Lutz Frölich

Lutz Frölich
Central Institute of Mental Health | CIMH · Abteilung für Gerontopsychiatrie

M.D. PH.D.

About

680
Publications
88,811
Reads
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24,173
Citations
Citations since 2017
167 Research Items
12666 Citations
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201720182019202020212022202305001,0001,5002,0002,500
201720182019202020212022202305001,0001,5002,0002,500
201720182019202020212022202305001,0001,5002,0002,500
Additional affiliations
July 2003 - present
Central Institute of Mental Health
Position
  • Head of Department
April 1994 - June 2003
University Hospital Frankfurt
Position
  • Attending Physician, Senior Researcher
April 1987 - March 1994
University of Wuerzburg
Position
  • Medical Doctor

Publications

Publications (680)
Article
After years of failed attempts to develop a disease-modifying therapy for Alzheimer's disease, consistent evidence in support of clinical efficacy was finally presented for a monoclonal antibody targeting the amyloid-β protofibrils. In addition to meeting the primary outcome of slowing clinical disease progression over 18 months, secondary clinical...
Article
Background: Apathy is the most frequent neuropsychiatric symptom in patients with dementia of the Alzheimer's type (DAT). We analyzed the influence of apathy on the resource use of DAT patients and their caregivers. Methods: Included were baseline data of 107 DAT patients from a randomized clinical trial on apathy treatment. The Resource Utiliza...
Article
Full-text available
Introduction: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. Methods: We performed whole-exome gene-based rare-variant association studies (RVASs) of...
Article
Full-text available
Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer’s disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau le...
Article
Full-text available
Introduction: Standardized cognitive assessment would enhance diagnostic reliability across memory clinics. An expert consensus adapted the Uniform Dataset (UDS)-3 for European centers, the clinician's UDS (cUDS). This study assessed its implementation acceptability and feasibility. Methods: We developed a survey investigating barriers, facilita...
Article
Introduction: Etiological diagnosis of neurocognitive disorders of middle-old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results....
Article
Full-text available
Background Frailty has been associated with a decline in sensory and motor function. However, given that different frailty measures were shown to overlap but also differ in their diagnostic properties, sensory and motor correlates of frailty might be different depending on the operationalization of frailty. Our objective was to identify sensory and...
Article
Full-text available
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...
Article
Mild cognitive impairment (MCI) is a common problem in old people, which can be distressing for patients and their families. The main feature of MCI is a decrease in cognitive performance with activities of daily living still unimpaired. The identification of treatable risk factors, recognition of early cognitive changes and a timely differential d...
Article
Full-text available
Background: Recent advances occurred in the field of Alzheimer's disease (AD) biomarkers and the introduction of a research framework grounded on a biomarker-based definition of AD might have fostered an increased clinical use of AD biomarkers. For this reason, an up-to-date depiction of the clinical use of AD biomarkers is needed. Objective: To...
Article
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Background: Consideration of many tests from different cognitive domains in defining mild cognitive impairment (MCI) is clinical routine, but guidelines for a neuropsychological operationalization of MCI are lacking. Objective: Among different operational MCI criteria, to identify those which are best in predicting either conversion to dementia,...
Article
Dementias are expensive diseases: the net annual cost in European healthcare is about € 28.000 per case with a strong stage dependency, of which medical care accounts for about 19%. Diagnostic costs, on the other hand, account for only a small proportion of the total costs. With changes in the guidelines, biomarker tests are becoming increasingly i...
Article
Full-text available
ApoE4, the strongest genetic risk factor for Alzheimer’s disease (AD), has been shown to be associated with both beta-amyloid (Aβ) and tau pathology, with the strongest evidence for effects on Aβ, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aβ42,...
Article
Full-text available
The original article [1] contained an error in co-author, Lars Bertram’s affiliation which has since been corrected.
Article
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Introduction: Global estimates on numbers of persons in early stages of Alzheimer's disease (AD), including prodromal and preclinical, are lacking, yet are needed to inform policy decisions on preventive measures and planning for future therapies targeting AD pathology. Methods: We synthesized the literature on prevalence across the AD continuum...
Article
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...
Article
Full-text available
Alzheimer’s disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with t...
Article
Full-text available
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...
Preprint
Full-text available
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...
Article
Alzheimer’s disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer’s disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the...
Article
Full-text available
Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts. Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeho...
Article
Full-text available
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...
Article
Within a 12‐week multicentre randomised controlled trial, standardised data on resource use of patients and their caregivers was collected using the Resource Utilization in Dementia (RUD) instrument. The aim of this study is to evaluate the insufficiently known influence of apathy on resource utilisation in Alzheimer's patients and their caregivers...
Article
The detection rate of people with neurocognitive disorder is low (20‐50%) even in highly developed countries. Early detection is a global priority (Aim 4 of WHO Global Action Plan on Dementia). Among the barriers to timely diagnosis in Europe is the migration status, which is currently increasing in prevalence, limiting access to specific assessmen...
Conference Paper
Alzheimer’s disease (AD) is defined as a clinic‐biological disease characterized by the abnormal deposition of amyloid and tau in the brain. AD biomarkers offer the perspective to confirm the presence of amyloid and tau pathology in vivo and supports their increasing use in clinical practice. The aim of this study is to investigate the clinical use...
Article
Neuropsychological assessment of mild cognitive impairment (MCI), a gateway for the biomarker‐based diagnosis, should follow a standard operating procedure to enhance the reliability of clinical diagnosis across centers and decrease costs to both patients and health‐care systems. A previous consensus adapted the NACC UDS‐3 for use in European memor...
Article
Full-text available
Zusammenfassung Die Alzheimer-Krankheit ist eine der großen Volkskrankheiten mit bisher allein symptomatischen Therapieoptionen. Neue Erkenntnisse zu einem Krankheitskontinuum mit einer sehr langen präklinischen und frühsymptomatischen Krankheitsphase sowie molekulare Therapiestrategien, die auf den Erkenntnissen zur molekularen Neurobiologie der E...
Article
Full-text available
Background: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. Methods: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cere...
Article
Full-text available
Background: Alzheimer's disease (AD) is a significant burden on patients and caregivers. How this burden increases as disease progresses has not been well researched. Objective: To assess the association of caregiver burden and quality of life with Alzheimer's disease severity and disease progression in community-dwelling patients in Germany, Sp...
Article
Full-text available
Introduction: Large studies on cognitive profiles of patients with mild cognitive impair- ment (MCI) due to Alzheimer’s disease (AD-MCI) compared to Parkinson’s disease (PD- MCI) are rare. Methods: Data from two multicenter cohort studies in AD and PD were merged using a unified base rate approach for the MCI diagnosis. Cognitive profiles were comp...
Article
Full-text available
Objective: Given the increasing cultural, linguistic diversity in Europe, there is a growing need for cognitive screening tools that minimize the influence of linguistic, cultural, and demographic differences as they are the first means to determine the need for further clinical evaluation of individuals with suspected cognitive impairment. This c...
Article
We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequen...
Preprint
Full-text available
Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (β-amyloid, total/phosphorylated tau, Nfl, YKL-40, and Neurogranin) to discover genes associated with t...
Article
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...
Article
Full-text available
Background Frailty is characterized by an age-related decline in multiple physiological systems, leading to a high vulnerability to stressors, adverse health outcomes, and low quality of life. Neuroscientific models of pathological aging emphasize the loss of sensorimotor stimulation and reduced neuromodulatory capacities as core processes in age-r...
Article
Full-text available
Alzheimer’s disease (AD) pathology is partly characterized by accumulation of aberrant forms of tau protein. Here we report the results of ADAMANT, a 24-month double-blinded, parallel-arm, randomized phase 2 multicenter placebo-controlled trial of AADvac1, an active peptide vaccine designed to target pathological tau in AD (EudraCT 2015-000630-30)....
Preprint
Full-text available
Background. This study aims to investigate the clinical use of the main Alzheimer’s disease (AD) biomarkers in patients with mild cognitive impairment (MCI) by examining the beliefs and preferences of clinicians and biomarker experts of the European Alzheimer’s Disease Consortium (EADC). Methods. Out of 306 contacted EADC professionals, 150 (101 cl...
Article
Zusammenfassung Die COVID-19-Pandemie stellt die Gesundheitssysteme international vor Herausforderungen, die über Prävention, akute und Intensivbehandlung schwerkranker Patienten hinausgehen. Ein erheblicher Teil derjenigen, die eine akute Infektion überstanden haben – und nicht nur alte Patienten –, leiden unter einem „Post-COVID-Syndrom“. Risikof...
Preprint
BACKGROUND: Physiological differences between males and females could contribute to the development of AD. Here, we examined metabolic pathways that may lead to precision medicine initiatives. METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, CSF biomarkers, brain imaging...
Article
INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured usin...
Article
Full-text available
Background: The COVID-19 pandemic and governmental lockdown measures disproportionally impact older adults. This study presents the results from a psychiatric helpline for older adults in Mannheim, Germany, during the lockdown, set up to provide information and psychosocial support. We aim to elucidate the needs of older adults, their reported cha...
Article
Full-text available
Background: Behavioral and psychological symptoms of dementia (BPSD) are quite challenging problems during the dementia course. Special Care Units for people with dementia (PwD) and BPSD (SCU-B) are residential medical structures, where BPSD patients are temporarily admitted, in case of unmanageable behavioral disturbances at home. Objective: RE...
Article
Background: Crossed cerebellar diaschisis (CCD) is a phenomenon with depressed metabolism and hypoperfusion in the cerebellum. Using arterial spin-labelling perfusion weighted magnetic resonance imaging (ASL PWI), we investigated the frequency of CCD in patients with Alzheimer's disease (AD) and differences between patients with and without CCD....
Article
Full-text available
Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured u...
Article
Full-text available
Background: There exists considerable variation in disease progression rates among patients with Alzheimer's disease (AD). Objective: The primary objective of this observational study is to assess the progression of AD by characterizing cognitive, functional, and behavioral changes during the follow-up period between 6 and 24 months. Methods:...
Article
Introduction The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease (AD). Based on previous results we hypothesized that benefits increase with long‐term intervention. Methods In this randomized, double‐blind, placebo‐controlled tri...
Article
Objective Synaptic loss plays a major role in Alzheimer’s disease (AD). However so far no neurochemical marker for synaptic loss has been introduced into clinical routine. By mass spectrometry beta-synuclein was established as a candidate marker. We now aimed to set up a novel ELISA for beta-synuclein for evaluation of its potential as a diagnostic...
Article
Full-text available
Background/aim: Sodium (23Na) MR imaging is a noninvasive MRI technique that has been shown to be sensitive to visualize biochemical information about tissue viability, their cell integrity, and cell function in various studies. The aim of this study was to evaluate differences in regional brain 23Na signal intensity between Alzheimer's disease (A...
Article
Full-text available
Background and purpose Careful counseling through the diagnostic process and adequate postdiagnostic support in patients with mild cognitive impairment (MCI) is important. Previous studies have indicated heterogeneity in practice and the need for guidance for clinicians. Methods A joint European Academy of Neurology/European Alzheimer’s Disease Co...
Article
Synaptic degeneration is a major hallmark of Alzheimer's disease (AD) and the best pathological correlate of cognitive dysfunction. Synaptic markers are therefore a highly desired read‐out for patient diagnosis and possible follow‐up in clinical trials in the mainly unsuccessful AD drug development. Several synaptic markers for AD are described in...
Article
Alzheimer’s disease is associated with increases in amyloid β and hyperphosphorylated tau which is thought to occur decades before the onset of clinical symptoms, leading to cell loss and inhibition. Finding biomarkers to detect these changes before neuronal loss and therefore permanent damage has occurred is integral. Current biomarkers using cere...
Article
The National Institute on Aging‐Alzheimer’s Association (NIA‐AA) proposed the ATN framework as a classification system for Alzheimer’s disease. The ATN framework helps to inform participant inclusion and potentially trial outcomes as clinical trials are increasingly targeting a range of pathologies. However, it is limited by biomarkers that are eit...
Preprint
Alzheimer’s disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD...
Preprint
Full-text available
Background The COVID-19 pandemic and governmental lockdown measures disproportionally impacts older adults. This study presents the results from a psychiatric helpline for older adults in Mannheim, Germany, during the lockdown, set up to provide information and psychosocial support measures. We aim to elucidate the needs of older adults, their repo...
Preprint
Full-text available
Deciphering the genetic landscape of Alzheimer’s disease (AD) is essential to define the pathophysiological pathways involved and to successfully translate genomics to potential tailored medical care. To generate the most complete knowledge of the AD genetics, we developed through the European Alzheimer’s Disease BioBank (EADB) consortium a discove...
Article
Full-text available
Background Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer’s disease (AD). It is largely unknown whether LPAs are associated with AD pathology and progression from mild cognitive impairment (MCI) to AD. Methods The current study was performed on cerebrospinal fluid (CSF) and plasma samples...
Article
Full-text available
Background Memory clinics (MC) are institutions specialized in the (differential) diagnostics, treatment, education, management and counseling of diseases related to dementia and their risk stages. In Germany, they have a variety of different organizational forms. Due to the growing diagnostic options in neurodegenerative diseases, the increasing d...
Article
Objectives: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counselling, management, and follow-up in European expert centers diagnosing pati...
Article
The etiology of Alzheimer's disease (AD) is under debate since its first description in 1906. Extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of tau protein characterize the histopathology of the disease. The 'amyloid cascade hypothesis' summarizes the molecular mechanisms leadin...
Article
BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein si...
Article
Full-text available
Objective Using standardized tests which have been normed on monolinguals for the assessment of bilinguals presents challenges to the accurate characterization of cognitive profile as the literature provides compelling evidence for the influence of bilingualism on cognitive abilities. However, little is known about the generalizability of these fin...
Article
Full-text available
Background and purpose Dementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important medical management issues including systematic medical follow‐up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia an...
Article
Full-text available
Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer’s disease. However, the temporal dynamics of this decline are inconsistent. Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an imp...
Article
Full-text available
A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R wit...
Article
Full-text available
Importance Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients’ and caregivers’ quality of life. Effective treatment options are needed. Objective To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apath...
Article
Full-text available
Background: Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ε4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation us...