Original Article
Age, Neuropathology, and Dementia
N Engl J Med 2009; 360:2302-2309May 28, 2009
- Abstract
Background
Research in Alzheimer's disease is focused mainly on younger old persons, whereas studies involving very old persons report attenuated relationships between the pathological features of Alzheimer's disease and dementia.
Methods
We assessed 456 brains donated to the population-based Medical Research Council Cognitive Function and Ageing Study from persons 69 to 103 years of age at death. We used a standard neuropathological protocol that included measures of the pathological features of Alzheimer's disease, cerebral atrophy, and cerebrovascular disease. Neuropathological variables were dichotomized to represent no burden or a mild burden of pathological lesions as compared with a moderate or severe burden. Logistic regression was used to estimate the effect of age on the relationship between neuropathological features and dementia.
Results
The difference in the prevalence of moderate and severe Alzheimer's-type pathological changes between persons with and those without dementia decreased with increasing age. The association between neocortical neuritic plaques and dementia was strong at 75 years of age (odds ratio, 8.63; 95% confidence interval [CI], 3.81 to 19.60) and reduced at 95 years of age (odds ratio, 2.48; 95% CI, 0.92 to 4.14), and similar attenuations with advancing age were observed in the association between other pathological changes related to Alzheimer's disease and dementia in all brain areas. In contrast, neocortical cerebral atrophy maintained a relationship with age in persons with dementia at both 75 years of age (odds ratio, 5.11; 95% CI, 1.94 to 13.46) and 95 years of age (odds ratio, 6.10; 95% CI, 2.80 to 13.28) and thus distinguished the cohort with dementia from the cohort without dementia.
Conclusions
The association between the pathological features of Alzheimer's disease and dementia is stronger in younger old persons than in older old persons. Age must be taken into account when assessing the likely effect of interventions against dementia on the population.
Media in This Article
Figure 1
Modeled and Observed Prevalence of Moderate or Severe Pathological Lesions According to Age.Table 1
Characteristics of the Respondents According to Age at Death.Article Activity
- Article
During the 20th century, interest in the dementias focused on specific disorders defined by criteria that were developed for patients who had onset of dementia before the age of 65 years, which had come to be considered by many as pathologically distinct from late-onset dementia.1 In the second half of that century, the distinction between early-onset and late-onset dementias was challenged by the realization that the hallmarks of Alzheimer's disease in older persons were indistinguishable from those in younger persons with Alzheimer's disease.2 Population epidemiologic studies of dementia have revealed a relentless rise in the incidence of dementia into old age,3 and clinically diagnosed Alzheimer's disease is considered to be the major subtype of dementia.4 The role of Alzheimer's disease in very old persons has become less clear since the contribution of vascular and other pathological changes has been recognized.5,6
Research in dementia is driven by the expectation that understanding the genetic and molecular findings underlying clinical subtypes of dementia will result in major prevention strategies for the whole population.7 The greatest demographic change is the increasing number of persons over 85 years of age, in whom most cases of dementia will occur.8 It is therefore important to know whether research findings in younger old persons, often in tertiary research settings, are relevant to older old persons in the population. Only a small number of brain-donation programs are linked to longitudinal, population-based studies of aging.9 Programs that have included persons in the oldest age groups consistently show that these persons have mixed neuropathological features10,11 and that those who die in their 80s and 90s may have pathological features of Alzheimer's disease without a diagnosis of dementia during life.12 Current diagnostic criteria that seek to define Alzheimer's disease, vascular dementia, and Lewy body dementia may not apply as well to the oldest old as to the younger old, in whom they were generated.
The relationship between underlying biology and clinical phenotype in the oldest old merits further examination, because current diagnosis, treatment, and management are predominantly shaped by research based on the younger old.13 Here we explore the effect of age on the relationship between the classic neuropathological features of dementia and the clinical manifestation of dementia in a population-based cohort of the elderly.
Methods
Population Selection and Interview Phases
The Medical Research Council Cognitive Function and Ageing Study (CFAS) is a multicenter, prospective, population-based study of older people in the United Kingdom. The study design and data on the prevalence and incidence of dementia have been previously reported and have been used in the development of international and national policies on dementia.5,8,10,14,15 The population base used was derived from lists of primary care physicians in specific geographic areas that included institutions that cared for elderly people. In five urban and rural centers in England and Wales, random samples of approximately 2500 persons aged 64 years or older underwent a screening interview that included the Mini–Mental State Examination (MMSE)16 and the Geriatric Mental State–Automated Geriatric Examination for Computer Assisted Taxonomy (GMS-AGECAT)17 items related to organic disorders. The response rate was 82%. Detailed assessment was conducted in a subsample of approximately 20% of subjects stratified according to the MMSE and the AGECAT organicity scores. The screening and assessment process was repeated after 2 years, and a further 20% of those not previously included were added to the assessment group. This assessment group was followed up again 6 years after baseline, and the entire remaining cohort was assessed 10 years after baseline. Additional interviews at 1, 3, and 8 years were conducted in samples of the assessment group. In a sixth center, 5200 people underwent similar assessments at baseline, 1 or 2 years, 3 or 4 years, 5 or 6 years, 8 years, and 10 years.
Those who took part in assessment interviews were asked whether they and their families were willing to consider brain donation after the respondent's death. The analysis presented here was based on 456 brains donated up to July 2004 (data set version 3.1).
Diagnosis of Dementia
Dementia status at death was determined on the basis of all information available for each respondent. This information was based on interviews during the last years of life, including the full GMS-AGECAT diagnostic algorithm17 that was equivalent to that in the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R), interviews with informants after the respondent's death when this was possible, and death certification. Dementia was diagnosed before death in 243 of the 456 respondents, and 183 were determined not to have dementia. Sufficient information for a diagnosis of dementia was not available for an additional 30 respondents, who were excluded from the analysis. The approach to the diagnosis of dementia in the CFAS is described in the Supplementary Appendix, available with the full text of this article at NEJM.org.
Neuropathological Assessment
Assessment by neuropathologists who were unaware of all clinical data was conducted according to a modified Consortium to Establish a Registry for Alzheimer's Disease (CERAD) protocol (www.cfas.ac.uk).10,18 Neuropathological lesions of Alzheimer's disease, diffuse plaques, neuritic plaques, and neurofibrillary tangles in the entorhinal, hippocampal, frontal, temporal, parietal, and occipital cortexes were classified into four categories (none, mild, moderate, and severe). Cortical atrophy was assessed macroscopically in each brain area, without knowledge of microscopical findings, and classified as absent, mild, moderate, or severe. Lewy bodies and hemorrhages, regional infarcts (>1 cm in diameter), and small-vessel disease (severe arteriosclerosis, lacunes, microinfarcts, or severe white-matter attenuation) were scored according to the CERAD protocol. Some subjects had more than one of the vascular pathological changes that were assessed. Inter-rater reliability for cerebral atrophy, tangles, plaques, Lewy bodies, and amyloid angiopathy was validated among contributing pathologists at the beginning of the study by circulating photographs of macroscopic findings and slides of microscopical findings.10
Statistical Analysis
Variables were dichotomized so that moderate and severe scores were considered to represent a significant burden of pathological lesions, as compared with no score and mild scores, which represented no burden or a low burden. In accordance with the CERAD protocol, maximum neocortical scores for each lesion and for atrophy were used. Logistic regression was used to model the effect of age on the relationship between neuropathological lesions and dementia. Each dichotomized pathological indicator was considered as an outcome, and the effects of age and dementia and their interaction were included in the model. Age at death was modeled as a continuous variable to estimate the association between pathology and dementia at different ages and to test for interactions. For analysis of the relationship between the prevalence of lesions and dementia at death, the subjects were divided into five age groups: under 80, 80 to 84, 85 to 89, 90 to 94, and over 94 years of age.
Sensitivity analyses were conducted for the effects of potential confounders. These analyses included sex, level of education, social class, time since last interview, and center, as well as the interaction of each of these with dementia. Further analyses included only those participants who received an assessment 1 year before death and excluded all those with prevalent dementia at baseline.
Results
Sample Characteristics
The sex, age, and dementia status of the members of the cohort at death are given in Table 1Table 1
Characteristics of the Respondents According to Age at Death.. More than 63% of donors were 85 years of age or older at death; 59% were women. Among those who had not received a diagnosis of dementia, there was no significant association between age and MMSE score at the most recent assessment before death. Among those who died with dementia, the MMSE score was lower (indicating poorer function) in the older groups. The time since the last interview was similar in all age groups. Among those who died without dementia, the causes of death were similar in those who had an autopsy and those who did not (the cause of death was cancer in 23% and 24% of respondents, respectively, and cardiovascular disease in 45% and 44%).Age and Alzheimer's Disease–Type Pathological Lesions
The distribution of each pathological lesion according to age group and dementia status is shown in Table 1 in the Supplementary Appendix. The modeled and observed prevalence rates of pathological changes are shown in Figure 1Figure 1
Modeled and Observed Prevalence of Moderate or Severe Pathological Lesions According to Age.. Among persons without dementia, the prevalence of moderate or severe neuritic plaques and of neurofibrillary tangles in each area increased with increasing age at death. The prevalence of these pathological changes in those who died with dementia either remained constant or tended to decline with age. Consequently, the difference in the burden of pathological lesions between persons who died with and those who died without dementia was less in those who died at older ages. In contrast, the prevalence of cortical atrophy was higher at all ages among those who died with dementia than among those who died without dementia.The association between pathological lesions and dementia, as estimated by our regression model, was compared in persons who died at 75 years of age and in those who died at 95 years of age (Table 2Table 2
Odds Ratios for the Association between Neuropathological Features and Dementia at Death, Modeled at the Ages of 75 and 95 Years.). These ages were selected in the model for comparison between younger and older persons. Atrophy of the hippocampus and the neocortex was strongly associated with dementia at all ages. Neuritic plaques and neurofibrillary tangles were strongly associated with dementia at 75 years of age, but the association was less strong at 95 years. This difference between the younger old and the older old was observed for both the hippocampus and the neocortex, although the effect was less striking for neocortical neurofibrillary tangles. Diffuse plaques were less strongly associated with dementia than were neuritic plaques at the age of 75 years, but by the age of 95 years these two neuropathological changes showed a similar association with dementia. Adjustment for demographic factors and inclusion only of participants who received a diagnosis of dementia close to death did not alter our findings (see Table 2 in the Supplementary Appendix).Vascular Pathological Features and Lewy Bodies
Small-vessel disease, infarcts, and the presence of more than one vascular pathological change were associated with dementia in the younger old. These associations were less pronounced in the older old, but the effect of age on the association was not significant. Lewy bodies were identified in 24 persons, 21 of whom were diagnosed with dementia, with no evidence of an association with age.
Discussion
This cohort-based study has sufficient power to model the pathological changes associated with dementia across the age range from 70 to 100 years. Using a careful definition of dementia status before death, we found that the relationship between the clinical manifestations of dementia and underlying neuropathological findings varies with age within this population-based cohort of brain donors. Our study confirms earlier reports of considerable overlap in the burden of neuropathological features of Alzheimer's disease between groups of the oldest old persons with dementia and those without dementia.10,19,20 In those dying without dementia, we confirm that the burden of Alzheimer's-type disease in the population increases with increasing age at death.12,21 In contrast, cortical atrophy remains strongly associated with dementia in all age groups.
The use of the primary care system registry of the United Kingdom ensured that the entire population in the areas chosen, including persons living in institutions, served as the basis for selection of the sample. The response rate at baseline was high, and all follow-up activity was assessed for potential bias due to attrition.22 The response rate among those who agreed to brain donation was high, considering the sensitive nature of this work, and has been scrutinized to exclude bias.10 The selection of persons to be interviewed for assessment of dementia, from whom the donor cohort was derived, was weighted toward the cognitively impaired, but no further bias in the donation process has been detected. Abrupt terminal decline could potentially affect our findings, but the diagnostic method makes it unlikely that this would have led to an inaccurate diagnosis of dementia. The 30 respondents for whom the diagnosis of dementia was doubtful were excluded from the analysis. The method for diagnosing dementia has been validated and is used widely in different settings.23,24 The assessment of dementia from informant reports was based on the DSM-III-R, an approach supported by the previous validation studies performed with the use of the GMS-AGECAT instrument.
If our findings were artifacts due to misclassification of persons with regard to dementia status, such misclassification would have to be differentially associated with age. It could be argued that extremely old persons might receive a diagnosis of dementia because of a greater prevalence of impairments, including vision and hearing, but the interviews take these possibilities into account. The severity of dementia also does not explain the convergence of neuropathological profiles at older ages in persons with and those without dementia, since the MMSE scores of those who died with and those who died without dementia appear to diverge slightly with increasing age. None of the sensitivity analyses led to different conclusions, a result suggesting that neither demographic factors nor the study design can explain our findings.
The neuropathological assessment was based on a modified CERAD protocol. We retained this basic assessment during the whole study to generate consistent data. The CERAD assessment relied on hematoxylin and eosin or ubiquitin staining to identify Lewy bodies; therefore, although our findings are robust, they need further confirmation with current techniques of staining.
Among those persons who died with dementia, the distribution of Alzheimer's-type pathological features remained roughly constant with increasing age, and consequently there was a decline in the association between the burden of Alzheimer's-type pathological features and dementia. With increasing age, there is a decrease in the ability to predict dementia on the basis of the burden of neuritic plaques in the hippocampus and neocortex and of neurofibrillary tangles in the hippocampus. Neuropathological validation of the diagnosis of Alzheimer's disease, based on confirmation of the presence of these changes, has a different meaning in the oldest old, because that same burden of pathological features may frequently be found in persons of the same age who do not have dementia. The association between neocortical neurofibrillary tangles and dementia during life remains strong at all ages, although the association is somewhat attenuated at increased ages. Previous studies support the idea of a convergence of Alzheimer's-type pathological features in people with and in those without dementia at very advanced ages: older persons with dementia have fewer Alzheimer's-type pathological features at death than do younger persons with dementia,25 indexes of cholinergic innervations converge between persons with and those without dementia at advanced ages,26,27 and the relationship between Alzheimer's-type pathological features and dementia is clearest in the younger old.28,29
These results suggest that additional factors determine the clinical expression of dementia in the oldest old. Hypothetically, these might include varying tolerance to neuropathological lesions; varying speed of lesion development, allowing compensatory processes; and interaction with coexisting illnesses. Neuronal and synaptic loss may represent an integral final common pathway mediating the effects of such factors. We found that cortical atrophy increases with age and continues to differentiate persons with dementia from those without dementia in all age groups, a finding echoing much earlier observations.30 Atrophy, a feature commonly seen on neuroimaging, emerges as a robust marker of the accumulation of pathological lesions and the failure of compensatory mechanisms, both of which lead to dementia. Atrophy reflects both Alzheimer's-type pathological changes and other factors, such as loss of neurons, axodendritic pruning, and reduced synaptic density, that occur in the course of normal aging and are a correlate of dementia.31 Perhaps if life span were sufficiently prolonged in some persons, aging changes in the brain, such as synaptic loss, could result in dementia without substantial Alzheimer's-type pathological changes.32
Mixed pathologic factors are common in the older brain and contribute to dementia and cognitive impairment.11,33,34 Coexisting pathological changes, often vascular, may lower the burden of Alzheimer's-type pathological features that are required to produce dementia and thus are potential confounders in an analysis of interactions between Alzheimer's-type pathological changes and age. However, a recent analysis of a smaller cohort, which was not representative of a population and which excluded those with any vascular disease in the brain, also showed an attenuated association between Alzheimer's-type pathological features and dementia in the oldest persons.35 To date, there is no protocol that has been widely validated and made operational that can score the diversity of vascular pathology encountered in the aging brain. Without such a protocol, analysis of the interaction between Alzheimer's-type and vascular pathological features remains limited.
The exponential relationship between age and the prevalence of dementia, combined with the increasing number of people surviving into old age, is driving the prevalence of dementia upward in the oldest old age groups. The CFAS, as a population-based study, can examine the implications of this increase. The study shows that the relationship between neuropathological indexes and dementia changes with age and that this change needs to be taken into account in models of dementia. Current disease-based classifications are based on discrete entities, such as Alzheimer's disease, vascular dementia, or mixed dementia. Our and other findings suggest this is a simplification and that the pathological basis of dementia should be considered as an interaction among pathological changes, compensatory mechanisms, and underlying synaptic dysfunction. Cognitive dysfunction in later life is a life-span issue and is affected by genetic, developmental, and lifestyle factors, accumulated neural insults, innate and acquired cerebral reserve and compensatory mechanisms, and age-related decline. The diverse interplay of these factors must account for the variation in cognitive outcome that is observed among individual persons for particular pathological changes in the brain that are associated with age. This holistic view offers the opportunity to explore diverse factors that underlie dementia and suggests that therapeutic interventions based solely on studies in younger cohorts in the context of the classic view of Alzheimer's disease will be less effective in the oldest old. Age cannot be neglected if the effect of dementia on the population is to be addressed and the most effective strategies are to be developed.
Supported by a grant (G9901400) from the Medical Research Council, United Kingdom.
No potential conflict of interest relevant to this article was reported.
Drs. Savva and Wharton contributed equally to this article.
We thank the respondents, their families, and their family physicians for all their help in the study and particularly for agreement to participate in the brain-donation program.
Source Information
From the Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge (G.M.S., C.B.); the Academic Unit of Pathology, University of Sheffield, Sheffield (S.B.W., P.G.I., G.F.); and the Medical Research Council Biostatistics Unit, Institute of Public Health, Cambridge (F.E.M.) — all in the United Kingdom.
Address reprint requests to Dr. Wharton at the Academic Unit of Pathology, University of Sheffield, Medical School, Beech Hill Rd., Sheffield S10 2RX, United Kingdom, or at s.wharton@sheffield.ac.uk.
- References
References
1
Amaducci LA ,Rocca WA ,Schoenberg BS . Origin of the distinction between Alzheimer's disease and senile dementia: how history can clarify nosology. Neurology 1986;36:1497-1499
Web of Science | Medline2
Tomlinson BE ,Blessed G ,Roth M . Observations on the brains of demented old people. J Neurol Sci 1970;11:205-242
CrossRef | Web of Science | Medline3
Matthews F ,Brayne C . The incidence of dementia in England and Wales: findings from the five identical sites of the MRC CFA Study. PLoS Med 2005;2:e193-e193
CrossRef | Web of Science | Medline4
Fratiglioni L ,Launer LJ ,Andersen K , et al. Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurology 2000;54:Suppl 5:S10-S15
Web of Science | Medline5
Hachinski VC ,Lassen NA ,Marshall J . Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet 1974;2:207-210
CrossRef | Web of Science | Medline6
Jellinger K ,Danielczyk W ,Fischer P ,Gabriel E . Clinicopathological analysis of dementia disorders in the elderly. J Neurol Sci 1990;95:239-258
CrossRef | Web of Science | Medline7
Brayne C . The elephant in the room -- healthy brains in later life, epidemiology and public health. Nat Rev Neurosci 2007;8:233-239
CrossRef | Web of Science | Medline8
Dementia UK. London: Alzheimer's Society, 2007.
9
Zaccai J ,Ince P ,Brayne C . Population-based neuropathological studies of dementia: design, methods and areas of investigation -- a systematic review. BMC Neurol 2006;6:2-2
CrossRef | Web of Science | Medline10
Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS)
CrossRef | Web of Science | Medline11
Schneider JA ,Arvanitakis Z ,Bang W ,Bennett DA . Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007;69:2197-2204
CrossRef | Web of Science | Medline12
Bennett DA ,Schneider JA ,Arvanitakis Z , et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006;66:1837-1844
CrossRef | Web of Science | Medline13
Schoenmaker N ,Van Gool WA . The age gap between patients in clinical studies and in the general population: a pitfall for dementia research. Lancet Neurol 2004;3:627-630
CrossRef | Web of Science | Medline14
Brayne C ,McCracken C ,Matthews FE . Cohort profile: the Medical Research Council Cognitive Function and Ageing Study (CFAS). Int J Epidemiol 2006;35:1140-1145
CrossRef | Web of Science | Medline15
Ferri CP ,Prince M ,Brayne C , et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-2117
CrossRef | Web of Science | Medline16
Folstein MF ,Folstein SE ,McHugh PR . “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198
CrossRef | Web of Science | Medline17
Copeland JR ,Dewey ME ,Griffiths-Jones HM . A computerized psychiatric diagnostic system and case nomenclature for elderly subjects: GMS and AGECAT. Psychol Med 1986;16:89-99
CrossRef | Web of Science | Medline18
Braak H ,Braak E . Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18:351-357
CrossRef | Web of Science | Medline19
Knopman DS ,Parisi JE ,Salviati A , et al. Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 2003;62:1087-1095
Web of Science | Medline20
Sonnen JA ,Larson EB ,Crane PK , et al. Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol 2007;62:406-413
CrossRef | Web of Science | Medline21
Green MS ,Kaye JA ,Ball MJ . The Oregon Brain Aging Study: neuropathology accompanying healthy aging in the oldest old. Neurology 2000;54:105-113
Web of Science | Medline22
Matthews FE ,Chatfield M ,Brayne C . An investigation of whether factors associated with short-term attrition change or persist over ten years: data from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). BMC Public Health 2006;6:185-185
CrossRef | Web of Science | Medline23
Copeland JR ,Dewey ME ,Saunders P . The epidemiology of dementia: GMS-AGECAT studies of prevalence and incidence, including studies in progress. Eur Arch Psychiatry Clin Neurosci 1991;240:212-217
CrossRef | Web of Science | Medline24
Prince M ,Acosta D ,Chiu H ,Scazufca M ,Varghese M . Dementia diagnosis in developing countries: a cross-cultural validation study. Lancet 2003;361:909-917
CrossRef | Web of Science | Medline25
Prohovnik I ,Perl DP ,Davis KL ,Libow L ,Lesser G ,Haroutunian V . Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease. Neurology 2006;66:49-55
CrossRef | Web of Science | Medline26
Perry EK ,Johnson M ,Kerwin JM , et al. Converging cholinergic activities in aging and Alzheimer's disease. Neurobiol Aging 1992;13:393-400
CrossRef | Web of Science | Medline27
Rossor MN ,Iversen LL ,Reynolds GP ,Mountjoy CQ ,Roth M . Neurochemical characteristics of early and late onset types of Alzheimer's disease. Br Med J (Clin Res Ed) 1984;288:961-964
CrossRef | Web of Science | Medline28
Berg L ,McKeel DW Jr ,Miller JP , et al. Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 1998;55:326-335
CrossRef | Web of Science | Medline29
Mann DM ,Yates PO ,Marcyniuk B . Some morphometric observations on the cerebral cortex and hippocampus in presenile Alzheimer's disease, senile dementia of Alzheimer type and Down's syndrome in middle age. J Neurol Sci 1985;69:139-159
CrossRef | Web of Science | Medline30
Hubbard BM ,Anderson JM . A quantitative study of cerebral atrophy in old age and senile dementia. J Neurol Sci 1981;50:135-145
CrossRef | Web of Science | Medline31
Terry RD ,Masliah E ,Salmon DP , et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572-580
CrossRef | Web of Science | Medline32
Terry RD ,Katzman R . Life span and synapses: will there be a primary senile dementia? Neurobiol Aging 2001;22:347-348
CrossRef | Web of Science | Medline33
Hachinski V ,Iadecola C ,Petersen RC , et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006;37:2220-2241
CrossRef | Web of Science | Medline34
Halliday G ,Ng T ,Rodriguez M , et al. Consensus neuropathological diagnosis of common dementia syndromes: testing and standardising the use of multiple diagnostic criteria. Acta Neuropathol (Berl) 2002;104:72-78
CrossRef | Web of Science | Medline35
Haroutunian V ,Schnaider-Beeri M ,Schmeidler J , et al. Role of the neuropathology of Alzheimer disease in dementia in the oldest-old. Arch Neurol 2008;65:1211-1217
CrossRef | Web of Science | Medline
- Citing Articles (74)
Citing Articles
1
Ansgar J. Furst, Gil D. Rabinovici, Ara H. Rostomian, Tyler Steed, Adi Alkalay, Caroline Racine, Bruce L. Miller, William J. Jagust. (2012) Cognition, glucose metabolism and amyloid burden in Alzheimer's disease. Neurobiology of Aging 33:2, 215-225
CrossRef2
JW Neal. (2012) Vascular dementia: why pathology is still important. Reviews in Clinical Gerontology 22:01, 35-51
CrossRef3
Madhav Thambisetty, Yang An, Anna Kinsey, Deepthi Koka, Muzamil Saleem, Andreas Gϋntert, Michael Kraut, Luigi Ferrucci, Christos Davatzikos, Simon Lovestone, Susan M. Resnick. (2012) Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment. NeuroImage 59:1, 212-217
CrossRef4
Alasdair M.J. MacLullich, Karen J. Ferguson, Louise M. Reid, Ian J. Deary, John M. Starr, Joanna M. Wardlaw, Brian R. Walker, Ruth Andrew, Jonathan R. Seckl. (2012) 11β-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline. Neurobiology of Aging 33:1, 207.e1-207.e8
CrossRef5
Jean C. Augustinack, Kristen E. Huber, Gheorghe M. Postelnicu, Sita Kakunoori, Ruopeng Wang, André J. W. Kouwe, Lawrence L. Wald, Thor D. Stein, Matthew P. Frosch, Bruce Fischl. (2012) Entorhinal verrucae geometry is coincident and correlates with Alzheimer’s lesions: a combined neuropathology and high-resolution ex vivo MRI analysis. Acta Neuropathologica 123:1, 85-96
CrossRef6
Annlia Paganini-Hill. (2012) Hypertension and Dementia in the Elderly: The Leisure World Cohort Study. International Journal of Hypertension 2012, 1-5
CrossRef7
M. R. Sabuncu, R. L. Buckner, J. W. Smoller, P. H. Lee, B. Fischl, R. A. Sperling, . (2011) The Association between a Polygenic Alzheimer Score and Cortical Thickness in Clinically Normal Subjects. Cerebral Cortex
CrossRef8
Michal Schnaider Beeri, Vahram Haroutunian, James Schmeidler, Mary Sano, Peter Fam, Aaron Kavanaugh, Alasdair M. Barr, William G. Honer, Pavel Katsel. (2011) Synaptic protein deficits are associated with dementia irrespective of extreme old age. Neurobiology of Aging
CrossRef9
Russell H. Swerdlow. (2011) Brain aging, Alzheimer's disease, and mitochondria. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1812:12, 1630-1639
CrossRef10
J. L. Robinson, F. Geser, M. M. Corrada, D. J. Berlau, S. E. Arnold, V. M.- Y. Lee, C. H. Kawas, J. Q. Trojanowski. (2011) Neocortical and hippocampal amyloid- and tau measures associate with dementia in the oldest-old. Brain 134:12, 3708-3715
CrossRef11
Mary Ganguli, Eric Rodriguez. (2011) Age, Alzheimer's disease, and the big picture. International Psychogeriatrics 23:10, 1531-1534
CrossRef12
John Q. Trojanowski, Harald Hampel. (2011) Neurodegenerative disease biomarkers: Guideposts for disease prevention through early diagnosis and intervention. Progress in Neurobiology 95:4, 491-495
CrossRef13
Berislav V. Zlokovic. (2011) Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nature Reviews Neuroscience
CrossRef14
Michael J. Valenzuela, Fiona E. Matthews, Carol Brayne, Paul Ince, Glenda Halliday, Jillian J. Kril, Marshall A. Dalton, Kathryn Richardson, Gill Forster,, Perminder S. Sachdev. (2011) Multiple Biological Pathways Link Cognitive Lifestyle to Protection from Dementia. Biological Psychiatry
CrossRef15
Ramit Ravona-Springer, Amos D Korczyn. (2011) Current conceptions of the etiology and risk factors for Alzheimer’s disease and their possible implications on the design of dementia clinical trials. Clinical Investigation 1:11, 1491-1503
CrossRef16
Chengxuan Qiu. (2011) Epidemiological findings of vascular risk factors in Alzheimer’s disease: implications for therapeutic and preventive intervention. Expert Review of Neurotherapeutics 11:11, 1593-1607
CrossRef17
Clayton F. MORAES, Tulio C. LINS, Einstein F. CARMARGOS, Janeth O. S. NAVES, Rinaldo W. PEREIRA, Otávio T. NÓBREGA. (2011) Lessons from genome-wide association studies findings in Alzheimer's disease. Psychogeriatricsno-no
CrossRef18
E. C. Mormino, A. Smiljic, A. O. Hayenga, S. H. Onami, M. D. Greicius, G. D. Rabinovici, M. Janabi, S. L. Baker, I. V. Yen, C. M. Madison, B. L. Miller, W. J. Jagust. (2011) Relationships between Beta-Amyloid and Functional Connectivity in Different Components of the Default Mode Network in Aging. Cerebral Cortex 21:10, 2399-2407
CrossRef19
Javier Olazarán Rodríguez, Félix Bermejo Pareja. (2011) Alteración cognitiva leve en la práctica clínica. Medicina Clínica 137:9, 414-418
CrossRef20
Karen S. SantaCruz, Joshua A. Sonnen, Maryam Kherad Pezhouh, Mark F. Desrosiers, Peter T. Nelson, Suzanne L. Tyas. (2011) Alzheimer Disease Pathology in Subjects Without Dementia in 2 Studies of Aging. Journal of Neuropathology and Experimental Neurology 70:10, 832-840
CrossRef21
Carrie Brumback-Peltz, Archana B. Balasubramanian, María M. Corrada, Claudia H. Kawas. (2011) Diagnosing dementia in the oldest-old. Maturitas 70:2, 164-168
CrossRef22
Julie E. Simpson, Paul G. Ince, Pamela J. Shaw, Paul R. Heath, Rohini Raman, Claire J. Garwood, Catherine Gelsthorpe, Lynne Baxter, Gillian Forster, Fiona E. Matthews, Carol Brayne, Stephen B. Wharton. (2011) Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer's pathology and APOE genotype. Neurobiology of Aging 32:10, 1795-1807
CrossRef23
E. C. Mormino, M. G. Brandel, C. M. Madison, S. Marks, S. L. Baker, W. J. Jagust. (2011) A Deposition in Aging Is Associated with Increases in Brain Activation during Successful Memory Encoding. Cerebral Cortex
CrossRef24
Eric Karran, Marc Mercken, Bart De Strooper. (2011) The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nature Reviews Drug Discovery 10:9, 698-712
CrossRef25
Angelo Scuteri, Peter M. Nilsson, Christopher Tzourio, Josep Redon, Stephane Laurent. (2011) Microvascular brain damage with aging and hypertension. Journal of Hypertension 29:8, 1469-1477
CrossRef26
Ben Schmand, Piet Eikelenboom, Willem A. van Gool, . (2011) Value of Neuropsychological Tests, Neuroimaging, and Biomarkers for Diagnosing Alzheimer's Disease in Younger and Older Age Cohorts. Journal of the American Geriatrics Societyno-no
CrossRef27
Joost Witlox, Kees J. Kalisvaart, Jos F.M. de Jonghe, Nicolaas A. Verwey, Mireille F.M. van Stijn, Alexander P.J. Houdijk, Han S. Traast, Alasdair M.J. MacLullich, Willem A. van Gool, Piet Eikelenboom. (2011) Cerebrospinal Fluid β-Amyloid and Tau Are Not Associated with Risk of Delirium: A Prospective Cohort Study in Older Adults with Hip Fracture. Journal of the American Geriatrics Society 59:7, 1260-1267
CrossRef28
Philip Scheltens, Kenneth Rockwood. (2011) How golden is the gold standard of neuropathology in dementia?. Alzheimer's and Dementia 7:4, 486-489
CrossRef29
Carlo Condello, Aaron Schain, Jaime Grutzendler. (2011) Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. Scientific Reports 1,
CrossRef30
Fischer Peter, Jungwirth Susanne, Hinterberger Margareta, Weissgram Silvia, Krampla Wolfgang, Leitha Thomas, Tragl Karl Heinz. (2011) “REVERSIBLE” ALZHEIMER'S DISEASE?. Journal of the American Geriatrics Society 59:6, 1137-1138
CrossRef31
J. Alex Becker, Trey Hedden, Jeremy Carmasin, Jacqueline Maye, Dorene M. Rentz, Deepti Putcha, Bruce Fischl, Douglas N. Greve, Gad A. Marshall, Stephen Salloway, Donald Marks, Randy L. Buckner, Reisa A. Sperling, Keith A. Johnson. (2011) Amyloid-β associated cortical thinning in clinically normal elderly. Annals of Neurology 69:6, 1032-1042
CrossRef32
Sergi G. Costafreda, Ivo D. Dinov, Zhuowen Tu, Yonggang Shi, Cheng-Yi Liu, Iwona Kloszewska, Patrizia Mecocci, Hilkka Soininen, Magda Tsolaki, Bruno Vellas, Lars-Olof Wahlund, Christian Spenger, Arthur W. Toga, Simon Lovestone, Andrew Simmons. (2011) Automated hippocampal shape analysis predicts the onset of dementia in mild cognitive impairment. NeuroImage 56:1, 212-219
CrossRef33
Clifford R. Jack, Marilyn S. Albert, David S. Knopman, Guy M. McKhann, Reisa A. Sperling, Maria C. Carrillo, Bill Thies, Creighton H. Phelps. (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's and Dementia 7:3, 257-262
CrossRef34
Peter T. Nelson, Elizabeth Head, Frederick A. Schmitt, Paulina R. Davis, Janna H. Neltner, Gregory A. Jicha, Erin L. Abner, Charles D. Smith, Linda J. Eldik, Richard J. Kryscio, Stephen W. Scheff. (2011) Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies. Acta Neuropathologica 121:5, 571-587
CrossRef35
Diego Albani, Mauro Tettamanti, Sara Batelli, Letizia Polito, Sabrina Dusi, Eleonora Ateri, Gianluigi Forloni, Ugo Lucca. (2011) Interleukin-1α, interleukin-1β and tumor necrosis factor-α genetic variants and risk of dementia in the very old: evidence from the “Monzino 80-plus” prospective study. AGE
CrossRef36
Alberto Granzotto, Silvia Bolognin, Janez Scancar, Radmila Milacic, Paolo Zatta. (2011) Beta-amyloid toxicity increases with hydrophobicity in the presence of metal ions. Monatshefte für Chemie - Chemical Monthly 142:4, 421-430
CrossRef37
J. A. R. Nicoll, G. M. Savva, J. Stewart, F. E. Matthews, C. Brayne, P. Ince. (2011) Association between APOE genotype, neuropathology and dementia in the older population of England and Wales. Neuropathology and Applied Neurobiology 37:3, 285-294
CrossRef38
T. A. Treves, A. D. Korczyn. (2011) Modeling the Dementia Epidemic. CNS Neuroscience & Therapeuticsno-no
CrossRef39
C. Tsopelas, R. Stewart, G. M. Savva, C. Brayne, P. Ince, A. Thomas, F. E. Matthews, . (2011) Neuropathological correlates of late-life depression in older people. The British Journal of Psychiatry 198:2, 109-114
CrossRef40
W. R. Brown, C. R. Thore. (2011) Review: Cerebral microvascular pathology in ageing and neurodegeneration. Neuropathology and Applied Neurobiology 37:1, 56-74
CrossRef41
Eloise H Kok, Teemu Luoto, Satu Haikonen, Sirkka Goebeler, Hannu Haapasalo, Pekka J Karhunen. (2011) CLU, CR1 and PICALM genes associate with Alzheimer's-related senile plaques. Alzheimer's Research & Therapy 3:2, 12
CrossRef42
Kenneth Rockwood. (2011) Biomarkers to Measure Treatment Effects in Alzheimer's Disease: What Should We Look for?. International Journal of Alzheimer's Disease 2011, 1-4
CrossRef43
Yong S. Shim, John C. Morris. (2011) Biomarkers Predicting Alzheimer's Disease in Cognitively Normal Aging. Journal of Clinical Neurology 7:2, 60
CrossRef44
Sudha Seshadri. 2011. Vascular Dementia and Vascular Cognitive Decline. , 252-267.
CrossRef45
Ugo Lucca, Mariateresa Garrì, Angela Recchia, Giancarlo Logroscino, Pietro Tiraboschi, Massimo Franceschi, Chiara Bertinotti, Anna Biotti, Elena Gargantini, Marilena Maragna, Alessandro Nobili, Luca Pasina, Carlotta Franchi, Emma Riva, Mauro Tettamanti. (2011) A Population-based study of dementia in the oldest old: the Monzino 80-plus Study. BMC Neurology 11:1, 54
CrossRef46
Jeroen JM Hoozemans, Annemieke JM Rozemuller, Elise S van Haastert, Piet Eikelenboom, Willem A van Gool. (2011) Neuroinflammation in Alzheimer's disease wanes with age. Journal of Neuroinflammation 8:1, 171
CrossRef47
Robert Laforce, Gil D Rabinovici. (2011) Amyloid imaging in the differential diagnosis of dementia: review and potential clinical applications. Alzheimer's Research & Therapy 3:6, 31
CrossRef48
Lidia Sinka, Enikö Kövari, Gabriel Gold, Patrick R. Hof, François R. Herrmann, Constantin Bouras, Panteleimon Giannakopoulos. (2010) Small Vascular and Alzheimer Disease-Related Pathologic Determinants of Dementia in the Oldest-Old. Journal of Neuropathology and Experimental Neurology 69:12, 1247-1255
CrossRef49
Jonathan M. Schott, Jonathan W. Bartlett, Nick C. Fox, Josephine Barnes, . (2010) Increased brain atrophy rates in cognitively normal older adults with low cerebrospinal fluid Aβ1-42. Annals of Neurology 68:6, 825-834
CrossRef50
C. R. Jack, H. J. Wiste, P. Vemuri, S. D. Weigand, M. L. Senjem, G. Zeng, M. A. Bernstein, J. L. Gunter, V. S. Pankratz, P. S. Aisen, M. W. Weiner, R. C. Petersen, L. M. Shaw, J. Q. Trojanowski, D. S. Knopman, . (2010) Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease. Brain 133:11, 3336-3348
CrossRef51
J L Holtzman. (2010) Are We Prepared to Deal With the Alzheimer's Disease Pandemic?. Clinical Pharmacology & Therapeutics 88:4, 563-565
CrossRef52
Ville Leinonen, Anne M. Koivisto, Sakari Savolainen, Jaana Rummukainen, Juuso N. Tamminen, Tomi Tillgren, Sannakaisa Vainikka, Okko T. Pyykkö, Juhani Mölsä, Mikael Fraunberg, Tuula Pirttilä, Juha E. Jääskeläinen, Hilkka Soininen, Jaakko Rinne, Irina Alafuzoff. (2010) Amyloid and tau proteins in cortical brain biopsy and Alzheimer's disease. Annals of Neurology 68:4, 446-453
CrossRef53
Costantino Iadecola. (2010) The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathologica 120:3, 287-296
CrossRef54
D. Dolan, J. Troncoso, S. M. Resnick, B. J. Crain, A. B. Zonderman, R. J. O'Brien. (2010) Age, Alzheimer's disease and dementia in the Baltimore Longitudinal Study of Ageing. Brain 133:8, 2225-2231
CrossRef55
K. Kantarci, M. L. Senjem, V. J. Lowe, H. J. Wiste, S. D. Weigand, B. J. Kemp, A. R. Frank, M. M. Shiung, B. F. Boeve, D. S. Knopman, R. C. Petersen, C. R. Jack. (2010) Effects of Age on the Glucose Metabolic Changes in Mild Cognitive Impairment. American Journal of Neuroradiology 31:7, 1247-1253
CrossRef56
C. Brayne, P. G. Ince, H. A. D. Keage, I. G. McKeith, F. E. Matthews, T. Polvikoski, R. Sulkava. (2010) Education, the brain and dementia: neuroprotection or compensation?: EClipSE Collaborative Members. Brain 133:8, 2210-2216
CrossRef57
Leonardo Pantoni. (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. The Lancet Neurology 9:7, 689-701
CrossRef58
John Q. Trojanowski, Hugo Vandeerstichele, Magdalena Korecka, Christopher M. Clark, Paul S. Aisen, Ronald C. Petersen, Kaj Blennow, Holly Soares, Adam Simon, Piotr Lewczuk, Robert Dean, Eric Siemers, William Z. Potter, Michael W. Weiner, Clifford R. Jack, William Jagust, Arthur W. Toga, Virginia M.-Y. Lee, Leslie M. Shaw. (2010) Update on the biomarker core of the Alzheimer's Disease Neuroimaging Initiative subjects. Alzheimer's and Dementia 6:3, 230-238
CrossRef59
J. M. Mc Donald, G. M. Savva, C. Brayne, A. T. Welzel, G. Forster, G. M. Shankar, D. J. Selkoe, P. G. Ince, D. M. Walsh, . (2010) The presence of sodium dodecyl sulphate-stable A dimers is strongly associated with Alzheimer-type dementia. Brain 133:5, 1328-1341
CrossRef60
Ruo-Li Chen, Joyce S. Balami, Margaret M. Esiri, Liang-Kung Chen, Alastair M. Buchan. (2010) Ischemic stroke in the elderly: an overview of evidence. Nature Reviews Neurology 6:5, 256-265
CrossRef61
Kurt A. Jellinger, Johannes Attems. (2010) Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathologica 119:4, 421-433
CrossRef62
B.B. Bendlin, C.M. Carlsson, C.E. Gleason, S.C. Johnson, A. Sodhi, C.L. Gallagher, L. Puglielli, C.D. Engelman, M.L. Ries, G. Xu, W. Wharton, S. Asthana. (2010) Midlife predictors of Alzheimer's disease. Maturitas 65:2, 131-137
CrossRef63
Masaaki Matsuoka, Yuichi Hashimoto. (2010) Humanin and the Receptors for Humanin. Molecular Neurobiology 41:1, 22-28
CrossRef64
G. D. Rabinovici, A. J. Furst, A. Alkalay, C. A. Racine, J. P. O'Neil, M. Janabi, S. L. Baker, N. Agarwal, S. J. Bonasera, E. C. Mormino, M. W. Weiner, M. L. Gorno-Tempini, H. J. Rosen, B. L. Miller, W. J. Jagust. (2010) Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden. Brain 133:2, 512-528
CrossRef65
Querfurth, Henry W., LaFerla, Frank M., . (2010) Alzheimer's Disease. New England Journal of Medicine 362:4, 329-344
Full Text66
A. von Gunten, K. Ebbing, A. Imhof, P. Giannakopoulos, E. Kövari. (2010) Brain Aging in the Oldest-Old. Current Gerontology and Geriatrics Research 2010, 1-10
CrossRef67
Niklas Mattsson, Henrik Zetterberg, kaj Blennow. (2010) Lessons from Multicenter Studies on CSF Biomarkers for Alzheimer's Disease. International Journal of Alzheimer's Disease 2010, 1-5
CrossRef68
Oliver Wirths, Tobias Bethge, Andrea Marcello, Anja Harmeier, Sadim Jawhar, Paul J. Lucassen, Gerd Multhaup, David L. Brody, Thomas Esparza, Martin Ingelsson, Hannu Kalimo, Lars Lannfelt, Thomas A. Bayer. (2010) Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease cases. Journal of Neural Transmission 117:1, 85-96
CrossRef69
Clifford R Jack, David S Knopman, William J Jagust, Leslie M Shaw, Paul S Aisen, Michael W Weiner, Ronald C Petersen, John Q Trojanowski. (2010) Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. The Lancet Neurology 9:1, 119-128
CrossRef70
Kamilia S Funder, Jacob Steinmetz, Lars S Rasmussen. (2009) Anaesthesia for the patient with dementia undergoing outpatient surgery. Current Opinion in Anaesthesiology 22:6, 712-717
CrossRef71
Majid Fotuhi, Vladimir Hachinski, Peter J. Whitehouse. (2009) Changing perspectives regarding late-life dementia. Nature Reviews Neurology 5:12, 649-658
CrossRef72
Chen, Liang-Wei, . (2009) Age, Neuropathology, and Dementia. New England Journal of Medicine 361:11, 1118-1118
Full Text73
Jillian J. Kril. (2009) Alzheimer disease: Alzheimer disease neuropathology in the oldest old. Nature Reviews Neurology 5:8, 411-412
CrossRef74
Ewbank, Douglas C., Arnold, Steven E., . (2009) Cool with Plaques and Tangles. New England Journal of Medicine 360:22, 2357-2359
Full Text
- Letters
