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Alzheimer’s disease puzzle remains unsolved despite new findings and theories

Alzheimer’s disease is incurable, relentless and as unstoppable as a steam roller. It is by far the most common form of dementia. Around one million people in Germany suffer from this degenerative brain disease. 105 years after the first description of the disease by the German neuropsychiatrist Alois Alzheimer, the disease still remains a mystery. Around 25,000 researchers worldwide are focusing on Alzheimer’s and are coming up with a broad range of theories and hypotheses on its pathogenesis and potential therapies. This was the tenor of a press conference held by the Alzheimer’s Research Initiative (Alzheimer Forschung Initiative e.V., AFI) during which the work of basic scientists from Ulm was presented.

Alzheimer’s researchers Prof. Dietmar Thal (centre) with his colleagues Irina Lungrin and Ajeot Rijal Upadhaya in their laboratory at the Centre for Clinical Research. © Pytlik

Dietmar Thal from the Institute of Pathology is funded by the Alzheimer’s Research Initiative for his work on the effects of amyloid ß plaques on human brain cells. These short-chain protein aggregates, which are typical of Alzheimer’s disease, are found inside as well as outside nerve cells. The 43-year-old Alzheimer’s expert has been professor of neuropathology at the University of Ulm since 2007. Prior to his current position, Thal spent six years at the University of Bonn as head of an Alzheimer’s workgroup.

Two of the three enzymes known to be involved in Alzheimer’s pathogenesis slice apart the amyloid precursor protein (APP) at the “wrong” sites. (APP was identified by Konrad Beyreuther, a renowned molecular biologist from Heidelberg, in 1986, as the cause of the brain-cell clogging plaques that are typical of Alzheimer’s.) The longer, insoluble APP fragments cannot be naturally removed from the body. They accumulate and stick together, initially forming soluble oligomers, before forming insoluble plaques that attach to neurons and prevent the transmission of signals.

Thal explains that these amyloid ß proteins (Aß proteins) do not accumulate in all brain regions simultaneously. They initially accumulate in the neocortex (cerebral cortex), then in the allocortical regions, the basal ganglia, the midbrain and eventually in the pons and cerebellum. The presence of dense tangles of Tau fibrils and Aß protein plaques in brain nerve cells is generally thought to contribute to disease pathology. Thal believes that these proteins contribute to disease pathology, but have not necessarily anything to do with the age at which people develop Alzheimer’s.

Many, but not all, old people develop Alzheimer’s

In 2008, a Dutch neurologist (Süddt. Zeitung, 10.6.2008: 115 und kein bisschen Alzheimer) refuted the common opinion that humans inevitably develop some form of dementia as they age. This was based on his observations of a female patient who died of cancer at the age of 115, without ever showing any signs of the protein build-up associated with Alzheimer’s disease. However, it is generally agreed that the risk of developing Alzheimer’s increases with age. 95% of all Alzheimer’s patients are over 65 and one in three people over 85 suffer from Alzheimer’s disease. According to the Alzheimer’s Research Initiative, every year around 200,000 people in Germany are diagnosed with Alzheimer’s. It is assumed that there will be around two million Alzheimer patients in Germany alone in 2030.

Thal will conduct further investigations in order to clarify whether only extracellular protein aggregates are toxic or whether intraneural protein aggregates also play a role in the pathogenesis of Alzheimer’s. Thal believes that this will provide him with information on optimal therapeutic targets: therapies need to target plaques with a damaging effect, rather than structures that regulate completely normal processes. Dietmar Thal uses transgenic mouse models for extra- and intracellular Aß protein aggregates and his goal is to identify the cell structures that are the first to be affected. He started his investigations in November 2010 and found that the experimental animals displayed initial nerve cell alterations as soon as five months after the experiments were first started.

Interim results have shown that soluble aggregations of the Aß protein, which consists of between 40 to 42 amino acids, play a major role in the pathogenesis of Alzheimer’s. These findings substantiate the hypothesis that it is the soluble amyloid oligomers rather than the insoluble plaques that contribute to Alzheimer’s pathogenesis. The Alzheimer’s Research Initiative quoted Thomas Bayer, a researcher from Göttingen and member of its advisory board: “Plaques are a kind of waste bin for the toxic Aß protein. It makes sense to counteract the development of Aß protein, but it is therapeutically wiser to leave the protein alone once it is present.” 

In future, Thal’s group of researchers aims to clarify why plaques do not always lead to nerve cell damage, which types of aggregates are toxic and which plaques also occur in healthy human brains. Thal knows of four extracellular plaque subtypes. He also aims to elucidate the interaction between the intracellular plaques and the dense tangle of Tau fibrils.

Hope of finding biomarkers in cerebrospinal fluid

Christine von Arnim, neuroscientist from Ulm and head of the memory consulting hour at the Ulm University Hospital, reported on the importance of biomarkers in cerebrospinal (CSF) fluid for the diagnosis of neurodegenerative diseases such as Alzheimer’s. She reported that the clinical symptoms of neurodegenerative diseases can be derived from CSF alterations, and that neuronal integrity seems to be defective very early on. However, the relationship between these two aspects is still unknown. In addition, there is as yet no answer to the question as to whether the protein plaques or the Tau fibrils mark the onset of disease. Christine von Arnim believes that the presence of biomarkers in the cerebrospinal fluid, which has become part of the “Alzheimer’s Disease and Dementia Guidelines”, are excellently suited for differentiating neurodegenerative diseases from depressions, but less suited for differentiating dementing diseases from one another. Fifty dementing diseases are currently known.

Christine von Arnim has gained fundamental insights into the cellular and molecular mechanisms of APP processing and has used imaging techniques to elucidate interactions between neural proteins involved in Alzheimer progression. These investigations have led to the identification of the GGA3 protein that plays a role in APP transport, which is why this protein is a potential Alzheimer biomarker candidate.

Basic research and clinical application

Thanks to the support of the Heidelberg Academy of Sciences (WIN-Kolleg), von Arnim was able to combine basic research with the clinical work she carries out as part of the memory consulting hour and was thus able to investigate the findings resulting from an interdisciplinary cooperative project (neuropsychology, analytical chemistry) in a cell model. The WIN project “Neuroplasticity and Immunology in the case of Cognitive Deterioration in Old Age” deals with clinically relevant secondary preventive approaches and the role of new biomarkers associated with Alzheimer’s dementia.

Von Arnim believes that the analysis of the association between genetic risk factors (according to AFI information, eight genes) using biomarkers considerably improves the researchers’ understanding of the pathological processes associated with Alzheimer’s disease. In cooperation with geneticists from the Max Planck Institute for Molecular Genetics (Lars Bertram), von Arnim’s group of researchers succeeded in identifying the association of genetic variations with beta amyloid found in cerebrospinal fluid. In future she will use cell cultures for further investigations aimed at developing new therapeutic approaches.

Alterations that are typical of Alzheimer’s are also found in children and young adults

Prof. Heiko Braak came up with new findings. The photo shows Braak with the classification scheme of Alzheimer stages that was named after him. © University of Ulm

New findings by Heiko Braak, visiting scientist at the University of Ulm, have generated a lot of material for discussion. Braak and his colleague and wife Kelly Del Tredici-Braak were the first to detect alterations that are typical of Alzheimer’s in the brains of children and young adults. The couple found tiny Tau protein aggregates in the brain of a six-year-old child. Braak investigated the brains of 42 young people aged between four and 29 years old for the presence of intraneuronal and extracellular protein aggregates associated with Alzheimer’s disease. The findings, which led Braak to develop new theories and question established ones, would initially appear to be of academic interest only, as Braak himself admits.

As things stand at the moment, Alzheimer’s can only be diagnosed in “people whose cerebral cortex displays major damage”, said a frustrated researcher at the press conference. Early disease stages do not reveal visible clinical symptoms. Preclinical symptoms such as those presented by Braak can only be identified from autopsies.

Future research

The Alzheimer researchers agreed that it will be quite some time before Tau protein-specific biomarkers or suitable imaging methods will become available and make it possible to diagnose the protein aggregates in living patients. The renowned Alzheimer’s researcher, however, could not refrain from gently criticising some of his fellow researchers with the rhetorical question as to why researchers around the world had previously mainly focused on beta amyloid proteins, and whether this was down to the fact that extracellular plaques were easier to identify than intracellular Tau fibrils while the patients were still alive.

During his investigations, Braak found Tau protein tangles in around one tenth of all 20- to 30-year-olds; however, he did not find any beta amyloid plaques. He was also able to confirm this in follow-up investigations. Braak firmly believes that this finding relativises the role of beta amyloid plaques, which are seen as the main cause of Alzheimer’s disease. Braak and Kelly Del Tredici-Braak investigated more than 2,000 brains of diseased people of all age groups. In contrast to usual practice, the two researchers not only looked at the cerebral cortex, but also at the brain stem, and found that neurofibrillary tangle formation may start quite early (before puberty or in early adulthood) in a brain area that is known as “locus coeruleus” (subcortical nuclei) rather than in the cerebral cortex.

The theory of infectious Tau protein

Tau pathology of brain hemispheres from the early to the final disease stage © Del Tredici/Braak

The couple found Tau aggregates in the autopsied brain tissue of a six-year-old. Braak concluded from these findings that the Tau protein represented the onset of Alzheimer’s disease and believes that abnormal, i.e. pathological Tau protein, spreads Alzheimer’s disease from one neuron to another, something that he compares with the course of an infection. He then postulated that Tau protein alterations start in the first decade of a person’s life, while clinical symptoms such as forgetfulness or difficulties in orientation tend to develop many decades later.

In 1991, the 73-year-old neuroanatomist developed the “Braak Stages” (and another system for Parkinson’s disease), an internationally applied classification system that describes six stages in Alzheimer’s disease. Braak was the director of the Institute of Clinical Anatomy at the University of Frankfurt until 2002 and has been visiting professor at the Centre for Clinical Research at the University of Ulm since 2009.


Braak, H./Del Tredici, K.: The pathological process underlying Alzheimer's disease in individuals under thirty, in: Acat Neuropathologica (2011), 121/s. 171-181, doi: 10.1007/s00401-010-0789-4)

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