Elsevier

The Lancet

Volume 397, Issue 10284, 24–30 April 2021, Pages 1577-1590
The Lancet

Seminar
Alzheimer's disease

https://doi.org/10.1016/S0140-6736(20)32205-4Get rights and content

Summary

In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60–80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies.

Introduction

Alzheimer's disease is the main cause of dementia and is quickly becoming one of the most expensive, lethal, and burdening diseases of this century.1 Since the Seminar published in 2016,2 important developments have taken place in the understanding of the underlying pathology, the recognition of multiple causative and protective genes, the identification of new blood-based and imaging biomarkers, and the first cautious signals of positive effects of disease-modifying treatments and lifestyle interventions. The aim of this new Seminar is to provide the reader with up to date insight into the field of Alzheimer's disease.

Section snippets

Clinical signs and symptoms

Three cases, in panel 1 (see also figure 1), illustrate the clinical spectrum of Alzheimer's disease. Case A highlights Alzheimer's disease that is determined genetically, as per the ongoing global initiatives of the Dominantly Inherited Alzheimer Network and Alzheimer Prevention Initiative and their associated clinical trials. Case B represents a language variant of Alzheimer's disease, usually occurring at a younger age (under 70 years), illustrating the difficulty in recognising Alzheimer's

Incidence and prevalence

In 2018, Alzheimer's Disease International estimated a dementia prevalence of about 50 million people worldwide, projected to triple in 2050, with two-thirds living in low-income and middle-income countries.20 The most recent data estimate that dementia prevalence in Europe will double by 2050.1 Accumulating evidence suggests that the incidence of dementia is declining in high-income countries,21 although evidence for a decline in prevalence is less convincing.22

Mortality

The relatively stable prevalence

Causative and risk genes

Studies of twins showed that the risk of Alzheimer's disease is 60–80% dependent on heritable factors.34 The common APOE ε4 allele explains a substantial part of, but does not completely account for the heritability of, Alzheimer's disease.35, 36 Large genome-wide association studies have been done to identify novel genetic variants in Alzheimer's disease, the latest of which to date investigated about 150 000 people with Alzheimer's disease and age-matched controls, and more than 300 000

Pathophysiology

Basic scientists designate the preclinical phase of Alzheimer's disease as the cellular phase. Alterations in neurons, microglia, and astroglia drive the insidious progression of the disease before cognitive impairment is observed.58 Neuro-inflammation,59 alterations in the vessels,60, 61 ageing,62 and dysfunction of the glymphatic system63 act upstream or in parallel to accumulating amyloid β in this cellular disease landscape. Amyloid β induces, via an unknown way, the spread of tau pathology,

Biomarkers

The biological definition of Alzheimer's disease is operationalised by the use of ATN biomarkers (appendix p 1).

Evidence for lifestyle changes

In 2019, WHO released the first guidelines for reduction of risk of cognitive decline and dementia.147 The guidelines acknowledge that, for some factors (eg, physical activity, diet, overweight or obesity, tobacco and alcohol use, hypertension, and diabetes), recommendations can be provided, although with different degrees of certainty. Some limitations in the current evidence include the scarcity of harmonisation (eg, exposure definition) and of long-term, randomised controlled trials, and

Conclusions

In the past 5 years, substantial progress has been made into understanding the pathophysiology and genetic basis of Alzheimer's disease. The amyloid β cascade hypothesis has been modified by a more thorough understanding of the cellular, preclinical, phase of Alzheimer's disease. Genetic studies have moved from pinpointing three causal genes and one risk gene to identifying a plethora of genes that can be put into a polygenic risk score for Alzheimer's disease. The developments in biomarker

Search strategy and selection criteria

Between Dec 1, 2019, and Sept 1, 2020, we searched the Cochrane Library for articles published exclusively in English during 2010–15, PubMed for articles published during 2016–20, and Embase for articles published during 2016–20. We used the search term “Alzheimer's disease” in combination with the following: “pathology”, “imaging”, “diagnosis”, “therapy”, “trials”, “epidemiology”, “CSF”, “genetics”, and “biomarkers”. We largely selected publications from the past 5 years, and especially

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