Astrocytes preferentially degrade apoE4: Impact on Aβ levels and neuronal plasticity in apoE targeted replacement mice (original) (raw)
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Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status
Journal of Neuropathology & Experimental Neurology, 2012
Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. A-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of AA 1
Neuropathology of Alzheimer disease: pathognomonic but not pathogenic
Acta Neuropathologica, 2006
Neuropathological changes in subjects with dementia are, by deWnition, end-stage phenomena. While such changes allow case characterization and lend themselves to disease classiWcation and modeling, the lesions themselves are not etiological. This truth would appear to be self-evident, yet the medical and scientiWc literature suggests otherwise. Indeed it is now customary to view amyloid plaques in Alzheimer disease as primary etiological, neurotoxic lesions and, hence, removing them (e.g., by immunotherapy) is believed to lead to clinical improvement. The foundation for this line of thinking lies in the existence of rare kindreds with mutations in amyloid-, or mutations believed to be involved in the processing of amyloid-, and then the extrapolation of the inherited condition to sporadic disease. We believe that this overall construct ignores early events that are more critical to onset and progression of sporadic disease. Likewise, we have studied subjects with sporadic Alzheimer disease, as well as early onset familial Alzheimer disease and Down's syndrome, over a spectrum of ages, and have found that markers of oxidative stress precede amyloid deposits in all three conditions. Amyloid and neuroWbrillary pathology in the Alzheimer brain show a decrease in oxidative stress relative to vulnerable but morphologically intact neurons, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. The pathology of neurodegenerative diseases should be viewed as the end-stage consequence, as opposed to cause, of the disease processes, so that early disease processes that are amenable to intervention can be properly recognized and treated.
Journal of Neuropathology & Experimental Neurology, 2012
Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. A-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that
Neuropathology of Cognitively Normal Elderly
Journal of Neuropathology and Experimental Neurology, 2003
Despite general agreement about the boundaries of Alzheimer disease (AD), establishing a maximum limit for Alzheimer-type pathology in cognitively intact individuals might aid in defining more precisely the point at which Alzheimer pathology becomes clinically relevant. In this study, we examined the neuropathological changes in the brains of 39 longitudinally followed, cognitively normal elderly individuals (24 women, 15 men; age range 74-95, median 85 years). Neuropathological changes of the Alzheimer type were quantified by determining neurofibrillary tangle (NFT) staging by the method of Braak and Braak and by quantification of the abundance of diffuse, cored, and neuritic plaque burden using the scheme developed by the Consortium to Establish a Registry for Alzheimer Disease (CERAD). Vascular, Lewy body, and argyrophilic grain pathology were also assessed. We found 34 subjects (87%) with a Braak stage ϽIV; 32 subjects (82%) with less than moderate numbers of cored plaques and 37 subjects (95%) with less than moderate numbers of tau-positive neuritic plaques. Many subjects had moderate or frequent diffuse plaques (n ϭ 19, 49%). By the National Institute on Aging-Reagan Institute (NIA-RI) criteria, none of our cases met criteria for high ''likelihood'' of AD. Four met NIA-RI criteria for intermediate ''likelihood.'' Seven cases met CERAD criteria for possible AD. Nineteen met Khachaturian criteria for AD. Only 1 subject had neocortical Lewy bodies. Small, old infarcts were common, but no subjects had more than 2 of these and none had a single large infarction. Thus, the majority of individuals who are cognitively normal near the time of their death have minimal amounts of tau-positive neuritic pathology (Braak stage ϽIV and neuritic plaques Ͻ6 per ϫ100 field in the most affected neocortical region). The few subjects with more severe AD pathology can be expected based on incidence rates of AD in the very elderly.
Clinicopathologic Studies in Cognitively Healthy Aging and Alzheimer Disease
Archives of Neurology, 1998
To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype.
Risk factors for cognitive decline in healthy older adults
Neurobiology of Aging, 2000
Epidemiology (n=120) were demented at the time of their final examination. Of these 92 met neuropathological criteria for AD. Forty-six sisters met neuropathological criteria for AD, but were not demented at their last assessment. The 2X sisters who were demented, but did not fulfill AD neuropathologlc criteria, had a variety of pathologies, including cerebral infarcts, dementia with Lewy bodies, hydrocephalus and hippocampal sclerosis. APOE-•4,when adjurted for age, education and other variables, was associated with an elevated risk for meeting neuropathologic criteria for AD(OR=S.R. 95% CI: 2.7-12. I). Individuals with one or more ~4 alleles who fulfilled AD neuropathological criteria had a significant increase in dementia risk (OR=6.1,95% Cl: 2.7-13.6) compared to those who neither fulfilled AD neuropathologic criteria nor had t4 alleles. By contrast, in a similar comparison, individuals with ~4 alleles who did not meet AD neuropathologlc criteria were not at increased risk for dementia (OR=O.6, 95% Cl: 0.1-3.2). A series of analyses demonstrated strong associations between the presence of ~4 alleles and the severity of neurofibrillay tangles and senile plaques in the hippocampus and neocmtex. The findmgs indicate a strong association between APOE-~4 genotypea and an increased severity of Alrheimer neuropathol?gy regardless of clinical outcome, but do not provide support for an a?socntion between APOE-~4 and dementia resulting from other pathologler.
Prevalence of Alzheimer's disease in very elderly people: A prospective neuropathological study
Neurology, 2001
Article abstract-Background: No previous autopsy-controlled, prospective, and population-based studies are available on the prevalence of AD in very elderly people. Objective: To study the point prevalence of neuropathologically defined AD in a population of people at least 85 years of age, stratified according to their APOE genotype. Methods: A populationbased sample of 532 (of a total population of 601) elderly Finnish individuals, aged 85 years or more, were clinically tested for dementia in 1991 (with follow-up studies of the survivors in 1994, 1996, and 1999) and genotyped for APOE. An autopsy involving neuropathologic diagnosis of AD according to modified consensus criteria was performed in 118 of 198 deceased subjects who had been demented on April 1, 1991, and in 62 of 201 nondemented individuals. Results: The prevalence of neuropathologically defined AD was 33%, whereas the prevalence of clinically diagnosed AD was 16%. There was a highly significant (p Ͻ 0.001) association between the APOE ⑀4 allele and AD: Sixty-three percent of APOE ⑀4 carriers and 20% of noncarriers had neuropathologic AD. The respective figures in subjects aged 90 years or more were 71 and 22%. Conclusions: The prevalence of neuropathologically defined AD is higher than that reported in most previous studies based on clinical diagnosis. The discrepancy between the neuropathologic and clinical diagnoses of AD in very elderly subjects may affect the results of population-based studies. The APOE genotype has a strong effect on the prevalence of neuropathologically defined AD, even after 90 years of age.