The purpose of this Research Topic is to discuss the latest developments in aging and
neurodegenerative diseases. Aging represents the major risk factor of the two most
relevant neurodegenerative diseases Parkinson’s disease (PD) and Alzheimer’s disease
(AD). It is generally accepted that symptoms of PD correlate with the severity of
degeneration of dopaminergic substantia nigra neurons. In most cases neuronal loss
during aging is not sufficient to cause clinical symptoms but only leads to a preclinical
state of PD. However, in a small number of our population, neurodegeneration
by aging gets accelerated by individual (e.g. brain injuries), environmental (e.g.
toxins) and genetic (e.g. mutations of the alpha-synuclein gene) factors to reach
the critical threshold for clinical symptoms during lifetime. Thus, neurodegeneration
in PD appears to represent the common final pathway of “normal brain aging” and
all other risk factors including genetics and the accumulation of the neurotoxic
alpha-synuclein protein.
While aging alone is generally agreed to be sufficient for at least the preclinical state of
PD, the situation in AD seems to be different. Aging as the major and well documented
risk factor of AD has been neglected for decades. Biochemical mechanisms of brain
aging and the cognitive deficits of “normal brain aging” were seen as two not related
and independent processes not related to AD. AD has always been characterized
for decades by the presence of histopathological alterations (extracellular
amyloid- containing plaques and intracellular tangles of hyperphosphorylated
tau-protein), by neurodegeneration (synaptic deficits and finally neuronal loss), as
well as by severe cognitive deficits clinically often accompanied by neuropsychiatric
symptoms like delusions, as already described in the first famous patient Auguste D
at the Psychiatric Hospital of Frankfurt.
If or if not one or both of the two histopathological hallmarks play a causative role
remains unclear until now. The discovery of homocygotic risk genes in most of
the very rare (probably less than 1%) cases of early onset AD which share increased
production of β-amyloid (Aβ) as one (but probably not the only one) common property
led to the hypothesis of Aβ as the major causative factor for the development of AD.
It was neglected that plaques density in the brain of AD patients did not correlate
with presence and severity of clinical symptoms, while synaptic deficits did so even
in first observations already published many years ago.
Based on the Amyloid hypothesis, many drug treatments to remove Aβ plaques
were developed. Even if all seemed to remove Aβ to some extent, all strategies failed to improve the symptoms of dementia. Thus, other concepts to explain the
development of clinical symptoms of AD over time are needed. These should include
the brain aging process not only as a statistical but also as a causative contributing
factor. These concepts should not only relay on cell or animal models but should
much more take into account the disease and the patients. A closer look at the
situation in PD will certainly be helpful.