Elsevier

The Lancet

Volume 388, Issue 10043, 30 July–5 August 2016, Pages 505-517
The Lancet

Seminar
Alzheimer's disease

https://doi.org/10.1016/S0140-6736(15)01124-1Get rights and content

Summary

Although the prevalence of dementia continues to increase worldwide, incidence in the western world might have decreased as a result of better vascular care and improved brain health. Alzheimer's disease, the most prevalent cause of dementia, is still defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality as proposed in the original amyloid hypothesis. Age-related, protective, and disease-promoting factors probably interact with the core mechanisms of the disease. Amyloid β42, and tau proteins are established core cerebrospinal biomarkers; novel candidate biomarkers include amyloid β oligomers and synaptic markers. MRI and fluorodeoxyglucose PET are established imaging techniques for diagnosis of Alzheimer's disease. Amyloid PET is gaining traction in the clinical arena, but validity and cost-effectiveness remain to be established. Tau PET might offer new insights and be of great help in differential diagnosis and selection of patients for trials. In the search for understanding the disease mechanism and keys to treatment, research is moving increasingly into the earliest phase of disease. Preclinical Alzheimer's disease is defined as biomarker evidence of Alzheimer's pathological changes in cognitively healthy individuals. Patients with subjective cognitive decline have been identified as a useful population in whom to look for preclinical Alzheimer's disease. Moderately positive results for interventions targeting several lifestyle factors in non-demented elderly patients and moderately positive interim results for lowering amyloid in pre-dementia Alzheimer's disease suggest that, ultimately, there will be a future in which specific anti-Alzheimer's therapy will be combined with lifestyle interventions targeting general brain health to jointly combat the disease. In this Seminar, we discuss the main developments in Alzheimer's research.

Introduction

Alzheimer's disease is the main cause of dementia and one of the great health-care challenges of the 21st century. In December, 2013, the G8 stated that dementia should be made a global priority and their ambition that a cure or a disease-modifying therapy should be available by 2025. Research since the discoveries of amyloid β (Aβ) and tau, the main components of plaques and tangles respectively, has provided detailed information about molecular pathogenetic events, yet little is known about the cause of Alzheimer's disease and no curative treatments are available. Furthermore, although the presence of Alzheimer's pathological changes are a sine qua non for diagnosis and sufficient to cause symptoms in some patients, several causes are implicated in patients who become symptomatic aged older than 75 years.

With the advent of modern techniques to image and measure brain processes and analyse big data (including genetic and genomic data), and with governments across the world increasingly prioritising dementia in national health-care agendas, there is hope that the rate of scientific progress will increase. In this Seminar, we present novel, promising findings from the rapidly evolving field of Alzheimer's research, which seem to provide a glimpse into a future when Alzheimer's disease might be cured or—perhaps even more likely—prevented. We describe the clinical context of the disease and novel developments in epidemiology, molecular genetics and pathophysiology, fluid biomarkers, imaging biomarkers, and treatment.

Section snippets

Clinical signs and symptoms

In panel 1, we describe two cases, which show the range of Alzheimer's disease in terms of age and clinical presentation. The first case is a typical presentation of dementia (memory impairment and executive dysfunction interfering with daily life activities)—elderly individuals, who are often on their own and increasingly dependent on others for care. The second is an atypical presentation, and all too often such clinical manifestations are not recognised by primary care doctors and others.

Epidemiology

An estimated 40 million people, mostly older than 60 years, have dementia worldwide, and this figure is projected to double every 20 years, until at least 2050.18 Within these estimates, both the number of people who develop the disease at a specific age and the survival time of those with the disease are assumed to remain stable for a given region. Projected increases in the prevalence of dementia are proportionally much higher for developing countries with young populations than for western

Lifestyle and vascular risk factors

Alzheimer's disease develops over a long preclinical period of several decades, which raises the question of the extent to which risk factors assessed in late life or shortly before onset of clinical symptoms are a result of developing pathological changes rather than a causal relation. Two different approaches have been taken to address this issue. Studies that were started decades ago and included people in early life or midlife allowed assessment of the relations between early-life or

Genetic susceptibility

APOE4 is the major genetic risk factor for Alzheimer's disease. Lifetime risk for Alzheimer's disease is more than 50% for APOE4 homozygotes and 20-30% for APOE3 and APOE4 heterozygotes, compared with 11% for men and 14% for women overall irrespective of APOE genotype.34 APOE4 has several effects on Alzheimer's disease. It interferes with Aβ clearance from the brain,35 and is also processed into neurotoxic fragments.36 Furthermore, mice that express APOE4 show disinhibition of a cyclophilin A

Pathophysiology

The past 30 years of Alzheimer's disease research have produced substantial evidence that accumulation of abnormally folded Aβ and tau proteins in amyloid plaques and neuronal tangles are causally related to neurodegenerative processes in patients' brains.47 Yet observational and pathological studies have generated overwhelming evidence for the complexity and multicausality of dementia.48 This complexity is increasingly recognised in basic and clinical studies too, and research is moving away

Core CSF biomarkers

Core CSF biomarkers for Alzheimer's disease are Aβ42, which shows cortical amyloid deposition; total tau (t-tau), which reflects the intensity of neurodegeneration; and phosphorylated tau (p-tau), which correlates with neurofibrillary pathological changes.70 These core CSF biomarkers have high diagnostic accuracy, with sensitivity and specificity of 85-90%, to identify prodromal Alzheimer's disease in the mild cognitive impairment stage.71, 72 When assessing the diagnostic performance of

Towards an inclusionary approach

Imaging has a key role in the clinical assessment of patients with suspected Alzheimer's disease. The traditional view that at least one structural scan (either CT or MRI) should be done at least once in every patient with cognitive impairment to rule out intracranial causes (eg, meningioma, subdural haematoma) has been complemented by the notion that the demonstration of regional atrophy in the medial temporal region can provide positive diagnostic information (panel 1).94 A visual scale

Treatment

The mainstay of treatment for Alzheimer's disease is supportive care from family and other caregivers. Patients with dementia have better quality of life in a predictable home environment that meets their daily needs. Familial caregivers need help to learn how to manage the progressive nature of the illness and guidance on how to mobilise the resources needed to maintain care for their loved one while preserving their own wellbeing.

Four drugs are used for the treatment of the dementia phase:

Secondary prevention, risk reduction, and other approaches

Several major trials investigating how to delay the onset of cognitive decline in individuals at high risk for Alzheimer's disease are underway. The Anti-Amyloid in Asymptomatic Alzheimer's disease (A4) study is testing whether solanezumab given monthly for 3 years could delay cognitive decline in cognitively healthy elderly patients with a positive amyloid PET scan.127 Four studies aiming to delay cognitive decline in individuals with high genetic risk are underway, two in families with a

Conclusions

Alzheimer's research is rapidly progressing. Advances in basic science and molecular diagnostics have provided unprecedented possibilities for drug development. In the aftermath of the G8 statement, there is no time to waste in trying to provide a better future for the patients of tomorrow, although improving care and help for today's patients should always remain a priority.

If progress accelerates as expected, a patient with early symptoms of Alzheimer's disease in 2025 will be treated

Search strategy and selection criteria

Between March 1, and Sept 15, 2015, we searched the Cochrane Library, PubMed, and Embase with the search term “Alzheimer's Disease” in combination with the terms “pathology”, “imaging”, “diagnosis”, “therapy”, “trials”, “epidemiology”, “CSF”, and “biomarkers” for articles published in any language since Jan 1, 2010. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. We largely selected publications from the past 5 years,

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