Insights into the pathological basis of dementia from population‐based neuropathology studies

Abstract

The epidemiological neuropathology perspective of population and community‐based studies allows unbiased assessment of the prevalence of various pathologies and their relationships to late‐life dementia. In addition, this approach provides complementary insights to conventional case–control studies, which tend to be more representative of a younger clinical cohort. The Cognitive Function and Ageing Study (CFAS) is a longitudinal study of cognitive impairment and frailty in the general United Kingdom population. In this review, we provide an overview of the major findings from CFAS, alongside other studies, which have demonstrated a high prevalence of pathology in the ageing brain, particularly Alzheimer's disease neuropathological change and vascular pathology. Increasing burdens of these pathologies are the major correlates of dementia, especially neurofibrillary tangles, but there is substantial overlap in pathology between those with and without dementia, particularly at intermediate burdens of pathology and also at the oldest ages. Furthermore, additional pathologies such as limbic‐predominant age‐related TDP‐43 encephalopathy, ageing‐related tau astrogliopathy and primary age‐related tauopathies contribute to late‐life dementia. Findings from ageing population‐representative studies have implications for the understanding of dementia pathology in the community. The high prevalence of pathology and variable relationship to dementia status has implications for disease definition and indicate a role for modulating factors on cognitive outcome. The complexity of late‐life dementia, with mixed pathologies, indicates a need for a better understanding of these processes across the life‐course to direct the best research for reducing risk in later life of avoidable clinical dementia syndromes.

Ageing-Related Neurodegeneration and Cognitive Decline

“…Concomitant pathologies in AD are often neglected in clinical settings, as they are not currently assessable during life. Notably, even in neuropathological settings, not all currently known concomitant alterations are always taken into consideration, and publications prior to 2014 do not include one of the major concomitant alterations, namely, TDP43 [41]. The definite diagnosis of AD is generally given in line with the level of ADNC pathology, as recommended in 2012 (i.e., none, low, intermediate, and high levels), while information about eventual concomitant pathologies might be lacking [6,8,42].…”

Controversial Past, Splendid Present, Unpredictable Future: A Brief Review of Alzheimer Disease History

“…This discussion was initiated by the findings in a Cambridge study in 2000, showing a marked overlap of different pathologies in demented and non-demented individuals [437] and was followed by the description of the TPD43 neuropathology at the turn of this century [438]. In fact, in the new century, several new pathologies are quite well established in the field of dementia [439], mainly the limbic-predominant age-related TDP-43 encephalopathy (LATE), whose prevalence rose to 40% in demented persons [440,441], but other less frequent new pathologies were also delineated [105,256,257,[442][443][444][445][446][447][448]. But the most notable discovery in the pathology of dementia was that the mixed pathology (NFT, SP, plus vascular and other neurodegenerative disorders, such as Lewy bodies, argyrophilic grains, and hippocampal sclerosis) was the most frequent finding in the brain of demented persons [105,174,437,[442][443][444][445][446][447][448][449].…”

“…In fact, in the new century, several new pathologies are quite well established in the field of dementia [439], mainly the limbic-predominant age-related TDP-43 encephalopathy (LATE), whose prevalence rose to 40% in demented persons [440,441], but other less frequent new pathologies were also delineated [105,256,257,[442][443][444][445][446][447][448]. But the most notable discovery in the pathology of dementia was that the mixed pathology (NFT, SP, plus vascular and other neurodegenerative disorders, such as Lewy bodies, argyrophilic grains, and hippocampal sclerosis) was the most frequent finding in the brain of demented persons [105,174,437,[442][443][444][445][446][447][448][449]. These facts changed the previous concept of the AD pathology as the most frequent pathology in elderly dementia, that could be true in young-aged ADAD, but not in the oldest old.…”