Alzheimer's Disease Clinical Trials Research Articles

Design of a Phase 2, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study to Assess the Efficacy, Safety, and Tolerability of BIIB080 in Subjects with Mild Cognitive Impairment Due to Alzheimer’s Disease or Mild Alzheimer’s Disease Dementia

AbstractBackgroundBIIB080 (formerly IONIS MAPT‐RX) is an antisense oligonucleotide (ASO) designed to bind to MAPT pre‐mRNA, promote its degradation, and prevent translation of all forms of tau protein. BIIB080 is, to our knowledge, the first tau targeting ASO to enter human clinical trials in Alzheimer’s disease (AD).BIIB080 was evaluated in Study ISIS 814907‐CS1 (NCT03186989) a Phase 1b, placebo‐controlled, double blind, multiple ascending dose clinical trial with 13‐week treatment period and 23‐week follow‐up period followed by an open‐label long term extension in patients with mild Alzheimer’s disease. BIIB080 was generally well tolerated. Importantly, robust, time‐dependent and dose‐dependent decreases in CSF total and phosphorylated tau were observed. Additionally, BIIB080 impacted aggregated tau pathology as measured by tau PET as early as 25 weeks.Based on the Phase 1b results, Biogen is conducting a Phase 2 study, Study 247AD201 (NCT05399888) that will evaluate the efficacy, safety, and tolerability of BIIB080 in participants with mild cognitive impairment (MCI) due to Alzheimer’s disease or mild Alzheimer’s disease dementia.MethodRandomized, double‐blind, placebo‐controlled, parallel‐group Phase 2 study (CELIA), is enrolling approximately 735 individuals aged 50‐80 years, with MCI due to Alzheimer’s disease or mild Alzheimer’s disease dementia, Clinical Dementia Rating (CDR) global score 0.5‐1, Mini Mental State Examination (MMSE) score 22‐30, objective evidence of cognitive impairment at Screening, and evidence of amyloid pathology as measured by PET or cerebrospinal fluid (CSF) sampling.The Phase 2 study will randomize participants to receive 1 of 3 different dose regimens of intrathecal (IT) BIIB080 or placebo every 12 or 24 weeks during the 76‐week placebo‐controlled period. The primary endpoint will assess the dose‐response in change from Baseline to Week 76 on the CDR‐SB.The study includes a tau PET substudy to assess the effect of BIIB080 on tau aggregates with 18F‐MK6240.ResultThe Ph2 CELIA study is currently recruiting participants.ConclusionThe ongoing Ph2 CELIA trial will assess the efficacy, safety and tolerability of BIIB080, compared to placebo in subjects with MCI due to Alzheimer’s disease or mild Alzheimer’s disease dementia.

Developing Topics.

APOE*2 and APOE*4 are respectively the strongest protective and risk-increasing genetic variants for late-onset Alzheimer's disease (AD), making APOE status highly relevant towards clinical trial design and AD research broadly. The associations of APOE genotypes with AD are importantly modulated by age, sex, race, ethnicity, and ancestry, but these associations remain unclear, particularly in historically understudied non-white samples. The study overview is shown in Figure.1. Various case-control, family-based, and longitudinal AD genetic cohorts were available through public repositories and underwent extensive genotype and phenotype quality control. These cohorts contributed data for Non-Hispanic Whites (NHW), Non-Hispanic Blacks (NHB), and Hispanics (HISP). Global ancestry was determined using SNPweights v2.1. Case-control logistic regression models evaluated the AD risk associations of APOE*2 dosage, APOE*4 dosage, and APOE genotype, with regard to APOE*33 as the reference, while adjusting for sex, array/batch/center, and global European, African, and Amerindian ancestry. Different stratified analyses, interaction models, and race/ethnicity heterogeneity tests were evaluated. APOE associations in East-Asians (EAS) were obtained through meta-analyses of published AD genetic studies, given the relative paucity of EAS in publicly available genetic cohorts. Compared to prior literature, we made several novel observations (Figure.2). Notably, the associations of APOE genotypes with AD risk were least pronounced in HISP, which was not explained by global ancestry. Further, not just APOE*4, but also APOE*2 followed a reduced association strength with AD risk according to the pattern of EAS > NHW > NHB > HISP (with the exception of APOE*2 in EAS, which showed no significant association). The sex-by-age-specific association of APOE*34 in NHW, which was shown to be stronger in women, was reproduced here at ages 60-70 years, and additionally replicated in NHB and HISP. There were no other significant sex-by-APOE interactions. Merited by recent advances in AD genetic cohorts, we provide the largest-to-date overview of APOE's associations with AD risk across important biological and demographic strata. We expect these insights to be critical to guide AD research and clinical trial design. With increased diversity and phenotype harmonization efforts in AD genetics, future extensions on this work are expected to provide additional insights.

Developing Topics.

Early and accurate diagnosis is critical as disease-modifying therapies for Alzheimer's disease (AD) become available and clinical trials are moving increasingly into early disease stages. The Learning ratio (LR) has demonstrated the highest sensitivity towards changes in memory, relative to other learning slope metrics. The current study examines the performance of LR within the ADNI cognitively normal population. Our analyses included 672 participants aged 55 to 90 years, diagnosed in ADNI as cognitively intact. After applying Jak/Bondi actuarial diagnostic criteria to the sample1, 2, 56 participants met actuarial criteria for MCI (actuarial-MCI), 253 had normal cognition with subjective memory complaints (actuarial-SMC), and 363 were cognitively normal without subjective complaints (actuarial-CN). We compared LR derived from the Rey Auditory Verbal Learning Test (RAVLT)3 and the Word Recall subtest of the ADAS-Cog4 between the diagnostic groups, and studied the effects of LR, diagnosis, and the interaction between LR and diagnosis on bilateral hippocampal volume and β-amyloid pathology. Actuarial-MCI performances on RAVLT LR and Word Recall LR were significantly worse than actuarial-SMC and actuarial-CN (ps<.005). No differences were seen between LRs for actuarial-CN and actuarial-SMC (ps>.05). The association between Word Recall LR and hippocampal volume was strongest in actuarial-MCI followed by actuarial-SMC, both of which displayed a positive relationship between the two variables, while actuarial-CN displayed a negative relationship (R2 = .209, p<.001, Figure 1A). Adding the interaction term improved model performance (R2 change = .007 p = .013). Similar trends were observed between RAVLT LR and diagnostic group predicting hippocampal volume, though the interaction was not significant (R2 = .208, p<.001, Figure 1B; R2 change = .001 p = .28). No main or interaction effects were observed between LR measures, diagnostic groups, and amyloid status (ps>.05, Figure 2). A subset of ADNI cognitively intact participants displayed MCI after applying Jak/Bondi actuarial norms, suggesting that ADNI diagnostic criteria may have under-pathologized memory loss in a subset of patients. The actuarial-MCI group displayed worse learning slopes and stronger relationships with hippocampal volume than CN participants with and without SMC. Applying the actuarial criteria to AD clinical trials - in conjunction with LR - may yield greater sensitivity in detecting those in the early stages of AD.

The role of nurses in recruiting Filipino, Korean, and Hispanic/Latino participants to preclinical Alzheimer’s disease trials.

AbstractBackgroundThe factors that influence clinical trial participation in the Filipino, Korean and Hispanic/Latino communities remain poorly understood. Nurses are well positioned to play a dynamic role in the recruitment of underrepresented communities to preclinical Alzheimer’s disease (AD) trials. This study used a community‐based nursing partnership model to gain insights into whether and how nurses serve as key gatekeepers within these communities.MethodSixty in‐depth stakeholder interviews were conducted with 20 Hispanic/Latino, 20 Filipino, and 20 Korean American nurses via Zoom. Nurses were recruited through a unique collaboration between community‐based Filipino, Korean and Hispanic/Latino professional nursing organizations and academic investigators. A semi‐structured interview guide was used to collect sociodemographic information and to assess nurses’ research attitudes and perspectives regarding the recruitment of underrepresented community members to AD preclinical trials.ResultOverall, 63% of nurses had &gt;20 years of clinical practice experience, 93% had a bachelors or graduate degree, 75% were fully employed, 14% were part‐time employed, 12% were retired, and 72% knew someone with a diagnosis of AD. Most Filipino (90%) and Korean (90%) nurses were not born in the US, as compared to Hispanic/Latino nurses (25%). Emergent themes were identified including the role of nurses as a (1) trusted source of health information, (2) patient advocate and community educator, and (3) liaison connecting key community stakeholders to AD trials. Commonalities in perspectives among the nursing groups about community members’ participation in trials included the role of familism in decision‐making, the need for strong family support, and reliance on family members, such as adult children, to communicate important health information. A notable difference between the nursing groups was that Hispanic/Latino nurses more often communicated in a non‐English (Spanish) language with patients as compared to Filipino and Korean nurses. All nursing groups, on average, exhibited positive attitudes towards research.ConclusionOur findings suggest that nurses can serve as a valuable vehicle for improving recruitment to preclinical AD clinical trials. Nurses are well positioned to engage with the community and provide culturally tailored patient, family, and community education.

A multi‐site study of Alzheimer’s disease neuroimaging and cognitive biomarkers in 2819 cognitively normal individuals

AbstractBackgroundDeveloping effective Alzheimer’s disease (AD) biomarkers in cognitively normal (CN) individuals is crucial. Prior studies have identified neuroimaging and cognitive measures that are sensitive to preclinical AD. However, the generalizability of these biomarkers in large, multi‐site cohorts and their power to predict disease progression remain unclear. Structural MRI, tau PET and standardized cognitive tests of 2819 CN adults were pooled from three studies to investigate the power of these measures in discriminating β‐amyloid positivity (A+/‐) and predicting disease progression.MethodsT1‐weighted MRI and cognitive data of 2819 CN (A‐/A+: 1180/1540, Table 2) individuals from ADNI, HABS and A4 were included. Baseline medial temporal lobe structural measures were extracted from MRI (complete list in Table 1). For participants with prospective longitudinal MRI or cognitive measures (4.5 years), annualized change rate of each measurement was estimated. ANCOVA and receiver operating characteristic analyses were used to test biomarker differences between A+/A‐. In 563 CN with cross‐sectional tau PET available, stepwise linear mixed effect modeling was performed to identify the subset of baseline cross‐sectional biomarkers (tau, MRI and cognition) that yields the optimal model (smallest Akaike information criterion) in predicting longitudinal atrophy and cognitive decline. The area under the curve (AUC) of each model in discriminating the first (fast) and last (slow progressors) tertiles of each longitudinal measurement was reported.ResultsSignificant differences between A+/A‐ (Table 2) were observed in cross‐sectional tau (most significant), cross‐sectional and longitudinal cognitive, as well as longitudinal structural MRI measures. When predicting disease progression with baseline measures (Figure 1‐a), tau (selected in all the models) and cognitive biomarkers were included in the most predictive models while MRI biomarkers did not provide additional information. The selected biomarkers can identify fast versus slow progressors with AUCs ranging from 0.63‐0.78 (Figure 1‐b).ConclusionsThe results demonstrated that both cross‐sectional (tau PET and cognition) and longitudinal biomarkers (MRI and cognition) are sensitive to amyloid status in CN. In addition, baseline tau PET and cognitive measures provide complementary information in predicting disease progression regardless of amyloid status. This indicates that these biomarkers may have important utility in preclinical AD clinical trials and normal aging studies.

Does the Timing of Alzheimer’s Disease vary by Severity of Intellectual Disability in Down Syndrome?

AbstractBackgroundTrisomy 21 causes Down syndrome (DS) and is a recognized cause of Alzheimer’s disease (AD). The triplication of the amyloid precursor protein gene leads to an overexpression of amyloid‐beta (Aβ), which accumulates into extracellular plaques, followed by intracellular neurofibrillary tau tangles (Lott &amp; Head, 2019). However, variability in the age of AD onset in DS spans 25+ years (Iulita et al., 2022). As the DS field moves to AD clinical trials, it is important to identify factors related to this variability, such as premorbid severity of intellectual disability (ID). We compared the age‐trajectory of the AD biomarkers Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type (full, mosaic, translocation) and APOE statusMethodAnalyses involved 361 adults with DS (M = 45.22 years, SD = 9.92) from the Alzheimer’s Biomarkers Consortium‐Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was recorded. PET was acquired using [11C] PiB for Aβ, and [18F] AV‐1451 for tau in 162 participants. Aβ was quantified using the centiloid method and tau was quantified as SUVR (reference: cerebellar cortex) in a composite region determined as the volume‐weighted average of select FreeSurfer 5.3, T1 MR‐based components.ResultsGeneral linear models controlling for site, age, trisomy type and APOE status indicated no significant effect of premorbid ID level by age on the cognitive outcomes (Figure 1a‐e). There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET (Figure 2a‐b). There was not a significant difference in age of those with mild cognitive impairment‐DS (MCI‐DS) or dementia by premorbid ID level (Figure 3).ConclusionThis study adds to the characterization of the time course of AD pathology and clinical symptomology in DS. Findings provide robust evidence of a similar time course in AD trajectory across severity of ID, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials. Premorbid IQ may have little effect on AD biomarkers in DS in contrast to findings in neurotypical populations.

APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry

Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields. To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry. This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies. The main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses. Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age-specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94). Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.

Symposium 08: Neuropsychological Considerations for Alzheimer's Disease Clinical Trials

Summary Abstract:The 2011 National Institute on Aging and Alzheimer's Association (NIA-AA) criteria for the diagnosis of Alzheimer's disease (AD) focused on clinical signs and symptoms to make a diagnosis of probable or possible AD. Under these criteria, emphasis was placed on gathering objective evidence of cognitive decline, which gave neuropsychologists a central role as diagnosticians in AD clinical trials. The release of the 2018 NIA-AA research framework put greater emphasis on the use of biomarkers, especially measures of amyloid, tau, and neurodegeneration, to define AD. Once AD is defined based on these biomarkers, it is staged via clinical signs and symptoms. Thus, the role of neuropsychologists has shifted from being central to diagnosis to a possibly more ancillary role of staging the disease once it is determined to be present. The move away from clinical signs towards biomarkers only became more prominent with the recent, controversial Food and Drug Administration approval of Aducanumab as an AD treatment based on evidence of change in biomarkers without clear evidence of clinical benefit. In this landscape, the fit of neuropsychologists in AD clinical trial research has become less clear.This symposium will address the role of neuropsychologists in modern AD clinical trial research. The presenters will highlight varied ways in which neuropsychologists can enrich and improve AD clinical trials. First, Dr. Dustin Hammers from Indiana University will discuss how neuropsychological methods can help us to understand which participants do, and perhaps more importantly, do not get enrolled in clinical trials. Second, Dr. Mirella Diaz-Santos from the University of California Los Angeles will summarize her work to enroll Hispanic individuals in the Human Connectome Project, improving inclusivity. Third, Dr. Tamar Gollan from the University of California San Diego will summarize her work on novel behavioral markers of AD risk discovered from the study of Spanish-English bilingual patients. Fourth, Dr. Andrew Kiselica from the University of Missouri will highlight psychometric considerations in interpreting clinically meaningfully change in AD clinical trials using data from the National Alzheimer's Coordinating Center. Fifth, Dr. Samantha John from the University of Nevada at Las Vegas will discuss the influence of race/ethnicity on how clinically meaningful change is defined using data from a diverse cohort.Dr. Kevin Duff will serve as discussant for this series of studies. He will highlight the important roles that neuropsychologists can play in improving AD clinical trial screening processes, expanding inclusion of diverse patients into trials, and enhancing interpretation of the clinical meaningfulness of trial results. He will also reflect on the future of neuropsychology's role in the AD clinical trial landscape and encourage audience questions and responses to the research presented.

5 Cognitive, Emotional, and Functional Predictors of Clinical Trial Enrollment

Objective:With participant recruitment being a top barrier to AD research progress, the rate of screen failure in Alzheimer’s disease (AD) clinical trials is unsustainable. Although steps have been undertaken to consider solutions to the continued recruitment shortage, there is unfortunately minimal emphasis on reducing screen failure rates based on study inclusion criteria. Here we present information attempting to understand the cognitive, emotional, and functional features of individuals who failed screening measures for AD trials.Participants and Methods:The current study is a retrospective, cross-sectional analysis. Thirty-eight participants (aged 50-83) having (1) previously received a clinical diagnostic workup at a transdisciplinary cognitive specialty clinic and (2) previously screened for a specific industry-sponsored clinical trial of MCI/early AD (EMERGE) met inclusion criteria. Previously collected clinical data were analyzed to identify predictors of AD trial screen pass/fail status.Results:Of the 38 participants in the current study, 14 screen passed into this AD clinical trial, and 24 screen failed. Higher screen failure rates were significantly related to gender, with 83% of female participants screen failing this AD trial versus 45% of male participants. There was no difference in age or education between screen pass/fail groups, nor were differences present for performance on visual or verbal memory tasks, or the MOCA. Conversely, those participants screen failing this AD clinical trial performed significantly worse on nonmemory cognitive domains pertaining to general fund of knowledge, working memory, and executive functioning. Additionally, the screen fail group reported greater levels of anxiety, but not depression nor endorsements on a measure of functional status.Conclusions:Worse performance on non-memory neuropsychological domains was related to screen failure status for the EMERGE AD clinical trial. This finding may be explained by the traditional recruitment pathway from clinic to trials, which beyond the diagnosis of interest is up to the opinion of the physician to determine “fit” for a trial. Higher screen failure rates may result from physicians erroneously viewing more globally-impaired patients as being more appropriate for an AD clinical trial, resulting in greater tendencies towards recruiting patients who are too severe to meet inclusion criteria for a trial. Recruiting patients into clinical trials earlier in their disease course - when disease severity is less - may result in reduced screen failure rates in AD trials. That we could not detect a relationship between memory-related tasks and screen fail/pass status may be explained by either (1) the measures used in the EMERGE trial were not as sensitive to subtle changes in memory, or (2) that memory dysfunction is necessary for a diagnosis of AD but not sufficient to distinguish who will be successfully screened into an AD clinical trial. Overall, these findings have the potential to advance the field by reducing screen failure rates in AD clinical trials by using information already available to clinical trial teams, which will enhance trial-recruitment infrastructure and encourage greater engagement of older adults in AD research.

44 Can Clinical Trial data Inform our Understanding of the role of Depressive Symptoms in Alzheimer's Disease?

Objective:Neuropsychiatric symptoms concerning mood are common in Alzheimer's disease (AD), but it is unclear if they are etiologically related to AD pathophysiology or due to factors considered to be non-pathogenic, such as small vessel cerebrovascular disease. New generation clinical trials for AD often enroll participants with evidence of AD pathophysiology, indexed by amyloid PET scanning, but who are cognitively asymptomatic. We used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to examine the extent to which depressive symptoms are associated with amyloid pathophysiology and small vessel cerebrovascular disease, in the form of white matter hyperintensities (WMH).Participants and Methods:The A4 study randomizes cognitively healthy older adults with evidence of amyloid pathophysiology on PET scanning. We used screening data, which included amyloid status (positive, negative) by visual read, amyloid PET standard uptake value ratio (SUVR) in cortical regions, and MRI data acquired in a subset (n=1,197, mean age 71.6 +/- 4.8 years, 57% women) to quantitate total WMH volume. Depressive symptoms were evaluated with the 15-item Geriatric Depression Scale, which we used both as a continuous variable and to define 'depressed' and 'non-depressed' groups, based on a cut score of &gt; 5. We examined whether 1) depressive symptoms and proportion of depressed individuals differed between amyloid positive and negative groups, 2) there is a relationship between amyloid SUVR and depressive symptoms that differs as a function of amyloid positivity status, and 3) there is a relationship between WMH volume and depressive symptoms that differs as a function of amyloid positivity status.Results:Although depressive symptom severity did not differ between groups (t=0.14, p=0.88), a greater proportion of individuals were classified as depressed in the amyloid negative group than the amyloid positive group (3.5% vs. 1.9%, X2=4.60, p=0.032). Increased amyloid SUVR was associated with increased GDS scores among amyloid positive individuals (r=0.117, p=0.002) but not among amyloid negative individuals (r=0.006, p=0.68, Positivity Status x SUVR interaction on GDS: ß=0.817, p=0.029). Increased WMH was associated with higher GDS scores (ß=0.105, p=0.017) but not differentially in amyloid positive and negative participants (Positivity Status x WMH interaction on GDS: ß=-0.010, p=0.243).Conclusions:These analyses have several implications. First, individuals who are screened to participate in a clinical trial but do not have evidence of amyloidosis may be misattributing concerns about underlying AD pathophysiology to depressive symptoms. Second, the severity of AD pathophysiology, indexed by amyloid PET SUVR, may drive a small increase in depressive symptomatology among individuals over visual diagnostic thresholds. Third, small vessel cerebrovascular changes are additionally associated with depressive symptoms but in a manner that is independent of AD pathophysiology. Overall, depressive symptoms and depression are likely multiply determined among prospective clinical trial participants for preclinical AD.

Passive Immunotherapies Targeting Amyloid-β in Alzheimer's Disease: A Quantitative Systems Pharmacology Perspective.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) protein accumulation in the brain. Passive immunotherapies using monoclonal antibodies for targeting Aβ have shown promise for AD treatment. Indeed, recent US FDA approval of aducanumab and lecanemab, alongside positive donanemab Phase III results demonstrated clinical efficacy after decades of failed clinical trials for AD. However, the pharmacological basis distinguishing clinically effective from ineffective therapies remains unclear, impeding development of potent therapeutics. This study aimed to provide a quantitative perspective for effectively targeting Aβ with antibodies. We first reviewed the contradicting results associated with amyloid hypothesis and the pharmacological basis of Aβ immunotherapy. Subsequently, we developed a quantitative systems pharmacology (QSP) model that describes the non-linear progression of Aβ pathology and the pharmacologic actions of the Aβ-targeting antibodies. Using the QSP model, we analyzed various scenarios for effective passive immunotherapy for AD. The model revealed that binding exclusively to the Aβ monomer has minimal effect on Aβ aggregation and plaque reduction, therefore antibody affinity towards Aβ monomer is unwanted, as it could become a distractive mechanism for plaque reduction. Neither early intervention, high brain penetration, nor increased dose alone could yield significant improvement of clinical efficacy for antibodies targeting solely monomers. Antibodies that bind all Aβ species but lack effector function exhibited moderate effects in plaque reduction. Our model highlights the importance of binding aggregate Aβ species and incorporating effector functions for efficient and early plaque reduction, guiding the development of more effective therapies for this devastating disease. Significance Statement Despite previous unsuccessful attempts spanning several decades, passive immunotherapies utilizing monoclonal antibodies for targeting amyloid-beta (Aβ) have demonstrated promise with two recent FDA approvals. However, the pharmacological basis that differentiates clinically effective therapies from ineffective ones remains elusive. Our study offers a Quantitative Systems Pharmacology (QSP) perspective, emphasizing the significance of selectively targeting specific Aβ species and importance of antibody effector functions. This perspective sheds light on the development of more effective therapies for this devastating disease.

Blood Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. The characteristic pathological manifestation of AD includes the deposition of extracellular insoluble β amyloid plaques and intracellular neurofibrillary tangles formed from hyperphosphorylated tau protein. Cost effective and minimally invasive peripheral blood-based biomarkers are critical for early AD diagnosis. Currently, the plasma based two fraction of β amyloid peptide ratio (Aβ42/40) and phosphorylated tau (p-tau) are considered as blood-based biomarkers for AD diagnosis. Recent research indicates that oxidative stress (OS) occurs prior to amyloid plaque (Aβ) formation and abnormal tau phosphorylation in AD. The imbalance of the master antioxidant, glutathione (GSH), and prooxidants (iron, zinc, and copper)─plays a crucial role in AD neurodegeneration. We present peripheral blood-based OS related biomarkers that are mechanistically involved in the disease process and may serve as a novel screening tool for early detection of AD onset. This OS based approach may also provide a quick and cost efficient method to monitor the effects of disease-modifying therapies in AD clinical trials.

Eligibility Rates among Racially and Ethnically Diverse US Participants in Phase 2 and Phase 3 Placebo-Controlled, Double-Blind, Randomized Trials of Lecanemab and Elenbecestat in Early Alzheimer Disease.

Many factors contribute to inadequate diversity in Alzheimer disease (AD) clinical trials. We evaluated eligibility rates among racial and ethnic groups at US sites in large global multisite trials in early AD. Using screening data from 4 randomized, double-blind, placebo-controlled clinical trials in early AD, we assessed rates of eligibility among racial and ethnic groups controlling for other demographic covariates. Each trial incorporated positron emission tomography and/or cerebrospinal fluid to evaluate brain amyloid pathology, as well as typical eligibility criteria used in early AD trials. Across the trials, 10,804 US participants were screened: 193 (2%) were of Hispanic ethnicity and Black race, 2,624 (25%) were of Hispanic ethnicity and White race, 118 (1%) were of non-Hispanic ethnicity (NH) and Asian race, 696 (7%) were of NH ethnicity and Black race, and 7,017 (65%) were of NH ethnicity and White race. Data from 156 participants who did not fit into these categories were excluded. Accounting for age, sex, and trial and using NH White participants as a reference group, we observed higher probabilities of ineligibility for amyloid biomarker criteria among Hispanic Black (odds ratio [OR] = 3.20, 95% confidence interval [CI] = 2.11-4.88), Hispanic White (OR = 4.15, 95% CI = 3.58-4.83), NH Asian (OR = 2.35, 95% CI = 1.23-4.55), and NH Black (OR = 3.75, 95% CI = 2.80-5.06) participants. Differential eligibility may contribute to underrepresentation of some minoritized racial and ethnic groups in early AD trials. Amyloid biomarker eligibility is a requirement to confirm the diagnosis of AD and for treatment with amyloid-lowering drugs and differed among racial and ethnic groups. ANN NEUROL 2024;95:288-298.

Effects of informant replacement in Alzheimer's disease clinical trials.

Alzheimer's disease (AD) trials require enrollment with an informant. We assessed relationships between informant replacement and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores across four AD trials. Using generalized estimating equations, we examined associations between replacement and change in ADCS-ADL between successive visits. We used analysis of covariance to estimate the association between replacement and 18-month change from baseline, and an F-test to compare the variance of this change. Among 1336 participants, 63 (≈5%) experienced replacement. Between-visit mean change in ADCS-ADL was 2.44 points lower comparing replacement to stable informants (95% confidence interval [CI]: -3.91, -0.98). The difference in between-visit mean absolute change was 2.38 points (95% CI: 1.24, 3.52). Replacement was not significantly associated with an 18-month change from baseline. The ratio of variances (replacement/stable) was 1.80 (95% CI: 1.19, 2.99). Informant replacement is associated with bias and increased variability between visits and increased variance for overall ADCS-ADL.

Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations.

Alzheimer's disease (AD) staging criteria lack standardized, empirical description. Well-defined AD staging criteria are an important consideration in protocol design, influencing a more standardized inclusion/exclusion criteria and defining what constitutes meaningful differentiation among the stages. However, many trials are being designed on the basis of biomarker features and the two need to be coordinated. The Alzheimer's Association Research Roundtable (AARR) Spring 2021 meeting discussed the implementation of preclinical AD staging criteria, and provided recommendations for how they may best be incorporated into clinical trials research. Discussion also included what currently available tools for global clinical trials may best define populations in preclinical AD trials, and if are we able to differentiate preclinical from clinical stages of the disease. Well-defined AD staging criteria are key to improving early detection, diagnostics, clinical trial enrollment, and identifying statistically significant clinical changes, and researchers discussed how emerging blood biomarkers may help with more efficient screening in preclinical stages.

Psychological Status of the Participants in Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia.

The SARS-CoV2 global pandemic impacted participants in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) risk of SARS-CoV2 infection. To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. The extent of use of mental health team services was explored considering different risk factors, and users and non-users of these services were compared. Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics was used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while the association with hyperlipidemia was negative. A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19.

Capturing Measures That Matter: The Potential Value of Digital Measures of Physical Behavior for Alzheimer's Disease Drug Development.

Alzheimer's disease (AD) is a devastating neurodegenerative disease and the primary cause of dementia worldwide. Despite the magnitude of AD's impact on patients, caregivers, and society, nearly all AD clinical trials fail. A potential contributor to this high rate of failure is that established clinical outcome assessments fail to capture subtle clinical changes, entail high burden for patients and their caregivers, and ineffectively address the aspects of health deemed important by patients and their caregivers. AD progression is associated with widespread changes in physical behavior that have impacts on the ability to function independently, which is a meaningful aspect of health for patients with AD and important for diagnosis. However, established assessments of functional independence remain underutilized in AD clinical trials and are limited by subjective biases and ceiling effects. Digital measures of real-world physical behavior assessed passively, continuously, and remotely using digital health technologies have the potential to address some of these limitations and to capture aspects of functional independence in patients with AD. In particular, measures of real-world gait, physical activity, and life-space mobility captured with wearable sensors may offer value. Additional research is needed to understand the validity, feasibility, and acceptability of these measures in AD clinical research.

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co-pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI-4 aims to address by enrolling a diverse cohort.

Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer's Disease.

Simufilam is a novel oral drug candidate in Phase 3 clinical trials for Alzheimer's disease (AD) dementia. This small molecule binds an altered form of filamin A (FLNA) that occurs in AD. This drug action disrupts FLNA's aberrant linkage to the α7 nicotinic acetylcholine receptor (α7nAChR), thereby blocking soluble amyloid beta1-42 (Aβ42)'s signaling via α7nAChR that hyperphosphorylates tau. Here, we aimed to clarify simufilam's mechanism. We now show that simufilam reduced Aβ42 binding to α7nAChR with a 10-picomolar IC50 using time-resolved fluorescence resonance energy transfer (TR-FRET), a robust technology to detect highly sensitive molecular interactions. We also show that FLNA links to multiple inflammatory receptors in addition to Toll-like receptor 4 (TLR4) in postmortem human AD brains and in AD transgenic mice: TLR2, C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 5 (CCR5), and T-cell co-receptor cluster of differentiation 4 (CD4). These aberrant FLNA linkages, which can be induced in a healthy control brain by Aβ42 incubation, were disrupted by simufilam. Simufilam reduced inflammatory cytokine release from Aβ42-stimulated human astrocytes. In the AD transgenic mice, CCR5-G protein coupling was elevated, indicating persistent activation. Oral simufilam reduced both the FLNA-CCR5 linkage and the CCR5-G protein coupling in these mice, while restoring CCR5's responsivity to C-C chemokine ligand 3 (CCL3). By disrupting aberrant FLNA-receptor interactions critical to AD pathogenic pathways, simufilam may promote brain health.

The relationship between learning slopes and Alzheimer’s Disease biomarkers in cognitively unimpaired participants with and without subjective memory concerns

ABSTRACT Objective: Learning slopes represent serial acquisition of information during list-learning tasks. Although several calculations for learning slopes exist, the Learning Ratio (LR) has recently demonstrated the highest sensitivity toward changes in cognition and Alzheimer’s disease (AD) biomarkers. However, investigation of learning slopes in cognitively unimpaired individuals with subjective memory concerns (SMC) has been limited. The current study examines the association of learning slopes to SMC, and the role of SMC in the relationship between learning slopes and AD biomarkers in cognitively unimpaired individuals. Method: Data from 950 cognitively unimpaired participants from the Alzheimer’s Disease Neuroimaging Initiative (aged 55 to 89) were used to calculate learning slope metrics. Learning slopes among those with and without SMC were compared with demographic correction, and the relationships of learning slopes with AD biomarkers of bilateral hippocampal volume and β-amyloid pathology were determined. Results: Learning slopes were consistently predictive of hippocampal atrophy and β-amyloid deposition. Results were heightened for LR relative to the other learning slopes. Additionally, interaction analyses revealed different associations between learning slopes and hippocampal volume as a function of SMC status. Conclusions: Learning slopes appear to be sensitive to SMC and AD biomarkers, with SMC status influencing the relationship in cognitively unimpaired participants. These findings advance our knowledge of SMC, and suggest that LR – in particular – can be an important tool for the detection of AD pathology in both SMC and in AD clinical trials.