Population-based analysis of pathological correlates of dementia in the oldest old

Abstract

Objective: The aim of this study was to analyze brain pathologies which cause dementia in the oldest old population.

Methods: All 601 persons aged ≥85 years living in the city of Vantaa (Finland), on April 1st, 1991 formed the study population of the Vantaa85 + study, 300 of whom were autopsied during follow-up (79.5% females, mean age-at-death 92 ± 3.7 years). Alzheimer's disease (AD) pathology (tau and beta-amyloid [Aβ]), cerebral amyloid angiopathy (CAA) and Lewy-related pathologies were analyzed. Brain infarcts were categorized by size (<2 mm, 2-15 mm, >15 mm) and by location. Brain hemorrhages were classified as microscopic (<2 mm) and macroscopic.

Results: 195/300 (65%) were demented. 194/195 (99%) of the demented had at least one neuropathology. Three independent contributors to dementia were identified: AD-type tau-pathology (Braak stage V-VI), neocortical Lewy-related pathology, and cortical anterior 2-15 mm infarcts. These were found in 34%, 21%, and 21% of the demented, respectively, with the multivariate odds ratios (OR) for dementia 5.5, 4.5, and 3.4. Factor analysis investigating the relationships between different pathologies identified three separate factors: (1) AD-spectrum, which included neurofibrillary tau, Aβ plaque, and neocortical Lewy-related pathologies and CAA (2) >2 mm cortical and subcortical infarcts, and (3) <2 mm cortical microinfarcts and microhemorrhages. Multipathology was common and increased the risk of dementia significantly.

Interpretation: These results indicate that AD-type neurodegenerative processes play the most prominent role in twilight cognitive decline. The high prevalence of both neurodegenerative and vascular pathologies indicates that multiple preventive and therapeutic approaches are needed to protect the brains of the oldest old.

Figure 1

The variance in eight quantitative variables, as analyzed using factor analysis: The variables (components) investigated consisted of counts of neurofibrillary tangles (tangles), percentage of cortical thickness covered by methenamine silver‐positive senile plaques (plaques), hemispheric and deep macroscopic infarcts, cortical micro infarcts <2 mm (MI), cortical microhemorrhages (MH), and the severity of cerebral amyloid angiopathy (CAA) in six brain regions, and the presence/absence of neocortical Lewy bodies, as illustrated in a three‐dimensional form. Three factors explaining the variability between the eight components investigated were extracted (Table 2) showing that the cluster of four variables (Factor 1, red color), consisted of tangles, plaques, CAA and the neocortical type of Lewy‐body‐related pathology, explained the majority of the variability between the variables.

Figure 2

Distribution of four dementia‐associated pathologies in demented and nondemented: Distribution and co‐occurrence of the three neuropathologies which associate independently with dementia: Braak stages V‐VI (blue color), neocortical Lewy‐related pathology (green color), and the presence of 2–15 mm infarcts in the anterior cortical regions (yellow color), and severe cerebral amyloid angiopathy (CAA) in the frontal lobe (red color, borderline association). Individual level presentation, one bar represents one subject.