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.

Keywords: Alzheimer's disease; Lewy body disease; dementia neuropathology; epidemiological neuropathology; population-representative neuropathology; vascular dementia.

FIGURE 1

Comparison of frequency of pathological lesions in individuals with and without dementia in the; A. 2001 dataset (n = 209), B. 2009 dataset (n = 456). NP neuritic plaques, DP diffuse plaques, NFT neurofibrillary tangles, CAA cerebral amyloid angiopathy, hippo/ERC hippocampus and entorhinal cortex. For the Alzheimer‐type lesions, frequencies are for moderate to severe measures according to CERAD.

FIGURE 2

Frequencies of pathology for different pathology types across three age groups, <80 yrs, 80‐89 yrs, >90 yrs shown as separate colour bars. Data from the 2001 dataset. NP neuritic plaques, DP diffuse plaques, NFT neurofibrillary tangles, CAA cerebral amyloid angiopathy, hippo/ERC hippocampus and entorhinal cortex.

FIGURE 3

A. Microinfarct in parietal cortex. B. Severe white matter pallor and vessel with severe arteriolosclerosis, characterised by complete loss of smooth muscle cells (arrow). C. Lacunar infarct in basal ganglia containing numerous foamy macrophages. D. Complicated small vessel disease in basal ganglia; vessel showing lipohyalinosis with foamy macrophages (solid arrow) and sclerosed vessel with blood pigment representing “microhaemorrhage” (open arrow). E. Thorn‐shaped astrocytes, a component of ARTAG, in entorhinal subpial cortex. E. Astrocyte with finely granular tau temporal cortex (arrow). Tau‐positive astrocyte processes present around a capillary (open arrow).

FIGURE 4

Scatterplot of Thal Aβ phase vs Braak and Braak NFT stage allowing identification of variation in relationships of these measures. Areas corresponding to PART‐definite and –possible are outlined with dotted lines. Reproduced from Wharton et al, Acta Neuropathol Commun 2019; 7:198.

FIGURE 5

Multiple pathologies, including neurodegenerative, vascular and ageing mechanisms, commonly coexist in the elderly and can combine to contribute to dementia. Modified from Rahimi and Kovacs 2014. Created with BioRender.com