Alector (United States)

BackgroundFrontotemporal dementia (FTD) is a heterogenous disorder characterized by early age of onset and changes in behavior or language. It is estimated that approximately 20% of patients have an autosomal dominant presentation. Mutations in the GRN, MAPT, or C9orf72 genes account for the majority of genetic FTD.MethodThe FTD Insights Survey was developed and executed by the Association for Frontotemporal Degeneration (AFTD) and the FTD Disorders Registry. This dataset contains 1,800 responses (US, UK, Canada) and is available to researchers. Responses to “Have you been tested to see if you carry a specific gene for FTD” were analyzed. Data was assessed for 1) FTD patients who selected “I am diagnosed with FTD” and 2) relatives who selected “I have a close biological relative with FTD” and didn’t select “I am diagnosed with FTD”.ResultTwenty‐three percent (23.3%, n = 51) of 219 patients received genetic testing. Individuals diagnosed with FTD with ALS (n = 9) reported the highest rates of genetic testing (88.9%, n = 8). A greater percentage of patients who completed genetic testing reported having at least one biological relative diagnosed with FTD compared to those who did not receive genetic testing (44.2% vs.12% respectively).Twelve percent (12.4%, n = 61) of 492 biological relatives received genetic testing. Relatives of individuals diagnosed with FTD with ALS (n = 39) reported the highest rates of genetic testing (25.6%, n = 10). Of relatives who responded yes (n = 95) to the question, “Does your family carry a gene for FTD”, 49.5% (n = 47) received genetic testing.ConclusionLess than a quarter of FTD patients received genetic testing despite genetic forms comprising a notable percentage of all FTD cases. Highest rates were reported for individuals diagnosed with FTD with ALS, and rates were higher with known family history. Low rates of genetic testing may exacerbate challenges facing families impacted by FTD such as assessing familial risk of developing FTD and determining eligibility for investigational drugs in development for genetic forms of FTD. Additional research is needed to better understand the accessibility of genetic testing and counseling. Taken together, these findings highlight the need to further raise awareness of genetic FTD with healthcare providers, patients, and biological relatives.

The objective is to describe the baseline characteristics of participants enrolled in INFRONT-3 (NCT04374136).

Changes to speech and language are common symptoms across different subtypes of frontotemporal dementia (FTD). These changes affect the ability to communicate, impacting everyday functions. Accurately assessing these changes may help clinicians to track disease progression and detect response to treatment. To determine which aspects of speech show significant change over time and to develop a novel composite score for tracking speech and language decline in individuals with FTD. We recruited individuals with FTD to complete remote digital speech assessments based on a picture description task. Speech samples were analyzed to derive acoustic and linguistic measures of speech and language, which were tested for longitudinal change over the course of the study and were used to compute a novel composite score. Thirty-six (16 F, 20 M; M age = 61.3 years) individuals were enrolled in the study, with 27 completing a follow-up assessment 12 months later. We identified eight variables reflecting different aspects of language that showed longitudinal decline in the FTD clinical syndrome subtypes and developed a novel composite score based on these variables. The resulting composite score demonstrated a significant effect of change over time, high test-retest reliability, and a correlation with standard scores on various other speech tasks. Remote digital speech assessments have the potential to characterize speech and language abilities in individuals with FTD, reducing the burden of clinical assessments while providing a novel measure of speech and language abilities that is sensitive to disease and relevant to everyday function.

BackgroundHeterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN.MethodsIn vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans.ResultsIn a mouse model of FTD-GRN, the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers.ConclusionsThese findings support the development of latozinemab for the treatment of FTD-GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial.Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204.

The Phase 1 study assessed safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AL003 in healthy volunteers (HV) and patients with mild to moderate AD.

Abstract BackgroundAlzheimer disease (AD) is a complex and heterogeneous disease. Most AD cases present sporadically, while 1‐2% of the cases have autosomal dominant AD (ADAD), carrying mutations in APP, PSEN1, and PSEN2. Among sporadic cases, several rare variants in TREM2, which is involved in immune response, are shown to increase AD risk. Most proteomic studies, while instrumental in identifying novel AD genes and pathways, focus on single tissues and mainly sporadic AD cases. Proteomic signatures for each genetically defined AD case will advance the understanding of the underlying biology of this heterogeneous disease and help us create prediction models for AD risk, onset, and progression.MethodWe generated deep proteomic profiles of brain (n=370), cerebrospinal fluid (CSF; n=699), and plasma (n=486) for sporadic AD, ADAD, and TREM2 risk‐variant carriers, from the Knight‐ADRC and DIAN cohorts. After stringent QC, 1079 proteins in brain, 713 in CSF, and 931 in plasma remained.ResultWe identified 150 proteins with differential levels between sporadic cases and controls, 371 for ADAD, and 134 for TREM2 carriers in at least one tissue (with Bonferroni‐corrected statistical significance). Of these, 36, 74 and 31 were replicated across tissue types for sporadic AD, ADAD, and TREM2 carriers, respectively. Using proteins that replicated across tissues, we created a prediction model for CSF and plasma with an AUC (AUC=0.79‐1.0) similar to (or better than) that of the well‐accepted CSF pTau/Aβ42 ratio. A model using 23 TREM2‐specific plasma proteins was able to discriminate between TREM2 carriers and controls (AUC=0.94) or sporadic AD cases (AUC=0.91) with high sensitivity and selectivity. Our pathway enrichment analysis validated pathways previously implicated in AD (such as APP, APOE, GSK3B, NOTCH3, PPP3R1 and PPP3CA) and identified novel pathways such as a Parkinson’s disease pathway (LRRK2 and α‐synuclein) and innate immune response pathways (MEK1, SHC1, and PDGF‐BB), including cytokine‐mediated signaling and a DAP12‐mediated pathway.ConclusionWith the first multi‐tissue proteomic study of genetically defined AD cases, we have uncovered multiple novel AD biomarker candidates. These findings not only help to elucidate specific pathways implicated in AD but ultimately support the clinical utility of predictive models based on proteomic signatures.