Marwan Noel Sabbagh

INTRODUCTION: Disease‐modifying therapies (DMTs) for Alzheimer's disease (AD) will increase diagnostic demand. A non‐invasive blood‐based biomarker (BBBM) test for detection of amyloid‐β pathology may reduce diagnostic barriers and facilitate DMT initiation.OBJECTIVE: To explore heterogeneity in AD care pathways and potential role of BBBM tests.METHODS: Survey of 213 healthcare professionals/payers in US/China/UK/Germany/Spain/France and two advisory boards (US/Europe).RESULTS: Current diagnostic pathways are heterogeneous, meaning many AD patients are missed while low‐risk patients undergo unnecessary procedures. Confirmatory amyloid testing (cerebrospinal fluid biomarkers/positron emission tomography) is utilized in few patients, resulting in diagnostic/treatment delays. A high negative‐predictive‐value test could streamline the diagnostic pathway by reducing unnecessary procedures in low‐risk patients; supporting confirmatory testing where needed. Imminent approval of DMTs will increase need for fast and reliable AD diagnostic tests.DISCUSSION: An easy‐to‐use, accurate, non‐invasive BBBM test for amyloid pathology could guide diagnostic procedures or referral, streamlining early diagnosis and DMT initiation.Highlights: This study explored AD care pathways and how BBBM may meet diagnostic demands Current diagnostic pathways are heterogeneous, with country and setting variations Many AD patients are missed, while low‐risk patients undergo unnecessary procedures An easy‐to‐use, accurate, non‐invasive BBBM test for amyloid pathology is needed This test could streamline early diagnosis of amyloid pathology and DMT initiation

Background: People with MCI and AD living in rural areas represent an understudied and underserved population in the broader AD landscape. Very little works have been done on rural cohorts by NIA‐designated Alzheimer’s Disease Research Centers (ADRCs) in the past. The Nevada Exploratory ADRC (NVeADRC) is specifically set to study AD and related dementias in rural individuals, and to systematically generate novel data on the clinical features of AD, clinical outcomes, and social determinants of health.Method: The leading scientific objectives of the NVeADRC are to: 1) understand the occurrence of AD and optimize treatment in underserved rural settings; 2) examine risk factors associated with the development of AD in rural areas; and 3) evaluate the trajectories and progression of AD in rural versus urban communities. The NVeADRC will deploy a top‐down strategy to: 1) establish a network of stakeholders and medical partners to increase awareness of dementia in rural communities and enroll rural participants in our research cohort; 2) develop a research enterprise for longitudinal studies on dementia in rural populations; 3) progressively implement a research infrastructure rooted in technology to facilitate standardized clinical data collection from patients in rural areas.Result: The data collected will be part of the National Alzheimer’s Coordinating Center (NACC) and shared with the larger scientific community to ultimately to improve healthcare for patients in rural areas. Target recruitment for the NVeADRC include 20 Mild Cognitive Impairment, 40 dementia due to Alzheimer’s disease and 40 cognitively normal subjects. In addition to the Uniform Data Set 3.0, we intend to collect volumetric MRI, biofluids (blood, saliva, and cerebrospinal fluid), as well as, a series of both static and dynamic social determinants of health on study subjects and their partners. All participants will be followed to voluntary withdrawal or autopsy.Conclusion: The NVeADRC represents a unique, high impact entity within the ADRC network, and will generate high‐quality biomedical data that advance AD/ADRD research on individuals living in underserved rural communities. As we grow our project, we intend to share biospecimens and data with the scientific community.

Purpose of Review: According to the amyloid cascade hypothesis, removing amyloid beta (Aβ) should cure Alzheimer’s disease (AD). In the past three decades, many agents have been tested to try to lower Aβ production, prevent Aβ aggregation, and dissolve Aβ deposits. However, the paucity in definitive preventative or curative properties of these agents in clinical trials has resulted in more avant-garde approaches to therapeutic investigations. Immunotherapy has become an area of focus for research on disease-modifying therapies for neurodegenerative diseases. In this review, we highlight the current clinical development landscape of monoclonal antibody (mAb) therapies that target Aβ plaque formation and removal in AD. Recent Findings: Multiple potential disease-modifying therapeutics for AD are in active development. Targeting Aβ with mAbs has the potential to treat various stages of AD: prodromal, prodromal to mild, mild, and mild to moderate. Monoclonal antibodies discussed here include aducanumab, lecanemab, solanezumab, crenezumab, donanemab, and gantenerumab. Summary: The final decision by the FDA regarding the approval of aducanumab will offer valuable insight into the trajectory of drug development for mAbs in AD and other neurodegenerative diseases. Future directions for improving the treatment of AD will include more inquiry into the efficacy of mAbs as disease-modifying agents that specifically target Aβ peptides and/or multimers. In addition, a more robust trial design for AD immunotherapy agents should improve outcomes such that objective measures of clinical efficacy will eventually lead to higher chances of drug approval.

Introduction: Dementia with Lewy bodies (DLB) is characterized by the toxic accumulation of α-synuclein protein inside neural cells; this results in neurodegeneration which is clinically accompanied by behavioral and psychological changes. DLB shares features with Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD), but also overlaps neurochemically and pathologically with Alzheimer’s disease. Symptomatic treatments for LBD differ in their effectiveness while disease-modifying and curative approaches are much needed. Areas covered: We explore emerging therapeutics for DLB through the lens of repurposing approved drugs and survey their potential for disease modifying actions in DLB. Given the complexity of DLB with multiple pathologies, potential therapeutic targets that could affect Lewy body pathology, or metabolism or neurotransmitters or immunomodulation were surveyed. We queried PubMed and ClinicalTrials.gov searches 2017–2020. Expert opinion: DLB is not simply aredux ofAD or PD; hence, treatments should not be exclusively duplicative ofAD or PD directed treatments. This opens amyriad of possibilities for therapeutic approaches that are disease specific or repurposed.

Background: Informant-based measures are effective screening tools for cognitive impairment. The Alzheimer’s Questionnaire (AQ) is a subjective, informant-based measure that detects amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) with high sensitivity and specificity and has been shown to predict amyloid burden. Objective: To determine whether informant-based report of cognitive decline correlates with hippocampal volume changes in MCI and AD. Methods: Retrospective chart review of 139 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ-Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ-Total. The AQ was used to assign diagnostic status. Thus, the relationship between the AQ and diagnostic status was excluded. Results: The sample include 88 female and 51 male participants. The mean age was 74.37±9.45, mean MOCA was 22.65±4.18, mean education was 14.80±3.35, and mean AQ score was 10.54±5.22. Hippocampal volume and the AQ correlation was r = –0.33 [95%CI –0.47 to –0.17], p < 0.0001. Conclusion: In a mixed-clinical sample of patients presenting to an outpatient memory disorders center, higher endorseme-nts of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision-making and demonstrate an additional relationship between clinical measures and volumetric MRI.

The critical role of primary care clinicians (PCCs) in Alzheimer’s disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease‐modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late‐in‐life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker‐confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker‐defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

Introduction: We examined the association between Alzheimer's disease (AD) and type 2 diabetes mellitus (DM) and hypothesized that diabetes is associated with an increased pathological burden in clinically and pathologically diagnosed AD. Methods: All data were obtained from the Uniform Data Set (UDS) v3, the Neuropathology Data Set, and the Researcher's Data Dictionary‐Genetic Data from the National Alzheimer's Coordinating Center. The dataset (37 cases with diabetes and 1158 cases without) relies on autopsy‐confirmed data in clinically diagnosed AD patients who were assessed for diabetes type in form A5 or D2 during at least one visit. Differences in scores were explored using a general linear model. Effect sizes were calculated using sample means and standard deviations (Cohen's d ). Results: The presence of diabetes was associated with a lower Thal phase of amyloid plaques (A score; 4.6 ± 0.79 vs. 4.3 ± 0.85, P < .05) and lower Braak stage for neurofibrillary degeneration (B score; 5.58 ± 0.72 vs. 5.16 ± 0.96, P < 0.05) but not for density of neocortical neuritic plaques (CERAD score‐C score). The National Institute on Aging–Alzheimer's Association Alzheimer's disease neuropathologic change (ABC score) was not different between AD+DM and AD‐DM. Discussion: This pilot study found a significantly lower Thal phase of amyloid plaques and Braak stage for neurofibrillary degeneration in AD‐confirmed individuals with diabetes compared to those without. Thus type 2 DM is not associated with increased AD pathology in clinically and pathologically confirmed cases of AD.

Introduction: A phase 2b clinical trial, HEADWAY‐DLB, was performed to assess treatment with intepirdine, a serotonin receptor antagonist, in patients with dementia with Lewy bodies (DLB). Methods: HEADWAY‐DLB was a multinational, double‐blind, randomized, placebo‐controlled study. Two hundred sixty‐nine DLB patients were randomized to receive placebo, 70 mg/day intepirdine, or 35 mg/day intepirdine over 24 weeks. The primary endpoint was change from baseline to week 24 on the Unified Parkinson's Disease Rating Scale–Part III (UPDRS‐III). Results: Both intepirdine groups did not demonstrate significant benefits over placebo at 24 weeks on the UPDRS‐III (35 mg/day: P = .1580, 70 mg/day: P = .6069). All other endpoints were not significant. Intepirdine was well tolerated, with a slightly higher incidence of gastrointestinal adverse events observed in the intepirdine groups versus placebo. Discussion: Intepirdine treatment did not lead to improvements over placebo in patients with DLB. As one of the largest DLB studies to date, HEADWAY‐DLB demonstrates that international trials for DLB are feasible within a reasonable timeframe.

Background: Informant‐based measures can be effective screening tools for cognitive impairment. The Alzheimer’s Questionnaire (AQ; Sabbagh et al., 2010) is a subjective, informant‐based measure that captures five cognitive domains associated with Alzheimer’s disease (AD). The AQ detects amnestic mild cognitive impairment (aMCI) and Alzheimer‐type dementia with high sensitivity and specificity, and has also been shown to predict amyloid burden. We hypothesize that a higher AQ score (greater functional impairment) correlates with lower hippocampal volumes.Method: Retrospective chart review of 131 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ‐Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ‐Total. As the AQ was used as a factor in assigning diagnostic status, thus the relationship between the AQ and diagnostic status was excluded from analyses.Result: The analyzed sample was 53% female with a mean of 73.96±10.48 years of age and 14.74±3.51 years of education. Sample means for the MoCA and AQ score were 22.16±4.39 and 10.62±5.29, respectively. Correlation between AQ score and HC volume (as reported as percentile) revealed an inverse relationship, such that higher AQ scores were associated with smaller hippocampal volumes (r =‐0.40 (95% CI ‐0.54 to ‐0.24), p<0.0001).Conclusion: In a mixed‐clinical sample of patients presenting to an outpatient memory disorders center, higher endorsements of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision‐making, and demonstrate an additional relationship with established AD biomarker outcomes with volumetric MRI.