Prevalence of mixed pathologies in the aging brain

Abstract

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.

Figure 1

Frequencies of different brain pathologies reported in the studies discussed in the present review. Box-plot representation of brain pathology frequencies (A) for all study subjects pooled together and (B) separately for individuals with or without (that is, with no) cognitive impairment (CI). AD defined as the frequency of AD-related pathology starting from Braak and Braak stages III to VI or National Institute on Aging–Reagan criteria intermediate or high likelihood, ignoring other pathologies. Mixed pathologies defined as AD plus any other pathology (see also Table 2). AD, Alzheimer’s disease; aSyn, α-synuclein; HS, hippocampal sclerosis; n, number of studies that report any values; TDP, TDP-43 proteinopathy; Vasc, vascular pathology.

Figure 2

Summary of the concept of mixed pathologies. The holistic approach suggests that the number of combinations of different neuropathological substrates might be very high. Different combinations are covered by the umbrella term mixed pathologies. Aβ, amyloid beta; AD, Alzheimer’s disease; ALB, amygdala predominant Lewy body pathology; AGD, argyrophilic grain disease; CAA, cerebral amyloid angiopathy; CBD, corticobasal degeneration; MSA, multiple system atrophy; PSP, progressive supranuclear palsy; TDP-43, TAR DNA-binding protein 43; TPD, tangle-predominant dementia.