100 years of Alzheimer’s disease research: are we any closer to a cure?

Abstract

Alzheimer’s disease (AD), the most common form of senile dementia, is characterized by a progressive disruption of memory, cognition, functional ability, mood and behavior. At the 100th anniversary of Alois Alzheimer’s (1864–1915) first description of AD, a tremendous amount of scientific insight into this devastating neurological affliction has been obtained; however, many gaps in our knowledge still remain. Our increased life expectancy and the demographics of our aging population cast significant healthcare concerns over the future management of AD. There are currently no curative or preventive treatments for this leading cause of cognitive failure, and pharmacological strategies directed at AD symptoms, and specifically targeted at the progressive and inflammatory nature of this brain degeneration, have met with disappointing results. In the second century of AD research, further objective studies, alternative pharmacological strategies, and the development of more efficacious drugs are clearly required to better address this complex and expanding healthcare problem. Alois Alzheimer first described the clinical and neuropathological findings of a novel neuropsychiatric disorder in a female patient who died of a progressive, atypical, senile psychosis, in 1906 at a meeting of European psychiatrists in Tubingen, Germany [1]. By the time he died, 9 years later, Alzheimer had become the first clinician–neuropathologist to correlate senile plaque (‘miliary foci’) and neurofibrillary tangle (‘fibrillar pathology’) densities with the degree of age-related senile dementia he observed in several AD patients. It is not as well known that Alzheimer also associated a peculiar cerebral vascular vessel involvement (‘focal lesions in the endothelium’) and angiogenesis (‘new vessel formation’) with the ‘steadily progressive disease process’ that now bears his name [1–5]. Over 100 years have passed since these original descriptions of AD; however, it was only in the last 40–50 years that several fundamental discoveries on the basic neuropathology and molecular neurobiology of senile plaques, neurofibrillary tangles and cerebrovascular changes have revolutionized our understanding of AD [2–34]. In part due to the concerns of the healthcare of our aging population, this complex neurological disorder now stands at the forefront of contemporary medical research. The ‘amyloid-β (Aβ) peptide cascade hypothesis’, that is, that Aβ peptide generation, speciation and aggregation, and Aβ peptide’s role as a trigger for brain-specific oxidative stress and inflammatory processes, lies at the very heart of the AD process, has advanced to the extent that the neurobiology of β-amyloid precursor protein (βAPP), and βAPP-derived peptides such as Aβ42, now represent one of the most thoroughly studied aspects of all of brain research [2–10]. However, despite these massive investigative efforts, the defining role of βAPP and Aβ42 peptides in the initiation and progression of AD remains largely unresolved, and the contributory role of neurofibrillary tangle formation to the AD process has received considerably less research attention [3–5]. Several relatively recent findings have not only expanded our insight into the pathogenic mechanisms of the AD process, but have had an impact on the direction of drug research and development and treatment strategies for targeting AD-specific pathways in the brain [3–8,11–19]. These include: