Alzheimer's Disease – the Most Common Form of Dementia
It starts with small memory gaps: forgetting a recent conversation, a house key that goes astray, a misplaced purse. The earliest observable symptoms of Alzheimer’s disease (AD) are often mistakenly thought to be signs of old age or manifestations of stress. AD is the most common form of dementia among older people. First described by German psychiatrist Alois Alzheimer in 1906, this irreversible, degenerative brain disease slowly destroys memory and thinking skills, eventually leaving patients unable to carry out even the simplest everyday tasks. In 2006 estimates suggested that more than 25 million people worldwide were living with Alzheimer’s disease. This number could pass the 100 million mark by 2050.
Increasing AD risk after the age of 65
Declining memory, especially short-term memory, is usually one of the first signs of AD. In moderate Alzheimer's disease, the damaging processes in the brain worsen and spread to the areas responsible for language, sensory processing, reasoning and behavior. In late-stage AD, the progressive loss of nerve cells in the brain may finally affect the patient’s fine motor skills, bladder, bowel and respiratory functions.
Although scientists know that Alzheimer’s disease involves the progressive failure of nerve cells, they do not yet fully understand the underlying causes. However, there are certain factors that increase a person’s risk of developing AD. Most individuals with the disease are 65 or older, and the likelihood of developing Alzheimer’s doubles about every five years after age 65. Other risk factors include a family history of AD and the inheritance of certain risk genes. Additional factors such as hypertension, high cholesterol, diabetes mellitus, oxidative stress and head traumas may also contribute to the risk of developing AD.
Plaques and tangles – the hallmarks of AD
One of the histopathological hallmarks of AD is the accumulation of extracellular plaques in the brain already very early in the course of the disease, before any symptoms are apparent. These plaques are the result of an abnormal cleavage process of a protein called APP (amyloid precursor protein). Under normal conditions, APP is snipped into three small fragments – alpha-amyloid, beta-amyloid and gamma-amyloid. In the brains of AD patients, however, too much beta-amyloid is produced, which overwhelms the brain’s ability to clear the excess amount of peptide. As a result, beta-amyloid accumulates and forms insoluble amyloid plaques, triggering a series of neurotoxic events and eventually leading to the degeneration of the brain’s nerve cells and to AD.
The second major finding in the Alzheimer's brain is neurofibrillary tangles composed of tau proteins. Tau is a normal component of the structure of nerve cells. In AD, however, phosphate groups become attached to tau (phosphorylation); they change the protein's structure and cause it to form the tangles which are involved in the pathogenesis of AD.
Early diagnosis is key
Although it is so common, Alzheimer's disease often goes unrecognized or is misdiagnosed in its early stages. Yet a precise diagnosis as early as possible is very important – it helps sufferers and families to understand cognitive deficits and behavioral changes better and enables them to prepare for worsening symptoms.
In fact, a definite diagnosis of Alzheimer’s disease is difficult at present. Beta-amyloid, the hallmark of AD, can only be detected post-mortem by autopsy. For a clinical diagnosis, physicians must rely on a number of diagnostic criteria to help them narrow down the likelihood of AD. These include a careful evaluation of the patient’s medical history, standard laboratory tests, a cognitive-state examination as part of neuropsychological testing, and brain imaging. Diagnosis of AD is thus time-consuming and can be especially difficult in patients in the early stages of the disease, in cases of mixed disease (co-morbidity), and in patients with a high IQ. Moreover, post-mortem histopathology studies have shown that the clinical diagnosis of AD is incorrect in 10-30 percent of patients. Thus, there is a high unmet medical need for better and earlier differentiation between the various dementia forms and especially of Alzheimer’s disease.
Approaches to AD therapy
New tools for early and more accurate AD diagnosis may not only help patients and family members to prepare better for the future, but also provide an improved basis for therapy decisions. Treatment of AD is currently based on symptomatic treatment with either acetyl choline esterase inhibitors (AChEIs), or the glutamate transmission modulator memantine. AChEIs are usually indicated for mild-to-moderate AD, while memantine is used to treat moderate-to-severe AD, often in combination with AChEIs. There is growing evidence that consistent early symptomatic treatment with currently available drugs substantially delays nursing-home placement compared to when treatment is initiated later.
While current therapeutic approaches ameliorate the symptoms rather than the underlying neuropathology of AD, the second generation of substances under investigation is to a large extent based on the amyloid hypothesis. They target different steps in the beta-amyloid-generating pathway, on the assumption that beta-amyloid plaques in the brain play an important causative role in nerve-cell degeneration. As with therapies currently available, new approaches are expected to yield maximum benefit when patients are treated early on in disease progression, i.e. before major brain damage has occurred. Moreover, researchers hope that early detection and imaging might help them to monitor the progress of the disease visually and thus provide more detailed information on its formation and impact. This could be used to further develop and improve AD treatment.
“At Bayer we are committed to the development of novel PET tracers contributing to the patient’s benefit,” says Thomas Balzer, MD, and Head of Global Clinical Development at Bayer HealthCare Pharmaceuticals’s Therapeutic Area Diagnostic Imaging. PET imaging with specific tracers may prove to be a valuable visual adjunct to clinical parameters in the differential diagnosis of dementia.
