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1.  Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study 
PLoS Medicine  2009;6(11):e1000180.
Researchers from the Medical Research Council Cognitive Function and Ageing Neuropathology Study carry out an analysis of brain pathologies contributing to dementia, within a cohort of elderly individuals in the UK who agreed to brain donation.
Background
Dementia drug development aims to modulate pathological processes that cause clinical syndromes. Population data (epidemiological neuropathology) will help to model and predict the potential impact of such therapies on dementia burden in older people. Presently this can only be explored through post mortem findings. We report the attributable risks (ARs) for dementia at death for common age-related degenerative and vascular pathologies, and other factors, in the MRC Cognitive Function and Ageing Study (MRC CFAS).
Methods and Findings
A multicentre, prospective, longitudinal study of older people in the UK was linked to a brain donation programme. Neuropathology of 456 consecutive brain donations assessed degenerative and vascular pathologies. Logistic regression modelling, with bootstrapping and sensitivity analyses, was used to estimate AR at death for dementia for specific pathologies and other factors. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%).
Conclusions
Such AR estimates cannot be derived from the living population; rather they estimate the relative contribution of specific pathologies to dementia at death. We found that multiple pathologies determine the overall burden of dementia. The impact of therapy targeted to a specific pathology may be profound when the dementia is relatively “pure,” but may be less impressive for the majority with mixed disease, and in terms of the population. These data justify a range of strategies, and combination therapies, to combat the degenerative and vascular determinants of cognitive decline and dementia.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Losing one's belongings and forgetting people's names is often a normal part of aging. But increasing forgetfulness can also be a sign of dementia, a group of symptoms caused by several disorders that affect the structure of the brain. The commonest form of dementia is Alzheimer disease. In this, protein clumps called plaques and neurofibrillary tangles form in the brain and cause its degeneration. Vascular dementia, in which problems with blood circulation deprive parts of the brain of oxygen, is also common. People with dementia have problems with two or more “cognitive” functions—thinking, language, memory, understanding, and judgment. As the disease progresses, they gradually lose their ability to deal with normal daily activities until they need total care, their personality often changes, and they may become agitated or aggressive. Dementia is rare before the age of 65 years but about a quarter of people over 85 years old have dementia. Because more people live to a ripe old age these days, the number of people with dementia is increasing. According to the latest estimates, about 35 million people now have dementia and by 2050, 115 million may have the disorder.
Why Was This Study Done?
There is no cure for dementia but many drugs designed to modulate specific abnormal (pathological) changes in the brain that can cause the symptoms of dementia are being developed. To assess the likely impact of these potentially expensive new therapies, experts need to know what proportion of dementia is associated with each type of brain pathology. Although some brain changes can be detected in living brains with techniques such as computed tomography brain scans, most brain changes can only be studied in brains taken from people after death (post mortem brains). In this study, which is part of the UK Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), the researchers look for associations between dementia in elderly people and pathological changes in their post mortem brains and estimate the attributable-risk (AR) for dementia at death associated with specific pathological features in the brain. That is, they estimate the proportion of dementia directly attributable to each type of pathology.
What Did the Researchers Do and Find?
Nearly 20 years ago, the MRC CFAS interviewed more than 18,000 people aged 65 years or older recruited at six sites in England and Wales to determine their cognitive function and their ability to deal with daily activities. 20% of the participants, which included people with and without cognitive impairment, were then assessed in more detail and invited to donate their brains for post mortem examination. As of 2004, 456 individuals had donated their brains. The dementia status of these donors was established using data from their assessment interviews and death certificates, and from interviews with relatives and carers, and their brains were carefully examined for abnormal changes. The researchers then used statistical methods to estimate the AR for dementia at death associated with various abnormal brain changes. The main contributors to AR for dementia at death included age (18% of dementia at death was attributable to this factor), plaques (8%), and neurofibrillary tangles (11%) in a brain region called the neocortex, small blood vessel disease (12%), and multiple abnormal changes in blood vessels (9%).
What Do These Findings Mean?
These findings suggest that multiple abnormal brain changes determine the overall burden of dementia. Importantly, they also suggest that dementia is often associated with mixed pathological changes—many people with dementia had brain changes consistent with both Alzheimer disease and vascular dementia. Because people with dementia live for variable lengths of time during which the abnormal changes in their brain are likely to alter, it may be difficult to extrapolate these findings to living populations of elderly people. Furthermore, only a small percentage of the MRC CFAS participants have donated their brains so the findings of this study may not apply to the general population. Nevertheless, these findings suggest that the new therapies currently under development may do little to reduce the overall burden of dementia because most people's dementia involves multiple pathologies. Consequently, it may be necessary to develop a range of strategies and combination therapies to deal with the ongoing dementia epidemic.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000180.
The US National Institute on Aging provides information for patients and carers about forgetfulness and about Alzheimer disease (in English and Spanish)
The US National Institute of Neurological Disorders and Stroke provides information about dementia (in English and Spanish)
The UK National Health Service Choices Web site also provides detailed information for patients and their carers about dementia and about Alzheimer disease
MedlinePlus provides links to additional resources about dementia and Alzheimer disease (in English and Spanish)
More information about the UK Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) is available
doi:10.1371/journal.pmed.1000180
PMCID: PMC2765638  PMID: 19901977
2.  Atherosclerosis, Dementia, and Alzheimer’s Disease in the BLSA Cohort 
Annals of neurology  2010;68(2):231-240.
Objective
Although it is now accepted that asymptomatic cerebral infarcts are an important cause of dementia in the elderly, the relationship between atherosclerosis per se and dementia is controversial. Specifically, it is unclear whether atherosclerosis can cause the neuritic plaques and neurofibrillary tangles that define Alzheimer neuropathology and whether atherosclerosis, a potentially reversible risk factor, can influence cognition independent of brain infarcts.
Methods
We examined the relationship between systemic atherosclerosis, Alzheimer type pathology and dementia in autopsies from 200 participants in the Baltimore Longitudinal Study of Aging (BLSA), a prospective study of the effect of aging on cognition, 175 of whom had complete body autopsies.
Results
Using a quantitative analysis of atherosclerosis in the aorta, heart and intracranial vessels, we found no relationship between the degree of atherosclerosis in any of these systems and the degree of Alzheimer’s type brain pathology. However, we found that the presence of intracranial but not coronary or aortic atherosclerosis significantly increased the odds of dementia, independent of cerebral infarction. Given the large number of individuals with intracranial atherosclerosis in this cohort (136/200), the population attributable risk of dementia related to intracranial atherosclerosis (independent of infarction) is substantial and potentially reversible.
Interpretation
Atherosclerosis of the intracranial arteries is an independent and important risk factor for dementia, suggesting potentially reversible pathways unrelated to Alzheimer’s pathology and stroke through which vascular changes may influence dementia risk.
doi:10.1002/ana.22055
PMCID: PMC3030772  PMID: 20695015
3.  Age, Alzheimer’s disease and dementia in the Baltimore Longitudinal Study of Ageing 
Brain  2010;133(8):2225-2231.
Recent studies suggest that dementia in the most elderly (90 years of age and above) is only modestly related to Alzheimer’s disease pathology. This raises the possibility that other, as yet unknown, disease processes may underlie dementia in this rapidly growing demographic group, and that efforts designed to combat Alzheimer’s disease may not be appropriate for treating dementia in very elderly subjects. To study this question more closely, we examined the relationship between neocortical Alzheimer-type brain pathology and dementia in consecutive autopsies from 209 participants in the Baltimore Longitudinal Study of Ageing, a prospective longitudinal cohort study of the effect of ageing on cognition. Almost half of the cohort was older than 90 years of age at death. We found that several measures of neocortical Alzheimer’s pathology, including the Consortium to Establish a Registry of Alzheimer’s Disease neuritic plaque score and the Braak neurofibrillary tangle score, remained significant predictors of dementia, independent of age. In participants older than 90 years of age, intracranial atherosclerosis emerged as an important predictor of dementia in subjects with low Alzheimer’s pathology scores, but did not mitigate the importance or population attributable risk of high Alzheimer’s pathology scores on the odds of dementia. There was evidence that the threshold score for neurofibrillary pathology to cause dementia increased in the oldest subjects, but this was offset by an overall increase in neurofibrillary pathology in this age group. We conclude that neocortical Alzheimer’s disease pathology remains significantly correlated with dementia, independent of age. In the most elderly, atherosclerosis also emerged as a cause of dementia in subjects with low Alzheimer’s pathology scores. We found no evidence for a significant number of elderly subjects having dementia without an apparent cause.
doi:10.1093/brain/awq141
PMCID: PMC3139933  PMID: 20647264
Alzheimer’s disease; pathology; ageing; natural history; neurodegenerative mechanisms
4.  HHEX_23 AA Genotype Exacerbates Effect of Diabetes on Dementia and Alzheimer Disease: A Population-Based Longitudinal Study 
PLoS Medicine  2015;12(7):e1001853.
Background
Research has suggested that variations within the IDE/HHEX gene region may underlie the association of type 2 diabetes with Alzheimer disease (AD). We sought to explore whether IDE genes play a role in the association of diabetes with dementia, AD, and structural brain changes using data from two community-based cohorts of older adults and a subsample with structural MRI.
Methods and Findings
The first cohort, which included dementia-free adults aged ≥75 y (n = 970) at baseline, was followed for 9 y to detect incident dementia (n = 358) and AD (n = 271) cases. The second cohort (for replication), which included 2,060 dementia-free participants aged ≥60 y at baseline, was followed for 6 y to identify incident dementia (n = 166) and AD (n = 121) cases. A subsample (n = 338) of dementia-free participants from the second cohort underwent MRI. HHEX_23 and IDE_9 were genotyped, and diabetes (here including type 2 diabetes and prediabetes) was assessed. In the first cohort, diabetes led to an adjusted hazard ratio (HR) of 1.73 (95% CI 1.19–2.32) and 1.66 (95% CI 1.06–2.40) for dementia and AD, respectively, among all participants. Compared to people carrying the GG genotype without diabetes, AA genotype carriers with diabetes had an adjusted HR of 5.54 (95% CI 2.40–7.18) and 4.81 (95% CI 1.88–8.50) for dementia and AD, respectively. There was a significant interaction between HHEX_23-AA and diabetes on dementia (HR 4.79, 95% CI 1.63–8.90, p = 0.013) and AD (HR 3.55, 95% CI 1.45–9.91, p = 0.025) compared to the GG genotype without diabetes. In the second cohort, the HRs were 1.68 (95% CI 1.04–2.99) and 1.64 (1.02–2.33) for the diabetes–AD and dementia–AD associations, respectively, and 4.06 (95% CI 1.06–7.58, p = 0.039) and 3.29 (95% CI 1.02–8.33, p = 0.044) for the interactions, respectively. MRI data showed that HHEX_23-AA carriers with diabetes had significant structural brain changes compared to HHEX_23-GG carriers without diabetes. No joint effects of IDE_9 and diabetes on dementia were shown. As a limitation, the sample sizes were small for certain subgroups.
Conclusions
A variant in the HHEX_23 gene interacts with diabetes to be associated with a substantially increased risk of dementia and AD, and with structural brain changes among dementia-free elderly people.
In a longitudinal study, Weili Xu and colleagues explore whether variants in two insulin pathway genes modify the association of type 2 diabetes with dementia and AD.
Editors' Summary
Background
Worldwide, about 44 million people have dementia, a group of degenerative, incurable brain disorders that mainly affect older people. Dementia is characterized by an irreversible decline in memory, communication, and other “cognitive” functions. The most common forms of dementia are Alzheimer disease, which is caused by the development of small clumps of proteins (β-amyloid plaques) around brain cells, and vascular dementia, which is caused by reduced blood flow to parts of the brain. Early symptoms of dementia include increasing forgetfulness and losing track of time. As the condition progresses, affected individuals gradually lose the ability to look after themselves and to communicate, and they may become anxious or aggressive. Eventually, affected individuals may lose control of various physical functions and many become totally dependent on specialist nurses and other professional carers for their day-to-day needs.
Why Was This Study Done?
Epidemiological studies (investigations that examine patterns of disease in populations) suggest that, among older individuals, having type 2 diabetes (a condition in which resistance to the hormone insulin leads to high blood sugar levels) is associated with a 50% increased risk of developing dementia. Even prediabetes (a blood sugar level that is high but not high enough to meet the criteria for diabetes) is associated with an increased risk of dementia. Prediabetes and diabetes increase the risk of vascular disease, but it is thought that polymorphisms (naturally occurring genetic variations) in the IDE/HHEX region of the human genome may be involved in the association between diabetes and dementia/Alzheimer disease. IDE encodes insulin-degrading enzyme, which clears insulin from cells but also degrades β-amyloid; HHEX encodes a transcription factor that controls IDE expression. In this population-based longitudinal study, the researchers explore whether two single nucleotide polymorphisms in this region—IDE_9 and HHEX_23—impact the association between diabetes and dementia. Population-based longitudinal studies measure the baseline characteristics of individuals in the general population and determine which individuals subsequently develop specific conditions.
What Did the Researchers Do and Find?
For their study, the researchers examined data collected from two cohorts (groups) of dementia-free elderly adults living in Stockholm, Sweden. Blood samples taken from 3,030 participants at baseline were used to determine which individuals had diabetes (type 2 diabetes or prediabetes) and to investigate which HHEX_23 and IDE_9 variants each individual carried (genotyping). The researchers also examined the brain structure of a subsample of the second cohort using magnetic resonance imaging (MRI). All the participants were followed for several years to see which individuals developed dementia/Alzheimer disease. In both cohorts, having diabetes was associated with a 60% increased risk of dementia/Alzheimer disease after adjusting for other characteristics that affect the development of these conditions. Pooled data from both cohorts indicated that, compared to people without diabetes carrying HHEX_23-GG (the human genome contains two copies [alleles] of each gene, and an individual carrying HHEX_23-GG has the nucleotide guanine at a particular position in both HHEX_23 copies), people with diabetes carrying HHEX_23-AA (adenine at that position in both HHEX_23 copies) had a 5-fold higher risk of developing dementia/Alzheimer disease. Other analyses indicated that the HHEX_23-AA genotype interacted with diabetes to substantially increase the risk of dementia/Alzheimer disease. Finally, MRI showed that, at baseline, HHEX_23-AA carriers with diabetes had structural brain changes compared to HHEX_23-GG carriers without diabetes, even though they were all free of dementia at the time.
What Do These Findings Mean?
These and other findings indicate that polymorphisms in HHEX_23, but not IDE_9, are involved in the association between diabetes, dementia, and structural brain changes. Thus, a genetic variant in HHEX_23 may play an important role in the development of Alzheimer disease and other forms of dementia among people with diabetes or prediabetes. These findings may not apply to younger or rural populations, and their accuracy may be affected by the use of a single blood sugar level reading to diagnose diabetes and prediabetes. Moreover, because some of the genotype/diabetes subgroups contained very few people, these findings need to be confirmed in additional studies. Further studies are also needed to understand the role of HHEX_23 in the association between diabetes and dementia. Importantly, however, these findings highlight the need to control diabetes to prevent the development of Alzheimer disease and other forms of dementia, particularly among HHEX_23-AA carriers.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001828.
The UK National Health Service Choices website provides information (including personal stories and links to additional resources) about dementia, vascular dementia, Alzheimer disease, and diabetes
The UK not-for-profit organization Alzheimer’s Society provides information for patients and carers about dementia, including personal experiences of dementia
The US not-for-profit organization Alzheimer’s Association also provides information for patients and carers about dementia, personal stories about dementia, and information about the association between diabetes and dementia
Alzheimer’s Disease International is the federation of Alzheimer disease associations around the world; it provides links to individual Alzheimer disease associations, information about dementia, and links to World Alzheimer Reports
MedlinePlus provides links to additional resources about dementia, Alzheimer disease, vascular dementia, and diabetes (in English and Spanish)
More information about the Kungsholmen Project and the Swedish National Study on Aging and Care–Kungsholmen, the projects that enrolled the cohorts used by the researchers for this study, is available
doi:10.1371/journal.pmed.1001853
PMCID: PMC4501827  PMID: 26173052
5.  Flavanols, Mild Cognitive Impairment, and Alzheimer's Dementia 
Alzheimer's disease (AD) is a dementing neurological disorder that results in progressive memory loss and cognitive decline thought to be associated with buildup of amyloid plaques and neurofibrillary tangles in the brain. Vascular Dementia (VaD) is another common dementing disorder characterized by decreased brain perfusion. Together, AD and VaD constitute mixed dementia, an extremely common type of dementia associated with aging. Neuroimaging research suggests that brain vascular atrophy results in mild cognitive impairment (MCI), a possible precursor for AD. Additionally, literature suggests that attention to cardiovascular risk factors such as hypertension could reduce or delay the incidence of mixed dementia. Furthermore, foods and beverages rich in natural antioxidant flavanoids (i.e. epicatechin and catechin) are currently being advocated as possible preventative agents for a number of pathological conditions ranging from coronary heart disease to dementia. Experimental evidence is mounting that oxidative stress is involved in the pathophysiology of AD, and numerous studies are indicating that polyphenolic antioxidants found in fruits and vegetables can be useful in countering this and blocking neuronal death. More specifically, several cocoa studies suggest that daily intake of cocoa flavanols leads to cardiovascular benefits including vasodilatation via a nitric oxide mechanism and increased brain perfusion. The following text will consider an important question that thus arises regarding the potential of flavanols as effective agents for the prevention and delay of the onset of brain vascular atrophy and subsequently MCI and AD. It will also review the molecular mechanisms through which flavanols operate to accomplish their protective effects.
PMCID: PMC2596318  PMID: 19079672
Brain vascular atrophy; mild cognitive impairment; Alzheimer's disease; flavanols; oxidative stress; antioxidants
6.  Cortical Neuritic Plaques and Hippocampal Neurofibrillary Tangles are Related to Dementia Severity in Elderly Schizophrenia Patients 
Schizophrenia research  2010;116(1):90-96.
Cognitive decline has been described in elderly patients with schizophrenia, but the underlying pathology remains unknown. Some studies report increases in plaques and neurofibrillary tangles, but there is no evidence for an increased risk for Alzheimer’s disease (AD) in elderly schizophrenics. Models of a decreased cerebral reserve suggest that increases in AD-related neuropathology below the threshold for a neuropathological diagnosis could be related to dementia severity in elderly schizophrenia patients. We tested this hypothesis in 110 autopsy specimens of schizophrenia patients , without a neuropatholgical diagnosis of AD or other neurdegenerative disorders. Furthermore, we assessed the effects of apolipoprotein E (ApoE) status, a known genetic risk factor for AD. Measures of density of neuritic plaques were obtained in five cortical regions, and the degree of hippocampal neurofibrillary tangles was rated. Dementia severity was measured prior to postmortem using the Clinical Dementia Rating (CDR) scale. In multivariate analyses of variance were conducted with the factors dementia severity, by ApoE4 carrier status. Hippocampal neurofibrillary tangles correlated with increased dementia severity (p < .05). Neuritic plaque density increased with greater dementia severity (p < .005), and ApoE4 carrier status (p < .005), and these differences were magnified by ApoE4 carrier status (p < .01). Even below the threshold for a neuropathological diagnosis of AD, neuritic plaques and hippocampal neurofibrillary tangles are associated with dementia severity in schizophrenia patients, even more so in the presence of genetic risk factors, suggesting that a decreased cerebral reserve in elderly schizophrenics may increase susceptibilty for dementia.
doi:10.1016/j.schres.2009.10.013
PMCID: PMC2795077  PMID: 19896333
Schizophrenia; Alzheimer’s Disease; Neuropathology
7.  Vascular Contributions to Cognitive Impairment and Dementia 
Background and Purpose
This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.
Methods
Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee.
Results
The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people.
Conclusions
Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.
doi:10.1161/STR.0b013e3182299496
PMCID: PMC3778669  PMID: 21778438
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
8.  Midlife blood pressure, plasma β amyloid and the risk for Alzheimer’s disease: the Honolulu Asia Aging Study 
Hypertension  2012;59(4):780-786.
Beta-amyloid (Aβ), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer’s disease (AD) and possibly vascular dementia (VaD). We investigated the joint association of mid-life BP and Aβ peptide levels with the risk for late-life AD and VaD. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965 – 2000). Mid-life BP was measured starting in 1971 participants mean age 58 years, Aβ was measured in specimens collected1980/82, and assessment of dementia and autopsy collection started in 1991/93. The outcome measures were prevalent (present in 1991/3) and incident AD (n= 53, including 38 with no contributing cardiovascular disease), and VaD (n=24). Cerebral amyloid angiopathy (CAA), β-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in post-mortem tissue. The risk for AD significantly increased with lower levels of plasma Aβ (Aβ1-40 hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.4 – 3.1; Aβ1-42 HR 1.6, 95% CI 1.1 – 2.3). Evidence of interaction between diastolic BP and plasma Aβ (1-40 pinteraction <0.05; 1-42 pinteraction <0.07) levels, indicated the Aβ-related risk for AD was higher when BP was higher. Low plasma Aβ was associated with the presence of CAA (ptrend<0.05), but not the other neuropathologies. Aβ plasma levels start decreasing at least 15 years before AD is diagnosed, and the association of Aβ to AD is modulated by mid-life diastolic BP. Elevated BP may compromise vascular integrity leading to CAA and impaired Aβ clearance from the brain.
doi:10.1161/HYPERTENSIONAHA.111.178962
PMCID: PMC3319436  PMID: 22392902
Amyloid; blood pressure; brain; aging; dementia
9.  Genetic Predisposition to Increased Blood Cholesterol and Triglyceride Lipid Levels and Risk of Alzheimer Disease: A Mendelian Randomization Analysis 
PLoS Medicine  2014;11(9):e1001713.
In this study, Proitsi and colleagues use a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset Alzheimer's Disease (LOAD) and find that genetic predisposition to increased plasma cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk.
Please see later in the article for the Editors' Summary
Background
Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.
Methods and Findings
We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n = 10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10−8 and trait specific scores using SNPs associated exclusively with each trait at p<5×10−8 were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR] = 1.005, 95% CI 0.82–1.24, p = 0.962 per 1 unit increase in HDL-c; OR = 0.901, 95% CI 0.65–1.25, p = 0.530 per 1 unit increase in LDL-c; OR = 1.104, 95% CI 0.89–1.37, p = 0.362 per 1 unit increase in triglycerides; and OR = 0.954, 95% CI 0.76–1.21, p = 0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance.
Conclusions
Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 44 million people worldwide have dementia, a group of brain disorders characterized by an irreversible decline in memory, communication, and other “cognitive” functions. Dementia mainly affects older people and, because people are living longer, experts estimate that more than 135 million people will have dementia by 2050. The commonest form of dementia is Alzheimer disease. In this type of dementia, protein clumps called plaques and neurofibrillary tangles form in the brain and cause its degeneration. The earliest sign of Alzheimer disease is usually increasing forgetfulness. As the disease progresses, affected individuals gradually lose their ability to deal with normal daily activities such as dressing. They may become anxious or aggressive or begin to wander. They may also eventually lose control of their bladder and of other physical functions. At present, there is no cure for Alzheimer disease although some of its symptoms can be managed with drugs. Most people with the disease are initially cared for at home by relatives and other unpaid carers, but many patients end their days in a care home or specialist nursing home.
Why Was This Study Done?
Several lines of evidence suggest that lipid metabolism (how the body handles cholesterol and other fats) is altered in patients whose Alzheimer disease develops after the age of 60 years (late onset Alzheimer disease, LOAD). In particular, epidemiological studies (observational investigations that examine the patterns and causes of disease in populations) have found an association between high amounts of cholesterol in the blood in midlife and the risk of LOAD. However, observational studies cannot prove that abnormal lipid metabolism (dyslipidemia) causes LOAD. People with dyslipidemia may share other characteristics that cause both dyslipidemia and LOAD (confounding) or LOAD might actually cause dyslipidemia (reverse causation). Here, the researchers use “Mendelian randomization” to examine whether lifetime changes in lipid metabolism caused by genes have a causal impact on LOAD risk. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if dyslipidemia causes LOAD, genetic variants that affect lipid metabolism should be associated with an altered risk of LOAD.
What Did the Researchers Do and Find?
The researchers investigated whether genetic predisposition to raised lipid levels increased the risk of LOAD in 10,578 participants (3,914 patients with LOAD, 1,675 elderly people without LOAD, and 4,989 population controls) using data collected in six genome wide studies looking for gene variants associated with Alzheimer disease. The researchers constructed a genotype risk score (GRS) for each participant using genetic risk markers for four types of blood lipids on the basis of the presence of single nucleotide polymorphisms (SNPs, a type of gene variant) in their DNA. When the researchers used statistical methods to investigate the association between the GRS and LOAD among all the study participants, they found no association between the GRS and LOAD.
What Do These Findings Mean?
These findings suggest that the genetic predisposition to raised blood levels of four types of lipid is not causally associated with LOAD risk. The accuracy of this finding may be affected by several limitations of this study, including the small proportion of lipid variance explained by the GRS and the validity of several assumptions that underlie all Mendelian randomization studies. Moreover, because all the participants in this study were white, these findings may not apply to people of other ethnic backgrounds. Given their findings, the researchers suggest that the observed epidemiological associations between abnormal lipid levels in the blood and variation in lipid levels for reasons other than genetics, or to LOAD risk could be secondary to variation in lipid levels for reasons other than genetics, or to LOAD, a possibility that can be investigated by studying blood lipid levels and other markers of lipid metabolism over time in large groups of patients with LOAD. Importantly, however, these findings provide new information about the role of lipids in LOAD development that may eventually lead to new therapeutic and public-health interventions for Alzheimer disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001713.
The UK National Health Service Choices website provides information (including personal stories) about Alzheimer's disease
The UK not-for-profit organization Alzheimer's Society provides information for patients and carers about dementia, including personal experiences of living with Alzheimer's disease
The US not-for-profit organization Alzheimer's Association also provides information for patients and carers about dementia and personal stories about dementia
Alzheimer's Disease International is the international federation of Alzheimer disease associations around the world; it provides links to individual associations, information about dementia, and links to World Alzheimer Reports
MedlinePlus provides links to additional resources about Alzheimer's disease (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001713
PMCID: PMC4165594  PMID: 25226301
10.  Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques(e–Pub ahead of print) 
Neurology  2010;75(13):1203-1210.
Objectives:
Observational and experimental studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer disease (AD); however, clinical trials and other observational studies, including the Adult Changes in Thought (ACT) study, show no protection or promotion of AD. The objective of this study is to determine the relationship between common dementia-associated pathologies and mid- to late-life NSAID exposure.
Methods:
We examined the association of mid- to late-life NSAID use with neuropathologic findings on 257 autopsies from ACT, a population-based study of brain aging and incident dementia. Cumulative standard daily doses (SDD) of nonselective NSAIDs were determined from ≥10 years of computerized pharmacy dispensing data. Analyses were adjusted for selection bias to broaden generalizability of results to 3,026 eligible participants in the ACT cohort. Seven pathologic indices were evaluated: intermediate or frequent score for neuritic plaques, Braak stages V or VI for neurofibrillary tangles, >2 cerebral microinfarcts, the presence of any neocortical Lewy bodies, any macroscopic infarcts, any amyloid angiopathy, and moderate or severe atherosclerosis.
Results:
Of the neuropathologic indices evaluated, only neuritic plaque score was significantly increased in participants with greater use of nonselective NSAIDs (p = 0.065), specifically in those with high levels of cumulative use: 1,000–2,000 SDD (adjusted relative risk [RR] 2.16, 95% confidence interval [CI] 1.02–4.25, compared to light/nonuse [<60 SDD]) and >2,000 SDD (adjusted RR 2.37, 95% CI 1.24–4.67).
Conclusions:
Increased neuritic plaque accumulation may explain the association between heavy use of nonselective NSAIDs and increased risk of dementia among ACT participants.
GLOSSARY
= amyloid angiopathy;
= Adult Changes in Thought;
= Alzheimer disease;
= Consortium to Establish a Registry for Alzheimer's Disease;
= confidence interval;
= cerebral microinfarct;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= Group Health Cooperative;
= Lewy body disease;
= neurofibrillary tangle;
= neuritic plaque;
= nonsteroidal anti-inflammatory drug;
= over-the-counter;
= relative risk;
= standard daily dose;
= vascular brain injury.
doi:10.1212/WNL.0b013e3181f52db1
PMCID: PMC3013492  PMID: 20811000
11.  Genetic Polymorphisms of a Novel Vascular Susceptibility Gene, Ninjurin2 (NINJ2), Are Associated with a Decreased Risk of Alzheimer's Disease 
PLoS ONE  2011;6(6):e20573.
Background
Accumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously.
Methods
A total of 275 Alzheimer's disease (AD) patients and 119 vascular dementia (VaD) patients aged 50 or older were recruited from three teaching hospitals from 2007 to 2010. Healthy controls (n = 423) with the same age of cases were recruited from the health checkup and volunteers worked at the hospital during the same time period. Five common (frequency >5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) in NINJ2 were genotyped to test for the association between sequence variants of NINJ2 and dementia risk, and how vascular risk factors modify this association.
Results
Homozygosity of two NINJ2 SNPs was significantly associated with a decreased risk of AD [rs11833579: adjusted odds ratio (AOR) = 0.43; 95% confidence interval (CI)  = 0.23–0.80; rs12425791: AOR  = 0.33, 95% CI  = 0.12–0.96]. Five common haplotypes (cumulative frequency  = 97%) were identified. The global test for the association between NINJ2 haplotypes and AD was significant (p = 0.03). Haplotype CAGGA was significantly associated with a decreased risk of AD (AOR  = 0.32, 95% CI  = 0.11–0.94). No associations were observed for VaD.
Conclusion
Inherited polymorphisms of the vascular susceptibility gene NINJ2 were associated with AD risk.
doi:10.1371/journal.pone.0020573
PMCID: PMC3108950  PMID: 21674003
12.  The apolipoprotein E allele epsilon 4 does not correlate with the number of senile plaques or neurofibrillary tangles in patients with Alzheimer's disease. 
BACKGROUND AND OBJECTIVES: Apolipoprotein E (apoE) has been implicated in regenerative processes in the brain after trauma, as well as in the pathogenesis of Alzheimer's disease. Inheritance of a specific apo epsilon allele (apo epsilon 4) determines in part the risk and the mean age at onset of Alzheimer's disease. ApoE has been found to bind isoform specifically to beta-amyloid protein, the major component of senile plaques, and to the microtubule associated protein tau, which forms paired helical filaments and neurofibrillary tangles. The aim was to further examine the relation between apo epsilon alleles, especially apo epsilon 4, and the development of neuropathological changes associated with Alzheimer's disease. METHODS: Brains of patients with Alzheimer's disease (n = 44) and vascular dementia (n = 11) and of age matched controls (n = 29) were studied. Senile plaques and neurofibrillary tangles in the hippocampus and frontal cortex were quantified. RESULTS: No correlation was found between the number of apo epsilon 4 alleles and the number of senile plaques and neurofibrillary tangles in the hippocampus or the frontal cortex of patients with Alzheimer's disease, or vascular dementia, or control groups. No significant differences in duration or severity of dementia were found between patients with or. without the apo epsilon 4 allele. No increased frequency of apo epsilon 4 was found in vascular dementia. CONCLUSION AND COMMENT: Although the apo epsilon genotype clearly affects whether Alzheimer's disease will develop or not, the present study suggests that it has no influence on pathology or clinical intellectual status, once the dementia has manifested itself. No increased apo epsilon 4 allele frequency was found in neuropathologically diagnosed patients with vascular dementia in whom concomitant Alzheimer's disease can be excluded.
PMCID: PMC486574  PMID: 8890772
13.  Carotid Atherosclerosis and Prospective Risk of Dementia 
Background and Purpose
Though vascular risk factors have been implicated in the development of all-cause dementia and Alzheimer’s disease (AD), few studies have examined the association between subclinical atherosclerosis and prospective risk of dementia.
Methods
Participants from the Baltimore Longitudinal Study of Aging (n=364, aged 60–95, median age=73, 60% male, 82% white) underwent initial carotid atherosclerosis assessment and were subsequently assessed for dementia and AD annually for up to 14 years (median=7.0). Cox proportional hazards models predicting (a) all-cause dementia and (b) AD were adjusted for age, sex, race, education, blood pressure, cholesterol, cardiovascular disease, diabetes, and smoking.
Results
Sixty participants developed dementia, with 53 diagnosed as Alzheimer’s disease. Raw rates of future dementia and AD among individuals initially (a) in the upper quintile of carotid intimal medial thickness (IMT) or (b) with bilateral carotid plaque were generally double the rates of individuals with IMT in the lower quintiles or no plaque at baseline. Adjusted proportional hazards models revealed a >2.5-fold increased risk of dementia and AD among individuals in the upper quintile of carotid IMT, and a nearly 2.0-fold increased risk of dementia among individuals with bilateral plaque.
Conclusions
Multiple measures of carotid atherosclerosis are associated with prospective risk of dementia. Individuals in the upper quintile of carotid IMT or bilateral carotid plaque were at greatest risk. These findings underscore the possibility that early intervention to reduce atherosclerosis may help delay or prevent onset of dementia and AD.
doi:10.1161/STROKEAHA.112.672527
PMCID: PMC3508298  PMID: 23103489
atherosclerosis; intimal medial thickness; dementia; Alzheimer’s disease
14.  Is apolipoprotein E4 an important risk factor for vascular dementia? 
Despite the fact that vascular dementia (VaD) represents the seconding leading cause of dementia in the USA, behind only Alzheimer’s disease (AD), there remains a lack of consensus on the pathological criteria required for diagnosis of this disease. A number of clinical diagnostic criteria exist but are poorly validated and inconsistently applied. It is clear that vascular risk factors play an important role in the etiology of VaD, including hypertension, stroke, diabetes, and atherosclerosis. Vascular risk factors may increase the risk for VaD by promoting inflammation, cerebral vascular disease, white matter lesions, and hippocampal sclerosis. Because vascular risk factors seem to impart a high degree of risk for conferring VaD, it seems logical that the apolipoprotein E (APOE) status of individuals may be important. APOE plays a critical role in transporting cholesterol in and out of the CNS and in AD it is known that harboring the APOE allele increases the risk of AD perhaps due to the improper functioning of this protein. The purpose of this review is to examine the important pathological features and risk factors for VaD and to provide a critical assessment of the current literature regarding whether or not apoE4 also confers disease risk in VaD. The preponderance of data suggests that harboring one or both APOE4 alleles elevates the risk for VaD, but not to the same extent as found in AD.
PMCID: PMC4128964  PMID: 25120729
Apolipoprotein E4 (APOE4); vascular dementia; pathology; risk factors; Alzheimer’s disease; neurofibrillary tangles; blood brain barrier; inflammation
15.  Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum 
Brain  2015;138(5):1370-1381.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer’s disease, was incorporated into the latest National Institute of Ageing – Alzheimer’s Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer’s disease dementia published by the National Institute of Ageing – Alzheimer’s Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem 11C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of 11C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. 11C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical 11C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer’s disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer’s disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted 11C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to 11C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer’s disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer’s disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with 11C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The 11C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1–2.
doi:10.1093/brain/awv050
PMCID: PMC4407190  PMID: 25805643
Alzheimer’s disease; neuropathology; Thal amyloid phase; Pittsburgh compound B; Braak tangle stage
16.  Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study 
Brain  2013;136(9):2707-2716.
Elevated plasma total homocysteine is associated with increased risk of dementia/Alzheimer’s disease, but underlying pathophysiological mechanisms are not fully understood. This study investigated possible links between baseline homocysteine, and post-mortem neuropathological and magnetic resonance imaging findings up to 10 years later in the Vantaa 85+ population including people aged ≥85 years. Two hundred and sixty-five individuals had homocysteine and autopsy data, of which 103 had post-mortem brain magnetic resonance imaging scans. Methenamine silver staining was used for amyloid-β and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, cerebral amyoloid angiopathy, and α-synuclein pathology. Magnetic resonance imaging was used for visual ratings of the degree of medial temporal lobe atrophy, and periventricular and deep white matter hyperintensities. Elevated baseline homocysteine was associated with increased neurofibrillary tangles count at the time of death: for the highest homocysteine quartile, odds ratio (95% confidence interval) was 2.60 (1.28–5.28). The association was observed particularly in people with dementia, in the presence of cerebral infarcts, and with longer time between the baseline homocysteine assessment and death. Also, elevated homocysteine tended to relate to amyloid-β accumulation, but this was seen only with longer baseline-death interval: odds ratio (95% confidence interval) was 2.52 (0.88–7.19) for the highest homocysteine quartile. On post-mortem magnetic resonance imaging, for the highest homocysteine quartile odds ratio (95% confidence interval) was 3.78 (1.12–12.79) for more severe medial temporal atrophy and 4.69 (1.14–19.33) for more severe periventricular white matter hyperintensities. All associations were independent of several potential confounders, including common vascular risk factors. No relationships between homocysteine and cerebral macro- or microinfarcts, cerebral amyoloid angiopathy or α-synuclein pathology were detected. These results suggest that elevated homocysteine in adults aged ≥85 years may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology. Randomized controlled trials are needed to determine the impact of homocysteine-lowering treatments on dementia-related pathology.
doi:10.1093/brain/awt206
PMCID: PMC3754457  PMID: 23983028
homocysteine; Alzheimer’s disease; Alzheimer pathology; cerebrovascular pathology; elderly
17.  Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias 
PLoS Genetics  2014;10(9):e1004606.
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Author Summary
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.
doi:10.1371/journal.pgen.1004606
PMCID: PMC4154667  PMID: 25188341
18.  Examination of the Clinicopathologic Continuum of Alzheimer Disease in the Autopsy Cohort of the National Alzheimer Coordinating Center 
To test the hypothesis that Alzheimer disease (AD) is a clinical and pathologic continuum between normal aging and end-stage dementia, we selected a convenience sample of subjects from the National Alzheimer Coordinating Center 2005 to 2012 autopsy cohort (n = 2,083) with the last clinical evaluation within 2 years before autopsy and no other primary neuropathologic diagnosis. Demographic and neuropathologic characteristics were correlated with the Clinical Dementia Rating–Sum of Boxes in the 835 subjects meeting these criteria. Both neuritic plaques and neurofibrillary tangles independently predicted Clinical Dementia Rating–Sum of Boxes. Severe small-vessel disease, severe amyloid angiopathy, and hippocampal sclerosis were also independently associated with the degree of cognitive impairment. By contrast, education was a strong independent protective factor against cognitive deficits. The cause of mild to moderate dementia remained uncertain in 14% of the patients. Inverse probability weighting suggests the generalizability of these results to nonautopsied cohorts. These data indicate that plaques and tangles independently contribute to cognitive impairment, that concurrent vascular disease strongly correlates with cognitive dysfunction even in a sample selected to represent the AD pathologic continuum, and that education further modifies clinical expression. Thus, multiple concomitant etiologies of brain damage and premorbid characteristics contribute to the uncertainty of AD clinicopathologic correlations based only on tangles and plaques.
doi:10.1097/NEN.0000000000000016
PMCID: PMC3962953  PMID: 24226270
Alzheimer disease; Cerebral amyloid angiopathy; Hippocampal sclerosis; Neuritic plaques; Neurofibrillary tangles; Small-vessel disease
19.  Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study 
PLoS Medicine  2015;12(6):e1001841.
Background
Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR).
Methods and Findings
We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP–AD associations from the International Genomics of Alzheimer’s Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62–0.91]; p = 3.4 × 10−3). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10−8). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51–0.89]; p = 6.5 × 10−3), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses.
Conclusions
Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure—or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications—may reduce AD risk.
Robert A. Scott and colleagues use genetic instruments to identify causal associations between known risk factors and Alzheimer's disease.
Editors' Summary
Background
Worldwide, about 44 million people have dementia, a group of brain degeneration disorders characterized by an irreversible decline in memory, communication, and other “cognitive” functions. Dementia mainly affects older people, and because people are living longer, experts estimate that more than 135 million people will have dementia by 2050. The most common form of dementia, which accounts for 60%–70% of cases, is Alzheimer disease (AD). The earliest sign of AD is often increasing forgetfulness. As the disease progresses, affected individuals gradually lose the ability to look after themselves, they may become anxious or aggressive, and they may have difficulty recognizing friends and relatives. People with late stage disease may lose control of their bladder and of other physical functions. At present, there is no cure for AD, although some of its symptoms can be managed with drugs. Most people with AD are initially cared for at home by relatives and other caregivers, but many affected individuals end their days in a care home or specialist nursing home.
Why Was This Study Done?
Researchers are interested in identifying risk factors for AD, particularly modifiable risk factors, because if such risk factors exist, it might be possible to limit the predicted increase in future AD cases. Epidemiological studies (investigations that examine patterns of disease in populations) have identified several potential risk factors for AD, including hypertension (high blood pressure), obesity, smoking, and dyslipidemia (changes in how the body handles fats). However, epidemiological studies cannot prove that a specific risk factor causes AD. For example, people with hypertension might share another characteristic that causes both hypertension and AD (confounding) or AD might cause hypertension (reverse causation). Information on causality is needed to decide which risk factors to target to help prevent AD. Here, the researchers use “Mendelian randomization” to examine whether differences in several epidemiologically identified risk factors for AD have a causal impact on AD risk. In Mendelian randomization, causal associations are inferred from the effects of genetic variants (which predict levels of modifiable risk factors) on the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if hypertension actually causes AD, genetic variants that affect hypertension should be associated with an altered risk of AD.
What Did the Researchers Do and Find?
The researchers identified causal associations between potentially modifiable risk factors and AD risk by analyzing the occurrence of single nucleotide polymorphisms (SNPs, a type of gene variant) known to predict levels of each risk factor, in genetic data from 17,008 individuals with AD and 37,154 cognitively normal elderly controls collected by the International Genomics of Alzheimer’s Project. They report that genetically predicted higher systolic blood pressure (SBP; the pressure exerted on the inside of large blood vessels when the heart is pumping out blood) was associated with lower AD risk (and with a higher probability of taking antihypertensive medication). Predicted smoking quantity was also associated with lower AD risk, but there was no evidence of causal associations between any of the other risk factors investigated and AD risk.
What Do These Findings Mean?
In contrast to some epidemiological studies, these findings suggest that hypertension is associated with lower AD risk. However, because genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication, it could be that exposure to such drugs, rather than having hypertension, reduces AD risk. Like all Mendelian randomization studies, the reliability of these findings depends on the validity of several assumptions made by the researchers and on the ability of the SNPs used in the analyses to explain variations in exposure to the various risk factors. Moreover, because all the participants in the International Genomics of Alzheimer’s Project are of European ancestry, these findings may not be valid for other ethnic groups. Given that hypertension is a risk factor for cardiovascular disease, the researchers do not advocate raising blood pressure as a measure to prevent AD (neither do they advocate that people smoke more cigarettes to lower AD risk). Rather, given the strong association between higher SBP gene scores and the probability of exposure to antihypertensive treatment, they suggest that the possibility that antihypertensive drugs might reduce AD risk independently of their effects on blood pressure should be investigated as a priority.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001841.
The UK National Health Service Choices website provides information (including personal stories) about Alzheimer disease
The UK not-for-profit organization Alzheimer’s Society provides information for patients and carers about dementia, including personal experiences of living with Alzheimer disease
The US not-for-profit organization Alzheimer’s Association also provides information for patients and carers about dementia and personal stories about dementia
Alzheimer’s Disease International is the federation of Alzheimer disease associations around the world; it provides links to individual Alzheimer associations, information about dementia, and links to world Alzheimer reports
MedlinePlus provides links to additional resources about Alzheimer disease (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
A PLOS Medicine Research Article by Proitsi et al. describes a Mendelian randomization study that looked for a causal association between dyslipidemia and Alzheimer disease
doi:10.1371/journal.pmed.1001841
PMCID: PMC4469461  PMID: 26079503
20.  Alzheimer's Disease: cholesterol, membrane rafts, isoprenoids and statins 
Abstract
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and the most prevalent form of dementia worldwide. AD is characterized pathologically by amyloid-β plaques, neurofibrillary tangles and neuronal loss, and clinically by a progressive loss of cognitive abilities. At present, the fundamental molecular mechanisms underlying the disease are unclear and no treatment for AD is known. Epidemiological evidence continues to mount linking vascular diseases, such as hypertension and diabetes, and hypercholesterolaemia with an increased risk for developing AD. A growing amount of evidence suggests a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques in AD development. Cholesterol and statins clearly modulate β-amyloid precursor protein (βAPP) processing in cell culture and animal models. Statins not only reduce endogenous cholesterol synthesis but also exert other various pleiotrophic effects, such as the reduction in protein isoprenylation. Through these effects statins modulate a variety of cellular functions involving both cholesterol (and membrane rafts) and isoprenylation. Although clearly other factors, such as vascular inflammation, oxidative stress and genetic factors, are intimately linked with the progression of AD, this review focuses on the present research findings describing the effect of cholesterol, membrane rafts and isoprenylation in regulating βAPP processing and in particular γ-secretase complex assembly and function and AD progression, along with consideration for the potential role statins may play in modulating these events.
doi:10.1111/j.1582-4934.2007.00054.x
PMCID: PMC3922347  PMID: 17635634
cholesterol; secretases; Alzheimer's disease; statins; isoprenoids; APP metabolism; Abeta; Tau; membrane rafts
21.  Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias 
Brain  2012;135(12):3749-3756.
A growing body of evidence demonstrates an association between vascular risk factors and Alzheimer’s disease. This study investigated the frequency and severity of atherosclerotic plaques in the circle of Willis in Alzheimer’s disease and multiple other neurodegenerative diseases. Semi-quantitative data from gross and microscopic neuropathological examinations in 1000 cases were analysed, including 410 with a primary diagnosis of Alzheimer’s disease, 230 with synucleinopathies, 157 with TDP-43 proteinopathies, 144 with tauopathies and 59 with normal ageing. More than 77% of subjects with Alzheimer’s disease had grossly apparent circle of Willis atherosclerosis, a percentage that was significantly higher than normal (47%), or other neurodegenerative diseases (43–67%). Age- and sex-adjusted atherosclerosis ratings were highly correlated with neuritic plaque, paired helical filaments tau neurofibrillary tangle and cerebral amyloid angiopathy ratings in the whole sample and within individual groups. We found no associations between atherosclerosis ratings and α-synuclein or TDP-43 lesion ratings. The association between age-adjusted circle of Willis atherosclerosis and Alzheimer’s disease–type pathology was more robust for female subjects than male subjects. These results provide further confirmation and specificity that vascular disease and Alzheimer’s disease are interrelated and suggest that common aetiologic or reciprocally synergistic pathophysiological mechanisms promote both vascular pathology and plaque and tangle pathology.
doi:10.1093/brain/aws271
PMCID: PMC3577102  PMID: 23204143
atherosclerosis; neuritic plaques; neurofibrillary tangles; synuclein; TDP-43
22.  Vascular dementia: prevention and treatment 
Clinical Interventions in Aging  2006;1(3):229-235.
Background:
Vascular dementia (VaD) is the most common cause of dementia in the elderly, second only to Alzheimer’s disease (AD). Between 1% and 4% of people of 65 years of age suffer from VaD and the prevalence appears to double every 5–10 years after the age of 65.
Summary:
Prevention aims to reduce the disease by eliminating its cause or main risk factors, particularly hypertension as well as diabetes mellitus, atherosclerosis, coronary artery disease, smoking, lipid abnormalities, and hyperhomocystinemia. Initial studies of several agents for symptomatic treatment were disappointing. However, there is growing evidence for cholinergic involvement in VaD and recent studies with cholinesterase inhibitors have shown improvement in cognitive, global function, and activities of daily living as compared with placebo and have been well tolerated.
Conclusion:
VaD is a common condition and its prevalence is likely to increase. As physicians we need to be diligent with regards to recognition of risk factors and vigorous intervention. Promising results have been seen in several clinical trials of cholinesterase inhibitors and no safety of tolerability issues have been noted.
PMCID: PMC2695177  PMID: 18046875
vascular dementia; prevention; treatment
23.  Epidemiological Aspects of Atherosclerosis in Patients Treated for Acute Atherothrombosis of Extremity Arteries 
Medical Archives  2014;68(5):329-331.
ABSTRACT
Introduction:
Risk factors for development of extremity artery atherosclerosis are the same as for coronary and cerebrovascular atherosclerosis namely, diabetes mellitus, hyperlipidemia, arterial hypertension, age and smoking. Atherosclerosis is polyarterial disease that clinically manifests itself most frequently in the form coronary, cerebrovascular or peripheral arterial disease (PAD). All of them have common, ominous and final pathologic step – atherosclerotic plaque rupture that might eventually lead to atherothrombosis and signs of ischemia. There are few studies of risk factor for peripheral artery disease (PAD). Aim of study: To identify prevalence of known risk factors for atherosclerosis in patients treated for acute atherothrombosis of extremity arteries.
Patients and methods:
Eighty patient were analyzed with regard to the prevalence of five risk factors for atherosclerosis (diabetes mellitus, smoking, hypertension, hyperlipidemia and age). 80 patients were divided into two groups (Group A and B) depending on country i.e. hospital where they received treatment for acute atherothrombosis of extremity artery. Group A consisted of patients treated at Clinic for vascular surgery in Sarajevo, while patients in Group B were treated in Trollhattan in Sweden at NAL hospital. This study was clinical, comparative, retrospective-prospective.
Results:
In group A, 20% of patients had diabetes mellitus while in group B prevalence of diabetics was lower (12,5%) but difference was not statistically significant p>0.05. Sixty percent of patients (60%) in group A were smokers. In Sweden, habit of smoking is not as common as in Balkan countries and consequently only 22,5% of patients were smokers in Group l, difference was statistically significant, p<0.05. In patients assigned to group A, 42.5% of them had diagnosis of hypertension while in Group B, 35% of patients were hypertensive. Difference was not statistically significant, p>0.05. 37.5% of patients in group A and 20% of patients in group B had hyperlipidemia. Difference was not statistically significant, p>0.05. In Group A mean age of patients was 67.85 years while mean age in Group B was 73.63. Age difference was statistically significant, p<0.05.
Conclusion:
Prevalence of risk factors of atherosclerosis in peripheral artery disease were evaluated in this study. Significant difference in prevalence of two risk factors were determined namely, smoking and mean age of occurrence of atherothrombosis. Quiting smoking and adopting healthier life habits may lead to reduction of prevalence PAD in younger patients in Bosnia and Herzegovina.
doi:10.5455/medarh.2014.68.329-331
PMCID: PMC4269536  PMID: 25568565
extremity arteries; atherosclerosis; acute atherothrombosis
24.  Imaging Vascular Disease and Amyloid in the Aging Brain: Implications for Treatment 
Summary
Vascular risk factors (e.g. hypertension, dyslipidemia and diabetes) are well known risk factors for Alzheimer’ disease. These vascular risk factors lead to vascular brain injuries, which also increase the likelihood of dementia. The advent of amyloid PET imaging has helped establish that vascular risk factors also lead to Alzheimer’s disease via pathways that are independent from vascular brain injuries, at least, when vascular brain injuries are measured as white matter lesions and infarcts. While vascular brain injuries (white matter lesions and infarcts) do not seem to influence amyloid pathology, some evidence from amyloid imaging suggests that increased vascular risk is related to increased amyloid burden. Furthermore, while vascular brain injuries and amyloid have an additive and independent impact on brain integrity, vascular risk factors might potentiate the impact of amyloid on cortical thickness on brain regions vulnerable to Alzheimer’s disease. New research should further explore and confirm, or refute, possible interactions between amyloid and vascular risk factors on brain integrity and cognition. Neuroimaging tools used to assess vascular brain integrity should also be expanded. Measuring cortical blood flow or damage to the capillary system might, for instance, give insight about how vascular risk factors can be associated to amyloid burden and impact. These findings also stress the need for monitoring vascular risk factors in midlife as a strategy for Alzheimer’s disease prevention.
doi:10.14283/jpad.2015.47
PMCID: PMC4381867  PMID: 25844350
Alzheimer’ disease; amyloid; vascular brain injuries; vascular risk factors; treatment
25.  Vascular Risk Factors: Imaging and Neuropathologic Correlates 
Cerebrovascular disease plays an important role in cognitive disorders in the elderly. Cerebrovascular disease and Alzheimer’s disease interact on several levels, one important level being the overlap in risk factors. The major vascular risk factors such as diabetes and impaired glycemic control, hypertension, obesity and hyper- or dyslipidemia have been associated both with Alzheimer’s disease and vascular dementia. The purpose of this review is to consider the context in which vascular dementia is diagnosed, place the pathophysiological consequences of cerebrovascular disease on cognition in the context of clinical and pathological Alzheimer’s disease, and then to consider the evidence for the role of major vascular risk factors in late-life cognitive impairment, changes in brain imaging and neuropathological changes. Midlife diabetes mellitus, hypertension and obesity are established risk factors for clinically defined Alzheimer’s disease as well as vascular dementia. The basis for these relationships could either be that the risk factors lead to microvascular brain disease, promote Alzheimer pathology or both. The associations of late-life onset diabetes mellitus, hypertension and obesity with cognitive impairment are either attenuated or reversed. The role of vascular risk factors in midlife should be the focus of public health efforts to reduce the burden of late-life cognitive impairment.
doi:10.3233/JAD-2010-091555
PMCID: PMC2883660  PMID: 20182020
Vascular Risk Factors; stroke; dementia; vascular dementia; cognitive impairment; diabetes; hypertension; obesity; hyperlipidemia

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