Genetic risk for Alzheimer’s disease (AD) may be conferred by the susceptibility polymorphism apolipoprotein E (APOE), where the ε4 allele increases the risk of developing late-onset Alzheimer’s disease but is not a definitive predictor of the disease, or by autosomal dominant mutations (e.g., the presenilins), which almost inevitably result in early-onset familial Alzheimer’s disease. The purpose of this study was to compare the psychological impact of using these two different types of genetic information to disclose genetic risk for AD to family members of affected patients.
Data were compared from two separate protocols. The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) Study is a randomized, multi-site clinical trial that evaluated the impact of susceptibility testing for Alzheimer’s disease with APOE in 101 adult children of Alzheimer’s disease patients. A separate study, conducted at the University of Washington, assessed the impact of deterministic genetic testing by disclosing presenilin-1, presenilin-2, or TAU genotype to 22 individuals at risk for familial Alzheimer’s disease or frontotemporal dementia. In both protocols, participants received genetic counseling and completed the Impact of Event Scale (IES), a measure of test-specific distress. Scores were analyzed at the time point closest to one year post-disclosure at which IES data were available. The role of genetic test result (positive vs. negative) and type of genetic testing (deterministic vs. susceptibility) in predicting log-transformed IES scores was assessed with linear regression, controlling for age, gender, and time from disclosure.
Subjects from the REVEAL Study who learned that they were positive for the susceptibility gene APOE ε4+ experienced similar, low levels of test-specific distress compared to those who received positive results of deterministic testing in the University of Washington study (p= 0.78). APOE ε4+ individuals in the susceptibility protocol experienced more test-specific distress than those who tested ε4− in the same study (p= 0.04); however, among those receiving deterministic test disclosure, the subjects who received positive results did not experience significantly higher levels of distress when compared to those who received negative results (p= 0.88).
The findings of this preliminary study, with limited sample size, suggest that the test-related distress experienced by those receiving positive results for a deterministic mutation is similar to the distress experienced by those receiving positive results from genetic susceptibility testing, and that the majority of participants receiving genotype disclosure do not experience clinically significant distress as indicated by IES scores one year after learning of their test results.
genetic susceptibility testing; deterministic testing; Alzheimer’s disease; APOE; genetic counseling
Susceptibility testing for common, complex adult-onset diseases is projected to become more commonplace as the rapid pace of genomic discoveries continues, and evidence regarding the potential benefits and harms of such testing is needed to inform medical practice and health policy. Apolipoprotein E (APOE) testing for risk of Alzheimer’s disease (AD) provides a paradigm in which to examine the process and impact of disclosing genetic susceptibility for a prevalent, severe and incurable neurological condition. This review summarizes findings from a series of multi-site randomized clinical trials examining psychological and behavioral responses to various methods of genetic risk assessment for AD using APOE disclosure. We discuss challenges involved in disease risk estimation and communication and the extent to which participants comprehend and perceive utility in their genetic risk information. Findings on the psychological impact of test results are presented (e.g., distress), along with data on participants’ health behavior and insurance purchasing responses (e.g., long term care). Finally, we report comparisons of the safety and efficacy of intensive genetic counseling approaches to briefer models that emphasize streamlined processes and educational materials. The implications of these findings for the emerging field of personal genomics are discussed, with directions identified for future research.
Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10–12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apoli-poprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD.
Alzheimer disease; dementia; guideline; genetic testing; genetic counseling
The number of elderly patients seeking clinical treatment for memory problems will rise sharply in coming years as our population ages. These patients present a challenge for diagnosis and prognosis since cognitive problems in older patients can arise from many etiologies, some of which are curable. With the development of clinically available biomarkers for detecting Alzheimer’s disease pathology in living patients, evaluation of cognitively impaired elderly patients is about to undergo a major paradigm shift. This article describes the two classes of biomarkers available for assessing Alzheimer’s disease risk: those that indicate presence of amyloid pathology and those that provide evidence of neuronal injury and neurodegeneration. We argue that, currently, incorporation of biomarkers of neurodegeneration can help in patient prognosis whereas tests for amyloid, if used in isolation, have potential for harm. Amyloid tests are clinically useful only when evidence suggests progressive cognitive decline or neurodegeneration.
Alzheimer’s disease; amyloid imaging; biomarker; florbetapir; MCI; mild cognitive impairment; MRI; PET
To test the hypothesis that harm avoidance, a trait associated with behavioral inhibition, is associated with risk of developing Alzheimer’s disease.
A total of 791 adults aged 55 years and older without dementia completed a standard self report measure of harm avoidance. They then underwent annual evaluations that included detailed cognitive testing and clinical classification of mild cognitive impairment, dementia and Alzheimer’s disease. In a uniform neuropathologic examination of those who died, counts of neuritic plaques diffuse plaques, and neurofibrillary tangles were standardized and combined to yield a pathologic measure of disease. The relation of harm avoidance to incidence of Alzheimer’s disease and related outcomes was estimated in analyses adjusted for age, sex, and education.
During a mean of 3.5 years of annual observation, 98 people (12.4%) developed incident Alzheimer’s disease. High level of harm avoidance (90th percentile) was associated with a more than twofold increase in risk of Alzheimer’s disease compared to a low score (10th percentile). Higher harm avoidance was also associated with increased incidence of mild cognitive impairment and more rapid decline in episodic memory, working memory, and perceptual speed (but not semantic memory or visuospatial ability). In 116 participants who died and underwent brain autopsy, harm avoidance was not related to a composite measure of plaques and tangles.
High level of the harm avoidance trait, indicating a tendency toward behavioral inhibition, is related to risk of developing Alzheimer’s disease and its precursor, mild cognitive impairment.
Harm avoidance; Alzheimer’s disease; mild cognitive impairment; cognitive decline; longitudinal studies; brain autopsy
It is known that individuals with Down syndrome develop Alzheimer’s disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer’s disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer’s disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer’s disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer’s disease in Down syndrome.
Genome-wide association study; Down syndrome; Alzheimer’s disease; PICALM; APOE
There is epidemiological evidence that cardiovascular risk factors (CVRF) also are risk factors for Alzheimer’s disease, but there is limited information on this from neuro-pathological studies, and even less from in vivo studies. Therefore, we examined the relationship between CVRF and amyloid-β (Aβ) brain burden measured by Pittsburgh Compound B-positron emission tomography (PiB-PET) studies in the Alzheimer’s Disease Neuroimaging Initiative.
Ninety-nine subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort who had a PiB-PET study measure, apolipoprotein E genotyping data, and information available on CVRF (body mass index [BMI], systolic blood pressure, diastolic blood pressure [DBP1 and cholesterol and fasting glucose test results) were included. Eighty-one subjects also had plasma cortisol C-reactive protein, and superoxide dismutase 1 measurements. Stepwise regression models were used to assess the relation between the CVRF and the composite PiB-PET score.
The first model included the following as baseline variables: age, clinical diagnosis, number of apolipoprotein ε4 alleles, BMI (P = .023), and DBP (P = .012). BMI showed an inverse relation with PiB-PET score, and DBP had a positive relation with PiB-PET score. In the second adjusted model, cortisol plasma levels were also associated with PiB-PET score (P = .004). Systolic blood pressure, cholesterol, or impaired fasting glucose were not found to be associated with PiB-PET values.
In this cross-sectional study, we found an association between Aβ brain burden measured in vivo and DBP and cortisol, indicating a possible link between these CVRF and Aβ burden measured by PiB-PET. These findings highlight the utility of biomarkers to explore potential pathways linking diverse Alzheimer’s disease risk factors.
Alzheimer disease; Vascular risk factors; PiB; Amyloid-β; Cortisol; Blood pressure; Body mass index
This paper describes the development and psychometric properties of a new scale for assessing the psychological impact of genetic susceptibility testing for Alzheimer’s disease (AD). The new instrument, The REVEAL Impact of Genetic Testing for Alzheimer’s disease (IGT-AD) was designed to examine the unique nature of genetic information and the disease course of AD. The scale was tested as a part of a multicenter clinical trial designed to evaluate the impact of AD risk assessment and data was collected from 276 participants in the study. Using an iterative process of Principal Component Analysis and Cronbach’s alpha, the final 16 item IGT-AD was found to have a two factor structure with excellent internal reliability. Construct validity was established by patterns of correlation with other standardized self-reported measures. This scale should be useful in the identification of patients who maybe susceptible to the negative effects of receiving genetic information, monitoring of patients who have received genetic information, and as a tool for researchers who wish to study the effects of genetic susceptibility testing for AD.
Alzheimer’s disease genetics; genetic testing; Alzheimer’s disease risk assessment
Memory loss and cognitive failure are increasingly being identified as potential risks with the recognized increase in life expectancy of the general population. As a result, the development of novel therapeutic strategies for disorders such as Alzheimer’s disease have garnered increased attention. The etiologies that can lead to Alzheimer’s disease are extremely varied, but a number of therapeutic options are directed against amyloid-β peptide and inflammatory cell regulation to prevent or halt progressive cognitive loss. In particular, inflammatory microglial cells may have disparate functions that in some scenarios lead to disability through the removal of functional neurovascular cells and in other circumstances foster tissue repair. Given the significance microglial cells hold for neurodegenerative disorders, we therefore examined the function that amyloid (Aβ1–42) has upon the microglial cell line EOC 2 and identified a novel role for the forkhead transcription factor FoxO3a and caspase 3. Here we show that Aβ1–42 leads to progressive injury and apoptotic cell loss in microglial cells that involves both early phosphatidylserine (PS) externalization and late genomic DNA fragmentation over a 24 hour course. Prior to these injury programs, Aβ1–42 results in the activation and proliferation of microglia as demonstrated by increased proliferating cell nuclear antigen (PCNA) expression and bromodeoxyuridine (BrdU) uptake. Both apoptotic injury as well as the prior activation and proliferation of microglial cells relies upon the presence of FoxO3a, since specific gene silencing of FoxO3a promotes microglial cell protection and prevents the early activation and proliferation of these cells. Furthermore, Aβ1–42 exposure maintained FoxO3a in an unphosphorylated “active” state and facilitated the cellular trafficking of FoxO3a from the cytoplasm to the cell nucleus to potentially lead to “pro-apoptotic” programs by this transcription factor. One apoptotic program in particular appears to involve the activation of caspase 3, since loss of FoxO3a through gene silencing prevents the induction of caspase 3 activity by Aβ1–42.
Alzheimer’s disease; amyloid; apoptosis; bromodeoxyuridine; caspases; forkhead transcription factors; FoxO3a; inflammation; microglia; oxidative stress; proliferating cell nuclear antigen
New criteria for the diagnosis of Alzheimer’s disease (AD) based on biomarker results have recently been developed and are currently undergoing extensive validation. The next few years may represent a time window where the diagnostic validity of biomarkers will be studied in highly specialized research settings. Biomarkers results will be used to direct clinical diagnosis and, whenever appropriate, therapy and management. This piece aims to stimulate discussion by identifying the ethical challenges involved in the use of biomarkers to make a diagnosis of mild cognitive impairment due to AD and disclose it to patients. At the individual level, these challenges are related to (i) the ethical appropriateness of implementing an ecological diagnostic research protocol, (ii) the related informed consent process, and (iii) the diagnostic disclosure. We justify the ethical legitimacy of implementing a research diagnostic protocol by referring to the respect of patients’ subjectivity and autonomy, and we suggest guidelines for informed consent development and diagnostic disclosure. All of the above points are discussed in light of the unique features of AD, currently scanty treatment options, and knowledge and uncertainties regarding the diagnostic value of biomarkers.
prodromal Alzheimer’s disease; informed consent; diagnosis disclosure; translational research; bioethics guideline
Numerous studies show that the pathology of Alzheimer's disease is present decades before a clinical diagnosis of dementia can be made. Given the likelihood that agents will become available that reliably delay onset and/or slow progression of Alzheimer's disease, it will be important to detect preclinical Alzheimer's disease as early as possible for maximal treatment effect. Detection of individuals by sensitive cognitive measures provides one way to identify people who are at high risk of developing clinical Alzheimer's disease. However, it is likely that those with considerable brain or cognitive reserve will be able to mask cognitive deficits until very close to the onset of the dementia, rendering such cognitive measures insensitive. Optimum biomarkers for Alzheimer's disease therefore need to target the severity of underlying brain pathology independently of brain reserve. Findings are presented showing the importance of higher education and larger brain size in masking the underlying disease pathology.
Alzheimer's disease; biomarkers; prevention
Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer’s disease. By assessing the accumulation of Aβ in people at risk of genetic forms of Alzheimer’s disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease.
Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer’s disease Colombian kindred aged 18–60 years were recruited from the Alzheimer’s Prevention Initiative’s registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer’s Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions. was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition.
We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3–33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. 18F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3–40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions.
These findings contribute to the understanding of preclinical familial Alzheimer’s disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer’s disease.
Avid Radiopharmaceuticals, Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.
The historical roots of Alzheimer’s disease provide a sound conceptual basis for linking the behavioral and neurological symptoms of the disease with the frequently associated pathology of amyloid plaques and neurofibrillary tangles. Out of these roots has grown the ‘amyloid cascade hypothesis’ – a vision of the etiology of Alzheimer’s that has spurred the discovery of many important insights into the neurobiology of the disease. Despite these successes, the wealth of new data now available to biomedical researchers urges a full review of the origins of Alzheimer’s and such a reconsideration is offered here. It begins with the most widely accepted risk factor for developing Alzheimer’s disease: age. Then, for an individual to progress from normal age-appropriate cognitive function to a condition where the full palette of clinical symptoms is expressed, three key steps are envisioned: 1) an initiating injury, 2) a chronic neuroinflammatory response and 3) a discontinuous cellular change-of-state involving most, if not all, of the cell types of the brain. The amyloid cascade is integrated into this sequence, but reconfigured as an amyloid deposition cycle. In this way, the pathology of amyloid plaques is envisioned as highly correlated with, but mechanistically distinct from, the three obligatory steps leading to Alzheimer’s disease. The implications of this new model are discussed with respect to our current diagnostic criteria and suggestions are put forward for expanding our future research efforts.
Health-related direct-to-consumer (DTC) genetic testing has been a controversial practice. Especially problematic is predictive testing for Alzheimer disease (AD), since the disease is incurable, prevention is inconclusive, and testing does not definitively predict an individual’s future disease status. In this paper, I examine two contrasting cases of subjects who learn through genetic testing that they have an elevated risk of developing AD later in life. In these cases, the subject’s emotional response to the result is related to how well prepared she was for the real-life personal implications of possible test results. Analysis leads to the conclusion that when groups of health-related genetic tests are offered as packages by DTC companies, informed consumer choice is rendered impossible. Moreover, I argue, this marketing approach contravenes U.S. Federal Trade Commission policies for non-deceptive commercial communications. I conclude by suggesting ways to improve the prospects for informed consumer choice in DTC testing.
direct-to-consumer genetic testing; APOE; informed consent
Despite the potential of the internet for informing clinical practice, little is know about physicians’ use of and attitudes about internet use for dementia care. We surveyed 373 physicians to inform development of on-line dementia education resources. Two thirds reported using internet-based resources in their clinical practices at least three times per week; 61% participated in on-line continuing medical education. Three fourths agreed that internet-based resources are helpful in clinical care but most expressed mixed views about quality of available information. Respondents reported limited awareness and use of dementia-specific internet resources, but expressed an interest in such information regarding screening, treatment, community resources, and patient education. National Institute on Aging-funded Alzheimer’s Disease Centers are in a unique position to disseminate on-line resources for physicians on dementia diagnosis, treatment, and care. Our study suggests that such a resource would be well received and utilized by physicians.
Alzheimer’s disease; Internet; Medical Education
Screening tests for Alzheimer’s disease lack sensitivity and specificity. We developed the AD8, a brief dementia screening interview validated against clinical and cognitive evaluations, as an improvement over current screening methods. Because insufficient follow-up has occurred to validate the AD8 against the neuropathologic findings of Alzheimer’s disease, we investigated whether AD8 scores correspond to impairment in episodic memory testing and changes in biomarkers of Alzheimer’s disease (cerebrospinal fluid and amyloid imaging with Pittsburgh compound B) characteristic of symptomatic Alzheimer’s disease. We also compared informant-based assessments with brief performance-based dementia screening measurements such as the Mini Mental State Exam. The sample (n = 257) had a mean age of 75.4 years with 15.1 years of education; 88.7% were Caucasian and 45.5% were male. The sample was divided into two groups based on their AD8 scores: those with a negative dementia screening test (AD8 score 0 or 1, n = 137) and those with a positive dementia screening test (AD8 score ≥2, n = 120). Individuals with positive AD8 scores had abnormal Pittsburgh compound B binding (P < 0.001) and cerebrospinal fluid biomarkers (P < 0.001) compared with individuals with negative AD8 scores. Individuals with positive AD8 tests and positive biomarkers scored in the impaired range on the Wechsler Logical Memory Story A (mean score 7.0 ± 4.5 for Pittsburgh compound B; mean score 7.6 ± 5.3 for cerebrospinal fluid amyloid beta protein 1–42). The AD8 area under the curve for Pittsburgh compound B was 0.737 (95% confidence interval: 0.64–0.83) and for cerebrospinal fluid amyloid beta protein 1–42 was 0.685 (95% confidence interval: 0.60–0.77) suggesting good discrimination. The AD8 had superior sensitivity in detecting early stages of dementia compared with the Mini Mental State Examination. The AD8 had a likelihood ratio of a positive test of 5.8 (95% confidence interval: 5.4–6.3) and likelihood ratio of a negative test of 0.04 (95% confidence interval: 0.03–0.06), increasing the pre-test probability of an individual having symptomatic Alzheimer’s disease. Individuals with AD8 scores of ≥2 had a biomarker phenotype consistent with Alzheimer’s disease and lower performance on episodic memory tests, supporting a diagnosis of Alzheimer’s disease. Informant-based assessments may be superior to performance-based screening measures such as the Mini Mental State Examination in corresponding to underlying Alzheimer’s disease pathology, particularly at the earliest stages of decline. The use of a brief test such as the AD8 may improve strategies for detecting dementia in community settings where biomarkers may not be readily available, and may enrich clinical trial recruitment by increasing the likelihood that participants have underlying biomarker abnormalities.
AD8; Alzheimer’s disease; screening; biomarkers; preclinical; cognition
Several modifiable health and lifestyle factors are consistently associated with dementia risk and it is estimated that significantly fewer people would develop dementia if the incidence of risk factors could be reduced. Despite this, Australians’ awareness of the health and lifestyle factors associated with dementia risk is low. Within a national community education campaign, Alzheimer’s Australia developed a dementia risk reduction website providing information about modifiable risk or protective factors for dementia.
This study aimed to assess the usefulness of the website content in improving knowledge and enabling adoption of recommended strategies, and to examine what additional resources consumers need.
Visitors to the website over a 3 month period were invited to complete an online survey, which asked them to rate their knowledge of dementia risk reduction before and after visiting the site, how important monitoring their health related behavior was to them before and after visiting the site, their current behavior related to health and lifestyle factors associated with dementia risk, their intentions to change behavior, and the usefulness of potential additional resources to help them do so.
For this study, 123 Australian adults responded to the survey. 44.7% (55/122) were aged over 60 and 82.1% (98/119) were female. Respondents’ ratings and comments indicated they generally found the content interesting, informative, and helpful to them. Respondents’ ratings of their knowledge about the links between health and lifestyle factors and dementia risk significantly increased after visiting the website (P<.001). Their ratings of how important monitoring what they do in relation to their health and lifestyle factors were also significantly increased after visiting the website (P<.001). Average ratings for how well respondents felt they were doing at the time in relation to specific risk or protective factors were generally high, suggesting many website visitors already had high levels of health motivation and healthy lifestyle behaviors. 55.6% (45/81) said that after visiting the website their intention to make lifestyle changes was strong. Only 27.1% (22/81) said their intention to visit their doctor to discuss dementia risk reduction was strong. Potential additional resources that would help people assess and address their personal dementia risk factors were rated as more helpful than general information resources.
A dementia risk reduction website providing information about the current evidence and practical strategies was of interest and was useful to the Australian community. Benefits for visitors included increased knowledge and increased motivation to address relevant behaviors. Many visitors to the site were already health conscious, indicating that more needs to be done to get dementia risk reduction messages to the wider community. More interactive and personalized resources in future interventions may offer additional benefits to individuals.
dementia; Alzheimer's disease; risk reduction behavior; health communication; evaluation studies
A genetic marker known as apolipoprotein E provides a clear signal of a person’s risk of developing Alzheimer’s disease and thus that person’s future need for long-term care. People who find that they have the variant of the trait that increases Alzheimer’s disease risk are more likely to purchase long-term care insurance after receiving this information. If the information is widely introduced into the insurance market, coverage rates could be affected in different ways, depending on who possesses that information. Policymakers will eventually need to confront the issue of the use of this and other markers in the pricing of long-term care insurance.
Of the estimated 5.3 million people with Alzheimer's disease in the United States, more than half would be classified as having moderate or severe disease. Alzheimer's disease is a progressive disorder with the moderate to severe stages generally characterized by significant cognitive, functional, and behavioral dysfunction. Unsurprisingly, these advanced stages are often the most challenging for both patients and their caregivers/families. Symptomatic treatments for moderate to severe Alzheimer's disease are approved in the United States and include the acetylcholinesterase inhibitor donepezil and the glutamate receptor antagonist memantine. Progressive symptomatic decline is nevertheless inevitable even with the available therapies, and therefore additional treatment options are urgently needed for this segment of the Alzheimer's disease population. An immediate-release formulation of donepezil has been available at an approved dose of 5-10 mg/d for the past decade. Recently, the United States Food and Drug Administration approved a higher-dose (23 mg/d) donepezil formulation, which provides more gradual systemic absorption, a longer time to maximum concentration (8 hours) versus the immediate-release formulation (3 hours), and higher daily concentrations. Herein, we review (1) the scientific data on the importance of cholinergic deficits in Alzheimer's disease treatment strategies, (2) the rationale for the use of higher-dose acetylcholinesterase inhibitors in patients with advanced disease, and (3) recent clinical evidence supporting the use of higher-dose donepezil in patients with moderate to severe Alzheimer's disease.
Vitamin B12 is a cofactor of methionine synthase in the synthesis of methionine, the precursor of the universal methyl donor S-Adenosylmethionine (SAMe), which is involved in different epigenomic regulatory mechanisms and especially in brain development. A Vitamin B12 deficiency expresses itself by a wide variety of neurological manifestations such as paraesthesias, skin numbness, coordination disorders and reduced nerve conduction velocity. In elderly people, a latent Vitamin B12 deficiency can be associated with a progressive brain atrophy. Moderately elevated concentrations of homocysteine (>10 µmol/L) have been associated with an increased risk of dementia, notably Alzheimer’s disease, in many cross-sectional and prospective studies. Raised plasma concentrations of homocysteine is also associated with both regional and whole brain atrophy, not only in Alzheimer’s disease but also in healthy elderly people. Clinician awareness should be raised to accurately diagnose and treat early Vitamin B12 deficiency to prevent irreversible structural brain damage.
Vitamin B12; elderly; Vitamin B12 deficiency; diagnostic of Vitamin B12 deficiency; brain atrophy; neuroenhancement
Comprehending the mechanisms underlying the pathophysiology of aging and Alzheimer’s disease has immense value for developing strategies that promote successful aging and prevent or cure Alzheimer’s disease. The first issue of the new journal, “Aging & Disease” comprises articles that discuss the current knowledge pertaining to changes in reelin signaling in normal & pathological forms of aging, memory and neurogenesis in Aging & Alzheimer’s disease, the efficacy of a non-steroidal anti-inflammatory drug aspirin in combination with docosahexaenoic acid for reducing the risk for Alzheimer’s disease, and the usefulness of stem cell transplantation for improving memory in aging and Alzheimer’s disease. The highlights and the importance of the above issues to Aging and Alzheimer’s disease are discussed in this commentary.
Aging; Alzheimer’s disease; Amyloid-beta; Anti-inflammatory drugs; Aspirin; Docosahexaenoic acid; glycogen synthase kinase-3; hippocampal neurogenesis; Learning; Memory; Neuroprotection; Reelin
Identification of preclinical Alzheimer’s disease (AD) is an essential first step in developing interventions to prevent or delay disease onset. In this study, we examine the hypothesis that deeper analyses of traditional cognitive tests may be useful in identifying subtle but potentially important learning and memory differences in asymptomatic populations that differ in risk for developing Alzheimer’s disease. Subjects included 879 asymptomatic higher-risk persons (middle-aged children of parents with AD) and 355 asymptotic lower-risk persons (middle-aged children of parents without AD). All were administered the Rey Auditory Verbal Learning Test at baseline. Using machine learning approaches, we constructed a new measure that exploited finer differences in memory strategy than previous work focused on serial position and subjective organization. The new measure, based on stochastic gradient descent, provides a greater degree of statistical separation (p =1.44 × 10−5) than previously observed for asymptomatic family history and non-family history groups, while controlling for apolipoprotein epsilon 4, age, gender, and education level. The results of our machine learning approach support analyzing memory strategy in detail to probe potential disease onset. Such distinct differences may be exploited in asymptomatic middle-aged persons as a potential risk factor for AD. (JINS, 2012, 18, 1–12)
Cohort study; Memory; Neuropsychological tests; Pre-symptomatic disease; Statistical models; Medical informatics
Alzheimer’s disease affects more than 35 million people worldwide but there is no known cure. Age is the strongest risk factor for Alzheimer’s disease but it is not clear how age-related changes impact the disease. Here, we used a mouse model of Alzheimer’s disease to identify age-specific changes that occur prior to and at the onset of traditional Alzheimer-related phenotypes including amyloid plaque formation. To identify these early events we used transcriptional profiling of mouse brains combined with computational approaches including singular value decomposition and hierarchical clustering.
Our study identifies three key events in early stages of Alzheimer’s disease. First, the most important drivers of Alzheimer’s disease onset in these mice are age-specific changes. These include perturbations of the ribosome and oxidative phosphorylation pathways. Second, the earliest detectable disease-specific changes occur to genes commonly associated with the hypothalamic-adrenal-pituitary (HPA) axis. These include the down-regulation of genes relating to metabolism, depression and appetite. Finally, insulin signaling, in particular the down-regulation of the insulin receptor substrate 4 (Irs4) gene, may be an important event in the transition from age-related changes to Alzheimer’s disease specific-changes.
A combination of transcriptional profiling combined with computational analyses has uncovered novel features relevant to Alzheimer’s disease in a widely used mouse model and offers avenues for further exploration into early stages of AD.
The objective of this manuscript is to provide a comprehensive review of the epidemiologic evidence linking the continuum of adiposity, hyperinsulinemia, and diabetes with Alzheimer’s disease. The mechanisms for these associations remain to be elucidated, but may include direct actions from insulin, advanced products of glycosilation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of Alzheimer’s disease. The evidence relating adiposity in old age to Alzheimer’s disease is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of Alzheimer’s disease. Hyperinsulinemia is a risk factor for diabetes, and numerous studies have shown a relation of diabetes with higher Alzheimer’s disease risk. Most studies fail the take into account the continuum linking these risk factors which may result in underestimation of their importance in Alzheimer’s disease. The implication of these associations is that a large proportion of the world population may be at increased risk of Alzheimer’s disease given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and diabetes. However, if proven causal, these associations also present a unique opportunity for prevention and treatment of Alzheimer’s disease.
adiposity; overweight; obesity; hyperinsulinemia; insulin; glucose; diabetes; alzheimer’s disease; cognitive impairment
Alzheimer’s disease is thought to be caused by an imbalance between amyloid-β (Aβ) production and clearance leading to Aβ accumulation in the Central Nervous System (CNS). Aβ production and clearance are key targets in the development of disease modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. Using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of patients with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared to controls. On average, there were no differences in Aβ42 or Aβ40 production rates. Thus, the common late-onset form of Alzheimer’s disease may involve an overall impairment of Aβ clearance.