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

An estimated 47 million people worldwide are living with dementia in 2015, and this number is projected to triple by 2050. In the absence of a disease-modifying treatment or cure, reducing the risk of developing dementia takes on added importance. In 2014, the World Dementia Council (WDC) requested the Alzheimer's Association evaluate and report on the state of the evidence on modifiable risk factors for cognitive decline and dementia. This report is a summary of the Association's evaluation, which was presented at the October 2014 WDC meeting. The Association believes there is sufficient evidence to support the link between several modifiable risk factors and a reduced risk for cognitive decline, and sufficient evidence to suggest that some modifiable risk factors may be associated with reduced risk of dementia. Specifically, the Association believes there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia. The Association also believes there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.

https://www.motherjones.com/files/baumgart_et_al_2015.pdf

Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective.

The relationship between body mass index (BMI) (in midlife and late-life) and dementia was investigated in meta-analyses of 16 articles reporting on 15 prospective studies. Follow-ups ranged from 3.2 to 36.0 years. Meta-analyses were conducted on samples including 25 624 participants evaluated for Alzheimer's disease (AD), 15 435 participants evaluated for vascular dementia (VaD) and 30 470 followed for any type of dementia (Any Dementia). Low BMI in midlife was associated with 1.96 [95% confidence interval (CI): 1.32, 2.92] times the risk of developing AD. The pooled relative risks for AD, VaD and Any Dementia for overweight BMI in midlife compared with normal BMI were 1.35 (95% CI:1.19, 1.54), 1.33 (95% CI: 1.02, 1.75) and 1.26 (95% CI: 1.10, 1.44), respectively. The pooled relative risks of AD and Any Dementia for obese BMI in midlife compared to normal BMI were 2.04 (95% CI: 1.59, 2.62) and 1.64 (95% CI: 1.34, 2.00), respectively. Continuous BMI in late-life was not associated with dementia. Small numbers of studies included in pooled analyses reduce generalizability of findings, and emphasize the need for publication of additional findings. We conclude that underweight, overweight and obesity in midlife increase dementia risk. Further research evaluating late-life BMI and dementia is required.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1467-789X.2010.00825.x

Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies.

That the renin–angiotensin system (RAS) is involved in regulation of blood pressure, vasoconstriction, sodium intake and potassium excretion is well established. Studies in the last few years have however documented new roles for this molecule as a pro-inflammatory molecule and more recently as a possible pro-fibrotic agent that contributes to progressive deterioration of organ function in disease. Binding of Ang II to its receptors (in particular AT1) mediates intracellular free radical generation that contributes to tissue damage by promoting mitochondrial dysfunction. Blocking Ang II signalling protects against neurodegenerative processes and promotes longevity in rodents. Altogether these findings open the unanticipated perspective for exploring Ang II signalling in therapeutic interventions in inflammatory diseases and aging-related tissue injury. This review extends from the discovery of Ang II and its implications in renal and cardiovascular physiology to cover the roles of the system in inflammation, tissue injury, autoimmunity, oxidative stress and aging.

https://www.embopress.org/doi/pdf/10.1002/emmm.201000080

Angiotensin II revisited: new roles in inflammation, immunology and aging

Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an important risk factor in the development of cognitive decline and Alzheimer’s disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE4, atrial fibrillation, thrombotic events, hypertension, hypotension, heart failure, high serum markers of inflammation, coronary artery disease, low cardiac index, and valvular pathology. In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia.

https://downloads.hindawi.com/archive/2012/367516.pdf

Cardiovascular Risk Factors Promote Brain Hypoperfusion Leading to Cognitive Decline and Dementia

Background: Hypertension appears to contribute to the development of dementia. Antihypertensive drugs may play an important role in altering the incidence or progression of dementia, particularly dementia of the vascular type; however, the neuroprotective effects of these agents in other types of dementia are not well characterized. Objectives: The main aims of this review were to examine the relationship between use of antihypertensive agents and the incidence and progression of Alzheimer's dementia (AD), vascular dementia (VaD), and unspecified dementia, and to consider whether these agents may be neuroprotective. Methods: A search of the English-language literature (January 1996–August 2009) was conducted using PubMed, Ovid MEDLINE, EBSCO MEDLINE, and the Cochrane Database of Systematic Reviews for publications mentioning both antihypertensive drugs and dementia. A combination of searches was performed using the following terms: antihypertensive drugs, dementia, cognitive impairment, Alzheimer's dementia, vascular dementia, progression of cognitive impairment, severity of cognitive impairment, severity of dementia, prevalence, and incidence. Searches were also performed using the names of antihypertensive drug classes. The bibliographies of all retrieved articles were reviewed for additional relevant publications. The focus was on randomized controlled trials, cohort studies, and case—control studies, excluding studies in animals, patients aged Results: Sixty–five potentially relevant articles were identified from the 536 publications retrieved by the literature search. After application of the exclusion criteria, 12 original studies were included in the review, all published between 1999 and 2008 and most involving patients with AD or VaD. The most frequently studied antihypertensive agents were calcium channel blockers (7 studies), diuretics (6 studies), and angiotensin-converting enzyme (ACE) inhibitors (6 studies). Overall, these medications appeared to be beneficial in dementia, but only ACE inhibitors and diuretics significantly reduced the risk for and progression of dementia in the majority of studies. Conclusions: Antihypertensive medications—particularly ACE inhibitors and diuretics—may be helpful in reducing the risk for and progression of dementia. Large randomized clinical trials are warranted to further explore the relationship between antihypertensive drugs and dementia.

Does use of antihypertensive drugs affect the incidence or progression of dementia? A systematic review.

This case report presents a 44-year-old man with a history of schizophrenia who developed neutropenia on risperidone therapy. The patient's laboratory reports showed a gradual decline of leukocytes and neutrophils after resolution and rechallenging. This was reversed with the discontinuation of risperidone and by switching to olanzapine. In this case report, we also discuss the updated evidence base for management of risperidone-induced neutropenia.

/pdf/risperidone-induced-reversible-neutropenia-4z4hhyp1si.pdf

Risperidone-induced reversible neutropenia

To the Editor: Varenicline, bupropion sustained release (SR), and nicotine replacement therapy are established and US Food and Drug Administration (FDA)–approved treatments for smoking cessation.1–3 Recently, there has been a surge of postmarketing reports to the FDA associating varenicline with depressive symptoms, fatigue, suicidal ideation, or in some cases death.4

Kairav Shah

Papers

Does use of antihypertensive drugs affect the incidence or progression of dementia? A systematic review.

Risperidone-induced reversible neutropenia

Addition of bupropion SR to varenicline alleviated depression and suicidal ideation: a case report.