Dementia has a significant impact on families and society.
According to statistics, there are over 55 million patients globally, costing more than 1.3 trillion US dollars.
In Taiwan alone, approximately 310,000 people are affected, with one person developing dementia for every 72 individuals.
As the prevalence of dementia increases with age and society trends towards aging, the burden on family and societal working-age populations is expected to worsen.
Therefore, advanced nations prioritize the treatment and prevention of dementia.
In 2011, President Obama signed the National Alzheimer's Project Act, ensuring an annual update of the national dementia plan and allocating substantial budgets for caregiver assistance and research.
Dementia is an acquired disease characterized by a decline in cognitive abilities affecting one or more cognitive domains (Note 1).
Although traditional definitions of dementia require a decline in at least two cognitive domains, the major neurocognitive disorder definition outlined in the DSM only necessitates a significant decline in a single cognitive domain, severe enough to interfere with daily functioning and independence.
The most common cause of dementia in older adults is Alzheimer's disease (AD), accounting for 60% to 80% of cases.
Since Alzheimer's disease is the most common cause of dementia and one of the main causes of morbidity and mortality in the elderly population, how to prevent and treat Alzheimer's disease has become an important issue in the prevention and treatment of dementia.
Alzheimer's disease is a neurodegenerative disorder with unclear etiology and pathogenesis.
The characteristic neuropathological changes include the diffuse neuritic plaques (extracellular beta-amyloid deposition) and neurofibrillary tangles composed of hyperphosphorylated tau (p-tau) protein accumulation within cells.
Additionally, brain cell death, loss of neuronal connections, and brain atrophy are common changes in the brains of Alzheimer's patients.
Due to the classical pathological finding of amyloid plaques in Alzheimer's disease, the "amyloid hypothesis" has been proposed, suggesting that extracellular amyloid senile plaques are the primary cause of Alzheimer's disease.
These plaques can generate oxidative stress, lead to chronic inflammation, and result in neuronal death and degeneration.
Therefore, preventing or removing plaques has become a key focus in Alzheimer's disease treatment.
With the advancement of technology, drugs that can remove plaque have finally become available in recent years.
This type of drug is Anti-amyloid monoclonal antibodies (MABs).
However, unexpectedly, although drugs such as "anti-Beta amyloid monoclonal antibodies" can indeed effectively remove plaques, the effect is not as stunning as expected (it can only slightly delay the deterioration but cannot improve cognitive function).
There are also serious side effects (cerebral edema and cerebral hemorrhage) that may occur in a small proportion (10 to 20%), and are expensive (a year's medication costs tens of thousands of dollars).
Since removing plaques does not lead to a significant improvement in the condition, and based on other clinical and research findings, the traditional "amyloid hypothesis" faces significant challenges.
In other words, Alzheimer's disease may have other potential causes.
Some hypotheses proposed by the scientific community include:
a. Intracellular Amyloid Hypothesis: Neuronal death occurs in the ultra-early phase before the aggregation of extracellular amyloid plaques. The accumulation of intracellular amyloid is the result of neuronal death caused by extracellular amyloid aggregation.
b. Tau Protein Hypothesis: Damage to tau protein occurs earlier than the accumulation of Aβ.
c. Abnormalities in cell self-repair and waste clearance functions: e.g. mitochondrial dysfunction; endoplasmic reticulum stress; impaired autophagy.
Although these hypotheses require further experimental validation, understanding that Alzheimer's or dementia may not have a simple, single cause is crucial.
This knowledge helps us take the next steps in prevention and treatment, as it holds new opportunities for intervention.
Note 1: Cognitive domains include learning and memory, language, executive function, complex attention, perceptual-motor skills, and social cognitive abilities.
Note 2:
Findings from studies on transgenic mouse models show that Aβ deposition in the brain forms plaques but does not lead to the formation of neurofibrillary tangles (accumulation of tau protein) and neuronal death.
Aβ extracellular accumulation is not cytotoxic and does not induce tau accumulation.
Aβ deposition may be an aging phenomenon unrelated to the onset of Alzheimer's disease.
Additionally, amyloid imaging in humans indicates that many normal individuals have amyloid deposits, and some Alzheimer's patients have minimal amyloid deposition.
The distribution of plaques in the brains of non-dementia patients is sometimes as widespread as in dementia patients, suggesting that Aβ deposition may be an aging-related phenomenon unrelated to Alzheimer's disease onset.
沈默的危機！勿讓失智症拖垮國家財政
https://news.cnyes.com/news/id/2248656
失智症防治照護政策綱領暨行動方案2.0 (含工作項目)衛生福利部https://www.mohw.gov.tw › ...
失智海嘯席捲全球，你我必須面對的真相
https://www.gvm.com.tw/article/19501
國家阿茲海默症計畫法案 National Alzheimer S Project Act
https://academic-accelerator.com/encyclopedia/zh/national-alzheimer-s-project-act
Alzheimer's Association
https://www.alz.org/asian/about/what_is_alzheimers.asp?nL=ZH&dL=ZH
8 Ways to Help Improve Your Brain Health
https://www.cdc.gov/aging/publications/features/healthy-body-brain.html
Uptodate:
Epidemiology, pathology, and pathogenesis of Alzheimer disease
Treatment of Alzheimer disease
Prevention of dementia
Risk factors for cognitive decline and dementia
罹患失智症有機會痊癒嗎？阿茲海默藥物開發的辛酸血淚史
https://pansci.asia/archives/124107
阿茲海默症新藥餘波
https://geneonline.news/fda-update-aduhelm/
淺談曇花一現的「阿茲海默症新藥」
https://health.gvm.com.tw/article/89801
百健阿茲海默藥Aduhelm 40%患者出現腦水腫/出血副作用
https://news.gbimonthly.com/tw/article/show.php?num=44640
百健放棄進軍歐洲
https://news.gbimonthly.com/tw/article/show.php?num=48754
阿茲海默症：新藥成功，股票大跌
https://professorlin.com/2021/03/22/阿茲海默症：新藥成功，股票大跌/
Lecanemab獲快速審查資格
https://news.gbimonthly.com/tw/article/show.php?num=45416
Lecanemab in Early Alzheimer’s Disease
https://www.nejm.org/doi/full/10.1056/NEJMoa2212948
Long-Term Health Outcomes of Lecanemab in Patients with Early Alzheimer’s Disease Using Simulation Modeling
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095799/
阿茲海默新藥來了，真的能治好老人失智嗎？
https://www.cw.com.tw/article/5126644
Donanemab in Early Alzheimer’s Disease
https://www.nejm.org/doi/full/10.1056/NEJMoa2100708
Alzheimer’s Association Statement on Donanemab Phase 3 Data Reported at AAIC 2023
禮來阿茲海默症新藥證實有效減緩35%認知衰退，有望年底獲FDA批准
https://health.gvm.com.tw/article/104587
Donanemab in Early Symptomatic Alzheimer Disease
The TRAILBLAZER-ALZ 2 Randomized Clinical Trial
Results from Lilly's Landmark Phase 3 Trial of Donanemab Presented at Alzheimer's Association Conference and Published in JAMA
延緩初期失智達6成，禮來阿茲海默新藥可望年底問世
一篇疑造假的論文會毀了阿茲海默症的研究嗎？
Alzheimer’s Disease and the β-Amyloid Peptide
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813509/
Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797629/
Intracellular amyloid hypothesis for ultra‐early phase pathology of Alzheimer's disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251586/
Endoplasmic reticulum dysfunction in Alzheimer's disease
https://pubmed.ncbi.nlm.nih.gov/24715417/
The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: Implications for Alzheimer's disease
https://www.sciencedirect.com/science/article/pii/S0925443914001318
ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments
https://www.nature.com/articles/s41419-022-05153-5
Endoplasmic reticulum stress responses in mouse models of Alzheimer's disease: Overexpression paradigm versus knockin paradigm
https://www.jbc.org/article/S0021-9258(20)39049-9/fulltext
Tau蛋白如何在腦內穿梭
https://geneonline.news/lrp1-tau-propagation/
記憶的小偷：阿茲海默症
https://geneonline.news/alzheimers-disease/
https://geneonline.news/alzheimer-disease-drug-amyloid-tau/
Mitochondrial Dysfunction in Alzheimer’s Disease: Opportunities for Drug Development
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9878959/
Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances
https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00376-6
The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis
https://pubmed.ncbi.nlm.nih.gov/35522844/
Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease
https://www.frontiersin.org/articles/10.3389/fnagi.2021.617588/full
The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment
https://www.sciencedirect.com/science/article/abs/pii/S053155652200136X
Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797541/
Autophagy in Alzheimer's disease
https://pubmed.ncbi.nlm.nih.gov/25870960/
Autophagy in Alzheimer’s disease pathogenesis: Therapeutic potential and future perspectives
https://www.sciencedirect.com/science/article/pii/S1568163721002117
Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques
https://www.nature.com/articles/s41593-022-01084-8
Enhancing autophagy in Alzheimer's disease through drug repositioning
https://www.sciencedirect.com/science/article/pii/S0163725822000651
Alzheimer’s Disease Progression Hypothesis Challenged
Amyloid Beta Protein Antibody
https://www.sciencedirect.com/topics/neuroscience/amyloid-beta-protein-antibody
