There are many ways in which age-related damage emerges in the brain, and the details of any one individual's cognitive function decline with age is a result of the interactions between all of the processes and specific dysfunctions involved. It is very complicated, which is what you get as the result of simple degenerative mechanisms operating in a complex machine. Think of rust in an intricate metal structure: the complexity of the many possible failure modes is a function of the structure, not the rust. Rust is simple. Aging research aimed at producing therapies should focus on manipulating and fixing the simple things, in other words work on ways to periodically repair the causative damage. If the focus is on the complex things, such as trying to fully understand and manipulate the operation of the brain in a damaged state, then progress will be slow, expensive, and produce only marginal benefits.
Owing to increased life expectancy, understanding the pathogenesis of age-associated cognitive decline is becoming more and more important. There are many causes of dementia, but neurodegenerative diseases are thought to be one of the most prevalent in the aging population. Indeed, during the last century neuropathological examinations, based mostly on silver stainings, have demonstrated that the brains of the majority of the individuals with cognitive decline show Alzheimer's disease (AD)-related pathologies, including neurofibrillary tangles and senile plaques.
The spectrum of mixed brain pathologies expands beyond accompanying vascular pathology in brains with Alzheimer's disease-related pathology. Co-occurrence of neurodegenerative non-Alzheimer's disease-type proteinopathies is increasingly recognized to be a frequent event in the brains of symptomatic and asymptomatic patients, particularly in older people. Owing to the evolving concept of neurodegenerative diseases, clinical and neuropathological diagnostic criteria have changed during the last decades. Autopsy-based studies differ in the selection criteria and also in the applied staining methods used.
The present review summarizes the prevalence of mixed brain pathologies reported in recent community-based studies. In these cohorts, irrespective of the clinical symptoms, the frequency of Alzheimer's disease-related pathology is between 19 and 67%, of Lewy body pathology is between 6 and 39%, of vascular pathologies is between 28 and 70%, of TDP-43 proteinopathy is between 13 and 46%, of hippocampal sclerosis is between 3 and 13% and, finally, of mixed pathologies is between 10 and 74%. Some studies also mention tauopathies. White-matter pathologies are not discussed specifically in all studies, although these lesions may be present in more than 80% of the aging brains.
In summary, community-based neuropathology studies have shown that complex constellations of underlying pathologies may lead to cognitive decline, and that the number of possible combinations increases in the aging brain. These observations have implications for the prediction of the prognosis, for the development of biomarkers or therapy targets, or for the stratification of patient cohorts for genome-wide studies or, eventually, for therapy trials.