Longitudinal clinical–pathological studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) ...as important factors in the development of Alzheimer’s disease (AD) and other forms of dementia. Older persons with AD pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis). These additional pathologies lower the threshold for clinical diagnosis of AD. Many of these findings from pathologic studies, especially for CVD, have been confirmed using sophisticated neuroimaging technologies. In vivo biomarker studies are necessary to provide an understanding of specific pathologic contributions and time course relationships along the spectrum of accumulating pathologies. In this review, we provide a clinical–pathological perspective on the role of multiple brain pathologies in dementia followed by a review of the available clinical and biomarker data on some of the mixed pathologies.
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.
The Religious Orders Study is a longitudinal clinical-pathologic cohort study of aging and Alzheimer's disease (AD). In this manuscript, we summarize the study methods including the study design and ...describe the clinical evaluation, assessment of risk factors, collection of ante-mortem biological specimens, brain autopsy and collection of selected postmortem data.
(1) review the relation of neuropathologic indices to clinical diagnoses and cognition proximate to death; (2) examine the relation of risk factors to clinical outcomes; (3) examine the relation of risk factors to measures of neuropathology; and (4) summarize additional study findings. We then discuss and contextualize the study findings.
Alzheimer’s dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer’s disease (AD) and other brain pathologies. We ...leveraged postmortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. Linear and logistic regressions examined the association of sex with each of the pathologic measures. Two-thirds of subjects were women (
n
= 971; 67%), with a mean age at death of 89.8 (SD = 6.6) years in women and 87.3 (SD = 6.6) in men. Adjusted for age and education, women had higher levels on a global measure of AD pathology (estimate = 0.102, SE = 0.022,
p
< 0.001), and tau tangle density in particular (estimate = 0.334, SE = 0.074,
p
< 0.001), and there was a borderline difference between women and men in amyloid-β load (estimate = 0.124, SE = 0.065,
p
= 0.056). In addition, compared to men, women were more likely to have more severe arteriolosclerosis (OR = 1.28, 95% CI:1.04–1.58,
p
= 0.018), and less likely to have gross infarcts (OR = 0.78, 95% CI:0.61–0.98,
p
= 0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors. These data help elucidate the neuropathologic footprint of sex difference in AD and other common brain pathologies of aging.
The Memory and Aging Project is a longitudinal, epidemiologic clinical-pathologic cohort study of common chronic conditions of aging with an emphasis on decline in cognitive and motor function and ...risk of Alzheimer's disease (AD). In this manuscript, we first summarize the study design and methods. Then, we present data on: (1) the relation of motor function to cognition, disability, and death; (2) the relation of risk factors to cognitive and motor outcomes, disability and death; (3) the relation of neuropathologic indices to cognitive outcomes; (4) the relation of risk factors to neuropathologic indices; and (5) additional study findings. The findings are discussed and contextualized.
Cognitive impairment associated with aging has emerged as one of the major public health challenges of our time. Although Alzheimer's disease is the leading cause of clinically diagnosed dementia in ...Western countries, cognitive impairment of vascular etiology is the second most common cause and may be the predominant one in East Asia. Furthermore, alterations of the large and small cerebral vasculature, including those affecting the microcirculation of the subcortical white matter, are key contributors to the clinical expression of cognitive dysfunction caused by other pathologies, including Alzheimer's disease. This scientific expert panel provides a critical appraisal of the epidemiology, pathobiology, neuropathology, and neuroimaging of vascular cognitive impairment and dementia, and of current diagnostic and therapeutic approaches. Unresolved issues are also examined to shed light on new basic and clinical research avenues that may lead to mitigating one of the most devastating human conditions.
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
Cortical iron has been shown to be elevated in Alzheimer's disease (AD), but the impact of the directly measured iron on the clinical syndrome has not been assessed. We investigated the association ...between post-mortem iron levels with the clinical and pathological diagnosis of AD, its severity, and the rate of cognitive decline in the 12 years prior to death in subjects from the Memory and Aging Project (n = 209). Iron was elevated (β SE = 9.7 2.6; P = 3.0 × 10
) in the inferior temporal cortex only in subjects who were diagnosed with clinical AD during life and had a diagnosis of AD confirmed post-mortem by standardized criteria. Although iron was weakly associated with the extent of proteinopathy in tissue with AD neuropathology, it was strongly associated with the rate of cognitive decline (e.g., global cognition: β SE = -0.040 0.005, P = 1.6 × 10
). Thus, cortical iron might act to propel cognitive deterioration upon the underlying proteinopathy of AD, possibly by inducing oxidative stress or ferroptotic cell death, or may be related to an inflammatory response.
Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of ...disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n
C4b
reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.
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.
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