Clinical Dementia Rating Sum Of Boxes Research Articles

A Two-Year Observational Study to Evaluate Conversion Rates from High- and Low-Risk Patients with Amnestic Mild Cognitive Impairment to Probable Alzheimer’s Disease in a Real-World Setting

Background: Predicting conversion to probable Alzheimer&s disease (AD) from amnestic mild cognitive impairment (aMCI) is difficult but important. A nomogram was developed previously for determining the risk of 3-year probable AD conversion in aMCI. Objective: To compare the probable AD conversion rates with cognitive and neurodegenerative changes for 2 years from high- and low risk aMCI groups classified using the nomogram. Methods: This prospective, multicenter, observational study was conducted in Korea. A total of patients were classified as high- or low-risk aMCI according to the nomogram and followed-up for 2 years to compare the annual conversion rate to probable AD and brain structure changes between the two groups. Results: In total, 176 (high-risk, 85; low-risk, 91) and 160 (high-risk, 77; low-risk, 83) patients completed the 1-year and 2-year follow-up, respectively. The probable AD conversion rate was significantly higher in the high-risk (Year 1, 28.9%; Year 2, 46.1%) versus low-risk group (Year 1, 0.0%; Year 2, 4.9%, both p < 0.0001). Mean changes from baseline in Seoul Neuropsychological Screening Battery-Dementia Version, Clinical Dementia Rating-Sum of Box, and Korean version of the Instrumental Activities of Daily Living scores and cortical atrophy index at Years 1 and 2 were significantly greater in the high-risk group (p < 0.0001). Conclusions: The high-risk aMCI group, as determined by the nomogram, had a higher conversion rate to probable AD and faster cognitive decline and neurodegeneration change than the low-risk group. These real-world results have clinical implications that help clinicians in accurately predicting patient outcomes and facilitating early decision-making. Trial Registration: ClinicalTrials.gov (NCT03448445)

Simplifying Alzheimer’s Disease Monitoring: A Novel Machine-Learning Approach to Estimate the Clinical Dementia Rating Sum of Box Changes Using the Mini-Mental State Examination and Functional Activities Questionnaire

Simplifying Alzheimer’s Disease Monitoring: A Novel Machine-Learning Approach to Estimate the Clinical Dementia Rating Sum of Box Changes Using the Mini-Mental State Examination and Functional Activities Questionnaire

Effectiveness of Personalized Hippocampal Network–Targeted Stimulation in Alzheimer Disease

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe and promising intervention for Alzheimer disease (AD). To investigate the effect of a 4-week personalized hippocampal network-targeted rTMS on cognitive and functional performance, as well as functional connectivity in AD. This randomized clinical trial, which was sham-controlled and masked to participants and evaluators, was conducted between May 2020 and April 2022 at a single Korean memory clinic. Eligible participants were between ages 55 and 90 years and had confirmed early AD with evidence of an amyloid biomarker. Participants who met the inclusion criteria were randomly assigned to receive hippocampal network-targeted rTMS or sham stimulation. Participants received 4-week rTMS treatment, with assessment conducted at weeks 4 and 8. Data were analyzed between April 2022 and January 2024. Each patient received 20 sessions of personalized rTMS targeting the left parietal area, functionally connected to the hippocampus, based on fMRI connectivity analysis over 4 weeks. The sham group underwent the same procedure, excluding actual magnetic stimulation. A personalized 3-dimensional printed frame to fix the TMS coil to the optimal target site was produced. The primary outcome was the change in the AD Assessment Scale-Cognitive Subscale test (ADAS-Cog) after 8 weeks from baseline. Secondary outcomes included changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Seoul-Instrumental Activity Daily Living (S-IADL) scales, as well as resting-state fMRI connectivity between the hippocampus and cortical areas. Among 30 participants (18 in the rTMS group; 12 in the sham group) who completed the 8-week trial, the mean (SD) age was 69.8 (9.1) years; 18 (60%) were female. As the primary outcome, the change in ADAS-Cog at the eighth week was significantly different between the rTMS and sham groups (coefficient [SE], -5.2 [1.6]; P = .002). The change in CDR-SOB (-4.5 [1.4]; P = .007) and S-IADL (1.7 [0.7]; P = .004) were significantly different between the groups favoring rTMS groups. The fMRI connectivity analysis revealed that rTMS increased the functional connectivity between the hippocampus and precuneus, with its changes associated with improvements in ADAS-Cog (r = -0.57; P = .005). This randomized clinical trial demonstrated the positive effects of rTMS on cognitive and functional performance, and the plastic changes in the hippocampal-cortical network. Our results support the consideration of rTMS as a potential treatment for AD. ClinicalTrials.gov Identifier: NCT04260724.

Clinical and Neuroimaging Predictors of Alzheimer's Dementia Conversion in Patients with Mild Cognitive Impairment Using Amyloid Positron Emission Tomography by Quantitative Analysis over 2 Years.

Patients with mild cognitive impairment (MCI) have a relatively high risk of developing Alzheimer's dementia (AD), so early identification of the risk for AD conversion can lessen the socioeconomic burden. In this study, 18F-Florapronol, newly developed in Korea, was used for qualitative and quantitative analyses to assess amyloid positivity. We also investigated the clinical predictors of the progression from MCI to dementia over 2 years. From December 2019 to December 2022, 50 patients with MCI were recruited at a single center, and 34 patients were included finally. Based on visual analysis, 13 (38.2%) of 34 participants were amyloid-positive, and 12 (35.3%) were positive by quantitative analysis. Moreover, 6 of 34 participants (17.6%) converted to dementia after a 2-year follow-up (p = 0.173). Among the 15 participants who were positive for amyloid in the posterior cingulate region, 5 (33.3%) patients developed dementia (p = 0.066). The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) at baseline was significantly associated with AD conversion in multivariate Cox regression analyses (p = 0.043). In conclusion, these results suggest that amyloid positivity in the posterior cingulate region and higher CDR-SOB scores at baseline can be useful predictors of AD conversion in patients with MCI.

Cost-Effectiveness of Lecanemab for Individuals With Early-Stage Alzheimer Disease.

Little is known regarding the cost-effectiveness of lecanemab (Leqembi), a monoclonal antibody approved by the US Food and Drug Administration in January 2023 for the treatment of mild cognitive impairment (MCI) or mild dementia due to Alzheimer disease (AD). This study aims to quantify the cost-effectiveness of lecanemab and how it varies based on the accuracy of AD testing and individuals' APOE ε4 status. Seven alternative test-treat-target strategies defined by combinations of testing approaches (PET, CSF, or plasma assay), treatment choices (standard of care [SoC] alone or lecanemab in addition to SoC), and targeting strategies (targeting APOE ε4 noncarriers or heterozygous patients or not) were compared. A hybrid decision tree-Markov cohort model was constructed with 5 states: (1) MCI (Clinical Dementia Rating-Sum of Boxes [CDR-SB] 0-4.5); (2) mild dementia (CDR-SB 4.6-9.5); (3) moderate dementia (CDR-SB 9.6-16); (4) severe dementia (CDR-SB >16); and (5) death. Effectiveness was measured by quality-adjusted life years and costs from third-party and societal perspectives were estimated in 2022 US dollars over a lifetime horizon. Among the 7 test-treat-target strategies, SoC alone was the optimal strategy from a cost-effectiveness perspective. Neither targeted lecanemab treatment nor treatment unrestricted by APOE ε4 genotype was cost-effective vs SoC alone, regardless of the test used to diagnose patients with early-stage AD. However, CSF assay followed by targeted treatment would become cost-effective if lecanemab is priced below $5,100 per year. These results were robust to the accuracy of diagnostic testing and rates of lecanemab discontinuation and adverse events. Neither targeted lecanemab treatment nor treatment unrestricted by APOE ε4 genotype is cost-effective vs SoC alone for patients with MCI or mild dementia due to AD. Lecanemab would be cost-effective in some settings if priced below $5,100 per year.

Efficacy and safety of gantenerumab in the treatment of Alzheimer's disease: A meta-analysis of randomized controlled trials

IntroductionGantenerumab has garnered considerable attention for its potential to modify the natural course of Alzheimer's disease. However, recent studies have shown mixed results for the use of this medication for the treatment of Alzheimer's Disease. Therefore, this review compared the effects of Gantenerumab with placebo in patients with Alzheimer's disease. MethodsLiterature searches were conducted in PubMed, Embase and Cochrane database from inception to December 2023. Two independent authors (MS and LV) performed the study selection, data extraction and quality assessment. The outcomes of this review were: Clinical Dementia Rating - Sum of Boxes (CDR-SB), the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Mini-Mental State Evaluation (MMSE) and the incidence of Amyloid-Related Imaging Abnormalities with Edema (ARIA-E) or Amyloid-Related Imaging Abnormalities with Hemosiderosis (ARIA-H). Meta-analysis were performed using Review Manager 5.4 (Cochrane Collaboration). ResultsFour studies reporting data for 2,848 patients were included in this review. The lenght of follow-up assessments ranged from 50 to 104 weeks. When compared to placebo, Gantenerumab was significantly associated with a lower ADAS-Cog score (MD -1.05; 95 % CI: -1.85 to -0.25) and lower MMSE score (MD -0.31; 95 % CI: -0.55 to -0.07). There were no differences in the CDR-SB score. Gantenerumab group had a higher incidence of ARIA-E (RR 8.94; 95 % CI: 6.22 to 12.84). ConclusionGantenerumab showed negative effects on cognitive outcomes of people with Alzheimer's Disease. There was a higher incidence of ARIA-E and ARIA-H for gantenerumab. Additional high quality studies are needed to draw more robust conclusions about this treatment.

Psychosis in Alzheimer’s disease is associated with specific changes in brain MRI volume, cognition and neuropathology

Psychosis in Alzheimer’s Disease (AD) is prevalent and indicates poor prognosis. However, the neuropathological, cognitive and brain atrophy patterns underlying these symptoms have not been fully elucidated. In this study, we evaluated 178 patients with AD neuropathological change (ADNC) and ante-mortem volumetric brain magnetic resonance imaging (MRI). Presence of psychosis was determined using the Neuropsychiatric Inventory Questionnaire. Clinical Dementia Rating Sum-of-boxes (CDR-SB) was longitudinally compared between groups with a follow-up of 3000 days using mixed-effects multiple linear regression. Neuropsychological tests closest to the time of MRI and brain regional volumes were cross-sectionally compared. Psychosis was associated with lower age of death, higher longitudinal CDR-SB scores, multi-domain cognitive deficits, higher neuritic plaque severity, Braak stage, Lewy Body pathology (LB) and right temporal lobe regional atrophy. Division according to the presence of LB showed differential patterns of AD-typical pathology, cognitive deficits and regional atrophy. In conclusion, psychosis in ADNC with and without LB has clinical value and associates with subgroup patterns of neuropathology, cognition and regional atrophy.

Exploring the association between cancer and cognitive impairment in the Australian Imaging Biomarkers and Lifestyle (AIBL) study

An inverse association between cancer and Alzheimer’s disease (AD) has been demonstrated; however, the association between cancer and mild cognitive impairment (MCI), and the association between cancer and cognitive decline are yet to be clarified. The AIBL dataset was used to address these knowledge gaps. The crude and adjusted odds ratios for MCI/AD and cognitive decline were compared between participants with/without cancer (referred to as C+ and C− participants). A 37% reduction in odds for AD was observed in C+ participants compared to C− participants after adjusting for all confounders. The overall risk for MCI and AD in C+ participants was reduced by 27% and 31%, respectively. The odds of cognitive decline from MCI to AD was reduced by 59% in C+ participants after adjusting for all confounders. The risk of cognitive decline from MCI to AD was halved in C+ participants. The estimated mean change in Clinical Dementia Rating-Sum of boxes (CDR-SOB) score per year was 0.23 units/year higher in C− participants than in C+ participants. Overall, an inverse association between cancer and MCI/AD was observed in AIBL, which is in line with previous reports. Importantly, an inverse association between cancer and cognitive decline has also been identified.

Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies

BackgroundIn an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated.ObjectivesTo optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB.DesignEvaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer’s disease (AD), were reviewed.Setting22 clinical sites in the US and 2 in the Netherlands.ParticipantsProbable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT).InterventionNeflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks.Measurements6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT).ResultsWithin AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen’s d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively.ConclusionIn addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

Disparate Dementia Risk Factors Are Associated with Cognitive Impairment and Rates of Decline in African Americans.

This study was undertaken to evaluate the frequency of modifiable dementia risk factors and their association with cognitive impairment and rate of decline in diverse participants engaged in studies of memory and aging. Modifiable dementia risk factors and their associations with cognitive impairment and cognitive decline were determined in community-dwelling African American (AA; n = 261) and non-Hispanic White (nHW; n = 193) participants who completed ≥2 visits at the Mayo Clinic Alzheimer Disease Research Center in Jacksonville, Florida. Risk factors and their associations with cognitive impairment (global Clinical Dementia Rating [CDR] ≥ 0.5) and rates of decline (CDR Sum of Boxes) in impaired participants were compared in AA and nHW participants, controlling for demographics, APOE ɛ4 status, and Area Deprivation Index. Hypertension, hypercholesterolemia, obesity, and diabetes were overrepresented in AA participants, but were not associated with cognitive impairment. Depression was associated with increased odds of cognitive impairment in AA (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 2.13-8.67) and nHW participants (OR = 2.79, 95% CI = 1.21-6.44) but uniquely associated with faster decline in AA participants (β = 1.71, 95% CI = 0.69-2.73, p = 0.001). Fewer AA participants reported antidepressant use (9/49, 18%) than nHW counterparts (57/78, 73%, p < 0.001). Vitamin B12 deficiency was also associated with an increased rate of cognitive decline in AA participants (β = 2.65, 95% CI = 0.38-4.91, p = 0.023). Modifiable dementia risk factors are common in AA and nHW participants, representing important risk mitigation targets. Depression was associated with dementia in AA and nHW participants, and with accelerated declines in cognitive function in AA participants. Optimizing depression screening and treatment may improve cognitive trajectories and outcomes in AA participants. ANN NEUROL 2024;95:518-529.

Type 2 Diabetes Moderates the Association Between Amyloid and 1-Year Change in Everyday Functioning in Older Veterans.

Type 2 diabetes mellitus (T2DM) affects ∼25% of Veterans, a prevalence rate double that of the general population. T2DM is associated with greater dementia risk and has been shown to exacerbate the impact of Alzheimer's disease (AD) risk factors on declines in daily functioning; however, there are few studies that investigate these patterns in older Veterans. This study sought to determine whether T2DM moderates the association between amyloid-β (Aβ) positron emission tomography (PET) and 1-year change in everyday functioning in older Veterans. One-hundred-ninety-eight predominately male Vietnam-Era Veterans without dementia from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) with (n = 74) and without (n = 124) T2DM completed Aβ PET imaging and everyday functioning measures, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Everyday Cognition (ECog). Linear mixed effects models tested the moderating role of T2DM on the association between Aβ PET and 1-year change in everyday functioning. The 3-way T2DM×Aβ PET×time interaction was significant for CDR-SB (p < 0.001) as well as the Memory (p = 0.007) and Language (p = 0.011) subscales from the ECog. Greater amyloid burden was associated with greater increases in functional difficulties, but only in Veterans with T2DM. Higher Aβ was only associated with declines in everyday functioning over 1 year in Veterans with T2DM. Given that people with T2DM are more likely to have co-occurring cerebrovascular disease, the combination of multiple neuropathologies may result in faster declines. Future studies should examine how diabetes duration, severity, and medications impact these associations.

Cochlear dysfunction as an early biomarker of cognitive decline in normal hearing and mild hearing loss.

Age-related hearing loss is an important risk factor for cognitive decline. However, audiogram thresholds are not good estimators of dementia risk in subjects with normal hearing or mild hearing loss. Here we propose to use distortion product otoacoustic emissions (DPOAEs) as an objective and sensitive tool to estimate the risk of cognitive decline in older adults with normal hearing or mild hearing loss. We assessed neuropsychological, brain magnetic resonance imaging, and auditory analyses on 94 subjects >64 years of age. We found that cochlear dysfunction, measured by DPOAEs-and not by conventional audiometry-was associated with Clinical Dementia Rating Sum of Boxes (CDR-SoB) classification and brain atrophy in the group with mild hearing loss (25 to 40dB) and normal hearing (<25dB). Our findings suggest that DPOAEs may be a non-invasive tool for detecting neurodegeneration and cognitive decline in the older adults, potentially allowing for early intervention.

Bayesian meta-analysis of phase 3 results of aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease.

Phase 3 trials using the anti-amyloid antibodies aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease dementia were heterogeneous in respect to statistical significance of effects. However, heterogeneity of results has not yet directly be quantified. We used Bayesian random effects meta-analysis to quantify evidence for or against a treatment effect, and assessed the size of the effect and its heterogeneity. Data were extracted from published studies where available and Web based data reports, assuming a Gaussian data generation process. We found moderate evidence in favor of a treatment effect (Bayes factor = 13.2). The effect was moderate to small with -0.33 (95% credible interval -0.54 to -0.10) points on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) scale. The heterogeneity parameter was low to moderate with 0.21 (0.04 to 0.45) CDR-SB points. Heterogeneity across studies was moderate despite some trials reaching statistical significance, while others did not. This suggests that the negative aducanumab and gantenerumab trials are in full agreement with the expected effect sizes.

Association Between Executive Dysfunction-Related Activities of Daily Living Disability and Clinical Dementia Rating Domain Patterns in Patients With Vascular Dementia and Age-Matched Patients With Alzheimer's Dementia.

Although the Clinical Dementia Rating (CDR) scale was originally developed to stage Alzheimer's dementia (AD), it is now used globally for various types of dementia. The aim of this study was to investigate the characteristic pattern of CDR domains and its association with neuropsychological findings and activities of daily living (ADL) in patients with vascular dementia (VaD) and patients with AD. We recruited very mild to mild VaD and AD patients who were age-matched among the first visitors to a dementia clinic. All subjects underwent a standardized clinical interview, physical and neurological examinations, and laboratory tests, including brain magnetic resonance imaging, according to the protocol of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease assessment battery. A total of 105 pairs of VaD and AD patients participated in this study. Although the adjusted scores on Korean version of the Mini-Mental State Examination were similar between the two groups, the VaD patients performed better on the Boston Naming Test, Word List Memory, Word List Recall, Word List Recognition, and Constructional Recall Test. However, the scores on global CDR, CDR sum of boxes, and ADL-related CDR domains were higher in VaD patients than in AD patients (p<0.001). The VaD patients also showed poor performances on the Disability Assessment for Dementia Scale, Frontal Assessment Battery, Executive Clock Drawing Task, and Stroop tests. Despite similar general cognitive function and better memory function, patients with VaD tend to be staged as severer dementia on the CDR scale than patients with AD because of more impaired ADL associated with executive dysfunction.

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

Background“Brain-predicted age” estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.MethodsWe modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education.ResultsAdvanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG.ConclusionsWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

Tau PET burden in Brodmann areas 35 and 36 is associated with individual differences in cognition in non-demented older adults.

The accumulation of neurofibrillary tau tangles, a neuropathological hallmark of Alzheimer's disease (AD), occurs in medial temporal lobe (MTL) regions early in the disease process, with some of the earliest deposits localized to subregions of the entorhinal cortex. Although functional specialization of entorhinal cortex subregions has been reported, few studies have considered functional associations with localized tau accumulation. In this study, stepwise linear regressions were used to examine the contributions of regional tau burden in specific MTL subregions, as measured by 18F-MK6240 PET, to individual variability in cognition. Dependent measures of interest included the Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini Mental State Examination (MMSE), and composite scores of delayed episodic memory and language. Other model variables included age, sex, education, APOE4 status, and global amyloid burden, indexed by 11C-PiB. Tau burden in right Brodmann area 35 (BA35), left and right Brodmann area 36 (BA36), and age each uniquely contributed to the proportion of explained variance in CDR-SB scores, while right BA36 and age were also significant predictors of MMSE scores, and right BA36 was significantly associated with delayed episodic memory performance. Tau burden in both left and right BA36, along with education, uniquely contributed to the proportion of explained variance in language composite scores. Importantly, the addition of more inclusive ROIs, encompassing less granular segmentation of the entorhinal cortex, did not significantly contribute to explained variance in cognition across any of the models. These findings suggest that the ability to quantify tau burden in more refined MTL subregions may better account for individual differences in cognition, which may improve the identification of non-demented older adults who are on a trajectory of decline due to AD.

Towards the future of ADRD diagnosis: combination of a brief digital cognitive battery and plasma biomarkers for diagnosis and prognosis of disease

AbstractBackgroundScalable and accurate diagnostic markers of Alzheimer’s disease and related dementias (ADRD) are urgently needed. A combination of a sensitive brief digital cognitive assessment and plasma biomarkers could represent a promising scalable alternative to standard diagnostic procedures. We evaluated the performance of the TabCAT Brain Health Assessment Cognitive Score (BHA‐CS) and plasma Aβ42/40, pTau‐181, NfL, and GFAP at predicting concurrent Aβ positivity on CSF or PET, concurrent disease severity, and future functional decline.MethodParticipants were 309 subjectively or objectively impaired older adults enrolled in longitudinal observational studies at UCSF (Table 1), who completed a blood draw and TabCAT‐BHA at baseline. Biomarker concentrations were measured using commercially available Quanterix kits. Receiver operating characteristic analyses were used to determine the accuracy of combined BHA‐CS and plasma biomarkers in discriminating between Aβ+/‐ status on CSF/PET at baseline. Multiple regressions were used to examine baseline associations of BHA‐CS and plasma markers with disease severity measured by Clinical Dementia Rating Sum of Boxes (CDR‐SB). Linear mixed effect models were used to examine the associations of baseline BHA‐CS and biomarker values with longitudinal decline on CDR‐SB. All analyses controlled for age, sex, education, and baseline diagnosis.ResultpTau‐181 was the strongest predictor of Aβ positivity (AUC = .745; 95%CI: .656‐.833), with no significant improvements in the AUC with the addition of any combination of markers (Figure 1). In a combined model with all markers included simultaneously, BHA‐CS (B = ‐0.678, P&lt;.001) and plasma NfL (B = 0.625, P = .01) were the only unique significant predictors of concurrent CDR‐SB. In a combined mixed model with all markers included simultaneously, baseline BHA‐CS, pTau‐181, NfL, and GFAP were unique significant predictors of CDR‐SB decline (Figure 2), and together accounted for 27% of longitudinal variance in CDR‐SB.ConclusionOur findings indicate unique and complementary roles of scalable digital cognitive and plasma biomarkers as diagnostic and prognostic markers of ADRD. At baseline, whereas pTau‐181 was most accurate at predicting Aβ positivity, a combination of BHA‐CS and NfL was most accurate at predicting concurrent disease severity. In longitudinal analyses, a model that combined baseline cognitive testing results and plasma pTau‐181, NfL, and GFAP was most accurate at predicting future decline.

CSF markers YKL40, sTREM2, and a‐synuclein enhance the Alzheimer’s disease A/T/N criteria to detect early changes in cognition

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial disease including pre‐clinical, prodromal and clinical phases. CSF “A/T/N” (Ab42, pTau181, tTau) biomarkers help characterize the biological state of AD. The primary aim was to assess contributions of eight CSF markers for predicting changes in cognition.MethodCSF from 237 participants (CN: 176[74.3%], MCI: 33[13.9%], AD: 28[11.8%]) of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing was used to measure Ab42 (GenII assay), pTau181, and tTau (Elecsys®) along with neurogranin, neurofilament light (NFL), α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells‐2 (sTREM2), s100 calcium‐binding protein B (s100B), and interleukin‐6 (IL‐6) from the NeuroToolKit (NTK) panel of exploratory prototype assays (all Roche Diagnostics International Ltd). NTK biomarker concentrations were measured amongst each of four ATN groups at baseline; 1) A‐/T‐/N‐ (reference group), 2) A+/T±/N± (amyloid+), 3) A‐/T±/N± (amyloid‐), and 4) A+/T+/N+. Change in cognition was assessed using the pre‐clinical Alzheimer’s cognitive composite (PACC) and the clinical dementia rating sum of boxes (CDR‐SB) scores, in all four ATN groups, stratified by low/high NTK biomarker over a minimum of 36 months. The primary outcome was defined as change in cognition in amyloid+ participants modulated by the addition of NTK markers to ATN groups.ResultA+/T+/N+ participants had faster cognitive decline on both PACC and CDR‐SB over time compared to all other groups (Figure 1A, PACC; Figure 1B, CDR‐SB). Within the amyloid+ group, participants with high sTREM2 (K+) had a faster rate of decline in PACC compared to those with low sTREM2 (K‐, p = 0.04; Figure 1C), whilst participants with high α‐synuclein had a faster increase in CDR‐SB compared with those with low α‐synuclein (p = 0.005; Figure 1D). Amongst participants who were A+/T+/N+, those with high YKL40 had a significantly faster rate of decline in PACC (p = 0.017; Figure 1E), and a faster increase in CDR‐SB, (p = 0.017; Figure 1F) compared with those who with low YKL40.ConclusionBiomarkers of microglial activation (sTREM2), synaptic function and synuclein metabolism (α‐synuclein), and astrocytic activation (YKL‐40) may be appropriate to discern rates of cognitive change within amyloid+ participants. Findings are being validated in a separate population.

GRADUATE I AND II: Factors that may influence participant response to subcutaneous gantenerumab

AbstractBackgroundGRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two Phase III trials that investigated the efficacy and safety of gantenerumab, a subcutaneous fully human monoclonal antibody that binds aggregated forms of amyloid‐beta, in participants with early Alzheimer’s disease (AD). Although the studies did not meet their primary endpoints, participant characteristics that might influence response to gantenerumab were evaluated.MethodEligible participants with early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) were randomized 1:1 to receive gantenerumab or placebo. Gantenerumab‐treated participants were up‐titrated to 510 mg subcutaneous gantenerumab every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Secondary endpoints of cognition (ADAS‐Cog13) and function (ADCS‐ADL, FAQ) were assessed. Pre‐specified and exploratory post‐hoc subgroup analyses on these endpoints were performed.ResultAcross endpoints, there were consistent trends towards larger point estimates of gantenerumab treatment effect compared with placebo at Week 116 in males (using CDR‐SB as representative example: GRADUATE I: 16% relative reduction (RR); GRADUATE II: 17% RR) vs females (GRADUATE I: 3% RR; GRADUATE II: –2% RR) and participants with MCI (GRADUATE I:15% RR; GRADUATE II:10% RR) vs mild AD (GRADUATE I: 4% RR; GRADUATE II: 2% RR). This pattern was not consistently seen when using CDR‐Global Score (0.5 vs &gt;0.5) to define disease stage. Compliers, defined as participants who received ≥90% of the intended cumulative dose, had an increased point estimate of treatment effect (CDR‐SB: GRADUATE I: 17% RR; GRADUATE II: 18% RR) vs non‐compliers (CDR‐SB: GRADUATE I: –1% RR; GRADUATE II: –3% RR). In a pooled analysis, a larger point estimate of treatment effect vs placebo was observed in East‐Asian vs Non‐East‐Asian countries (CDR‐SB: RR 38% vs 5%). The East‐Asian population had lower baseline weight, greater treatment compliance, and accordingly higher plasma exposure, than the Non‐East‐Asian population, suggesting this observation is not driven by racial differences in treatment response.ConclusionSubgroup analyses in the GRADUATE studies provide insights into participant characteristics that may influence the degree of clinical response to gantenerumab treatment. Higher gantenerumab exposure may result in greater clinical efficacy.

Efficacy results from the unique long‐term randomised controlled double‐blind LipiDiDiet trial with a multinutrient intervention in prodromal AD/MCI_AD

AbstractBackgroundLifestyle factors such as nutrition and diet are modifiable risk factors for the progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). A small number of interventions recently showed cognitive and functional benefits. It is unclear however how long these benefits will last, requiring long‐term studies.LipiDiDiet was the first AD double‐blind, placebo‐controlled trial clinical trial to show a significant and sustainable benefit, including a 45% reduction in decline on CDR‐SB performance in a prodromal study population evaluating a multinutrient formulation (Soininen Lancet Neurology 2017; Soininen Alz&amp;Dem 2021). We now extended the analysis from 3 years to up to 6 years of active intervention to investigate long‐term effects.MethodLipiDiDiet is a 6‐year randomised, double‐blind, placebo‐controlled trial, investigating the effects of a nutritional intervention in individuals with prodromal AD/MCIAD. 311 individuals with prodromal AD (IWG‐1) were randomized to active (125ml once‐a‐day drink; Fortasyn Connect [Souvenaid]) or a calorie‐matched control. Following the first 2 years of intervention, participants could opt‐in for annual extensions up to a maximum of 6‐year double‐blind intervention. Individual participants progressing to mild dementia were provided AD medication and/or open‐label active product and could continue in the trial. Main outcomes included Neuropsychological Test Battery (NTB) composites on cognition and memory, and the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Modified intention‐to‐treat analyses were performed over 4‐6 years of intervention using a joint model combining longitudinal and survival data.ResultAdding data from all participants who completed the 4‐year visit while still on double‐blind treatment (n = 38) to the previously performed joint model analyses on the 3‐year data showed that the initially observed benefits on cognition, memory, and CDR‐SB appear to have continued beyond 3 years. These and other ongoing analyses are addressing the statistical challenges specific to long‐term AD trials including non‐random patterns of missing data.ConclusionIn addition to the already demonstrated sustainable benefits of Fortasyn Connect in individuals with prodromal AD/MCIAD, combined with feasibility of its long‐term use without indications for health concerns, we now report first results indicating that benefits on cognition, memory, and CDR‐SB are sustained over 4 years.