Alzheimer's Trials Research Articles

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&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.

Views and perceptions of amyloid imaging in a preclinical Alzheimer’s disease trial

AbstractBackgroundStudies have shown that many cognitively unimpaired older individuals are interested in learning their Alzheimer’s disease (AD) biomarker results. Yet, little is known about what motivates participation in preclinical AD trials that require amyloid biomarker testing and disclosure, and whether these motivations differ by biomarker results (elevated or not‐elevated amyloid).MethodUsing data from the EARLY trial, a preclinical AD trial testing the safety and efficacy of a BACE1 inhibitor, we analyzed participant responses on the Views and Perceptions of Amyloid Imaging (VPAI) scale (Table 1) that was collected during the screening process; that is, before undergoing biomarker testing and disclosure. Participants were asked to rate how important 9 potential reasons for seeking amyloid imaging were to them. Response options included “not at all” (1), “a little” (2), “somewhat” (3), “very” (4), and “extremely” (5). We categorized raw scores into binary responses; those with high endorsement (scores ≥4) and those with low‐to‐moderate endorsement (scores <4). We stratified participant responses by amyloid group to examine whether their biomarker status impacted participant item‐level VPAI scores.ResultPrior to biomarker testing and disclosure, participants most often endorsed the desire to contribute to research as a motivation to participate (Table 1). In general, the not‐elevated amyloid group had higher endorsement for the VPAI items than the elevated amyloid group. The proportions of participants endorsing “confirm feeling that I might be developing dementia” and “preparing family members” were observed to be higher among participants with elevated compared to not‐elevated amyloid; whereas “curiosity” was endorsed by a higher proportion of the not‐elevated amyloid group.ConclusionWhile there are individual differences in reasons for seeking an amyloid scan, preclinical AD trial participants may be largely motivated by altruistic factors. Differences in factors that motivate participants to learn biomarker results may be apparent between amyloid groups even before biomarker disclosure.

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 & 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.

Estimating attrition in mild-to-moderate Alzheimer’s disease and mild cognitive impairment clinical trials

BackgroundParticipant retention is a key factor that affects clinical trial integrity. Trial protocols estimate attrition as a function of sample size calculations. Alzheimer’s disease (AD) is an area of active treatment development. We aimed to quantify the association between trial duration and completion rates and provide guidance for estimating attrition in AD trial protocols.MethodsUsing the Alzforum and ClinicalTrials.gov databases, we analyzed retention data from 125 mild-to-moderate AD and 12 mild cognitive impairment (MCI) clinical trials. We compared the rates of completion between trial arms (active vs. control) and ran regression models to test the hypothesis that trials with longer study duration have lower trial completion using all available data and restricting to placebo data. Our primary outcome was the odds of trial completion for a 6-month increase in trial duration. From the regression model, we estimated the proportion of participants completing 6-, 12-, and 18-month trials.ResultsWe found that 21 (17%) mild-to-moderate AD trials and 1 (8%) MCI trial demonstrated greater dropout in treatment compared to placebo arms. For every 6-month increase in trial duration, there was a 27% decrease in the odds of trial completion (OR = 0.73; 95% CI 0.66, 0.81; p < 0.001) among participants in mild-to-moderate AD trials and a 55% decrease (OR = 0.45; 95% CI 0.36, 0.57; p < 0.001) among participants in MCI trials. The proportion of participants in the placebo group completing 6-, 12-, and 18-month trials were estimated to be 85.2%, 80.0%, and 73.3% for mild-to-moderate AD trials and 91.9%, 84.2%, and 71.3% for MCI trials, respectively.ConclusionsLonger duration trials may be underpowered to demonstrate estimated treatment effects and may suffer from a greater risk of bias than do shorter trials.

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.

3 Ethnoracial Differences in Anchor Agreement and MCID Estimation in Alzheimer’s Disease

Objective:Alzheimer’s disease (AD) clinical trials lack diverse representation, limiting their generalizability. In addition, the clinical meaningfulness of observed changes during treatment may vary as a function of participant characteristics. Defining meaningful change in AD within diverse ethnoracial groups is therefore greatly needed. Meaningful change in AD trials can be assessed by three different anchors: participants, informants, or clinicians. Previous research has suggested that estimations of the minimal clinically important difference (MCID) vary by disease severity, choice of anchor, and anchor agreement. These relationships have been studied primarily within non-Hispanic white (NHW) samples. This project evaluates anchor-based MCID within and across the three most prevalent ethnoracial groups in the United States, non-Hispanic White (NHW), Hispanic/Latino (H/L), and Black/African-American (B/AA).Participants and Methods:Data from the National Alzheimer’s Coordinating Center Uniform Dataset (NACC UDS) were used to investigate MCID within older adults (ages 50+) diagnosed as cognitively normal or cognitively impaired due to suspected AD. Data were taken from all versions of the UDS and consisted of all available participants with two consecutive annual visits. The identified sample (N=22,043) is approximately 83.6% NHW, 4.7% H/L, and 11.7% B/AA. Participant, informant, and clinician anchor variables were utilized to compare proportions of anchor agreement within and across ethnoracial groups. MCID on the Mini-Mental State Exam (MMSE) was estimated within each ethnoracial group and compared across the independent variables of anchor agreement and disease severity (cognitively normal (CN), mild cognitive impairment (MCI), and dementia) in 2x3 ANOVAs.Results:Participant age (M = 71.56, SD = 9.03) did not significantly differ across ethnoracial groups; years of education significantly differed across groups, p &lt; .001, with NHW (M=15.83 SD=3.05), H/L (M=12.49, SD=5.01), and B/AA (M=14.42, SD=3.22). Across all three anchors (participant, informant, clinician), unanimous agreement about the presence or absence of a decline in functioning was present in about 75.1% of the full sample. To further explore agreement differences across groups, anchor agreement was classified into a 3-level variable: 1) agreement that the participant remained stable over time, 2) agreement that the participant declined, and 3) disagreement. The proportion of each level within each ethnoracial group was significantly different, (x2(4, n = 22,043) = 179.16, p &lt; .001, phi = .09, NHW (34.5% agreement-stable, 41.4% agreement-declined, 24.1% disagreement), H/L (30.5%, 42.6%, 26.9%, respectively), and B/AA (42.2%, 28.1%, 29.7%, respectively). MCID estimates on the MMSE followed similar trends within each ethnoracial group. There was a significant main effect of disease severity, such that MCID estimates increased in magnitude with increasing disease severity. There were no significant main effects of anchor agreement for any ethnoracial group. Within the NHW sample only, an interaction effect between diagnostic severity and anchor agreement was significant (p = .007).Conclusions:Across ethnoracial groups, MCID estimates on the MMSE are reliably influenced by the severity of disease. However, the benefit of anchor-based MCID estimates may vary by ethnoracial group with respect to both anchor choice and use of anchor agreement. The origins of anchor disagreement and perceived stability in functioning warrant further exploration.

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.

33 Associations Between Long-Term Forgetting and Slow Wave Activity in Autosomal-Dominant Alzheimer’s Disease: Findings from the Colombia-Boston (COLBOS) Biomarker Study

Objective:Sleep contributes to memory retention and recall. Alzheimer’s disease (AD) patients experience decreased slow wave activity (SWA) during sleep. This decrease in SWA is associated with impaired memory consolidation (Lee et al., 2020). Long-term forgetting (LTF) over days or weeks has been linked to memory consolidation deficits and has been suggested as an early marker of AD that could be useful for identifying at-risk individuals for preclinical AD trials (Weston et al., 2018). Here, we examined associations between LTF and SWA in a sample of Presenilin-1 (PSEN1) E280A mutation carriers with autosomal dominant Alzheimer’s disease and non-carrier family members. Carriers of this mutation usually develop dementia in their forties (Fuller et al., 2019).Participants and Methods:Fourteen cognitively unimpaired PSEN1-E280A mutation carriers and sixteen age-matched non-carriers (mean age: 34.2 years) from the Colombia-Boston (COLBOS) biomarker study were included. Participants completed an overnight polysomnogram (PSG) and memory testing (NEUROPSI Word List) at 3-time points: 1) the night before PSG: immediate recall (Day1-ImmRecall) and a 20-minute delayed recall (Day1-DelayedRecall), 2) recall the following day (Day2-recall), and 3) recall one week later (Day7-recall). SWA was measured as the ratio 0. 6-1Hz/0.6-4Hz in frontopolar and frontotemporal regions and was calculated for sleep stages N2+N3 (slow wave sleep) based on an automated staging algorithm. Each participant’s LTF was calculated as the percent retention between Day 1 immediate recall and Day 7 recall (Butler, 2009). Mann-Whitney U tests were used to compare differences in recall, SWA, and LTF between groups. Spearman’s correlation was used to examine the associations between memory recall at different time points and SWA, as well as between LTF and SWA.Results:On Day 1, carriers had lower performance in immediate recall (p=0.02), compared to non-carriers, but there were no group differences in the 20-minute delayed recall. Carriers also recalled fewer words on Day 2 (p=0.03) and Day 7 (p=0.009) and had greater LTF (p=0.03). There were no group differences in SWA. In our overall sample, worse performance on word list delayed recall on Day 1, Day 2, and Day 7 was associated with less SWA across both frontotemporal (Day1: p=0.04, Day2: p=0.02, Day7: p=0.02) and frontopolar (all Ps&lt;0.01) regions. In carriers, only worse performance on Day 1 delayed recall was associated with lower SWA in the frontopolar region (r= 0.535; p=0.049). Memory recall on other days was not associated with SWA in any brain regions. Additionally, greater LTF was associated with less SWA across both frontopolar (r= 0.507; p=0.005) and frontotemporal regions (r= 0.463 p= 0.01).Conclusions:Preliminary findings suggest that long-term forgetting is associated with less slow- wave activity in preclinical autosomal dominant Alzheimer’s disease. These results also suggest that SWA may be related to pre-sleep learning and subsequent overnight memory consolidation processes. LTF testing may be useful in selecting individuals for preclinical AD trials. Future research on the impact of slow wave activity on LTF may be useful in identifying ways to enhance short- and long-term memory consolidation in individuals at greater risk for dementia.

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.

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.

Re-Addressing Dementia by Network Medicine and Mechanism-Based Molecular Endotypes.

Alzheimer's disease (AD) and other forms of dementia are together a leading cause of disability and death in the aging global population, imposing a high personal, societal, and economic burden. They are also among the most prominent examples of failed drug developments. Indeed, after more than 40 AD trials of anti-amyloid interventions, reduction of amyloid-β (Aβ) has never translated into clinically relevant benefits, and in several cases yielded harm. The fundamental problem is the century-old, brain-centric phenotype-based definitions of diseases that ignore causal mechanisms and comorbidities. In this hypothesis article, we discuss how such current outdated nosology of dementia is a key roadblock to precision medicine and articulate how Network Medicine enables the substitution of clinicopathologic phenotypes with molecular endotypes and propose a new framework to achieve precision and curative medicine for patients with neurodegenerative disorders.

Precision Medicine for Preventing Alzheimer's Disease: Analysis of the ADAPT Study.

The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was the first-ever large-scale anti-inflammatory prevention trial targeting Alzheimer's disease. The overall goal of this study was to evaluate predictive blood biomarker profiles that identified individuals most likely to be responders on NSAID treatment or placebo at 12 and 24 months. Baseline (n = 193) and 12-month (n = 562) plasma samples were assayed. The predictive biomarker profile was generated using SVM analyses with response on treatment (yes/no) as the outcome variable. Baseline (AUC = 0.99) and 12-month (AUC = 0.99) predictive biomarker profiles were highly accurate in predicting response on Celecoxib arm at 12 and 24 months. The baseline (AUC = 0.95) and 12-month (AUC = 0.9) predictive biomarker profile predicting response on Naproxen were also highly accurate at 12 and 24 months. The baseline (AUC = 0.93) and 12-month (AUC = 0.99) predictive biomarker profile was also highly accurate in predicting response on placebo. As with our prior work, the profiles varied by treatment arm. The current results provide additional support for a precision medicine model for treating and preventing Alzheimer's disease.

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.

Validation of 3- and 5-point severity scales to assess ARIA-E.

Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) offer the promise of disease modification and are emerging treatment options in Alzheimer's disease. Anti-Aβ mAbs require brain magnetic resonance imaging (MRI) examinations to detect anti-amyloid-induced amyloid-related imaging abnormalities (ARIA), important adverse drug reactions associated with some anti-Aβ mAbs currently available in the United States and in clinical development. We present a simple rating system for ARIA-edema (ARIA-E) that can assess severity on a 3- or 5-point scale based upon a single linear measurement of the largest area of lesion, and dissemination in space, termed the 3-point Severity Scale of ARIA-E (SSAE-3) and the 5-point Severity Scale of ARIA-E (SSAE-5), respectively. MRI results were collected from 75 participants from the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) studies of gantenerumab. Three neuroradiologists experienced with the detection of ARIA-E were selected to read all cases independently. One rater was then chosen for a second read to assess intra-reader reproducibility. The three raters had high agreement in identifying and grading ARIA-E. The Cohen/Fleiss kappa (κ) scores (95% confidence interval [CI]) for the inter- and intra-reader comparisons for SSAE-3 and SSAE-5 were 0.79 (0.70-1.00), 0.94 (0.94-1.00), 0.73 (0.66-1.00), and 0.90 (0.90-1.00), respectively. Our study suggests that SSAE-3 and SSAE-5 are valid ARIA-E rating scales for use in routine clinical practice by experienced radiologists in specialized settings. The application of these scales in everyday use in clinical practice will support the expansion of anti-Aβ mAbs as a treatment option for people living with Alzheimer's disease. A simple rating scale is needed to rate severity of amyloid-related imaging abnormalities-edema (ARIA-E) in both research and clinical settings.The 3- and 5-point Severity Scales of ARIA-E (SSAE-3/-5) have good inter- and intra-reader agreement.The SSAE-3/-5 have been used in most major Alzheimer's disease (AD) trials to date and are suitable for large-scale use in routine clinical practice, which may help support the expansion of anti-amyloid antibodies as treatment options for AD.

Recruitment methods and yield rates for a multisite clinical trial exploring risk reduction for Alzheimer's disease (rrAD).

The risk reduction for Alzheimer's disease (rrAD) trial was a multisite clinical trial to assess exercise and intensive vascular pharmacological treatment on cognitive function in community-dwelling older adults at increased risk for Alzheimer's disease. Eligibility, consent, and randomization rates across different referral sources were compared. Informal interviews conducted with each site's project team were conducted upon study completion. Initially, 3290 individuals were screened, of whom 28% were eligible to consent, 805 consented to participate (87.2% of those eligible), and 513 (36.3% of those consented) were randomized. Emails sent from study site listservs/databases yielded the highest amount (20.9%) of screened individuals. Professional referrals from physicians yielded the greatest percentage of consented individuals (57.1%). Referrals from non-professional contacts (ie, friends, family; 75%) and mail/phone contact from a site (73.8%) had the highest yield of randomization. Professional referrals or email from listservs/registries were most effective for enrolling participants. The greatest yield of eligible/randomized participants came from non-professional and mail/phone contacts. Future trials should consider special efforts targeting these recruitment approaches. Clinical trial recruitment is commonly cited as a significant barrier to advancing our understanding of cognitive health interventions.The most cited referral source was email, followed by interviews/editorials on the radio, television, local newspapers, newsletters, or magazine articles.The referral method that brought in the largest number of contacts was email but did not result in the greatest yield of consents or eligible participants.The sources that yielded the greatest likelihood of consent were professional referrals (ie, physician), social media, and mail/phone contact from study site.The greatest yield of eligible/randomized participants came from non-professional contacts and mail/phone contact from a site.Findings suggest that sites may need to focus on more selective referral sources, such as using contact mailing and phone lists, rather than more widely viewed recruitment sources, such as social media or TV/radio advertisements.

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.

Alzheimer Disease Biomarkers: Moving from CSF to Plasma for Reliable Detection of Amyloid and tau Pathology.

Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of "core" AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1-42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway. Here we describe the clinical significance of CSF and plasma AD biomarkers to detect disease pathology throughout the Alzheimer continuum and correlate with imaging biomarkers. Use of the AT(N) classification by CSF and imaging biomarkers provides a more objective biologically based diagnosis of AD than clinical diagnosis alone. Significant progress in measuring CSF AD biomarkers using extensively validated highly automated assay systems has facilitated their transition from research use only to approved in vitro diagnostics tests for clinical use. We summarize development of plasma AD biomarkers as screening tools for enrollment and monitoring participants in therapeutic trials and ultimately in clinical care. Finally, we discuss the challenges for AD biomarkers use in clinical trials and precision medicine, emphasizing the possible ethnocultural differences in the levels of AD biomarkers. CSF AD biomarker measurements using fully automated analytical platforms is possible. Building on this experience, validated blood-based biomarker tests are being implemented on highly automated immunoassay and mass spectrometry platforms. The progress made developing analytically and clinically validated plasma AD biomarkers within the AT(N) classification scheme can accelerate use of AD biomarkers in therapeutic trials and routine clinical practice.

Timing of Alzheimer's Disease by Intellectual Disability Level in Down Syndrome.

Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimer's disease (AD). The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site. Analyses involved adults with DS from the Alzheimer's Biomarkers Consortium-Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was based on IQ or mental age scores prior to dementia concerns. PET was acquired using [11C] PiB for Aβ, and [18F] AV-1451 for tau. Cognitive data was available for 361 participants with a mean age of 45.22 (SD = 9.92) and PET biomarker data was available for 154 participants. There was not a significant effect of premorbid ID level by age on cognitive outcomes. There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET. There was not a significant difference in age at time of study visit of those with mild cognitive impairment-DS or dementia by premorbid ID level. Findings provide robust evidence of a similar time course in AD trajectory across premorbid ID levels, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials.

Antibody-Mediated Clearance of Brain Amyloid-β: Mechanisms of Action, Effects of Natural and Monoclonal Anti-Aβ Antibodies, and Downstream Effects.

Immunotherapeutic efforts to slow the clinical progression of Alzheimer's disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither Aβ vaccination nor IVIG slowed disease progression. Despite conflicting phase III results, the monoclonal antibody Aducanumab received Food and Drug Administration (FDA) approval for treatment of AD in June 2021. The only treatments unequivocally demonstrated to slow AD progression to date are the monoclonal antibodies Lecanemab and Donanemab. Lecanemab received FDA approval in January 2023 based on phase II results showing lowering of PET-detectable Aβ; phase III results released at that time indicated slowing of disease progression. Topline results released in May 2023 for Donanemab's phase III trial revealed that primary and secondary end points had been met. Antibody binding to Aβ facilitates its clearance from the brain via multiple mechanisms including promoting its microglial phagocytosis, activating complement, dissolving fibrillar Aβ, and binding of antibody-Aβ complexes to blood-brain barrier receptors. Antibody binding to Aβ in peripheral blood may also promote cerebral efflux of Aβ by a peripheral sink mechanism. According to the amyloid hypothesis, for Aβ targeting to slow AD progression, it must decrease downstream neuropathological processes including tau aggregation and phosphorylation and (possibly) inflammation and oxidative stress. This review discusses antibody-mediated mechanisms of Aβ clearance, findings in AD trials involving Aβ vaccination, IVIG, and anti-Aβ monoclonal antibodies, downstream effects reported in those trials, and approaches which might improve the Aβ-clearing ability of monoclonal antibodies.

Clinical effects of Lewy body pathology in cognitively impaired individuals.

There is poor knowledge about the clinical effects of Lewy body (LB) pathology in patients with cognitive impairment, especially when coexisting with Alzheimer's disease (AD) pathology (amyloid-β and tau). Using a seed amplification assay, we analyzed cerebrospinal fluid for misfolded LB-associated α-synuclein in 883 memory clinic patients with mild cognitive impairment or dementia from the BioFINDER study. Twenty-three percent had LB pathology, of which only 21% fulfilled clinical criteria of Parkinson's disease or dementia with Lewy bodies at baseline. Among these LB-positive patients, 48% had AD pathology. Fifty-four percent had AD pathology in the whole sample (17% of mild cognitive impairment and 24% of patients with dementia were also LB-positive). When examining independent cross-sectional effects, LB pathology but not amyloid-β or tau, was associated with hallucinations and worse attention/executive, visuospatial and motor function. LB pathology was also associated with faster longitudinal decline in all examined cognitive functions, independent of amyloid-β, tau, cognitive stage and a baseline diagnosis of dementia with Lewy bodies/Parkinson's disease. LB status provides a better precision-medicine approach to predict clinical trajectories independent of AD biomarkers and a clinical diagnosis, which could have implications for the clinical management of cognitive impairment and the design of AD and LB drug trials.