The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia

Abstract

Background: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population.

Methods: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies.

Findings: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]).

Interpretation: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted.

Funding: Gates Ventures.

Figure 1

Crude prevalence and distributions of the 12 included neuropathologies across cohorts (ACT, CC75C, CFAS FHS, HAAS, and ROSMAP) by age group Cohorts were excluded from comparisons when they did not have data on a specific neuropathology. Neuropathologies are grouped into three groups (low, moderate, and high confidence) illustrating the confidence in harmonisation across cohorts based on an assessment of ascertainment methods and comparisons of crude prevalence. Arteriolosclerosis in CC75C is a binary measure and therefore the two categories correspond to absent and present. ACT=Adult Changes in Thought. CC75C=Cambridge City over-75s Cohort Study. CERAD=Consortium to Establish a Registry for Alzheimer's disease. CFAS=Cognitive Function and Ageing Studies. FHS=Framingham Heart Study. HAAS=Honolulu-Asia Aging Study. LATE-NC=limbic-predominant age-related TDP-43 encephalopathy neuropathologic change. ROSMAP=Religious Orders Study and Memory and Aging Project.

Figure 2

Correlation matrix describing inter-variability of neuropathological measures, summarised across cohorts (ACT, CC75C, CFAS FHS, HAAS, and ROSMAP) Correlations were first assessed within each cohort individually, and then pooled together using random-effects meta-analysis. Each cohort contributed to a given correlation when the pair of variables of interest in each correlation existed within a given dataset and were not perfectly collinear (no zero contingency cells). Numbers are shown when the correlation is statistically significant at the level of α=0·05. ACT=Adult Changes in Thought. CC75C=Cambridge City over-75s Cohort Study. CERAD=Consortium to Establish a Registry for Alzheimer's disease. CFAS=Cognitive Function and Ageing Studies. FHS=Framingham Heart Study. HAAS=Honolulu-Asia Aging Study. LATE-NC=limbic-predominant age-related TDP-43 encephalopathy neuropathologic change. ROSMAP=Religious Orders Study and Memory and Aging Project.

Figure 3

Co-occurrence of six key neuropathologies by clinical dementia status from data pooled across five cohorts (ACT, CC75C, CFAS FHS, and ROSMAP) Each bar represents the number of individuals with a unique combination of pathologies, as indicated by the filled in circles below. Individuals without dementia at death, who had a gap of greater than 2 years between the last study visit and death, were assigned a dementia status of missing in all studies except CFAS and CC75C, which included procedures to contact family informants in such circumstances. ACT=Adult Changes in Thought. CC75C=Cambridge City over-75s Cohort Study. CFAS=Cognitive Function and Ageing Studies. FHS=Framingham Heart Study. LATE-NC=limbic-predominant age-related TDP-43 encephalopathy neuropathologic change. ROSMAP=Religious Orders Study and Memory and Aging Project.