Symptoms of early Alzheimer's disease and new treatment options

In order to establish public discussion on fundamental topics regarding diagnosis, therapy and care of dementia patients that show a concrete need for action, the “Interdisciplinary discussion forum on ethical, economic and medical challenges before the onset of dementia” was founded at the beginning of 2020. found together. Current developments in the therapeutic area are discussed as well as ethical problems, gaps in care and special topics such as the use of biomarkers to risk stratify patients in the early diagnosis of Alzheimer's disease. Interdisciplinary expertise is provided by various actors and experts in the healthcare system from the areas of science, ethics, medical care or healthcare providers, politics as well as self-government institutions and research-based drug manufacturers. In view of current developments in the diagnostic field and in anticipation of the possible approval of disease-modifying therapies, this first publication focuses specifically on the diagnosis of early symptoms of Alzheimer's disease and their requirements for the assessment of therapeutic effectiveness.

background

>> At the end of 2021, almost 1.8 million people were living with dementia in Germany, of which almost 1.2 million were women and 0.6 million men (1, 2). According to estimates by the World Health Organization (WHO), around 55.2 million people worldwide were affected by dementia in 2019, with Europe in second place with 14.1 million people suffering from dementia. The disease is strongly associated with age: data from Europe show an increase in prevalence from 1.9% in 65-69 year olds to over 36% in those over 90 years old (3).
Alzheimer's disease is the most common cause of dementia, with a proportion of up to 80% (4). As a chronic, progressive, degenerative disease of the central nervous system, it is understood as a continuum in which different symptom clusters define the stages of the disease (5). The clinical manifestation and the psychological test evidence, recorded using the previously available cognitive test procedures and methods for assessing everyday skills, are preceded by a long-term preclinical phase (6). The phase of transition from the phase of the continuum without clinical symptoms to detectable clinical symptoms can, in addition to memory disorders, be accompanied by non-specific psychiatric symptoms, e.g. B. Reduced drive or depressed mood. For methodological reasons, the type and extent of these symptoms cannot be adequately recorded in this transition phase. At the beginning of clearly clinically manifest Alzheimer's disease, specific impairments in the consolidation of episodic memory performance occur (amnestic MCI). The more global mild neurocognitive disorder is diagnosed when at least one domain of cognitive performance is impaired while everyday skills are essentially preserved. The mild cognitive disorder and the mild neurocognitive disorder are therefore syndromes in the intermediate range between normal performance and dementia (7). As the disease progresses further, dementia develops, i.e. H. such a significant impairment in areas of cognitive performance that everyday skills are impaired (Fig. 1).
The earliest symptom of clinical Alzheimer's disease is impairment of episodic memory consolidation.
tions, sometimes accompanied by uncharacteristic, partly reactive, partly biologically justified, non-specific neuropsychiatric symptoms. In the case of mild neurocognitive disorder (ICD-11) or mild neurocognitive disorder (DSM-5), there may be deficits in one or more areas - if specific biomarkers are detected (see below), this is Alzheimer's-related mild cognitive disorder. Characteristic amyloid deposits or amyloid peptides can be detected in the brain or cerebrospinal fluid (CSF) (8). Finally, Alzheimer's dementia represents the advanced stage of Alzheimer's disease in the late phase of the disease with increasing loss of cognitive abilities and loss of independence in old age due to impaired everyday functions based on irreversible structural damage to the brain.
The latest prevalence estimates based on current literature research and a model that included biomarker-confirmed pathology of Alzheimer's disease highlight the previously undiscovered proportion of people who are in the early stages of the disease (9). The number of people with preclinical Alzheimer's disease worldwide is estimated at around 315 million, which corresponds to 17% of all people aged ≥50 years (including 52% women); The number of people with prodromal Alzheimer's disease is estimated at approximately 69 million worldwide, which corresponds to 3.7% of all people aged ≥50 years (57% women). These data can be interpreted to mean that the majority of individuals with Alzheimer's pathology do not suffer from dementia but are in the early stages of the disease. Against this background, early detection, information and advice as well as early treatment and prevention of dementia are becoming increasingly important insofar as they are accompanied by specific advice or treatment options. In particular, these numbers make the optimal time window for dementia prevention clear (9).

Pathogenetic process of Alzheimer's disease
During the pathogenetic process, cerebral autoaggregation of amyloid peptides to form amyloid plaques, aggregation of tau fibrils, and neuroinflammation occur, leading to neurodegeneration at the cellular level and clinically to cognitive decline (10, 11). According to the amyloid cascade hypothesis, the appearance of cerebral amyloid deposits precedes tau pathology and is considered a necessary condition for the progression of Alzheimer's disease (12). Furthermore, the changes in the immune system triggered by protein aggregates are an important pathogenetic factor as a driver of neurodegeneration (13). The two neuropathological markers (changed amounts of amyloid-beta peptide and tau protein in the brain or CSF) can be detected long before the first clinical symptoms appear.

Turning point in the treatment of Alzheimer's disease: disease-modifying therapies
So far, only therapies for the symptomatic treatment of Alzheimer's disease in the dementia stage have been approved in Europe. These medications aim to improve or at least stabilize cognitive deficits and everyday skills as well as reduce the behavioral problems associated with dementia.
Over the past 10-15 years, active ingredients have been intensively developed and researched that target the pathophysiology of the neurodegenerative processes in Alzheimer's disease. These so-called disease-modifying therapies (DMT) are specifically aimed at neuropathological molecular processes that are at the beginning of the cascade of pathological events, such as: B. amyloid aggregation (14). Therefore, the concept of DMT for the treatment of Alzheimer's disease specifically targets the early stages using biomarkers as a diagnostic basis. Confirmation of the diagnosis in early stages requires the examination of biomarkers, as the phenotype, e.g. B. in contrast to cognitive deficits in depressive disorders, alone is not sufficient (15).

Early detection of Alzheimer's disease: biomarker candidates
For the chronology of the pathophysiological changes in the course of Alzheimer's disease, Jack et al. 2010 a model supported by many findings, which was realigned several times in the following years and was groundbreaking for the basis of new pharmacological interventions (5, 16, 17). This differentiates between biomarkers for amyloid pathology, tau pathology and neurodegeneration (ATN classification).
To detect amyloid pathology, the pathologically relevant fragment amyloid beta1–42 (Aß1–42) and the Aß42/40 ratio can be determined in the CSF using a lumbar puncture. The Aβ42/40 ratio can improve the sensitivity and specificity of Alzheimer's disease detection compared to Aβ1–42 (18). Another option is to measure the cerebral amyloid level using positron emission tomography (PET). Various studies have been able to demonstrate a correlation between cerebral amyloid tracer binding and a reduced Aβ1–42 concentration or Aβ42/40 ratio in the CSF (19, 20).
Detection of total tau (tTau) protein in CSF indicates neuronal loss and neurodegeneration and correlates with the concentration of phosphorylated tau protein (pTau) in CSF in Alzheimer's disease ( 18 , 21 ). The detection and quantification of tau pathology in Alzheimer's disease is carried out by measuring pTau in the cerebrospinal fluid. To date, only tau-PET tracers that are currently under development are in scientific use to detect cerebral tau deposition. Studies have shown a positive correlation between cerebral tau deposition measured by tau PET and concentrations of pTau and tTau protein in CSF as well as histopathological detection of tau (22–24). When appropriate cognitive testing procedures are used, there are correlations between biomarkers and memory performance (25, 26).
The pattern of brain atrophy can be assessed using structural magnetic resonance imaging (MRI). In particular, medial temporal lobe atrophy is considered typical of neurodegeneration in the presence of Alzheimer's disease. Fluorodeoxyglucose (FDG)-PET can be used to visualize cerebral glucose metabolism, which indicates synaptic dysfunction and the extent of neurodegeneration. Typical of Alzheimer's disease is hypometabolism in the medial parietal lobe (praecuneus) and in the temporoparietal and frontal brain areas (27).
Based on the model of Jack et al. The current understanding is that the disease begins long before symptoms begin with amyloid
deposits begin, which can first be detected by CSF or PET examinations in the preclinical stage. Tau pathology subsequently spreads across the medial temporal lobes and both tTau and pTau concentrations in the CSF become noticeable as this spread to other brain regions; In vivo, the spread can be visualized using Tau-PET. This is followed by neurodegeneration, the result of which - cerebral atrophy - can be detected using MRI and neuronal dysfunction can be detected using FDG-PET.
As neurodegeneration progresses, in addition to the markers of amyloid metabolism and neurodegeneration, cognitive deficits and cerebral atrophy also become measurable (Fig. 2). The impairment begins as a disorder with a mnestic deficit in which everyday functions are still undisturbed. Those affected cannot classify the non-specific impairment that is often present at this time; neither does the currently prevailing routine clinical care.
Diagnostics using amyloid PET is currently only used to a very limited extent outside of the research context. The reimbursement of costs is only granted by the G-BA as part of the ENABLE study in the test phase (28). The subject of the test study is the question of whether patients with a confirmed diagnosis of dementia but an unknown cause benefit from an additional examination using amyloid PET.
The use of blood-based tests could potentially supplement early detection in primary care settings and allow a higher proportion of people to undergo qualified examination in memory clinics. The use of plasma-based biomarkers for early detection is less risky for patients, less complicated to use (even outside specialist centers) and cheaper than, for example, B. PET, MRI or invasive CSF puncture, but not yet validated (29, 30). Blood-based biomarkers have so far only played a role in the research context, although this could change in a few years with the approval of adequate biomarker tests for routine diagnostics and care.
Both the introduction of blood biomarkers into care and the approval of disease-modifying therapies will fundamentally change the therapeutic situation and the diagnostic approach to dementia-related diseases. The coordination of possible therapies with the necessary diagnostic procedures will ultimately require institutional and precise clarification.
Need to adapt the diagnostic approach
In the 1980s, according to the common definition of dementia, the presence of significant everyday deficits in patients was required for both the diagnosis and the therapeutic approach. During this time, neuropsychological tests were used in the form of composite scales that measured the severity of individual clinical deficits in multiple cognitive domains - such as episodic memory, attention and language - by summing up the deficits in these areas.
Drugs are currently being developed that target the pathophysiology of Alzheimer's disease. Active ingredients are being investigated in phase III studies on symptomatic patients with mild cognitive impairment or mild dementia (12). However, clinical proof of effectiveness was only achieved in the most recent study using a drug that targets the pathophysiological process of Alzheimer's disease. These study results (as of December 2022) show for the first time significant clinical results and a connection between an antibody-mediated reduction in amyloid deposits in the brain and a simultaneous slowing of the decline in mental abilities in Alzheimer's patients in early stages. The clinical relevance of the currently published study results is still the subject of discussion.
A possible explanation for the lack of quantitative proof of effectiveness in previous studies is that the drugs were used too late - namely at a stage in which deficits in multiple areas were already present. There are two problems associated with this: the progression of the disease is recorded differently on clinical scales depending on time and severity and thus escapes detection due to a lack of sensitivity (31), and secondly, the tissue damage may have already led to such a pronounced cell death that the The clinical symptoms resulting from the tissue damage can no longer be influenced in a relevant way.
If there is evidence, the development of therapeutic strategies for early stages of the disease requires a change in the diagnostic approach and the assessment of the therapeutic effect. Instead of global scales, specific and sensitive cognitive testing procedures must be used. In the case of Alzheimer's disease, the earliest symptoms are impairment of episodic memory and spatial orientation in unfamiliar environments. Other symptoms, such as apraxia and speech disorders, only appear as the disease progresses (32). Cognitive testing for the early diagnosis of Alzheimer's disease must therefore include detailed testing of episodic memory skills and spatial orientation. In addition to these cognitive testing procedures, biomarker studies must be carried out (15).
At the same time - but independent of the diagnostic procedure and measurement of therapeutic effectiveness - there is a need, for health policy reasons and for reasons of acceptance within the broader medical profession, to demonstrate the prognostic significance of early symptoms and the significance of biomarker diagnostics for clinical symptoms.
The clinical judgment of general practitioners regarding the presence of dementia is more specific than sensitive (33). It is hypothetical - although not yet investigated - that the clinical judgment of doctors with years of experience in dementia diagnosis is also very specific with regard to recognizing the onset of dementia - although less sensitive than with the accompanying use of a standardized procedure aimed at early diagnosis. To date, these findings have not been incorporated into the staged diagnosis of Alzheimer's disease.
Health policy consequences
A significant increase in patients with Alzheimer's disease is expected in the coming years. Due to demographic developments, assuming constant prevalence rates, it is estimated that up to 2.8 million people aged 65 and over in Germany will be suffering from dementia in 2050 (1). According to the Alzheimer Europe organization, the numbers in Western Europe will probably double by 2040 (34), and according to WHO projections, 139 million people worldwide will be living with dementia in 2050 (35). These figures illustrate the explosive nature of the development of this widespread disease, which, as a global epidemic burden, has immense social, economic and health policy effects. According to cost analyses, the social costs of dementia in Europe alone in 2010 are estimated at 105.6 billion euros (36).
Although progress has been made in Germany in recent years
Legislators have taken steps in the right direction, but there is a particular need to catch up in early detection. For example, the National Dementia Strategy promotes many measures to improve care, but with little focus on early intervention. The increasing development of biomarkers for the early detection and prediction of dementia also requires early reflection, including a discourse on ethical, social and legal aspects. Therefore, according to the consensus of the experts of the Interdisciplinary Dementia Forum, it is urgently necessary to open up new avenues for collaboration between practicing doctors and expert centers as well as for infrastructure and logistics.
As early as 2020, the G-BA issued a guideline for testing amyloid PET in dementia (37). In February 2022, study supervision was commissioned to test amyloid PET in dementia in order to ensure quality and close the gap between clinical research and health services research. The German Center for Neurodegenerative Diseases e. V. (DZNE) is supporting the test study on behalf of the G-BA and will evaluate it (28). The results of the test study should enable the G-BA to make a safe decision about the medical benefits of amyloid PET in the presence of dementia of unclear origin. This was a first step in the legislature's decision-making process as to whether this examination method may be provided as a statutory medical service and whether it will be paid for by health insurance companies in the future. In order to implement early diagnosis of Alzheimer's disease for usable therapy, further reforms are necessary to standardize and strengthen diagnostic pathways so that incentives for access, service providers and service providers are aligned. Demands for ethically correct dementia prediction have already been formulated in the joint statement of German associations and specialist societies (38). This includes new impulses for participation-oriented communication, research into the effects of prediction as well as guidelines for laboratories and advice as well as agreements with authorized test providers.
As part of a suitable catalog of measures, it is primarily essential to destigmatize Alzheimer's disease. For example, “Alzheimer’s” continues to be directly linked to the final stage of dementia among patients and doctors. However, the course of Alzheimer's disease shows that it correlates with increasing age and extends over a relatively long period of time, with dementia ultimately characterizing the final stage. However, this is often mistakenly taken to be a characteristic of the entire duration of the disease. Social stigma and a lack of information often prevent patients from seeking help on their own, which often results in patients seeing their doctor late.
The view of Alzheimer's disease therefore requires a different social and medical emphasis. The choice of adequate measuring instruments to test cognitive deficits and the use of biomarkers would allow the early and accurate identification and diagnosis of patients with Alzheimer's disease. Germany should take advantage of the opportunities in both the development and the financial viability of high-quality test procedures for predicting Alzheimer's dementia using biomarkers.
Conclusion
The meaning and task of diagnostics with regard to the detection of dementia has changed. While the task used to be to diagnose and characterize a dementia syndrome at an early stage, today the task and challenge is to diagnose diseases that lead to a dementia syndrome in the pre-dementia stage. For this purpose, specific cognitive test procedures must be used, which are related to the early symptoms of Alzheimer's disease, as well as biomarkers.
Both the diagnostic instruments for measuring the therapeutic effectiveness in the predementia stage, including the selection of endpoints in clinical studies, must be sensitive for this stage - otherwise the possible effectiveness of pathophysiology-oriented drugs could be underestimated and this could lead to a health economic misassessment.
The diagnostic instruments for measuring therapeutic effectiveness in the predementia stage should directly reflect everyday-relevant performance (“ecological validity” of the test procedure) - in this way, cognitive testing is identical to the recording of a patient-relevant endpoint. <<

Author's statement
The above statement was presented and discussed during a video conference with the authors of the “Interdisciplinary Dementia Forum” expert group on December 16, 2022. The implementation of the scientific interdisciplinary discussion forums and the participation of the authors were financially supported by the company Eisai GmbH, Frankfurt. M. Riepe received a fee for preparing the publication, the other authors L. Frölich, J. Gohde, H. Herholz, F. Jessen, H. Rebscher, J. Bausch received no fee. The authors declare that there are no other conflicts of interest. Miss Dr. Andrea Rathmann-Schmitz, MEDAHCON GmbH, Bonn, received reimbursement from Eisai GmbH for the medical writing of the manuscript.

thanksgiving
The authors would like to thank Eisai GmbH for sponsoring the interdisciplinary discussion forums to make the project possible. The authors would also like to thank Dr. Rathmann-Schmitz for editorial support and critical review of the manuscript as part of the publication preparation.