BACKGROUND:Most antidepressants do not independently treat impaired cognition associated with major depressive disorder (MDD). Elevated brain cortisol levels are associated with both MDD and cognitive impairment. Emestedastat is a brain-penetrant, intracellular cortisol synthesis inhibitor. AIMS:The XanaCIDD trial aimed to determine whether emestedastat 10 mg could improve both cognitive impairment and depression in a population with persistent MDD and cognitive impairment. METHOD:Participants had a diagnosis of MDD, with persistent depression (Hamilton Rating Scale for Depression-17 ≥17) and cognitive impairment (coding test ≤0.5 s.d. of normal). Randomised treatment (1:1) was continued for 6 weeks (week 6), with 4 weeks' blinded follow-up (week 10). The primary end-point was cognition (composite of attention/working memory) at week 6. Depression end-points included Montgomery-Åsberg Depression Rating Scale (MADRS) and Patient Global Impression of Severity (PGI-S). Analyses used a mixed model for repeated measures (cognitive impairment and MADRS one-sided tests, others two-sided) and Cohen's d effect size. No adjustments were made for multiple comparisons. RESULTS:A total of 165 participants were enrolled and treated: 134 (81%) were on background antidepressants, 62% were female, mean prior number of MDD episodes was 10 and mean coding z-score was -1.47. There was no benefit on the primary cognitive end-point at week 6 (p = 0.17 favouring placebo), with the cognitive composite improving markedly in both groups without correlation to depressive symptoms or baseline characteristics (R2 ≤ 0.02). The trend towards benefit on the prespecified secondary depression end-point, MADRS, began at week 6 and was maximal at week 10 (2.7 points, Cohen's d 0.43, p = 0.05). A trend towards potential emestedastat benefit in PGI-S scores was also maximal at week 10 (p = 0.12). Mild-moderate transaminase elevations were seen in 10% of emestedastat participants (≤2 times normal in 7 of 8 cases, 1 discontinuation) versus 1% of the placebo group. CONCLUSIONS:There was no benefit of emestedastat on the primary end-point of cognitive impairment and a large placebo effect, without correlation of cognitive impairment to depression changes or baseline characteristics. Trends towards potential antidepressant activity suggest that emestedastat may be a novel antidepressant worthy of further investigation.

Alzheimer’s disease is a devastating neurodegenerative disorder with a complex pathogenesis. One main pathological feature utilised in diagnosis is neurodegeneration or neuronal injury, which is reflected in reductions in cerebral glucose metabolism measured by [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET). Here we evaluated the involvement of glial reactivity measured with magnetic resonance spectroscopy (MRS) and cerebral blood flow measured with arterial spin labelling (ASL) on [18F]FDG PET as a measure of cerebral glucose metabolism. 123 people living with early Alzheimer’s disease who completed baseline evaluations on the evaluating liraglutide in Alzheimer’s disease trial were enrolled. Participants completed [18F]FDG PET scans with arterial input, T1 weighted MRI, single-voxel 1 HMRS, and pulsed ASL scans at Imperial College London Clinical Imaging Facility. The Totally Automatic Robust Quantitation in NMR (TARQUIN) package was used to process MRS scans and identify the concentration of myo-inositol within the posterior cingulate cortex (PCC), a marker of glial activation. Oxford-ASL was utilised to process ASL and quantify cerebral blood flow in the PCC. Finally, spectral analysis was performed on the [18F]FDG PET scans to assess the cerebral metabolic rate of glucose in the PCC. Pearson’s correlations were performed between the cerebral metabolic rate of glucose, cerebral blood flow and glial activity measured by the level of myo-inositol in the PCC. Increased cerebral glucose metabolism was correlated with higher myo-inositol in this sample of Alzheimer’s disease participants. In contrast, cerebral blood flow was not associated with cerebral glucose metabolism. Here we demonstrate that increased glial reactivity contributes to [18F]FDG PET signal in the early stages of Alzheimer’s disease. In response to early neuronal injury, astrocytes and microglia may become activated and enhance regional rates of glucose consumption. Hence, the contribution from these cells in addition to neurons should be considered in interpreting [18F]FDG PET as a measure of cerebral glucose metabolism. Interestingly, cerebral blood flow did not influence glucose metabolism. Microglia and astrocyte reactivity may contribute to an increase the cerebral glucose metabolism while neuronal loss and synaptic function may contribute to lower glucose metabolism measured by [18F]FDG in the early stages of Alzheimer's disease.

Recent therapeutic successes in the treatment of Alzheimer’s disease (AD), and diagnostic tools such as blood-based biomarkers, have energised the field to develop more specific diagnostics and therapies following the best principles of precision medicine. Large, ‘real-world’ cohorts are needed to understand whether these, and other future breakthroughs, are valid when employed in the wider AD community. Our cohort study will provide a well-phenotyped (combining data on risk factors for neurodegenerative disease, cognitive assessment results, disease biomarkers and genetics) population aged 50 and above across the spectrum of risk for, and the earliest disease stages of, neurodegeneration (beginning in Scotland). Participants complete an innovative cognitive testing battery (combining elements of the ACE-R (including MMSE), TICS, RBANS and digital cognitive tests), assessments of global functioning, questionnaires about risk factors for neurodegenerative disease, physical health assessments and collection of blood samples for clinical blood tests and storage for future research. A sub-set of participants are invited to join the Enhanced Phenotyping cohort and additionally undergo brain MRIs and lumbar punctures. Cerebrospinal fluid will be analysed for amyloid beta-42, phosphorylated tau-181 and total tau, with additional aliquots stored for future research use. Participants will be followed up every 6 months to complete questionnaires, with more comprehensive visits annually. A minimum of 3000 participants will be recruited to the Enhanced Phenotype cohort with an estimated 7,000 in the cohort overall. A total of 11 participants have been recruited to the cohort to date (mean age: 69 years; 6 (55%) female). Mean ACE-R and MMSE scores are 92 and 28 respectively. Data collection is ongoing with recruitment anticipated to continue throughout 2024 and 2025, with a minimum of 100 participants recruited by July 2024. Baseline data, including AD biomarker status where available, will be presented at AAIC 2024. This an ambitious project aiming to recruit a deeply phenotyped, real-world representative cohort of participants across the spectrum of risk for, and in the earliest stages of, neurodegenerative conditions. The data and samples collected as part of this cohort will be invaluable to better understanding disease trajectories, and developing and testing new diagnostics and therapeutics.

Many tests have been used to study memory in Alzheimer’s disease (AD) and related dementias. At the turn of the century, these assessments included the CANTAB system, MMSE, Cognitive Drug Research (CDR), RBANS, and Cogstate, along with a large set of established paper and pencil tests. Several additional assessments have been developed and used in observational studies and clinical trials since 2000, including the mini-cog (2000) and MOCA (2005) as well as the NIH toolbox (2004). However, since the registration of the first AD drugs, the preferred cognitive assessment has been the ADAS-cog. This is despite several substantial criticisms levelled at this test and despite expanding options in cognitive assessments. The ADAS-cog has issues with ceiling effects, lack of parallel forms of the praxis and language tests and generally poor content validity, and the attempt to add items to the ADAS-cog to solve these issues has not been successful. The persistent use of the ADAS-cog seems unaffected, despite the fact that better tests of some missing domains, such as verbal fluency, coding, attention and working memory have all demonstrated assay sensitivity in early AD. The lack of assay sensitivity of the ADAS-cog in mild AD (MMSE 21 to 26) in the phase 2 AN1792 study, presented side-by-side with the newly proposed NTB showing comparable mild and moderate sensitivity, inspired development of several optimized cognitive composites for early AD stages from 2010-2020. These included the PACC to separate amyloid positive and negative individuals, and the APCC, API-LOAD and PACC-5 for measuring progression in the pre-MCI stage. Also in the late 2010s, additional composite outcomes were proposed that included both cognition and global or functional scale items, and were intended primarily for the early AD stage of disease (ADCOMS, iADRS). While the ADAS-Cog has aided in the search for effective AD treatments, a reflection on the past 25 years of the development of cognitive assessments reveals that much effort has been spent to overcome its deficiencies and the AD world would experience more rapid advancement if we make better use of the tools we have and continue to address deficiencies.

INTRODUCTION:Pharmacological restoration of septin filament integrity has the potential to provide symptomatic benefit and disease modification in Alzheimer's disease (AD). METHODS:REM127, a septin modulator, was assessed in mild-to-moderate AD (EudraCT: 2022-000080-43) in a phase 2a trial (n = 14). PRIMARY ENDPOINTS:safety and tolerability; exploratory endpoints: pharmacokinetics, cerebrospinal fluid (CSF) biomarkers, electroencephalography (EEG), and functional outcomes. RESULTS:In participants on active therapy, dose-dependent increases in serum aminotransferase were observed, leading to study discontinuation. CSF hyperphosphorylated tau (P-tau181), endpoints reflecting synaptic function and cognitive outcomes, were changed significantly (p < 0.05) to normal compared to placebo. DISCUSSION:REM127 triggers off-target liver adverse effects. Anticipated on-target outcomes suggest septin modulation has symptomatic benefit and modifies processes underlying AD. Results are considered exploratory as statistical power is constrained due to the small sample size caused by early termination. Further investigation of the therapeutic concept using an optimized septin molecular glue with an improved safety profile is warranted. HIGHLIGHTS:Septin 6/7 molecular glue REM127 was assessed in symptomatic participants with Alzheimer's disease (AD). REM127 triggers off-target effects suggesting liver adverse effects. REM127 brain exposure was consistent with saturated target engagement. Biomarker and cognitive outcomes were changed consistent with therapeutic benefit. Septin modulation may restore synaptic function and mitigate pathology in AD.

Neurological conditions, including dementia, pose a major public health challenge, contributing to a significant and growing clinical, economic, and societal burden. Traditionally, research and clinical practice have focused on diseases like dementia in isolation. However, in an ageing, multimorbid population, this approach is becoming increasingly inadequate. Recognising brain health as a lifelong attribute influenced by various health determinants, this paper explores the concept of brain health, identifies key challenges in assessing it effectively, and examines how digital biomarkers could provide a versatile measurement framework to enhance monitoring and facilitate earlier intervention. Finally, we outline future directions to help advance definitions of meaningful aspects of brain health integration, and practical adoption of digital biomarkers, enhancing our capacity to measure and preserve ‘brain health capital’ or ‘brain span’ across the lifecourse.

Xanamem TM (Emestedastat) is an oral, selective 11β-HSD1 inhibitor designed to reduce cortisol production in the brain under development for the treatment of AD. Clinical trials have demonstrated adequate target engagement by PET, improvements in cognitive performance in healthy older adults, and attenuation of decline in pTau181-elevated clinically diagnosed AD patients at doses of 10mg daily. The recent positive results from the XanaCIDD trial in Major Depressive Disorder (MDD) validate the target as well as the 10mg daily dose of Xanamem. XanaCIDD was a Phase 2, proof-of-concept trial of 10 mg Xanamem daily in MDD patients with a current depressive episode (HamD >17) and a cognitive deficit (DSST at least 0.5 SD below age and educational norms). Participants were randomized in a double-blind design 1:1 to Xanamem 10mg or placebo for 6 weeks (Week 6), with 4 weeks follow-up (Week 10). The primary endpoint was a customized Cogstate test battery (CTB) comprising three tests of attention and working memory at Week 6. Secondary endpoints included assessment of depression with the MADRS and Participant Global Impression of Severity scores (PGI-S). Clinical effect sizes were described by the Cohen’s d statistic (Cd) with ≥0.2 considered to be clinically meaningful. Both active and placebo groups improved substantially on the Cogstate CTB slightly favoring placebo (p=0.17). In the mITT population (n=165), a clinically and statistically significant benefit on MADRS was seen at Week 10 (2.7 points, Cd=0.43, p<0.05). In 76 patients taking SSRI medication, Xanamem benefit on MADRS was greater at the same timepoint (4.5 points, Cd=0.63, p=0.03). Xanamem showed a trend towards higher response rates at Week 10 (50% MADRS reduction, 34% Xanamem vs. 22% placebo, p=0.08). Trends towards improvement in PGI-S scores favored the Xanamem group from Week 2 and were clinically significant at Weeks 4, 6 and 10 (p<0.2). There was a low incidence of treatment-related adverse events which were generally mild or moderate and similar between treatment groups. These data suggest validation of the hypothesis that controlling CNS tissue cortisol production may be beneficial for the treatment of AD as well as MDD.

Automated analysis of connected speech is emerging as a promising digital biomarker of Alzheimer's disease (AD). Considering the reliance of connected speech on multiple interacting cognitive functions, fine-grained analysis may have the potential to capture subtle cognitive deficits in the very early stages of AD. In this study, we identified reliable acoustic and linguistic speech features, and examined the association between amyloid-beta (Aβ) pathology and longitudinal connected speech in cognitively normal elderly. We included 50 cognitively normal (age 68.4±6.8 years, n  = 29 female, n  = 23 Aβ-positive) adults from three clinical cohorts at Alzheimer Center Amsterdam (Table 1). Aβ-status was based on local cut-offs for ptau/Aβ42 ratio in cerebrospinal-fluid or visual inspection of amyloid positron emission tomography imaging. The testing paradigm consisted of a five-day remote burst assessment, comprising seventeen tablet-based speech tasks (picture description, journal-prompt storytelling, verbal-fluency, 10 min/day administration time), which was repeated at 2 weeks and 12, 18, and 24 months. Various acoustic-and linguistic features (e.g. pauses, noun/pronoun use), were extracted from the voice recordings. Mean scores were calculated over the five-day burst. The association between Aβ-pathology and speech features was investigated using linear mixed models separately for each task. Based on the repeated assessment at 2 weeks, 10 acoustic and 8 linguistic speech features were identified as having good test-retest reliability (ICC > 0.75). At baseline, differences between Aβ-positive and Aβ-negative individuals in these features were generally non-significant. However, we found trends towards a higher pause-to-word ratio (picture description: beta=0.05, p  = 0.040; journaling: beta=0.07, p  = 0.032) and higher pronoun-to-noun ratio (picture description: beta=0.03, p  = 0.033) in Aβ-positive individuals. Furthermore, we observed differences in longitudinal trajectories on various pause measures between groups, indicating stable speech metrics in Aβ-negative individuals versus more pauses in Aβ-positive individuals. Our results provide indications that Aβ-pathology is associated with altered metrics of connected speech in cognitively healthy adults, both at a single time point and longitudinally, albeit with small effects. This supports the notion that remote multi-day connected speech assessments have the potential to serve as a digital biomarker for subtle cognitive changes in preclinical AD, for example in observational studies and decentralized trials.

BackgroundAssessment of cognitive decline in the earliest stages of Alzheimer disease (AD) is important but challenging. AD is a neurodegenerative disease characterized by gradual cognitive decline. Disease stages range from preclinical AD, in which individuals are cognitively unimpaired, to mild cognitive impairment (MCI) and dementia. Digital technologies promise to enable detection of early, subtle cognitive changes. Although the field of digital cognitive biomarkers is rapidly evolving, a comprehensive overview of the reporting of psychometric properties (ie, validity, reliability, responsiveness, and clinical meaningfulness) is missing. Insight into the extent to which these properties are evaluated is needed to identify the validation steps toward implementation. ObjectiveThis scoping review aimed to identify the reporting on quality characteristics of smartphone- and tablet-based cognitive tools with potential for remote administration in individuals with preclinical AD or MCI. We focused on both psychometric properties and practical tool characteristics. MethodsThis scoping review was conducted following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. In total, 4 databases (PubMed, Embase, Web of Science, and PsycINFO) were systematically searched from January 1, 2008, to January 5, 2023. Studies were included that assessed the psychometric properties of cognitive smartphone- or tablet-based tools with potential for remote administration in individuals with preclinical AD or MCI. In total, 2 reviewers independently screened titles and abstracts in ASReview, a screening tool that combines manual and automatic screening using an active learning algorithm. Thereafter, we manually screened full texts in the web application Rayyan. For each included study, 2 reviewers independently explored the reported information on practical and psychometric properties. For each psychometric property, examples were provided narratively. ResultsIn total, 11,300 deduplicated studies were identified in the search. After screening, 50 studies describing 37 different digital tools were included in this review. Average administration time was 13.8 (SD 10.1; range 1-32) minutes, but for 38% (14/37) of the tools, this was not described. Most tools (31/37, 84%) were examined in 1 language. The investigated populations were mainly individuals with MCI (34/37, 92%), and fewer tools were examined in individuals with preclinical AD (8/37, 22%). For almost all tools (36/37, 97%), construct validity was assessed through evaluation of clinical or biological associations or relevant group differences. For a small number of tools, information on structural validity (3/37, 8%), test-retest reliability (12/37, 32%), responsiveness (6/37, 16%), or clinical meaningfulness (0%) was reported. ConclusionsNumerous smartphone- and tablet-based tools to assess cognition in early AD are being developed, whereas studies concerning their psychometric properties are limited. Often, initial validation steps have been taken, yet further validation and careful selection of psychometrically valid outcome scores are required to demonstrate clinical usefulness with regard to the context of use, which is essential for implementation.

Selecting the optimal dose for clinical development is especially problematic for drugs directed at CNS-specific targets. For drugs with a novel mechanism of action, these problems are often greater. We describe Xanamem’s clinical pharmacology, including the approach to dose selection and proof-of-concept studies. Xanamem is an isoform 1 specific inhibitor of 11-βHSD which acts to reduce the tissue production of cortisol. Xanamem is under clinical development as a pro-cognitive and disease modifying drug for Alzheimer’s disease as well as other neurological and psychiatric diseases involving CNS dysregulation of cortisol. Elevation of CNS cortisol has been associated with impaired cognition, neuroinflammation, and neuronal death. Clinical pharmacology analyses included pharmacokinetic and pharmacodynamic data from SAD and MAD dose trials in healthy volunteers; population pharmacokinetics; cognition from patients in a phase 2a trial in Alzheimer’s disease; multiple dose PET target occupancy study to determine target inhibition in the brain in healthy elderly participants and Alzheimer’s patients; two phase 1b trials in healthy older participants that assessed safety; and pharmacodynamic endocrinology and quantitative cognitive parameters. Xanamem demonstrated high CNS target occupancy at all doses studied by PET (5-30 mg/day). At doses of 5 to 70 mg/day ACTH levels approximately doubled at steady-state. After first doses, plasma cortisol was slightly reduced but was not decreased at steady-state in doses of ≤ 10mg/day but was within normal levels. In three trials Xanamem demonstrated pro-cognitive effects, primarily on attention and working memory (5-20 mg/day). Xanamem also demonstrated potentially disease modifying treatment effects in mild AD in patients with biomarker positive AD (elevation of plasma pTau181) as shown by decrease in the rate of CDR-SB worsening over 12 weeks (10 mg/day) versus placebo. This series of trials demonstrates that the optimal dose of Xanamem can be selected based on CNS PET occupancy data coupled with pharmacodynamic endocrinology and quantitative cognition testing. Pro-cognitive and potentially disease modifying effects were observed at doses consistent with high CNS target occupancy. Xanamem is now in larger Phase 2 clinical outcome trials in MDD and mild/mod AD.

Abstract Background Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer’s disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aβ) pathology of speech acoustics measured over multiple assessments in a remote setting. Methods Fifty cognitively unimpaired adults (Age 68 ± 6.2 years, 58% female, 46% Aβ-positive) completed remote, tablet-based speech assessments (i.e., picture description, journal-prompt storytelling, verbal fluency tasks) for five days. The testing paradigm was repeated after 2–3 weeks. Acoustic speech features were automatically extracted from the voice recordings, and mean scores were calculated over the 5-day period. We assessed feasibility by adherence rates and usability ratings on the System Usability Scale (SUS) questionnaire. Test-retest reliability was examined with intraclass correlation coefficients (ICCs). We investigated the associations between acoustic features and Aβ-pathology, using linear regression models, adjusted for age, sex and education. Results The speech assessment was feasible, indicated by 91.6% adherence and usability scores of 86.0 ± 9.9. High reliability (ICC ≥ 0.75) was found across averaged speech samples. Aβ-positive individuals displayed a higher pause-to-word ratio in picture description (B = -0.05, p = 0.040) and journal-prompt storytelling (B = -0.07, p = 0.032) than Aβ-negative individuals, although this effect lost significance after correction for multiple testing. Conclusion Our findings support the feasibility and reliability of multi-day remote assessment of speech acoustics in cognitively unimpaired individuals with and without Aβ-pathology, which lays the foundation for the use of speech biomarkers in the context of early AD.

OBJECTIVE We aimed to investigate whether item response theory (IRT)-based scoring allows for a more accurate, responsive, and less biased assessment of everyday functioning than traditional classical test theory (CTT)-based scoring, as measured with the Amsterdam Instrumental Activities of Daily Living Questionnaire. METHOD In this longitudinal multicenter study including cognitively normal and impaired individuals, we examined IRT-based and CTT-based score distributions and differences between diagnostic groups using linear regressions, and investigated scale attenuation. We compared change over time between scoring methods using linear mixed models with random intercepts and slopes for time. RESULTS Two thousand two hundred ninety-four participants were included (66.6 ± 7.7 years, 54% female): n = 2,032 (89%) with normal cognition, n = 93 (4%) with subjective cognitive decline, n = 79 (3%) with mild cognitive impairment, and n = 91 (4%) with dementia. At baseline, IRT-based and CTT-based scores were highly correlated (r = -0.92). IRT-based scores showed less scale attenuation than CTT-based scores. In a subsample of n = 1,145 (62%) who were followed for a mean of 1.3 (SD = 0.6) years, IRT-based scores declined significantly among cognitively normal individuals (unstandardized coefficient [B] = -0.15, 95% confidence interval, 95% CI [-0.28, -0.03], effect size = -0.02), whereas CTT-based scores did not (B = 0.20, 95% CI [-0.02, 0.41], effect size = 0.02). In the other diagnostic groups, effect sizes of change over time were similar. CONCLUSIONS IRT-based scores were less affected by scale attenuation than CTT-based scores. With regard to responsiveness, IRT-based scores showed more signal than CTT-based scores in early disease stages, highlighting the IRT-based scores' superior suitability for use in preclinical populations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

BACKGROUND AND OBJECTIVES:It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups. METHODS:Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (βtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years. RESULTS:We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (βtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction. DISCUSSION:In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.

Magnetic resonance spectroscopy (MRS) is a non-invasive method of evaluating metabolite levels in the cerebral cortex. Measurable metabolites can provide markers of neuronal damage, glial activation and, neurotransmission, pathological features of Alzheimer’s disease. Here we sought to establish the effectiveness of several metabolites as biomarkers for Alzheimer’s disease. 198 participants with a single-voxel 1 H MRS scan were enrolled (n = 170 participants living with Alzheimer’s disease, n = 28 healthy controls). All participants underwent 3-tesla magnetic resonance imaging and cognitive assessment with the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-cog). An experienced radiographer placed an 8cm 3 voxel within the posterior cingulate cortex for single-voxel 1 H MRS acquisition. Scans were then processed to evaluate levels of N-acetylaspartate, myo-inositol, choline, and glutamate. Creatine peak was additionally evaluated as a reference. N-acetylaspartate/creatine, myo-inositol /creatine, choline/creatine ratios and glutamate were compared between Alzheimer’s participants and controls to calculate the effect size. Correlations were then performed between metabolite ratios and ADAS-cog scores. N-acetylaspartate/creatine effectively distinguished between Alzheimer’s patients and healthy controls (Cohens D = 0.83) with a lowered ratio in Alzheimer’s participants. Elevated glutamate signal and myo-inositol/creatine ratios were also displayed in Alzheimer’s patients (Cohens D = 0.62 and 0.69, respectively). Choline/creatine ratio displayed no significant difference between groups (Cohens D = 0.26). Lower N-acetylaspartate /creatine and glutamate correlated with higher ADAS-cog scores (r = -0.29, p < 0.001, CIs: -0.42 to -0.14 and r = -0.30, p < 0.001, CIs: -0.44 to -0.16, respectively). Myo-inositol and choline failed to correlate with cognitive impairment. N-acetylaspartate, a signature of neuronal damage, is an effective biomarker of Alzheimer’s disease and associated cognitive decline. Enhanced glial activity, measured with myo-inositol, was shown in Alzheimer’s disease, suggesting that glial-reactivity markers deserve consideration in the diagnosis of Alzheimer’s disease. Glutamate demonstrated the strongest association with cognitive impairment, despite showing a smaller effect size than N-acetylaspartate and myo-inositol in distinguishing between Alzheimer’s patients and controls. Together we establish MRS is a useful, non-invasive biomarker of several pathological processes involved in the development of Alzheimer’s. Evaluation of N-acetylaspartate, glutamate, and myo-inositol may aid in the diagnosis of neurodegenerative disease, detecting markers undetectable by conventional MRI methodology.

Xanamem ® is a brain-penetrant inhibitor of 11-beta hydroxysteroid dehydrogenase type 1, which converts intracellular cortisone to cortisol and is highly expressed in brain regions such as the hippocampus. Elevated plasma and CSF cortisol is strongly associated with cognitive decline. Effects of Xanamem on cognition were assessed in 3 independent, placebo-controlled, double-blind trials. The XanaHES (n = 42, 20 mg) and XanaMIA (n = 105, 5 & 10 mg) Phase 1b trials used the computerised Cogstate system to assess cognition in normal, older volunteers. The XanADu-X biomarker extension study (n = 72, 10 mg) explored clinical and cognitive outcomes in subgroups (n = 34 each) of the XanADu Phase 2a AD trial with higher (H) or lower (L) plasma p-Tau181 in a new prospective analysis. To compare the results across trials, we focus on the cognitive effect sizes measured by the Cohen’s statistic (treatment effect vs. placebo / pooled baseline standard deviation). Xanamem was safe and well-tolerated with no treatment-related SAEs and the predominantly mild AEs were generally equally distributed between Xanamem and placebo. In XanaHES and XanaMIA, a pattern of clinically significant improvements was observed in attention and working memory compared to placebo in the Xanamem groups, with Cohen’s d ranging up to 1.27. Improvements from baseline were observed in both Xanamem and placebo in domains of episodic memory and executive function without a treatment difference. In XanADu, Xanamem demonstrated clinically significant benefit with a Cohen’s d of 0.41 on the CDR-SB compared to placebo in the H group but not in the L group. In both L and H groups improvements in executive function were seen favouring Xanamem (Cohen’s d = 0.34 and 0.26, respectively) and the MMSE (Cohen’s d = 0.32 and 0.16, respectively). There were no improvements observed on original XanADu primary outcome measures of ADAS-Cog14 and ADCOMs. Xanamem displays activity in multiple domains of cognition including attention, working memory, and executive function with clinically meaningful effects in normal subjects and in patients with p-Tau-elevated mild AD. These data suggest Xanamem may be both a pro-cognitive drug and disease-modifying agent and guide design of future trials.

Speech is a complex process, relying on multiple interacting cognitive functions. Fine-grained speech analysis offers the potential for measuring subtle cognitive deficits in early-stage Alzheimer’s disease (AD). As such, digital recordings of natural speech are a promising digital biomarker, particularly when measured in bursts (repeated short measurements). This pilot study focused on the usability of remote speech bursts to assess natural speech in cognitively normal (CN) adults with and without AD pathologic change. Additionally, the association between amyloid-beta (Aβ)-pathology and speech characteristics was examined. We included 49 CN older adults from AMYPAD-PNHS(location VUmc), SCIENCe, and Amsterdam Dementia Cohort (Age mean(M) = 68±standard deviation(SD) = 6, n = 28(57%) female, n = 23(47%) Aβ-positive, Table 1). Aβ-status was based on local cut-offs for Aβ 1-42 -concentrations in cerebrospinal-fluid or visual inspection of amyloid positron emission tomography (PET)-imaging. The remote burst assessment comprised seventeen tablet-based a)picture description, b)journal-prompt storytelling and c)verbal-fluency subtasks, administered over five consecutive days in an unsupervised home-setting. Daily administration time was approximately 10 minutes. To assess usability, participants completed the system usability scale (SUS). Various acoustic features, including silent pauses, pause-to-word-ratio and mean intensity (i.e., perceived loudness), were extracted from the voice recordings, and mean burst scores were calculated over the five-day period. The association between Aβ-status and acoustic features was investigated using two-sample t-tests stratified by subtask. The 49 participants rated usability with a mean SUS-score of 86(SD = 10). For example, 46(94%) participants thought the assessment-app was easy to use (Figure 1). Ratings were lower in Aβ-positive ( M = 83±10) than Aβ-negative individuals ( M = 88±9, p = 0.02), reflecting good and excellent usability respectively. Regarding the association between Aβ-status and acoustic features, more silent pauses were observed for Aβ-positive ( M = 0.30±0.09) compared to Aβ-negative individuals ( M = 0.25±0.06, p = 0.025, Figure 2) in the storytelling subtask. No group differences for pause-to-word-ratio or mean intensity were observed ( p >0.05). Remote burst assessment of speech is feasible in CN Aβ-positive and Aβ-negative adults. Additionally, preliminary results demonstrated that Aβ-pathology was related to more silent pauses, indicating its potential as a digital AD biomarker. These findings support remote burst speech assessments in monitoring cognitive changes, for example in observational studies and decentralized clinical trials of preclinical AD.

There is growing interest in the development of speech markers as novel, non-invasive biomarkers of early Alzheimer’s disease (AD). Before including such speech assessments in clinical trials, the technology must be tested to confirm feasibility of administration and acceptability with the target population to ensure future engagement. This study aimed to assess feasibility and acceptability in an at-risk population receiving automated administration of cognitive tasks over the telephone during the Speech on the Phone Assessment (SPeAk) study [35]. A second goal of the study was to assess participant acceptability of receiving cognitive test results - an important consideration for psychological safety. Participants (n = 68, mean age 70.43 years, 52.9% male) completed a baseline – administered by a trained researcher - and three month follow up visit – administered by an automated phonebot. Tasks included a spontaneous speech assessment and cognitive battery (immediate and delayed recall, digit span and verbal fluency). Participants were randomized to receive their cognitive test results after the final or after each study visit. Participants completed acceptability questionnaires electronically after each study visit. Retention was high (98.5%), with few technical issues (n = 6.7%), there was good inter rater reliability, and test scores were similar when administered by phonebot compared to human administrator in most subtests. A significant lower mean score in digit span was noted at follow up. These findings indicate general feasibility of the assessment. Participants preferred a human tester but rated the automated assessments as acceptable and would be happy to complete a phonebot assessment again, confirming the ease of use of the technology and comfort of completing cognitive tasks on the phone. Participants generally reported feeling happy to receive their cognitive tests results, and this disclosure did not cause participants to feel worried. The results from this usability and acceptability analysis suggests that completing this brief battery of cognitive tests via a telephone call is both acceptable and feasible in a midlife-to-older adult population in the UK, living at risk for AD.

Varoglutamstat (PQ912) is an oral, small molecule inhibitor of glutaminyl cyclase, preventing the formation of neurotoxic N3pE amyloid. A Phase 2a study (NCT02389413, Scheltens et al., 2018) reported encouraging first evidence of varoglutamstat’s disease-modifying activity, most importantly with statistically significant changes from baseline in working memory after only 12 weeks of treatment. VIVIAD (NCT04498650, Vijverberg et al., 2021) is an informed multicenter, randomized, placebo-controlled, double-blind, parallel group dose-finding Phase 2b study in 250 patients with Mild Cognitive Impairment (MCI) and early Alzheimer´s disease (AD). Treatment duration varies between 48 and 96 weeks depending on the time of inclusion, with participants receiving 300mg or 600mg varoglutamstat, or placebo, twice-daily (BID). The participants’ disease status at time of inclusion was confirmed by Abeta 1-42 and phospho-tau CSF biomarker profiles, various cognition tests including MMSE, DSST/WAIS-IV Coding test (WAIS-IV), and A-IADL-Q. Primary outcome is a composite score of the cognitive domains attention and working memory using the Cogstate Neuropsychological Test Battery (Cogstate NTB). Enrollment has been completed, with a total of N = 259 patients randomized. The 300mg BID varoglutamstat arm was switched to 600mg BID based on positive independent Data Safety Monitoring Board review in June 2022. As of April 14, 2023, 23 patients had completed 96 weeks of treatment. The study will continue until the last patient has completed 48 weeks of treatment with the corresponding follow-up visit. While most AD trials focus on cognitive tests assessing memory deficits rather than working memory and attention, VIVIAD uses WAIS-IV to select patients with rescuable cognitive deficits in the target domains. In contrast to MMSE, WAIS-IV performance shows a reasonably good correlation with the primary outcome measures. Comparing baseline data of male and female participants showed no significant gender differences except for Abeta 1-42 levels. The use of MMSE and DSST/WAIS-IV together with CSF biomarkers is a valuable tool in identifying and recruiting patients with MCI or mild AD. The strategy of recruiting individuals with evidence of baseline deficits on the WAIS-IV Coding test has successfully enriched the study cohort with respect to deficits in attention and working memory, enabling reliable assessment of potential cognitive improvement after treatment.

Preclinical evidence in transgenic models of Alzheimer’s disease (AD) suggests that liraglutide, a GLP1 analogue, exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and reducing insulin resistance, and increasing the proliferation of neuronal progenitor cells. ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild to moderate AD conducted at 24 centres in the UK. As a part of this study, a total of 204 Alzheimer’s participants were randomised to receive either liraglutide or placebo as a daily subcutaneous injection for 12 months. All subjects underwent volumetric MRI scans at baseline and during follow up. Volumetric changes from baseline to follow up in MRI scans were evaluated using both regional volume analysis and voxel based morphometric analysis MRI analysis demonstrated that temporal lobe volume, total grey matter volume and frontoparietal volume change was lower in liraglutide treated patients compared to the placebo group. Voxel based morphometry (VBM) analysis demonstrated that liraglutide-treated participants showed a slower reduction in whole cortical grey matter, frontal, temporal and parietal lobe volume in participants treated with liraglutide compared to placebo. In the ELAD study, participants with mild to moderate AD who received liraglutide had slower reduction in MRI volume and cognition compared to the placebo demonstrating a potential benefit of liraglutide in the treatment of Alzheimer’s disease. These findings highlight the potential of GLP-1 analogues in the treatment of Alzheimer’s disease

Glucose is the primary energy source required for the homeostatic function of the brain. Glucose transporter 1 (GLUT1) present at the blood-brain barrier is a key regulator of glucose transport into the brain. Reduced GLUT1 expression is shown to exacerbate Alzheimer’s pathology in rodent models. Here we aimed to establish whether there are regional differences in ineffective glucose transport amongst people living with Alzheimer’s disease. 125 participants diagnosed with Alzheimer’s dementia, with an [ 18 F]FDG scan with atrial input were enrolled. All participants underwent 3-tesla magnetic resonance imaging and [18F]FDG scan with continuous and discrete arterial sampling. Spectral analysis was performed to create 1-minute input-response function parametric maps. To produce glucose transfer maps we applied the following equation; K1 ⁎ Ca / τ (K1 = 1-minute IRF map, Ca = Plasma glucose concentration, τ = 1.48 a lumped constant). Glucose transfer maps were then coregistered to the participants’ structural MRI and normalised to MNI space. Regional mean glucose transfer was then calculated for the anterior cingulate cortex, frontal lobe, hippocampus, parahippocampus, occipital lobe, parietal lobe, posterior cingulate cortex, striatum, temporal lobe, and thalamus. A within-subject ANOVA was then performed to evaluate the regional differences in cerebral glucose transport. The parahippocampus exhibited the lowest rate of glucose transfer in comparison to all other regions (p < 0.001), followed by the hippocampus. The striatum and occipital lobe demonstrated the regions of the highest mean glucose transportation from blood to the brain. In terms of brain lobes, the temporal lobe showed the lowest rates of glucose transfer, followed by the parietal lobe, then frontal and occipital (p < 0.001). We demonstrate dysfunctional BBB glucose transport in Alzheimer’s disease, with prominent glucose transport abnormalities localised in the parahippocampus. Impaired glucose transport was most apparent within temporal lobe structures. Targeting glucose transfer may be an effective way of treating Alzheimer’s disease.