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.

Patterns of Tau and α-Synuclein Pathology in the Visual System

“…In addition to evaluating cases with only AD-type tau pathology, we also pooled cases with different concomitant tau pathologies together, since these cases are more representative of ageing in the human brain [35,36]. We detected a weaker correlation between LGN and occipital pathology.…”

Cerebral Multimorbidity in Aging

“…The frequency of neurodegenerative lesions in different studies has been summarized recently 5 . ADrelated pathology, previously suggested to be the most frequent type of cerebral lesions in the elderly, according to the statistical evaluation of 12 community-based studies, based on Braak, CERAD and NIA criteria, ranged from 19 to 67%, while in other studies AD pathology occurred between 42 and 100% 23 .…”

“…Co-occurrence of AD and non-AD type proteinopathies or other superimposed pathologies, in particular cerebrovascular lesions, are frequently occurring in the brains of both cognitively unimpaired and impaired aged individuals, whereas the presence of a single disease is rather the exception than the rule [11][12][13][14] . Multiple pathologies are suggested to interact in promoting cognitive and other clinical symptoms in the aged 5,14,15 . AD, in particular, often presents with comorbid processes, including cerebrovascular disease, Lewy body (LB) pathology, argyrophilic grain disease (AGD), transactivation response DNA binding protein 43 (TDP-43), hippocampal sclerosis, and other non-AD pathologies 5,14,[16][17][18] .…”

“…Multiple pathologies are suggested to interact in promoting cognitive and other clinical symptoms in the aged 5,14,15 . AD, in particular, often presents with comorbid processes, including cerebrovascular disease, Lewy body (LB) pathology, argyrophilic grain disease (AGD), transactivation response DNA binding protein 43 (TDP-43), hippocampal sclerosis, and other non-AD pathologies 5,14,[16][17][18] . Many of these lesions may have been missed clinically despite modern diagnostic criteria 19 and could not be identified at postmortem examination without modern morphological and molecular-biological analyses using revised guidelines for the neuropathological diagnosis of major brain diseases [20][21][22] .…”

“…Although Alzheimer disease (AD) and other neurodegenerative disorders that are caused by deposition of misfolded proteins (proteinopathies) are most prevalent in aged people, about two-thirds of aged human brains contain substantial nonAlzheimer pathology [3][4][5] . Cognitively intact elderlies may show substantial AD-related pathology, while in the oldestold group (age 80+ years) 6,7 , much of cognitive decline may not be due to common neurodegenerative pathologies 8,9 , but to multiple pathologies 10 .…”