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
SeminarAlzheimer's disease
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
References (170)
- et al.
Alzheimer's disease
Lancet
(2016) - et al.
Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria
Lancet Neurol
(2007) - et al.
Revising the definition of Alzheimer's disease: a new lexicon
Lancet Neurol
(2010) - et al.
The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
Alzheimers Dement
(2011) - et al.
NIA-AA Research Framework: toward a biological definition of Alzheimer's disease
Alzheimers Dement
(2018) - et al.
Vascular dysfunction—the disregarded partner of Alzheimer's disease
Alzheimers Dement
(2019) - et al.
Alzheimer's disease drug development pipeline: 2019
Alzheimers Dement (NY)
(2019) - et al.
Biomarker-based prognosis for people with mild cognitive impairment (ABIDE): a modelling study
Lancet Neurol
(2019) - et al.
The characterisation of subjective cognitive decline
Lancet Neurol
(2020) - et al.
Survival after dementia diagnosis in five racial/ethnic groups
Alzheimers Dement
(2017)
Duration of preclinical, prodromal, and dementia stages of Alzheimer' s disease in relation to age, sex, and APOE genotype
Alzheimer Dementia
The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study
Lancet Neurology
Dementia prevention, intervention, and care: 2020 report of the Lancet Commission
Lancet
Vascular dysfunction in the pathogenesis of Alzheimer's disease—a review of endothelium-mediated mechanisms and ensuing vicious circles
Neurobiol Dis
Understanding Alzheimer disease at the interface between genetics and transcriptomics
Trends Genet
The genetic landscape of Alzheimer disease: clinical implications and perspectives
Genet Med
Mutations in ABCA7 in a Belgian cohort of Alzheimer's disease patients: a targeted resequencing study
Lancet Neurol
The cellular phase of Alzheimer's disease
Cell
Alzheimer disease: an update on pathobiology and treatment strategies
Cell
TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia
Neuron
CSF Abeta1–42—an excellent but complicated Alzheimer's biomarker—a route to standardisation
Clin Chim Acta
Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
Lancet Neurol
Dementia in Europe Yearbook 2019: estimating the prevalence of dementia in Europe
Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease
Neurology
A brief history of “Alzheimer disease”: multiple meanings separated by a common name
Neurology
Dementia is not synonymous with Alzheimer's disease
Sci Transl Med
Applying the ATN scheme in a memory clinic population: the ABIDE project
Neurology
Clinicians' communication with patients receiving a mild cognitive impairment diagnosis: the ABIDE project
PLoS One
Personalized risk for clinical progression in cognitively normal subjects—the ABIDE project
Alzheimers Res Ther
ATN classification and clinical progression in subjective cognitive decline: The SCIENCe project
Neurology
ABIDE Delphi study: topics to discuss in diagnostic consultations in memory clinics
Alzheimers Res Ther
Development and usability of ADappt: web-based tool to support clinicians, patients, and caregivers in the diagnosis of mild cognitive impairment and Alzheimer disease
JMIR Form Res
World Alzheimer Report 2018. The state of the art of dementia research: new frontiers
The changing prevalence and incidence of dementia over time—current evidence
Nat Rev Neurol
Recent global trends in the prevalence and incidence of dementia, and survival with dementia
Alzheimers Res Ther
Survival in memory clinic cohort is short, even in young-onset dementia
J Neurol Neurosurg Psychiatry
Prevalence of biologically vs clinically defined Alzheimer spectrum entities using the National Institute on Aging-Alzheimer's Association research framework
JAMA Neurol
Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults
JAMA Neurol
Sex differences in CSF biomarkers vary by Alzheimer's disease stage and APOE ɛ4 genotype
Neurology
Associations between vascular risk across adulthood and brain pathology in late life: evidence from a British birth cohort
JAMA Neurol
Association of intracranial atherosclerotic disease with brain beta-amyloid deposition: secondary analysis of the ARIC study
JAMA Neurol
Midlife atherosclerosis and development of Alzheimer or vascular dementia
Ann Neurol
Role of genes and environments for explaining Alzheimer disease
Arch Gen Psychiatry
Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls
Neurobiol Aging
Alzheimer's disease: analyzing the missing heritability
PLoS One
Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk
Nat Genet
Common polygenic variation enhances risk prediction for Alzheimer's disease
Brain
Polygenic risk score analysis of pathologically confirmed Alzheimer disease
Ann Neurol
Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease
Proc Natl Acad Sci USA
Genomic variants, genes, and pathways of Alzheimer's disease: an overview
Am J Med Genet B Neuropsychiatr Genet
Cited by (1515)
A novel hybrid ensemble based Alzheimer's identification system using deep learning technique
2024, Biomedical Signal Processing and ControlNavigating the metabolic maze: anomalies in fatty acid and cholesterol processes in Alzheimer’s astrocytes
2024, Alzheimer's Research and Therapy