Can Alzheimer's disease be prevented 25 years in advance?

▎The content team editor of WuXi AppTec recently, the University of Washington School of Medicine announced the launch of an international clinical trial for high-risk young people with genetic risk of early-onset Alzheimer’s disease.
25 years before the expected onset, the intervention of drugs under investigation will be evaluated.
Whether to clear amyloid β (Aβ) to slow down or stop the disease
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Alzheimer's disease is becoming one of the most burdened diseases
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Studies have shown that after the diagnosis of Alzheimer's disease, the median survival time of patients is about 6 years
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Trying to intervene earlier and find better solutions is inseparable from a deepening understanding of Alzheimer's disease
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The world’s top medical journal "The Lancet" launched a Seminar article this year specifically for Alzheimer’s disease, sorting out important medical advances in this field in recent years, covering content from clinical manifestations, pathology, genetic factors, to Biomarkers for diagnostic testing, as well as the positive effects of disease mitigation treatments and life>
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In addition, "The Lancet-Neurology" also published a new review at the end of the year, focusing on blood test biomarkers for Alzheimer's disease
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The review pointed out that early detection and monitoring of Alzheimer's disease by "blood tests" is becoming a reality
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In today's content, we will synthesize these two important reviews and take stock of the latest understanding of promoting earlier and more comprehensive diagnosis and treatment of Alzheimer's disease
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Image source: 123RF Clinical manifestations: A continuous course of 15-25 years Different types of Alzheimer's disease have different clinical manifestations
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Alzheimer's disease, which is inherited early, may have cognitive problems at about 40 years of age, including memory loss and loss of multitasking ability
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Alzheimer's disease, which is mainly manifested as a decline in language function, occurs more in younger (under 70) people, and memory problems are usually not the primary and most prominent feature
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Alzheimer's disease, which is typical, mainly manifested as forgetfulness, is more common in patients over 70 years of age
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▲The occurrence and development of Alzheimer's disease is a long-term continuous process (picture source: reference [1]) Overall, the occurrence and development of Alzheimer's disease is a continuous process that lasts 15-25 years
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It should be noted that in the absence of any symptoms, the patient may have pathological changes, and dementia is the final result of long-term pathological changes
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In the dementia stage of Alzheimer's disease, the severity of the patient's neurobehavioral symptoms is sufficient to have a significant impact on daily life
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The loss of independence is the main feature that distinguishes dementia from mild cognitive impairment
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Pathological changes: Amyloid plaques and tau protein are the core features.
From a pathological point of view, Aβ, tau protein, and related cellular responses are currently generally recognized as the main mechanisms
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In addition, the vascular system, the blood-brain barrier, the lymphatic system and other clearance systems of the brain, the peripheral immune system, and the gastrointestinal microbiome may also have an impact
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The understanding of the preclinical stage ("cell stage") of Alzheimer's disease expands the hypothesis of the Aβ cascade-the cellular stage accumulates earlier than Aβ or occurs at the same time, leading to the spread of tau lesions
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Before cognitive impairment is observed, changes in neurons, microglia and astrocytes will promote the latent progression of the disease
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Microglia-mediated inflammation may play a central role in the pathogenesis, and a considerable number of Alzheimer's disease risk genes are concentrated in this pathway
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Although the mechanism is not clear, Aβ can induce the spread of tau, which is related to neuronal apoptosis
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Genetic effects: APOE is the strongest risk genetic twin.
Studies suggest that the risk of Alzheimer's disease is 60%-80% depending on genetic factors
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With the deepening of genetic research, the precise location of 3 causal genes and 1 risk gene in the past has now developed to determine more than 40 risk genetic loci related to Alzheimer's disease to perform polygenic risk scores.
(PRS) can distinguish patients with Alzheimer's disease with 75%-85% accuracy
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Among them, APOE alleles have the strongest association.
APOEε4 is associated with a 3-4 times increase in the risk of Alzheimer’s disease, while other single risk genes have a much smaller impact on disease risk (risk increase of 5%-20%) )
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Judging from the functions involved in these risk genes, in addition to Aβ metabolism, immune response, cholesterol, lipid dysfunction, endocytosis, and vascular factors also play a role in the development of Alzheimer's disease
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 ▲ Genetic factors of Alzheimer's disease
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(A) Genetic variants that cause disease or a strong risk of increased risk (B) Genetic variants that are usually covered by genome-wide studies (C) Protective genetic variants are more rare (picture source: Reference [1]) On the contrary, other genes are associated with reduced risk , It is related to the protection of cognitive health
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Compared with non-carriers, carriers of APOEε2 alleles have a life-long risk of Alzheimer's disease approximately 2 times lower, and those who are homozygous carriers of APOEε2 alleles have a very low risk of developing the disease
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The rare Ala673Thr mutation in the APP gene is associated with long-term cognitive health
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The rare Pro522Arg amino acid change in the PLCG2 gene is associated with a nearly 2-fold decrease in the risk of dementia and a 2.
3-fold increase in the chance of cognitive health reaching 100 years old
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A pair of APOE3 genes carrying the Christchurch mutation may offset the harmful effects of the PSEN1 mutation, and the klotho longevity gene may allow high-risk populations to "dodge" Alzheimer's disease
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Diagnosis: From clinical to biomarker overall, the diagnostic criteria for Alzheimer's disease is undergoing a transition from clinical diagnosis, to clinically combined biomarkers, to more purely biological diagnosis
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At present, the clinical diagnosis of Alzheimer’s disease is mainly based on the National Institute of Aging (NIA) and Alzheimer’s Association (AA) standards, emphasizing that the course of Alzheimer’s disease is divided into preclinical and mild.
For the degree of cognitive impairment and dementia, the core clinical standards are mainly based on the cognitive or behavioral symptoms confirmed by the medical history and examination
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The development of biomarkers has also advanced the biological definition of diagnosis and laid the foundation for early diagnosis
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NIA-AA proposed the ATN framework, which divides biomarkers into three categories: A: Amyloid T: Phosphorylated tau (ptau) protein N: Neurodegeneration, measured by total tau protein in the ATN framework, the presence of Aβ (Regardless of the presence or absence of ptau protein and neurodegeneration) is regarded as a pathological change of Alzheimer's disease, and the diagnosis of the disease is based on the test results of Aβ and ptau protein
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However, due to the fact that standardized operating procedures have not yet been established and other reasons, the current ATN framework is not yet suitable for widespread use in clinical practice
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Biomarkers help early diagnosis and treatment.
At present, new biomarkers, including PET scanning and plasma analysis of Aβ and ptau, have shown great application prospects in clinical and research
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The significance of some of the markers has been relatively clear
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3 "best validated" neuroimaging biomarkers: MRI: medial temporal lobe atrophy 18FDG (fluorodeoxyglucose)-PET: FDG metabolism decline in the medial parietal lobe, posterior temporal lobe and posterior cingulate cortex, which can measure nerves Denatured amyloid-PET: Among them, cortical Aβ deposits, MRI is usually recommended as the first imaging examination after clinical evaluation; amyloid-PET is the most meaningful for ruling out Alzheimer's disease, while 18FDG-PET is for nerves The evaluation of degenerative diseases and the prediction of short-term clinical results are valuable
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In addition, Tau-PET can distinguish Alzheimer's disease from other neurodegenerative tau pathologies
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The established cerebrospinal fluid (CSF) biomarkers include Aβ1-42, Aβ1-40, ptau181, and total tau
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CSF markers that reflect axonal damage and synaptic dysfunction are also receiving attention.
Among them, neurogranin has great potential, is specific to Alzheimer's disease, and will increase in the early stages
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Among blood biomarkers, the three closest to clinical application are Aβ, ptau and neurofilament light chain protein (NfL)
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Aβ concentration can be sensitively measured for patient screening and treatment effect monitoring; multiple studies have confirmed that plasma ptau181 and ptau217 can be used for efficient diagnosis; NfL is particularly promising in the diagnosis of frontotemporal dementia
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In addition, GFAP (glial fibrillary acidic protein), which reflects the activation of glial cells, also shows potential
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Image source: 123RF intervention treatment: from symptomatic to changing the course of the disease, non-pharmacological interventions provide opportunities for prevention
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The strongest risk factors for Alzheimer's disease are advanced age (usually over 65) and carrying the APOEε4 allele
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Women are also more likely to get sick
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In addition, cardiovascular risk factors and unhealthy life>
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Prevention trials have shown that "multi-pronged" healthy life>
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The "Lancet" major report also pointed out that by changing 12 risk factors, nearly 40% of dementia can be prevented
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Research suggests that although life>
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Drug therapy At present, cognitive enhancement therapy for Alzheimer's disease includes cholinesterase inhibitors and memantine, which is also the current main treatment standard for patients with Alzheimer's disease
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Research on therapies that specifically target the psychiatric symptoms of Alzheimer's disease or dementia is making progress
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Pimavanserin's indications for the treatment of hallucinations and delusions in patients with Alzheimer's disease are being evaluated by the FDA
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As many as 70% of Alzheimer's patients experience restlessness
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Brexpiprazole, escitalopram, prazosin, dextromethorphan + quinidine, dextromethorphan + bupropion and other programs are being evaluated in the trial
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The FDA has approved suvorexant for the treatment of insomnia in patients with mild to moderate Alzheimer's disease
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In addition to symptomatic treatment, the goal of global new drug research and development for Alzheimer's disease has shifted to change the course of the disease
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Including anti-Aβ, anti-tau and anti-inflammatory strategies, a variety of disease-modifying therapies are entering the later stages of clinical trials
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Aβ is the most common target in phase 2-3 clinical trials
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More and more evidence shows that the removal of Aβ oligomers and plaques by monoclonal antibodies can slow down the progression of the disease; these treatments also help reduce ptau, neurogranin and NfL in the cerebrospinal fluid
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Based on its reduction in surrogate endpoint amyloid plaques, aducanumab has been approved to treat Alzheimer's disease in 2021
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Donanemab delayed the clinical progression of patients with early Alzheimer's disease by 32% in a phase 2 trial
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Lecanemab and gantenerumab are expected to receive three phases of data in the second half of 2022
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Tau is another important target.
Several different monoclonal antibodies under study are designed to act on the cell-to-cell spread of tau, and other small molecules target tau aggregation and neurofibrillary tangles formation
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Therapies under investigation for other mechanisms also involve prevention of infection, neuroprotection through growth factors and mitochondria
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Early recognition and multimodal treatment are expected to be realized.
In the past 5 years, we have a deeper understanding of the pathophysiology and genetic basis of Alzheimer’s disease; the development of biomarker diagnosis has prompted people to think about how to detect earlier Alzheimer's disease; these advancements also provide insights for prevention and treatment
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At present, as the global aging process continues to accelerate, as one of the most common neurodegenerative diseases among the elderly, Alzheimer's disease is also an important aspect of the "healthy aging" issue
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On January 11, 2022, WuXi AppTec will join hands with the Singapore Agency for Science and Technology Research (A*STAR) and Davos Alzheimer's Collaborative to jointly host the first healthy aging forum online, from the United States, Nearly 30 top aging experts from the United Kingdom, Singapore, and China will gather here to point us to the future direction of healthy aging
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This forum will also set up special discussions to focus on the Alzheimer's disease response plan
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Dr.
Niranjan Bose, Managing Director of Health and Life Sciences at Gates Ventures, Mr.
Ivan Cheung, President of Eisai America and Global President of Eisai Neurology Division, Mr.
George Vradenburg, Co-Chairman of the Davos Alzheimer's Disease Cooperation Organization, and F-Prime Dr.
Stacie Weninger, President of the Biomedical Research Program, will jointly bring their thoughts and insights on this important public health issue
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▲The 2022 WuXi AppTec Health Aging Forum adopts an "invitation approval system" and does not charge any participation fees.
Professionals in the global medical and health fields are welcome to participate
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