Harald J Hampel

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Verified

Harald verified their affiliation via an institutional email.

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• MD, PhD, MA, MSc
• Chief Medical Officer & Senior Vice President at Eisai US

MRI-based hippocampus volume, a core feasible biomarker of Alzheimer’s disease (AD), is not yet widely used in clinical patient care, partly due to lack of validation of software tools for hippocampal volumetry that are compatible with routine workflow. Here, we evaluate fully-automated and computationally efficient hippocampal volumetry with FSL-F...

Background Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer’s disease (AD). Objective In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD. Methods Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD co...

In this “centenary” paper, an expert panel revisited Hans Berger’s groundbreaking discovery of human resting state electroencephalographic (rsEEG) alpha rhythms (8–12 Hz) in 1924, his foresight of substantial clinical applications in patients with “senile dementia,” and new developments in the field, focusing on Alzheimer’s disease (AD), the most p...

Background With the recent approval of disease modifying therapies (DMT) for early Alzheimer’s disease, there is a need for prescribing physicians to accurately communicate expectations of treatment effects to patients and their care partners. To better understand potential challenges and solutions to enhance this communication, physicians were sur...

Background PET quantification of brain tau pathology aids in Alzheimer’s disease staging and patient screening. This study assesses whether the phosphorylated to nonphosphorylated plasma Tau217 ratio (pTau217R) predicts regional tau PET standardized uptake value ratio (SUVR) and accurately identifies subjects with different levels of tau accumulati...

Background Timely identification of mild cognitive impairment (MCI) is key to early intervention. While primary care providers are the most likely entry point to detect early signs of MCI, their detection rates are low. Building upon a published study, we used electronic health records (EHR) to develop a clinically enhanced MCI risk prediction algo...

Background Recent advances in diagnostics have made it possible to identify early signs of the pathophysiological changes underlying Alzheimer’s Disease (AD) via blood tests. However, the use of blood‐based biomarkers (BBBMs) for the early detection of AD may be limited in primary care settings despite its potential for wide access and early detect...

Background New innovations take a long time to be utilized into routine healthcare due to intrinsic and practical barriers. Implementation science can identify such barriers and offer potential solutions to speed up this process. Blood‐based biomarkers (BBBMs) may enable scalable confirmation of amyloid pathology in the Alzheimer’s disease (AD) car...

To understand the potential benefits of emerging Alzheimer's disease (AD) therapies within and beyond clinical trial settings, there is a need to advance current outcome measurements into meaningful information relevant to all stakeholders. The relationship between the impact on disease biology and clinically measurable outcomes in cognition, funct...

Background Depression and circadian rhythm disruptions are non-cognitive neuropsychiatric symptoms (NPS) that can appear at any stage of the Alzheimer's disease (AD) continuum. Evidence suggests that NPS are linked to AD pathophysiology and hippocampal dysfunction. Objective To examine structural white matter (WM) connectivity and its association...

BACKGROUND This study examines whether phosphorylated plasma Tau217 ratio (pTau217R) can predict tau accumulation in different brain regions, as measured by positron emission tomography (PET) standardized uptake value ratio (SUVR), for staging Alzheimer's disease (AD). METHODS Plasma pTau217R was measured using immunoprecipitation‐mass spectrometr...

Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically...

Background Neuropsychiatric symptoms (NPS), including depression and circadian rhythm disruptions, are early non‐cognitive markers along the Alzheimer’s Disease (AD) continuum. These pathological states are thought to resemble AD pathogenesis, both of which are characterized by a marked decline in adult hippocampal neurogenesis. Method 96 elderly...

Plasma pTau181, a marker of amyloid and tau burden, was evaluated as a prognostic predictor of clinical decline and Alzheimer's disease (AD) progression of amyloid‐positive (Aβ+) patients with mild cognitive impairment (MCI). The training cohort for constructing the Bayesian prediction models comprised 135 Aβ+ MCI clinical trial placebo subjects. P...

BACKGROUND This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aβ) 42/Aβ40 in predicting brain amyloid levels measured by positron emission tomography (PET) Centiloid (CL) for Alzheimer's disease (AD) staging and screening. METHODS Quantification of plasma pTau217R and Aβ42/Aβ40 employed...

Alzheimer's disease (AD) is a complex, progressive primary neurodegenerative disease. Since pivotal genetic studies in 1993, the ε4 allele of the apolipoprotein E gene (APOE ε4) has remained the strongest single genome-wide associated risk variant in AD. Scientific advances in APOE biology, AD pathophysiology and ApoE-targeted therapies have brough...

Recent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer 's disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generat...

This is a plain language summary of an article published in the journal Brain. People with Alzheimer's disease may receive treatments that target amyloid-β – a protein in the brain that is one of the key characteristics of Alzheimer's disease when it is present in higher levels than normal. This article is about amyloid-related imaging abnormalitie...

Background Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer’s disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. Objective To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. Methods In this retrospect...

Limited evidence exists on the economic burden of individuals who progress from mild cognitive impairment (MCI) to Alzheimer disease and related dementia disorders (ADRD). To assess the all-cause health care resource utilization and costs for individuals who develop ADRD following an MCI diagnosis compared to those with stable MCI. This was a retro...

Background Timely detection and diagnosis of early‐stage Alzheimer’s disease (AD) become increasingly relevant with the introduction of new therapies. Electronic health records (EHR) data present an opportunity to identify cases with elevated risk of undiagnosed cognitive impairment and triage them for further evaluation. Such triage tools are crit...

Background Prediction of longitudinal cognitive decline for patients with mild dementia using baseline characteristics will be useful for designing optimal clinical trials and real‐world patient monitoring. This can be accomplished via machine‐learning models using baseline clinical characteristics. Adding plasma pTau181 and brain region volumes ma...

Background Non‐invasive methods for detecting neurofibrillary tangles that spread throughout the brain are needed for efficiently screening patients in Alzheimer’s disease (AD) clinical trials. This can be accomplished via machine‐learning models using baseline clinical characteristics. Adding plasma pTau181 and brain region volumes may improve det...

Background Indicators of cognitive reserve (CR) moderate the effect of brain pathophysiology on cognitive deficits in the Alzheimer’s Disease (AD) continuum. In a previous study on individuals with subjective memory complaint (SMCs), a condition at risk for AD, from the INSIGHT‐preAD cohort, we found that CR using educational attainment (Edu) as a...

Background As novel therapies emerge, timely detection and diagnosis of early Alzheimer’s disease (AD) become increasingly relevant. While primary care would be the most suitable setting for early detection, diagnosis rates of mild cognitive impairment (MCI) are low and systematic screening of asymptomatic individuals is currently not recommended....

BACKGROUND Models for forecasting individual clinical progression trajectories in early Alzheimer's disease (AD) are needed for optimizing clinical studies and patient monitoring. METHODS Prediction models were constructed using a clinical trial training cohort (TC; n = 934) via a gradient boosting algorithm and then evaluated in two validation co...

Background Identifying individuals with mild cognitive impairment (MCI) who are likely to progress to Alzheimer’s disease and related dementia disorders (ADRD) would facilitate the development of individualized prevention plans. We investigated the association between MCI and comorbidities of ADRD. We examined the predictive potential of these como...

Background Donepezil is an approved therapy for the treatment of Alzheimer’s disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to donepezil differs in m...

Neurological and psychiatric diseases have high degrees of genetic and patho-physiological heterogeneity, irrespective of clinical manifestations. Traditional medical paradigms have focused on late-stage syndromic aspects of these diseases , with little consideration of the underlying biology. Advances in disease modeling and methodological design...

Background Neurosyphilis-associated cognitive and behavioral impairment— historically coined as “general paralysis of the insane”— share clinical and neuroradiological features with the neurodegenerative disease spectrum, in particular Alzheimer’s disease (AD). Anatomopathological similarities have been extensively documented, i.e., neuronal loss,...

Excess accumulation and aggregation of toxic soluble and insoluble amyloid-β species in the brain are a major hallmark of Alzheimer's disease. Randomized clinical trials show reduced brain amyloid-β deposits using monoclonal antibodies that target amyloid-β and have identified magnetic resonance imaging signal abnormalities called amyloid-related i...

Introduction: Alzheimer's disease (AD) is a disease continuum from pathophysiologic, biomarker and clinical perspectives. With the advent of advanced technologies, diagnosing and managing patients is evolving. Methods: A systematic literature review (SLR) of practice guidelines for mild cognitive impairment (MCI) and AD dementia was performed fo...

Timely detection of the pathophysiological changes and cognitive impairment caused by Alzheimer's disease (AD) is increasingly pressing because of the advent of biomarker-guided targeted therapies that may be most effective when provided early in the disease. Currently, diagnosis and management of early AD are largely guided by clinical symptoms. F...

What is this summary about? This plain language summary of an article published in Molecular Psychiatry, reviews the evidence supporting the role of the amyloid-β (Aβ) pathway and its dysregulation in Alzheimer's disease (AD), and highlights the rationale for drugs targeting the Aβ pathway in the early stages of the disease. Why is this important?...

Background Donepezil is an approved therapy for the treatment of Alzheimer’s disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to Donepezil differs in m...

Neurological and psychiatric diseases have high degrees of genetic and pathophysiological heterogeneity, irrespective of clinical manifestations. Traditional medical paradigms have focused on late-stage syndromic aspects of these diseases, with little consideration of the underlying biology. Advances in disease modeling and methodological design ha...

Detection of brain amyloid‐b (Ab) pathology using blood‐based tests would be considerably more convenient for patients, in addition to being a faster and more cost‐effective method for screening and monitoring patients in clinical trials. Using patient screening data from internal clinical trials, we derive signatures for brain Ab detection using p...

Acetylcholinesterase inhibitors (ChEI) are the global standard of care for the symptomatic treatment of Alzheimer's disease (AD) and show significant positive effects in neurodegenerative diseases with cognitive and behavioral symptoms. Although experimental and large-scale clinical evidence indicates the potential long-term efficacy of ChEI, prima...

Background: Increasing evidence indicates that β-secretase 1 (BACE1) activity and concentration in blood are candidate biomarkers for Alzheimer's disease (AD). Investigating potential demographic, biological, and clinical determinants of BACE1 in the blood matrix is the critical step to validate and qualify BACE1 bio-indicators for different conte...

Introduction: This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late-life cognitive decline due to progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker-informed pathophysi...

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, i...

Background: Human neuropathological studies indicate that the pontine nucleus Locus Coeruleus (LC) undergoes significant and early degeneration in Alzheimer's Disease. This line of evidence alongside experimental data suggests that the LC functional/structural decay may represent a critical factor for Alzheimer's Disease pathophysiological and cli...

Converging translational and clinical research strongly indicates that altered immune and inflammatory homeostasis (neuroinflammation) plays a critical pathophysiological role in Alzheimer's disease (AD), across the clinical continuum. A dualistic role of neuroinflammation may account for a complex biological phenomenon, representing a potential ph...

The reconceptualization of Alzheimer’s disease (AD) as a clinical and biological construct has facilitated the development of biomarker-guided, pathway-based targeted therapies, many of which have reached late-stage development with the near-term potential to enter global clinical practice. These medical advances mark an unprecedented paradigm shif...

What is this summary about? This is a plain language summary of an article published in Alzheimer’s & Dementia. It looks at a type of test called a lumbar puncture (also known as spinal tap) used in people suspected of having Alzheimer’s disease or some other form of dementia. This summary focuses on how to do a lumbar puncture safely. Why is this...

What is this summary about? This is a plain language summary of an article published in Nature Reviews Neurology. It explains how Alzheimer's disease is diagnosed. It also looks at whether a newer way to assess people with Alzheimer's disease could help improve how the condition is diagnosed, monitored, and treated. Why is this important? Alzheime...

Introduction: α-syn aggregates represent the pathological hallmark of synucleinopathies as well as a frequent copathology (almost 1/3 of cases) in AD. Recent research indicates a potential role of α-syn species, measured in CSF with conventional analytical techniques, in the differential diagnosis between AD and synucleinopathies (such as DLB). Pi...

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 ris...

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 ris...

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, i...

With population growth and aging, the number of people with dementia and related disorders will grow substantially in the years ahead, bringing with it significant societal, health‐care, and economic challenges. Here, we analyze dementia policies of seven major countries in Asia/Pacific, Europe, and North America to identify opportunities for early...

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. Objective:...

Objective Cholinergic degeneration and β-amyloid contribute to brain atrophy and cognitive dysfunction in Alzheimer’s disease (AD) and Lewy body disease (LBD), but their relationship has not been comparatively evaluated. Methods In this cross-sectional study, we recruited 28 normal controls (NC), 55 patients with AD mild cognitive impairment (MCI)...

Purpose: To test whether correcting for unspecific signal from the cerebral white matter increases the sensitivity of amyloid-PET for early stages of cerebral amyloidosis. Methods: We analyzed 18F-Florbetapir-PET and cerebrospinal fluid (CSF) Aβ42 data from 600 older individuals enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), in...

Introduction: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. Methods: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns,...

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study res...

In oncology, comprehensive omics and functional enrichment studies have led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor’s clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic intervent...

Noninvasive brain stimulation techniques (NiBS) have gathered substantial interest in the study of dementia, considered their possible role in help defining diagnostic biomarkers of altered neural activity for early disease detection and monitoring of its pathophysiological course, as well as for their therapeutic potential of boosting residual cog...

Background The cognitive reserve (CR) moderate the effect of brain pathophysiology on cognitive deficits in Alzheimer's Disease (AD) continuum. In a previous study on individuals with subjective memory complaint (SMCs), a condition at risk for AD, from the INSIGHT‐preAD cohort, we found that CR altered the association of amyloid load with neurophys...

Background Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ. In a recent multinational, phase 2, double‐blind, placebo‐controlled, study utilizing a Bayesian design with response adaptive randomization, 10‐mg/kg bi‐weekly lecanemab reduced brain Ab levels and slowed decline in cognition a...

Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer’s disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established b...

Introduction The clinical validation and qualification of biomarkers reflecting the complex pathophysiology of neurodegenerative diseases (NDDs) is a fundamental challenge for current drug discovery, development and next-generation clinical practice. Novel ultrasensitive detection techniques and protein misfolding amplification assays hold the pote...

Breakthroughs in the development of highly accurate fluid and neuroimaging biomarkers have catalysed the conceptual transformation of Alzheimer disease (AD) from the traditional clinical symptom-based definition to a clinical–biological construct along a temporal continuum. The AT(N) system is a symptom-agnostic classification scheme that categoriz...

Molecular and brain regional/network-wise pathophysiological changes at preclinical stages of Alzheimer's disease (AD) have primarily been found through knowledge-based studies conducted in late-stage mild cognitive impairment/dementia populations. However, such an approach may compromise the objective of identifying the earliest spatial-temporal p...

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study res...

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of...

Recent advances in developing disease‐modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health‐care systems toward biomarker‐guided early detection, diagnosis, and therapeutic decision‐making. Appropriate incorporation of cere...

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormaliti...

Alzheimer’s disease (AD) is characterized by non-linear, genetic-drivenpathophysiological dynamics with high heterogeneity in biological alterations and disease spatial-temporal progression. Human in-vivo and post-mortem studies point out a failure of multi-level biological networks underlying AD pathophysiology, including proteostasis (amyloid-β a...

Vascular contribution to cognitive impairment (VCI) and dementia is related to etiologies that may affect the neurophysiological mechanisms regulating brain arousal and generating electroencephalographic (EEG) activity. A multidisciplinary expert panel reviewed the clinical literature and reached consensus about the EEG measures consistently found...

Introduction: Tau protein misfolding and accumulation in toxic species is a critical pathophysiological process of Alzheimer's Disease (AD) and other neurodegenerative disorders (NDDs). Tau biomarkers, namely cerebrospinal fluid (CSF) total-tau (t-tau), 181-phosphorylated tau (p-tau) and tau-PET tracers, have been recently embedded in the diagnost...

Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer's disease (AD). A robust body of evidence demonstrates an associat...

Background: Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer's disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE...

The traditional approach to biomarker discovery for any pathology has been through hypothesis-based research one candidate at a time. The objective of this study was to develop an agnostic approach for the simultaneous screening of plasma for consistent molecular differences between a group of individuals exhibiting a pathology and a group of healt...

Background Neurofilament light (NFL) chain and total Tau (t‐Tau) proteins are established biomarkers of axonal degeneration. Increased plasma concentrations of both proteins are associated with worsening rate of cognitive performance, cerebral atrophy, and hypometabolism in prodromal and dementia phases of Alzheimer’s disease (AD). Few studies expl...

Background Parkinson’s disease (PD) is the second‐most common neurodegenerative disorder that affects 2–3% of the population ≥ 65 years of age and may belong to cognitive deficits and dementia in 50% of cases. Disease with Lewy Bodies (DLB) is emerging as another important cause of dementia in pathological aging. PD and DLB are both due to intra‐ne...

Background Neuroinflammation – a crucial early pathomechanistic alteration of Alzheimer's disease (AD) – may represent either a detrimental or a compensatory mechanism or both, based on the disease stage. YKL‐40, a glycoprotein highly expressed in human glia cells, is a candidate biomarker to in vivo track glial‐related neuroinflammation in AD. Few...

Background Cognitive reserve (CR) is present in Alzheimer’s disease (AD) seniors with high education attainment making them clinically resilient to extended brain neuropathology and neurodegeneration. Here we tested whether subjective memory complaint (SMC) seniors with AD neuropathology and high education attainment may present abnormal eyes‐close...

Background The aim of the present study was to investigate the association between brain amyloid β (Aβ) accumulation and cortical microstructural changes in cognitively normal individuals with subjective memory complaints. Method A total of 258 individuals (100 males,158 females) from the Investigation of Alzheimer’s Predictors in Subjective Memor...

Background The preclinical phase of Alzheimer’s disease (AD) is characterized by cortical microstructural changes before the appearance of clinical symptoms. Previous studies have shown that women can present significantly faster age‐related decline than men [Filon et al., 2016; Barnes et al., 2005; Ferretti et al., 2018]. The aim of the present st...