The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

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Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

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 ...

Vascular Contributions to Cognitive Impairment and Dementia A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

At present, about 33·9 million people worldwide have Alzheimer's disease (AD), and prevalence is expected to triple over the next 40 years. The aim of this Review was to summarise the evidence regarding seven potentially modifiable risk factors for AD: diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity. Additionally, we projected the effect of risk factor reduction on AD prevalence by calculating population attributable risks (the percent of cases attributable to a given factor) and the number of AD cases that might be prevented by risk factor reductions of 10% and 25% worldwide and in the USA. Together, up to half of AD cases worldwide (17·2 million) and in the USA (2·9 million) are potentially attributable to these factors. A 10-25% reduction in all seven risk factors could potentially prevent as many as 1·1-3·0 million AD cases worldwide and 184,000-492,000 cases in the USA.

The projected effect of risk factor reduction on Alzheimer's disease prevalence

Background Criteria for the clinical diagnosis of Alzheimer's disease (AD) were established in 1984. A broad consensus now exists that these criteria should be revised to incorporate state-of-the-art scientific knowledge. Methods The National Institute on Aging (NIA) and the Alzheimer's Association sponsored a series of advisory round table meetings in 2009 whose purpose was to establish a process for revising diagnostic and research criteria for AD. The recommendation from these advisory meetings was that three separate work groups should be formed with each assigned the task of formulating diagnostic criteria for one phase of the disease: the dementia phase; the symptomatic, pre-dementia phase; and the asymptomatic, preclinical phase of AD. Results Two notable differences from the AD criteria published in 1984 are incorporation of biomarkers of the underlying disease state and formalization of different stages of disease in the diagnostic criteria. There was a broad consensus within all three workgroups that much additional work is needed to validate the application of biomarkers for diagnostic purposes. In the revised NIA-Alzheimer's Association criteria, a semantic and conceptual distinction is made between AD pathophysiological processes and clinically observable syndromes that result, whereas this distinction was blurred in the 1984 criteria. Conclusions The new criteria for AD are presented in three documents. The core clinical criteria of the recommendations regarding AD dementia and MCI due to AD are intended to guide diagnosis in the clinical setting. However, the recommendations of the preclinical AD workgroup are intended purely for research purposes.

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Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques-which are frequently surrounded by dystrophic neurites-and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis.

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Epidemiology of Alzheimer disease

Context Lower plasma -amyloid 42 and 42/40 levels have been associated with incident dementia, but results are conflicting and few have investigated cognitive decline among elders without dementia. Objective To determine if plasma -amyloid is associated with cognitive decline and if this association is modified by measures of cognitive reserve. Design, Setting, and Participants We studied 997 black and white communitydwelling older adults from Memphis, Tennessee, and Pittsburgh, Pennsylvania, who were enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998 with 10-year follow-up in 2006-2007. Participant mean age was 74.0 (SD, 3.0) years; 55.2% (n=550) were female; and 54.0% (n=538) were black. Main Outcome Measures Association of near-baseline plasma -amyloid levels (42 and 42/40 measured in 2010) and repeatedly measured Modified Mini-Mental State Examination (3MS) results. Results Low -amyloid 42/40 level was associated with greater 9-year 3MS cognitive decline (lowest -amyloid tertile: mean change in 3MS score, �6.59 [95% confidence interval [CI], �5.21 to �7.67] points; middle tertile: �6.16 [95% CI, �4.92 to �7.32] points; and highest tertile: �3.60 [95% CI, �2.27 to �4.73] points; P.001). Results were simi

https://jamanetwork.com/journals/jama/articlepdf/645162/joc05173_261_266.pdf

Association of Plasma β-Amyloid Level and Cognitive Reserve With Subsequent Cognitive Decline

Background Several studies support a role for cardiovascular risk factors in cognitive aging. The metabolic syndrome, a constellation of cardiovascular risk factors, is common in elderly people. A growing but conflicting body of literature suggests that the metabolic syndrome may be associated with cognitive impairment. Objective To investigate the association between the metabolic syndrome and its components and incident cognitive impairment in older women. Design We prospectively determined if the metabolic syndrome and its components were associated with a 4-year risk of developing cognitive impairment (dementia, mild cognitive impairment, or low global cognitive test score). Setting The study was conducted at 180 clinical centers in 25 countries. Participants A total of 4895 older women (mean age, 66.2 years) with osteoporosis who were part of an ancillary study to determine clinically relevant cognitive impairment were included in this study. These women were free of baseline cognitive impairment and had metabolic syndrome component measures. Main Outcome Measures Clinically significant cognitive impairment was defined to include women with clinically adjudicated dementia or MCI and women who had a Short Blessed test score greater than 6 (consistent with impairment), but whose cases were not clinically adjudicated. Logistic regression analysis was used to examine the association between presence of the metabolic syndrome and development of clinically significant cognitive impairment. Results A total of 497 women (10.2%) had the metabolic syndrome and, of these, 36 (7.2%) developed cognitive impairment compared with 181 (of 4398 or 4.1%) without the syndrome (age-adjusted odds ratio, 1.66; 95% confidence interval, 1.14-2.41). The mean (SD) number of metabolic syndrome components for all women was 1.0 (1.1); 518 women (10.6%) were obese, 895 (18.3%) had hypertriglyceridemia, 1200 (24.5%) had low high-density lipoprotein cholesterol levels, 1944 (39.7%) had high blood pressure, and 381 (7.8%) had high fasting blood glucose levels. There was a 23.0% age-adjusted increase in the risk of developing cognitive impairment (odds ratio, 1.23; 95% confidence interval, 1.09-1.39) per unit increase in the number of components. Further multivariable adjustment somewhat reduced the effect. Conclusion We found an association between the metabolic syndrome and the number of components and risk of developing cognitive impairment in older women. Additional studies are needed to determine if screening and close management of these at-risk elderly women would diminish the incidence of cognitive impairment.

https://jamanetwork.com/journals/jamaneurology/articlepdf/1033005/noc80112_324_328.pdf

The metabolic syndrome and development of cognitive impairment among older women.

Background. Patients with mild cognitive impairment (MCI) may be especially vulnerable to the side effects of potentially inappropriate medications (PIMs), especially those that impair cognition. Methods. We conducted a cross-sectional study to determine the prevalence of PIM use among 689 patients with MCI. We used the 2003 Beers Criteria for cognitive impairment to identify PIMs. We then determined if certain patients were more likely to use PIMs. Results. There were 143 (20.8%) patients with MCI taking a PIM: 108 (15.7%) patients were taking one PIM and 35 (5.1%) patients were taking two or more PIMs. The most common PIMs were anticholinergics (35.7%) and benzodiazepines (31.5%). Patients were more likely to be taking PIMs if they were women and were taking a greater number of medications and less likely if they had a history of myocardial infarction. Conclusions. Patients with MCI are frequently taking PIMs that may negatively affect cognition. Future research is needed to assess whether cognitive impairment symptoms are improved if PIM use is reduced.

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Potentially Inappropriate Medication Use in Older Adults With Mild Cognitive Impairment

Background Diagnostic criteria for mild cognitive impairment (MCI) include no significant functional decline, but recent studies have suggested that subtle deficits often exist. It is not known whether these differ by MCI type. We investigated the level and type of functional impairment among patients with MCI. Methods We studied 498 patients, evaluated at the Alzheimer's Disease Research Centers of California between 2006 and 2009, who had multidisciplinary evaluations by experts, including neurologic examination and neuropsychological testing. Patients were diagnosed with MCI and subtype was determined using cognitive domain scores. In a cross-sectional descriptive study, we examined whether functional impairment differed by MCI subtype, using the Blessed Roth Dementia Rating Scale (range: 0–17, higher scores indicating more impairment). Results Among the participants, the mean age was 75.4 years, 50.7% were women, and 81.7% were white. Patients with amnestic- (n = 392, 78.7%) and nonamnestic-type (n = 106, 21.3%) MCI had similar total Blessed Roth Dementia Rating Scale (1.6 and 1.5, respectively; P = .84) and Mini-Mental State Examination (26.5 and 26.7, respectively; P = .60) scores. Patients with amnestic MCI were more likely to have difficulty in remembering lists and recalling recent events ( P P = .01 for both), as compared with those with nonamnestic MCI. Conclusions Despite the MCI diagnostic criteria suggesting no functional impairment, our results indicate that patients with MCI experience mild functional deficits that vary according to the type of MCI.

Andrea Weston

Papers

Association of Plasma β-Amyloid Level and Cognitive Reserve With Subsequent Cognitive Decline

The metabolic syndrome and development of cognitive impairment among older women.

Potentially Inappropriate Medication Use in Older Adults With Mild Cognitive Impairment

Functional deficits among patients with mild cognitive impairment

Plasma β-Amyloid Level, Cognitive Reserve, and Cognitive Decline—Reply