ABCLEAR3 populations, the co-primary outcomes as well as all other clinical outcomes were statistically significant. ABCLEAR3 blarcamesine group vs. placebo at Week 48 (ADAS-Cog13 difference of −4.179 [95% CI −6.512, −1.845]; P=0.0005; ADCS-ADL difference of +3.131 [95%CI 0.720, 5.542]; P=0.0111; CDR-SB difference of −1.076 [95% CI −1.645, −0.508]; P=0.0002; QoL-AD Patient improvement from baseline of 0.334 [95% CI −1.164, 1.833] and difference of 1.848 [95% CI 0.455, 3.241]; P=0.0095). The clinical outcomes were strongest in the blarcamesine 30 mg cohort (ADAS-Cog13 difference of −4.739 [95% CI −7.370, −2.108]; P=0.0004; ADCS-ADL difference of +4.245 [95%CI 1.518, 6.972]; P=0.0024; CDR-SB difference of −1.414 [95% CI −2.054, −0.775]; PCONCLUSIONS AND RELEVANCE Blarcamesine group demonstrated a balanced safety profile with no associated neuroimaging adverse events. The respective once-daily oral 30 mg blarcamesine cohort in the respective ABCLEAR1, ABCLEAR2, and ABCLEAR3 populations demonstrates further improvement of the already adequate safety profile of the ITT population and hence representing the dose with the most balanced benefit-to-risk ratio. In both ABCLEAR2 and ABCLEAR3 populations significant slowing in decline and even stabilization of clinical worsening was demonstrated. Blarcamesine group vs. placebo was 75.9% reduction in decline at 48 weeks in the total blarcamesine group and was 84.7% in the 30 mg dose group, respectively on the prespecified co-primary cognitive endpoint ADAS-Cog13 in the ABCLEAR3 population. Blarcamesine demonstrated consistently significantly improved clinical effect for all clinical endpoints, which was in accordance with significant and further reduced brain atrophy. Furthermore, a significant absolute improvement in Quality of Life (QoL-AD) scores indicating a reversal of negative trajectory for Alzheimer’s disease patients from baseline to end of trial was observed. The Phase IIb/III ANAVEX2-73-AD-004 clinical study confirmed blarcamesine’s consistent efficacy leading to improved cognitive stabilization with continued benefit in the open-label-extension study ATTENTION-AD up to 192 weeks. Evidenced by the Precision Medicine paradigm, including in a prespecified ABCLEAR1 population, a consistent significant improvement for all clinical endpoints in the ABCLEAR2 and ABCLEAR3 populations, respectively, was demonstrated. Coupled with a convenient once daily, oral pill administration, blarcamesine could represent a novel treatment option for up to ∼70% of early AD patients benefiting from further improved outcomes using directed Precision Medicine to alleviate significant medical and economic burden. TRIAL REGISTRATION Clinicaltrials.gov: NCT03790709; Open-label extension NCT04314934 FUNDING This work was funded by Anavex Life Sciences. Key Message Within a heterogeneous Alzheimer’s disease (AD) population, clinical utility of disease-modifying drug candidates could be enhanced via a Precision Medicine approach of treating those with target-relevant genetic profiles, excluding missense gene populations. This effective targeting could alleviate significant medical and economic burden.

Background Among plasma biomarkers for Alzheimer’s disease (AD), pTau181 and pTau217 are the most promising. However, transition from research to routine clinical use will require confirmation of clinical performance in prospective cohorts and evaluation of cofounding factors. Method pTau181 and pTau217 were quantified using, Quanterix and ALZpath, SIMOA assays in the well-characterised prospective multicentre BALTAZAR (Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk) cohort of participants with mild cognitive impairment (MCI). Results Among participants with MCI, 55% were Aβ+ and 29% developed dementia due to AD. pTau181 and pTau217 were higher in the Aβ+ population with fold change of 1.5 and 2.7, respectively. MCI that converted to AD also had higher levels than non-converters, with HRs of 1.38 (1.26 to 1.51) for pTau181 compared with 8.22 (5.45 to 12.39) for pTau217. The area under the curve for predicting Aβ+ was 0.783 (95% CI 0.721 to 0.836; cut-point 2.75 pg/mL) for pTau181 and 0.914 (95% CI 0.868 to 0.948; cut-point 0.44 pg/mL) for pTau217. The high predictive power of pTau217 was not improved by adding age, sex and apolipoprotein E ε4 (APOEε4) status, in a logistic model. Age, APOEε4 and renal dysfunction were associated with pTau levels, but the clinical performance of pTau217 was only marginally altered by these factors. Using a two cut-point approach, a 95% positive predictive value for Aβ+ corresponded to pTau217 >0.8 pg/mL and a 95% negative predictive value at Conclusions Plasma pTau217 and pTau181 both correlate with AD, but the fold change in pTau217 makes it better to diagnose cerebral amyloidosis, and predict cognitive decline and conversion to AD dementia.

Background: Subjective cognitive complaints (SCC) signal risk of objective cognitive decline. To better understand the bio‐behavioral factors that signal cognitive trajectories at‐risk for the earliest stages of Alzheimer’ disease, there is a need for well‐phenotyped large‐scale population‐based cohorts with longitudinal assessments.Method: From the INTUITION decentralized observational brain health study (NCT0505895), using app‐collected self‐report data, we compared the demographic, clinical, and neuropsychological profiles of 2045 SCC versus 4090 age‐ and education‐matched cognitively normal (CN) participants. The SCC cohort was defined by age (> = 50 years) and presence of significant cognitive concerns based on total scores> = 4 on the 14‐item Cognitive Function Instrument (CFI‐14). Using customized assessments from Cambridge Cognition, Pattern Recognition Memory (PRM), Paired Associates Learning (PAL), Spatial Working Memory (SWM), and Match‐to‐Sample (MTS) tests were performed. SCC participants were stratified and compared by presence or absence of dementia risk factors (first‐degree family history of dementia (FH+/FH‐) or 2+ cardiovascular risk factors (CVRF2+/CVRF2‐)).Result: Cognitive and neuropsychiatric symptom‐burden were greater among the SCC cohort compared to CN participants (e.g., E‐Cog‐12: 1.8(0.5) vs 1.2(0.3), pathological PHQ2 (Total> = 3): 14% vs 2.7%, pathological GAD‐2(Total> = 3): 11.8% vs 1.9%, respectively p<0.001). Lifestyle factors differed, with SCC participants reporting lower level of physical activity, higher substance use and impaired sleep, relative to CN. Among SCC participants the prevalence of CVRF2+ and FH+ were 53.2% and 37.8%, respectively; and 43% (CVRF2+) and 33.5% (FH+) among CN. Among SCC, individuals with CVRF2+ were more likely to be older, male, and with higher rates of anxiety/depression symptoms. Mean total CFI‐14 scores were similar between FH+/FH‐ or CVRF2+/CVRF2‐, but item‐level CFI profiles differed (e.g., word‐finding complaints in FH+/CVRF2+). SCC scored lower on key CANTAB outcomes (e.g., PAL/PRM) evaluated compared to CN. Both CVRF2+ and FH+ participants with SCC performed worse on cognitive measures of learning (SWM) and attention (MTS) compared to CVRF2‐ and FH‐ respectively.Conclusion: In a large, decentralized cohort, SCC was associated with higher burden of modifiable and non‐modifiable risk factors. First‐degree family history of dementia and cardiovascular disease, when coupled with SCC, revealed more severe measurable objective cognitive deficits. Future work will assess individual longitudinal cognitive trajectories.

Neurofilament light chain (NfL) is a potential diagnostic and prognostic plasma biomarker for numerous neurological diseases including Alzheimer’s disease (AD). In this study, we investigated the relationship between baseline plasma concentration of Nfl and Mild Cognitive Impairment in participants who did and did not have a clinically determined diagnosis of dementia by the end of the three-year study. Additionally, we explored the connection between baseline plasma concentration of NfL and AD dementia patients, considering their demographics, clinical features, and cognitive profiles. A total of 350 participants from the Biomarker of AmyLoid pepTide and AlZheimer’s diseAse Risk (BALTAZAR) multicenter prospective study were investigated: 161 AD dementia participants and 189 MCI participants (of which 141 had amnestic MCI and 48 non-amnestic MCI). Plasma biomarkers were measured at baseline and the progression of clinical and cognitive profiles was followed over the three years of follow-up. Baseline plasma NfL concentration increased across the Alzheimer’s disease continuum with a mean NfL value of 17.1 ng/mL [SD = 6.1] in non-amnestic MCI, 20.7 ng/mL [SD = 12.0] in amnestic MCI, and 23.1 ng/mL [SD = 22.7] in AD dementia patients. Plasma NfL concentration correlated with age, body mass index (BMI), and global cognitive performance and decline, as measured by the Mini-Mental State Examination (MMSE). MMSE scores decreased in parallel with increasing plasma NfL concentration, independently of age and BMI. However, NfL concentration did not predict MCI participants’ conversion to dementia within three years. Discussion: Baseline plasma NfL concentration is associated with cognitive status along the AD continuum, suggesting its usefulness as a potential informative biomarker for cognitive decline follow-up in patients.

The knowledge of protein dynamics or turnover in patients provides invaluable information related to certain diseases, drug efficacy, or biological processes. A great corpus of experimental and computational methods has been developed, including by us, in the case of human patients followed in vivo . Moving one step further, we propose here a new modeling approach to capture the highly relevant notion of population protein dynamics. Using two data sets, we show that models inspired by population pharmacokinetics can accurately capture protein turnover within a cohort of individuals, even in presence of substantial inter-individual variability. Such models pave the way for comparative studies searching for altered dynamics or biomarkers in diseases.

Introduction During the last decade, physical activity (PA) (or “exercise”) has been identified as one of the main modifiable factors that influence the development of Alzheimer’s disease (AD) pathophysiology. We performed an umbrella review to summarize the evidence on the association between PA/exercise and the risk of developing AD risk, and the effect of exercise interventions on the progression of AD. Methods A systematic search was performed in PubMed, SportDiscus, Cochrane Library and Web of Science (March 2022) to identify meta-analyses assessing the association between PA and the incidence of AD, and assessing the effect of exercise interventions on patients with AD. Results Twenty-one studies were included. The results with strongest evidence revealed the positive effects of PA on AD risk. Specifically, meeting the WHO recommendations for PA was associated with a lower risk of AD. They also revealed positive effects of exercise on cognitive function, physical performance, and functional independence. Conclusions There is strong evidence of a protective effect of regular PA against AD risk; however, the dose–response association remains unclear. Physical exercise seems to improve several dimensions in patients with AD, although research is warranted to elucidate the exercise characteristics that promote the greatest benefits.

Background and Objectives To elaborate a new algorithm to establish a standardized method to define cutoffs for CSF biomarkers of Alzheimer disease (AD) by validating the algorithm against CSF classification derived from PET imaging. Methods Low and high levels of CSF phosphorylated tau were first identified to establish optimal cutoffs for CSF β-amyloid (Aβ) peptide biomarkers. These Aβ cutoffs were then used to determine cutoffs for CSF tau and phosphorylated tau markers. We compared this algorithm to a reference method, based on tau and amyloid PET imaging status (ADNI study), and then applied the algorithm to 10 large clinical cohorts of patients. Results A total of 6,922 patients with CSF biomarker data were included (mean [SD] age: 70.6 [8.5] years, 51.0% women). In the ADNI study population (n = 497), the agreement between classification based on our algorithm and the one based on amyloid/tau PET imaging was high, with Cohen9s kappa coefficient between 0.87 and 0.99. Applying the algorithm to 10 large cohorts of patients (n = 6,425), the proportion of persons with AD ranged from 25.9% to 43.5%. Discussion The proposed novel, pragmatic method to determine CSF biomarker cutoffs for AD does not require assessment of other biomarkers or assumptions concerning the clinical diagnosis of patients. Use of this standardized algorithm is likely to reduce heterogeneity in AD classification.

Primary Sjögren’s syndrome (pSS) can be associated with neurological and cognitive involvement, negatively affecting patients’ quality of life. The aim of this study was to assess whether pSS patients are at higher risk of hospitalization for neurological diseases. Through a nationwide retrospective study using the French Health insurance database (based on International Classification for Disease codes, ICD-10), we selected patients hospitalized with new-onset pSS between 2011 and 2018. We compared the incidence of hospitalization for dementia, multiple sclerosis (MS), encephalitis, and peripheral neuropathy with an age- and sex-matched (1:10) hospitalized control group. Adjusted Hazard Ratios (aHR) considered confounding factors, particularly socio-economic status and cardiovascular diseases. We analyzed 25,661 patients hospitalized for pSS, compared with 252,543 matched patients. The incidence of hospitalization for dementia was significantly higher in pSS patients (aHR = 1.27 (1.04–1.55); p = 0.018), as well as the incidence of hospitalization for MS, encephalitis, and inflammatory polyneuropathies (aHR = 3.66 (2.35–5.68), p < 0.001; aHR = 2.66 (1.22–5.80), p = 0.014; and aHR = 23.2 (12.2–44.5), p < 0.001, respectively). According to ICD-10 codes, pSS patients exhibited a higher incidence of hospitalization for dementia, encephalitis, MS, and peripheral neuropathies than controls. Physicians must be aware of these neurological risks to choose the most appropriate diagnostic work-up.

Background: Tau hyperphosphorylation at Threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer disease (AD). However, it remains unclear whether pT217 could be modified in other tauopathies. Using immunoprecipitation and mass spectrometry, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid beta (Aβ) 42/40 ratio in cognitively normal controls, and individuals with AD, Progressive Supranuclear Palsy (PSP), Corticobasal Syndrome (CBS), and sporadic and familial Frontotemporal Dementia (FTD).Method: CSF Aβ, tau and phosphorylated tau (p‐tau) were measured using immunoprecipitation and quantitative mass spectrometry methods. Amyloid and tau Positron Emission Topography (PET) imaging were measured in a subset of participants and analyzed for correlation. Quadrant analyses were performed to assess amyloid and p‐tau positivity.Result: We confirmed the strong association between CSF Aβ 42/40 and pT217 measures in most samples. Individuals with AD had high CSF pT217/T217 and low Aβ 42/40. In contrast, controls and the majority of patients with other tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio relative to controls. Most of these individuals were identified as MAPT R406W mutation carriers, a tau mutation leading to 3R+4R tauopathy similar to AD but without amyloid pathology. Diagnostic accuracies of CSF Aβ 42/40 alone, CSF pT217/T217 alone, and combination of both biomarkers were examined. We show that combination of both biomarkers can separate MAPT R406W carriers from control (AUC=0.960) and other tauopathies that are primarily 4R tauopathies (AUC=0.934).Conclusion: We demonstrate the importance of measuring both CSF Aβ 42/40 and pT217/T217 to improve AD diagnosis and differentiate MAPT R406W mutation carriers. This supports that changes in CSF pT217/T217 ratio is not a specific biomarker for AD but reflects common downstream tau pathology in these two 3R+4R tauopathies.