like poor memory and difficulty learning new information, which can make it really hard

像是記憶力差和學習新信息困難，這可能使它真的很難

to function independently.

獨立運作。 通常癡呆是由對大腦中細胞的某種損傷造成的

Usually dementia's caused by some sort of damage to the cells in the brain, which can

其可以來自多種疾病。 阿茲海默症

be from a variety of diseases.

現稱為阿茲海默症是癡呆症的最常見原因。

Alzheimer's disease, now referred to as Alzheimer disease, is the most common cause

阿茲海默症被認為是神經變性疾病 意味著它對大腦中的神經元引起變異或損失

of dementia.

特別是在皮質中，這可能會導致癡呆症狀的特徵

Alzheimer disease is considered a neurodegenerative disease, meaning it causes the degeneration,

這可能會導致癡呆症狀的特徵

or loss, of neurons in the brain, particularly in the cortex.

雖然阿茲海默症的原因尚未完全了解 兩個主要的，但在其過程中經常被討論

This, as you might expect, leads to the symptoms characteristic of dementia.

的兩個主要參與者是斑塊和纏結。好，所以這裡

Although the cause of Alzheimer disease isn't completely understood, two major players that

我們有一個神經元在大腦中的細胞膜。你有這種

are often cited in its progression are plaques and tangles.

稱為澱粉樣前體蛋白的分子，或APP， 這個傢伙一端在細胞內

Alright, so here we've got the cell membrane of a neuron in the brain.

而另一端在細胞外。這個傢伙被認為幫助神經元生長

In the membrane, you've got this molecule called amyloid precursor protein, or APP,

和損傷後自我修復。由於APP的蛋白質， 就像其他蛋白質，它被使用

one end of this guy's in the cell, and the other end's outside the cell.

隨著時間的過去，它被分解和回收。 通常，它被稱為alpha分泌酶的酶

It's thought that this guy helps the neuron grow and repair itself after an injury.

和它的伙伴，γ分泌酶切割。這個切碎的肽是可溶的

Since APP's a protein, just like other proteins, it gets used and over time it gets broken

之後會消失，一切都很好。但是，如果另一種酶

down and recycled.

β分泌酶，與γ分泌酶配合，那麼我們有一個問題，這個剩餘的片段是不溶的，

Normally, it gets chopped up by an enzyme called alpha secretase and it's buddy, gamma

並產生稱為澱粉樣蛋白β的單體。 這些單體傾向於更具化學性“粘性”

secretase.

並且僅在神經元外部結合在一起 並形成所謂的β-澱粉樣蛋白斑塊

This chopped up peptide is soluble and goes away, and everything's all good.

- 這些單體的這些團塊 這些斑塊可能潛在地進入神經元之間

If another enzyme, beta secretase, teams up with gamma secretase, then we've got a problem,

這可能妨礙神經元至神經元信號傳導 如果腦細胞不能接收信號和傳遞信息

and this leftover fragment isn't soluble, and creates a monomer called amyloid beta.

那麼大腦功能如記憶可能嚴重受損。

These monomers tend to be more chemically “sticky”, and bond together just outside

這些斑塊也被認為可以啟動免疫應答

the neurons, and form what are called beta-amyloid plaques—these clumps of lots of these monomers.

並引起可能損害周圍神經元的發炎 澱粉樣斑塊還可以沉積在

These plaques can potentially get between the neurons, which can get in the way of neuron-to-neuron

腦中的血管周圍，稱為澱粉樣血管病 會削弱了血管的管壁

signaling.

並且增加了出血或破裂並失血的風險

If brain cells can't signal and relay information, then brain functions like memory can be seriously

這裡是澱粉樣斑塊在組織學上的圖像，這些團塊是β澱粉樣蛋白的積累，這些都發生在細胞外。

impaired.

00:02:45,510 --> 00:02:50,459 阿茲海默症的另一個大部分是纏結 這些實際上發現在細胞內

It's also thought that these plaques can start up an immune response and cause inflammation

而不是β-澱粉樣蛋白斑 就像其他細胞一樣，神經元通過其細胞骨架保持在一起

which might damage surrounding neurons.

其部分由微管組成 這些軌道樣結構基本上

Amyloid plaque can also deposit around blood vessels in the brain, called amyloid angiopathy,

像礦車一樣沿著微管運輸營養物和分子

which weakens the walls of the blood vessels and increases the risk of hemorrhage, or rupture

一種稱為tau的特殊蛋白質確保這些軌道不會分開，就像枕木一樣

and blood loss.

雖然尚未完全理解，不過認為β澱粉樣蛋白斑

Here's an image of amyloid plaque on histology, these clumps are buildups of beta amyloid,

積聚在引發神經元內部的通路，會導致激酶的激活

and this is happening outside the cell.

酶將磷酸基團轉移至tau蛋白。 然後tau蛋白改變形狀

Another big part of alzheimer disease are tangles, and these are actually found inside

停止支持微管，並與其他tau蛋白結塊，或被糾纏

the cell, as opposed to the beta-amyloid plaques.

並導致阿茲海默症 - 神經原纖維纏結的產生

Just like other cells, neurons are held together by their cytoskeleton, which is partly made

具有纏結和非功能性微管的神經元不能發出信號

up of microtubules, these track-like structures essentially act like a minecart shipping nutrients

並且有時會經歷凋亡或程序性細胞死亡

and molecules along the length of the cell.

這裡是組織學的圖像顯示在細胞內 形成的這些神經原纖維纏結

A special protein called tau makes sure these tracks don't break apart, kind of like railway

當神經元死亡時，大規模變化開始發生在大腦中

ties.

一個，大腦萎縮或收縮，並且迴旋變窄， 這是大腦的脊髓狀化

Although again, not completely understood, it's thought that the beta amyloid plaque

隨著那些變窄， 作為在迴旋之間的溝槽的sulci變得更寬

build-up initiates pathways inside the neuron that leads to activation of kinase, an enzyme

隨著萎縮，大腦中的腦室充滿流體的腔變大

that transfers phosphate groups to the tau protein.

所以這是病理生理的一部分 但為什麼這會發生在一些人而不是其他人？

The tau protein then changes shape, stops supporting the microtubules, and clumps up

阿茲海默症可以分為兩組 - 散發性和家族性

with other tau proteins, or gets tangled, and leads to the other characteristic finding

散發性用於描述晚發型，其中確切的原因不是很好地定義

of Alzheimer disease–neurofibrillary tangles.

並可能是遺傳和環境風險因素的組合

Neurons with tangles and non-functioning microtubules can't signal as well, and sometimes end

而且散發性占絕大多數情況 隨著散發性阿茲海默症，風險隨年齡增長顯著

up undergoing apoptosis, or programmed cell death.

影響約1％的60-65歲的人和50％的85歲以上的人 事實上

Here's an image of histology showing these neurofibrillary tangles formed inside the

已被鑑定為可能有助於阿茲海默症風險增加的基因是

cell.

載脂蛋白E基因或APOE-e4的e4等位基因。 研究人員已經表明

As neurons die, large scale changes start to take place in the brain, for one, the brain

遺傳一個e4等位基因的患者發展阿茲海默症 的風險增加

atrophies, or shrinks, and the gyri get narrower, which are the characteristic ridges of the

並且對於繼承了兩個e4等位基因的患者 而言風險增加更多。

brain.

載脂蛋白E有助於分解β-澱粉樣蛋白，但是e4等位基因

As those get narrower, the sulci, which are the grooves between the gryi, get wider.

似乎不如其它等位基因，如APOE-e2等位基因有效

With atrophy, the ventricles, fluid-filled cavities in the brain, get larger.

這意味著患者更傾向於形成β-澱粉樣斑塊

So that's the pathophysiology part, but why does this happen in some people and not

家族性阿茲海默症用於描述某些顯性基因被遺傳的病例

others?

其加速疾病的進展，因此有時家族性阿茲海默症

Well Alzheimer disease can be split into two groups - sporadic and familial.

稱為早發性阿茲海默症 家族性佔5％至10％的病例

Sporadic's used to describe the late-onset type where the exact cause isn't very well

並且可由幾種基因突變引起 首先，第14對染色體或第1對染色體

defined, and is probably a combination of genetic and environmental risk factors.

的PSEN-1或PSEN-2基因突變分別 與早發性阿茲海默症有關。

Sporadic accounts for the vast majority of cases.

這些早老素-1或早老素-2的基因編碼 兩者是γ-分泌酶的蛋白質亞基。

With sporadic Alzheimer's, the risk increases significantly with age, affecting around 1%

這些PSEN-1或PSEN-2基因中的突變 可改變γ分泌酶剔除APP的位置

of people age 60-65, and 50% of people over age 85.

產生不同長度的β澱粉樣蛋白分子 這似乎更容易的結塊和形成斑塊。

In fact, a gene that's been identified as possibly contributing to an increased risk

另一種已知的阿茲海默症的遺傳原因是

of alzheimer disease is the e4 allele of apolipoprotein E gene, or APOE-e4.

21三體綜合徵或唐氏綜合徵， 其涉及第21對染色體的額外複製。

Researchers have shown that the risk of developing alzheimer disease increases for patients that

事實證明，負責產生APP的基因位於第21對染色體上

inherit one e4 allele, and increases even more for patients who inherited two e4 alleles,

這意味著具有唐氏綜合徵的人具有額外的APP基因

one from each parent.

因此推測APP的表達增加 並且可能增加澱粉樣蛋白斑塊的量

Apolipoprotein E helps break down beta-amyloid, but the e4 allele seems to be less effective

因此，家族性阿茲海默症通常在40歲前發作

than other alleles, like the APOE-e2 allele, meaning patients are more likely to develop

阿茲海默症的症狀惡化，因為斑塊和纏結累積 並且神經元損傷累積

beta-amyloid plaques.

在早期，症狀甚至可能不可檢測，因為它發作時，

Familial alzheimer disease is used to describe cases where some dominant gene was inherited

患者會丟失短期記憶，例如他們可能不能記住

that speeds up the progression of the disease, so sometimes familial alzheimer disease is

他們早餐吃什麼 然後他們進一步喪失運動技能

referred to as early onset Alzheimer's.

使得像吃飯沒有幫助變得十分困難 語言也受到影響，使得溝通更加困難

Familial accounts for between 5 and 10% of cases, and can be caused by several gene mutations.

最終，他們失去長期記憶，如忘記配偶的名字

First, mutations in the PSEN-1 or PSEN-2 genes genes on chromosome 14 or chromosome 1, respectively,

甚至結婚，逐漸變得更加迷失方向

have been linked to early-onset Alzheimer's.

這可能是危險的，因為他們可能從家裡徘徊，迷路。

These genes encode for presenilin-1 or presenilin-2, both protein subunits of gamma-secretase.

在後期，他們變得臥床不起 最常見的死亡原因實際上是感染，如肺炎。

Mutations in these PSEN-1 or PSEN-2 genes can change the location where gamma secretase

00:07:57,580 --> 00:08:01,610 阿茲海默症的診斷是非常困難的，因為確定性地顯示 一個人患有阿茲海默症的唯一方法

chops APP, producing different length beta amyloid molecules, which seem to be better

是通過在屍體解剖後進行腦活組織檢查。

at clumping up and forming plaques.

因此，通常臨床醫生在排除其他癡呆的原因之後進行診斷。

Another known genetic cause of Alzheimer's is trisomy 21, or down syndrome, which involves

目前，沒有治療阿茲海默症的方法 雖然有藥物存在

an extra copy of chromosome 21.

但作用微弱並且沒有任何明顯或確定地停止阿茲海默症發作。

It turns out that the gene responsible for producing APP is located on chromosome 21,

which means that people with down syndrome have an extra APP gene, and so presumably

increased expression of APP, and possibly increased amounts of amyloid plaque.

For this reason, familial Alzheimer disease often progresses by age 40.

Symptoms of Alzheimer disease worsen as plaques and tangles build up, and neuronal damage

accumulates.

In the early stages, symptoms may not even be detectable, as it progresses, patients

lose short-term memory, like for example they may not be able to remember what they had

for breakfast that morning.

They then progress to loss of motor skills, making things like eating difficult without

help.

Also language becomes affected, making it more difficult to communicate.

Eventually they lose long-term memory, like forgetting the name of their spouse or even

that they're married, and progressively become more disoriented, which can be dangerous,

because they might wander from home and get lost.

In late-stage, they become bedridden, and the most common cause of death is actually

infection, like pneumonia.

Diagnosis of Alzheimer disease is really tough, because the only way to definitively show

that a person had Alzheimer's is by performing a brain biopsy after autopsy.

Usually a clinician will therefore make a diagnosis after excluding other causes of

dementia.

Currently, there isn't any cure for Alzheimer disease, some medications exist, but the benefits

are small and there haven't been any medications that clearly and definitively halt the progression

of Alzheimer's.