Multiple pathologies are common and related to dementia in the oldest-old: The 90+ Study

Abstract

Objective: The purpose of this study was to examine the role of multiple pathologies in the expression of dementia in the oldest-old.

Methods: A total of 183 participants of The 90+ Study with longitudinal follow-up and autopsy were included in this clinical-pathologic investigation. Eight pathologic diagnoses (Alzheimer disease [AD], microinfarcts, hippocampal sclerosis, macroinfarcts, Lewy body disease, cerebral amyloid angiopathy, white matter disease, and others) were dichotomized. We estimated the odds of dementia in relation to each individual pathologic diagnosis and to the total number of diagnoses. We also examined dementia severity in relation to number of pathologic diagnoses.

Results: The presence of multiple pathologic diagnoses was common and occurred more frequently in those with dementia compared with those without dementia (45% vs 14%). Higher numbers of pathologic diagnoses were also associated with greater dementia severity. Participants with intermediate/high AD pathology alone were 3 times more likely to have dementia (odds ratio = 3.5), but those with single non-AD pathologies were 12 times more likely to have dementia (odds ratio = 12.4). When a second pathology was present, the likelihood of dementia increased 4-fold in those with intermediate/high AD pathology but did not change in those with non-AD pathologies, suggesting that pathologies may interrelate in different ways.

Conclusions: In the oldest-old, the presence of multiple pathologies is associated with increased likelihood and severity of dementia. The effect of the individual pathologies may be additive or perhaps synergistic and requires further research. Multiple pathologies will need to be targeted to reduce the burden of dementia in the population.

Figure 1. Distribution of single and multiple pathologies in oldest-old participants without (A) and with (B) dementia

AD = intermediate/high likelihood of Alzheimer disease; CAA = moderate/severe cerebral amyloid angiopathy; HS = hippocampal sclerosis present; LBD = limbic/neocortical Lewy bodies; macroinfarcts = 2 or more lacunar or large infarcts; microinfarcts = 3 or more microinfarcts; Other includes one participant with glioblastoma and no dementia and one participant with corticobasal degeneration and dementia; SAE = white matter disease/subcortical arteriolosclerotic leukoencephalopathy.

Figure 2. Venn diagram showing the number of oldest-old participants with no pathologies or combinations of 4 different pathologies

AD = intermediate/high likelihood of Alzheimer disease; CAA = cerebral amyloid angiopathy; Other = hippocampal sclerosis, Lewy body disease, one participant with corticobasal degeneration but no other pathologies, and one participant with glioblastoma but no other pathologies; Vascular = 3+ microinfarcts, 2+ macroinfarcts, and subcortical arteriolosclerotic leukoencephalopathy.

Figure 3. Adjusted MMSE score by number of pathologies in participants with dementia

From a linear regression with MMSE score as the outcome, number of pathologies as the main predictor, and adjusted for age at death, sex, interval between last MMSE score and death, and duration of dementia (years between dementia diagnosis and death). Duration of dementia was 4.9 years in people with no pathologies, 4.1 years in people with 1 pathology, 5.0 years in people with 2 pathologies, 6.6 years in people with 3 pathologies, and 6.3 years in people with 4 pathologies. MMSE = Mini-Mental State Examination.