Summary Background Few data on the pathology of cerebral vessel disease, dementia, and cognition are available. We examined the association of cerebral atherosclerosis and arteriolosclerosis ...neuropathology with probable and possible Alzheimer's disease dementia and cognitive function. Methods This cross-sectional study included men and women aged 65 years or older who had yearly clinical assessments and had agreed to brain autopsy at the time of death, as part of one of two cohort studies of ageing (The Religious Orders Study and the Rush Memory and Aging Project). Individuals without dementia or with Alzheimer's disease dementia, and with complete neuropathological data, are included in our analyses. We used neuropsychological data proximate to death to create summary measures of global cognition and cognitive domains. Clinical data recorded between 1994 and 2015 were used to determine presence of Alzheimer's disease dementia. Systematic neuropathological assessments documented the severity of cerebral large vessel (atherosclerosis) and small vessel (arteriolosclerosis) disease. By use of regression analyses adjusted for demographics, gross and microscopic infarcts, and Alzheimer's disease pathology, we examined associations of vessel disease severity (mild, moderate, and severe) with odds of probable and possible Alzheimer's disease dementia and cognitive function. Findings Study enrolment began in January, 1994, and two cohort studies are ongoing. 1143 individuals were included in our analyses (median age at death 88·8 years; 478 42% with Alzheimer's disease dementia). Moderate-to-severe atherosclerosis was present in 445 (39%) individuals, and arteriolosclerosis in 401 (35%) individuals. Each level increase in the severity of atherosclerosis or arteriolosclerosis was associated with significantly higher odds of Alzheimer's disease dementia (odds ratio OR for atherosclerosis 1·33, 95% CI 1·11–1·58; OR for arteriolosclerosis 1·20, 1·04–1·40). Atherosclerosis was associated with lower scores for global cognition (estimate −0·10 SE 0·04, p=0·0096) and four cognitive domains (episodic memory −0·10 0·04, p=0·017; semantic memory −0·11 0·05, p=0·018; perceptual speed −0·14 0·04, p=0·00080; and visuospatial abilities −0·13 0·04, p=0·0080), but not working memory (−0·05 0·04, p=0·21). Arteriolosclerosis was associated with lower scores for global cognition (estimate −0·10 0·03, p=0·0015) and four domains (episodic memory −0·12 0·04, p=0·00090; semantic memory −0·10 0·04, p=0·013; working memory −0·07 0·03, p=0·045; perceptual speed −0·12 0·04, p=0·0012), and a non-significant association was noted for visuospatial abilities (−0·07 0·03, p=0·052). Findings were unchanged in analyses controlling for the presence of APOE ε4 allele or vascular risk factors. Interpretation Cerebral atherosclerosis and arteriolosclerosis are associated with Alzheimer's disease dementia, and are also associated with low scores in most cognitive domains. Cerebral vessel pathology might be an under-recognised risk factor for Alzheimer's disease dementia. Funding US National Institutes of Health.
Objective
Mixed neuropathologies are the most common cause of dementia at the population level, but how different neuropathologies contribute to cognitive decline at the individual level remains ...unknown. We quantified the contribution of 9 neuropathologies to cognitive loss at an individual level.
Methods
Participants (n = 1,079) came from 2 longitudinal clinical–pathologic studies of aging. All completed 2 + cognitive evaluations (maximum = 22), died, and underwent neuropathologic examinations to identify Alzheimer disease (AD), other neurodegenerative diseases, and vascular pathologies. Linear mixed models examined associations of neuropathologies with cognitive decline and estimated the proportion of cognitive loss accounted for by each neuropathology at a person‐specific level.
Results
Neuropathology was ubiquitous, with 94% of participants having 1+, 78% having 2+, 58% having 3+, and 35% having 4+. AD was most frequent (65%) but rarely occurred in isolation (9%). Remarkably, >230 different neuropathologic combinations were observed, each of which occurred in <6% of the cohort. The relative contributions of specific neuropathologies to cognitive loss varied widely across individuals. Although AD accounted for an average of about 50% of the observed cognitive loss, the proportion accounted for at the individual level ranged widely from 22% to 100%. Lewy bodies and hippocampal sclerosis also had potent effects, but again their impacts varied at the person‐specific level.
Interpretation
There is much greater heterogeneity in the comorbidity and cognitive impact of age‐related neuropathologies than currently appreciated, suggesting an urgent need for novel therapeutic approaches that embrace the complexity of disease to combat cognitive decline in old age. Ann Neurol 2018;83:74–83
Objective
The degree to which Alzheimer's versus other neuropathologies contribute to the risk of Alzheimer's dementia is unknown. We examined the risk of Alzheimer's dementia attributable to ...pathologic AD and 8 other neuropathologies.
Methods
Participants (n = 1,161) came from 2 clinical‐pathological studies of aging. Multivariable logistic regression models examined associations of 8 neuropathological indices with Alzheimer's dementia and quantified the percentage of cases attributable to each. Furthermore, because some dementia cases are not driven by common neuropathologies, we re‐estimated the attributable risks after empirically adjusting for such cases.
Results
Of 1,161 persons, 512 (44.1%) had Alzheimer's dementia at time of death. With the exception of microinfarcts, all neuropathological indices were independently associated with greater odds of Alzheimer's dementia. Two hundred ten (41.0%) Alzheimer's dementia cases were attributable to pathological AD. Separately, 8.9% were attributable to macroscopic infarcts, 10.8% to Lewy bodies, 5.2% to hippocampal sclerosis, 11.7% to transactive response DNA‐binding protein 43, 8.1% to cerebral amyloid angiopathy, 6.0% to atherosclerosis, and 5.2% to arteriolosclerosis. A total of 83.3% of cases were attributable to all 8 indices combined. However, after further adjustment for cases driven by other factors, a total of 67.5% of cases were attributable to all 8 neuropathologic indices combined.
Interpretation
Pathological AD accounts for a considerable percentage of Alzheimer's dementia cases, but multiple other neuropathologies also contribute. In total, just over two‐thirds of Alzheimer's dementia cases are attributable to common age‐related neuropathologies, suggesting that other disease and resilience factors are important. ANN NEUROL 2019;85:114–124.
Objective
To investigate the association of hippocampal sclerosis (HS) with TAR‐DNA binding protein of 43kDa (TDP‐43) and other common age‐related pathologies, dementia, probable Alzheimer disease ...(AD), mild cognitive impairment (MCI), and cognitive domains in community‐dwelling older subjects.
Methods
Diagnoses of dementia, probable AD, and MCI in 636 autopsied subjects from the Religious Order Study and the Rush Memory and Aging Project were based on clinical evaluation and cognitive performance tests. HS was defined as severe neuronal loss and gliosis in the hippocampal CA1 and/or subiculum. The severity and distribution of TDP‐43 were assessed, and other age‐related pathologies were also documented.
Results
HS was more common in those aged >90 years (18.0%) compared to younger subjects (9.2%). HS cases commonly coexisted with TDP‐43 pathology (86%), which was more severe (p < 0.001) in HS cases. Although HS also commonly coexisted with AD and Lewy body pathology; only TDP‐43 pathology increased the odds of HS (odds ratio OR = 2.63, 95% confidence interval CI = 2.07–3.34). In logistic regression models accounting for age, TDP‐43, and other common age‐related pathologies, HS cases had higher odds of dementia (OR = 3.71, 95% CI = 1.93–7.16), MCI, and probable AD (OR = 3.75, 95% CI = 2.01–7.02). In linear regression models, including an interaction term for HS and TDP‐43 pathology, HS with coexisting TDP‐43 was associated with lower function in multiple cognitive domains, whereas HS without TDP‐43 did not have statistically significant associations. TDP‐43 without HS was separately related to lower episodic memory.
Interpretation
The combined roles of HS and TDP‐43 pathology are significant factors underlying global cognitive impairment and probable AD in older subjects. Ann Neurol 2015;77:942–952
To assess the burden of mortality attributable to Alzheimer disease (AD) dementia in the United States.
Data came from 2,566 persons aged 65 years and older (mean 78.1 years) without dementia at ...baseline from 2 cohort studies of aging with identical annual diagnostic assessments of dementia. Because both studies require organ donation, ascertainment of mortality was complete and dates of death accurate. Mortality hazard ratios (HRs) after incident AD dementia were estimated per 10-year age strata from proportional hazards models. Population attributable risk percentage was derived to estimate excess mortality after a diagnosis of AD dementia. The number of excess deaths attributable to AD dementia in the United States was then estimated.
Over an average of 8 years, 559 participants (21.8%) without dementia at baseline developed AD dementia and 1,090 (42.4%) died. Median time from AD dementia diagnosis to death was 3.8 years. The mortality HR for AD dementia was 4.30 (confidence interval = 3.33, 5.58) for ages 75-84 years and 2.77 (confidence interval = 2.37, 3.23) for ages 85 years and older (too few deaths after AD dementia in ages 65-74 were available to estimate HR). Population attributable risk percentage was 37.0% for ages 75-84 and 35.8% for ages 85 and older. An estimated 503,400 deaths in Americans aged 75 years and older were attributable to AD dementia in 2010.
A larger number of deaths are attributable to AD dementia in the United States each year than the number (<84,000 in 2010) reported on death certificates.
Objective
Mixed pathologies are common in older persons with dementia. Little is known about mixed pathologies in probable Alzheimer disease (AD) and about the spectrum of neuropathology in mild ...cognitive impairment (MCI). The objective of this study was to investigate single and mixed common age‐related neuropathologies in persons with probable AD and MCI.
Methods
The study included 483 autopsied participants from the Religious Orders Study and the Rush Memory and Aging Project with probable AD (National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria), MCI (amnestic and nonamnestic), or no cognitive impairment. We excluded 41 persons with clinically possible AD and 14 with other dementias. We documented the neuropathology of AD (National Institute on Aging–Reagan criteria), macroscopic cerebral infarcts, and neocortical Lewy body (LB) disease.
Results
Of 179 persons (average age, 86.9 years) with probable AD, 87.7% had pathologically confirmed AD, and 45.8% had mixed pathologies, most commonly AD with macroscopic infarcts (n = 54), followed by AD with neocortical LB disease (n = 19) and both (n = 8). Of the 134 persons with MCI, 54.4% had pathologically diagnosed AD (58.7% amnestic; 49.2% nonamnestic); 19.4% had mixed pathologies (22.7% amnestic; 15.3% nonamnestic). Macroscopic infarcts without pathologically diagnosed AD accounted for 4.5% of probable AD, 13.3% of amnestic MCI, and 18.6% of nonamnestic MCI. Pure neocortical LB disease was uncommon in all persons with cognitive impairment (<6%). Microscopic infarcts (without macroscopic infarcts) were common as a mixed pathology, but rarely accounted for a clinical diagnosis of probable AD (n = 4) or MCI (n = 3).
Interpretation
Clinically diagnosed probable AD and MCI, even amnestic MCI, are pathologically heterogeneous disorders, with many persons exhibiting mixed pathologies. Ann Neurol 2009;66:200–208
The relationship of cerebral vessel pathology to brain microinfarcts is not fully understood. We examined associations of cerebral vessel pathology with microinfarcts among community‐dwelling persons ...who came to autopsy. Brain specimens were derived from 1,066 deceased subjects (mean age‐at‐death = 88 years, 65% women) participating in a cohort study of aging. Microinfarcts were classified by number, age and location. Severity of vessel pathologies was graded semi‐quantitatively. Almost a third of subjects (n = 300; 28%) had at least one chronic microinfarct, including 128 cortical only, 120 subcortical only, and 47 with both. Moderate‐to‐severe atherosclerosis was present in 430 (41%) subjects, arteriolosclerosis in 382 (36%), and amyloid angiopathy in 374 (35%). The odds of one or multiple microinfarct(s) was increased for more severe atherosclerosis (OR =1.22; 95%CI: 1.03–1.45), arteriolosclerosis (OR =1.18; 95%CI: 1.02–1.37) and amyloid angiopathy (OR =1.13; 95%CI: 1.00–1.28). Separately, the odds of subcortical microinfarct(s) was increased for atherosclerosis (OR =1.49; 95%CI: 1.20–1.84) and arteriolosclerosis (OR =1.39; 95%CI: 1.16–1.67) but not amyloid angiopathy; whereas the odds of cortical microinfarct(s) was increased for amyloid angiopathy (OR =1.26; 95%CI: 1.09–1.46) only. While cerebral vessel pathologies are associated with microinfarct burden, atherosclerosis and arteriolosclerosis are associated with subcortical microinfarcts, and amyloid angiopathy with cortical microinfarcts.
We tested the hypothesis that dividing attention would strengthen the ability to detect mild cognitive impairment (MCI) and specific cognitive abilities from Timed Up and Go (TUG) performance in the ...community setting. While wearing a belt-worn sensor, 757 dementia-free older adults completed TUG during two conditions, with and without a concurrent verbal serial subtraction task. We segmented TUG into its four subtasks (i.e., walking, turning, and two postural transitions), and extracted 18 measures that were summarized into nine validated sensor metrics. Participants also underwent a detailed cognitive assessment during the same visit. We then employed a series of regression models to determine the combinations of subtask sensor metrics most strongly associated with MCI and specific cognitive abilities for each condition. We also compared subtask performances with and without dividing attention to determine whether the costs of divided attention were associated with cognition. While slower TUG walking and turning were associated with higher odds of MCI under normal conditions, these and other subtask associations became more strongly linked to MCI when TUG was performed under divided attention. Walking and turns were also most strongly associated with executive function and attention, particularly under divided attention. These differential associations with cognition were mirrored by performance costs. However, since several TUG subtasks were more strongly associated with MCI and cognitive abilities when performed under divided attention, future work is needed to determine how instrumented dual-task TUG testing can more accurately estimate risk for late-life cognitive impairment in older adults.
To examine the associations of physical activity, Alzheimer disease (AD), and other brain pathologies and cognition in older adults.
We studied 454 brain autopsies from decedents in a ...clinical-pathologic cohort study. Nineteen cognitive tests were summarized in a global cognitive score. Total daily physical activity summarized continuous multiday recordings of activity during everyday living in the community setting. A global motor ability score summarized 10 supervised motor performance tests. A series of regression analyses were used to examine associations of physical activity, AD, and other brain pathologies with global cognition proximate to death controlling for age, sex, education, and motor abilities.
Higher levels of total daily activity (estimate 0.148, 95% confidence interval 0.053-0.244, SE 0.049,
= 0.003) and better motor abilities (estimate 0.283, 95% confidence interval, 0.175-0.390, SE 0.055,
< 0.001) were independently associated with better cognition. These independent associations remained significant when terms for AD and other pathologies were added as well as in sensitivity analyses excluding cases with poor cognition or dementia. Adding interaction terms, the associations of total daily activity and motor abilities with cognition did not vary in individuals with and without dementia. The associations of AD and other pathologies with cognition did not vary with the levels of total daily activity or motor abilities.
Physical activity in older adults may provide cognitive reserve to maintain function independent of the accumulation of diverse brain pathologies. Further studies are needed to identify the molecular mechanisms underlying this potential reserve and to ensure the causal effects of physical activity.
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