有關阿爾茨海默病的研究一直以來都被所謂的“宗教戰爭”（把相關理論的核心詞首字母縮寫放在一起，正好是宗教徒的單詞——譯注）所困擾：“浸禮宗教徒”（BAPtists）堅稱由β-淀粉樣蛋白（beta-amyloid proteins）形成的斑塊會影響并最終殺死神經細胞，從而導致了阿爾茨海默癥；“道教徒”（TAUists）認為這一疾病的罪魁禍首是神經纖維纏結——即扭曲的tau蛋白——在神經細胞中堆積；“無神論者”（ATHIEsts）則相信盡管這些都是引發阿爾茨海默癥的因素，但其他事情（anything else）可能才是病癥惡化的最終元兇。

正如我在最近的文章（“為什么阿爾茨海默病的最新藥物讓這么多人疑惑不解”）中所說，“浸禮宗教徒”的勢力最為龐大，在學術研究和藥物研發的前沿都積累了一代人甚至幾代人的支持。淀粉樣蛋白假說的支持者甚至有了新的生物學模型來解釋這個病變過程開始和加速的過程。正如作者勞拉·拜勒在《科學通訊》（Science News）的一篇流暢清楚的特稿中所述，這個觀點“明確自洽”。

一般在睡眠時，大腦會不斷清理游離的β-淀粉樣蛋白（又被稱作Aβ），這些是神經細胞自身產生的蛋白質殘余。如果睡眠中斷，垃圾清理過程也會終止。拜勒寫道：“學界越來越多人達成共識：大腦沒有機會清理神經細胞產生的全部Aβ，于是它們開始在大腦細胞的縫隙中積聚，就像溝槽里的垃圾一樣。如果Aβ積聚得過多，就可能形成斑塊，我們認為這最終會導致炎癥等問題，促成tau蛋白的形成，后者似乎會摧毀神經細胞，引發阿爾茨海默癥。”

確實，借助正子斷層掃描技術，我們可以看到只要一晚不睡，即使在健康的大腦中，這種游離的蛋白質也會迅速增加，在特定的大腦區域甚至會多達5%。阿爾茨海默癥本身會中斷睡眠，這只會加速并加重這一病態循環。不過該理論也有缺陷，其中之一就是先有雞還是先有蛋的謎題，如拜勒所說：“如果阿爾茨海默癥會影響睡眠，又會被睡眠所影響，那究竟哪個在前呢？”

另一個缺陷，或者至少說是干擾因子，在于人們通過在研究性的臨床試驗，對淀粉樣蛋白的清理劑進行過多次測試，但阿爾茨海默癥的進程卻從未因此終止。正如我最近所說，百健（Biogen）和衛材（Eisai）的抗淀粉樣蛋白藥物BAN2401最近在第二階段試驗中獲得的結果也并未改變這一情況。盡管接受試驗性抗體的患者在認知能力上或許有所改善，但結果似乎沒有體現出許多人希望甚至預期的效果。

在此之上的另一個重量級問題在于：我們可以把它稱為“七噸的謎題”——或是“阿爾茨海默奇異屋中的大象”：為什么大象在年老后不會經歷類似的大腦退化？

非洲象（Loxodonta africana）的大腦幾乎比人類大三倍，其中約有2,570億個神經細胞，我們人類只有大約1,000億個（盡管大象的大部分神經細胞都在大腦皮層之外）。但弗吉尼亞大學（University of Virginia）著名的已退休研究教授邁克爾·加斯唐在他的著作《大象的理智與情感》（Elephant Sense and Sensibility）中寫道，暮年大象的記憶力似乎相當驚人。象群的首領記得幾十年前曾去過的遙遠地點，并會把這些知識傳給下一代非洲象。

此外，在我們所知的范圍內（畢竟我們很難問大象昨天早餐吃了什么），似乎沒什么證據表明老象的智力會出現下滑。迄今為止，我們在少數老象死后解剖的大腦中，也沒有找到淀粉樣蛋白斑塊積聚的證據。

至于睡眠可以清理大腦的理論，在大象身上也不太適用：大體上說，這種生物睡得很少。（一項研究表明，野象每天只睡兩小時，被囚禁的大象會睡得長一些。）無論如何，如果大象要在睡覺期間清理任何淀粉樣蛋白，那留給它們的時間并不多。

一個可能的解釋是大象的大腦可能有其他生物機制，讓神經細胞歷經數十年依舊能全力運轉。

但另一個理論則與機制無關——而是直指大象生活的核心：它們高度社會化。這些動物一生都聚集在一起，有著緊密的家族關系，一代接一代。年邁的大腦依舊保持活躍，是否與此有些關系呢？

事實上，許多研究認為事實或許正是如此。有關人類的幾項研究似乎證實，強有力的社會聯系會降低老年人出現認知損害的風險，而相反的情況（脫離社會）會讓神經退化狀況加劇。

不幸的是，這樣的證據可能為美國的阿爾茨海默癥致死案例增加提供了線索。從2000年至2015年，阿爾茨海默癥致死的人數增加了123%。歸根結底，這樣悲傷的數據可能反映了我們破碎的社會結構——以及當今家庭中代際交流的缺乏——或許，它確實是阿爾茨海默癥的生物或化學驅動因素。

所以，讓“浸禮宗教徒”“道教徒”和“無神論者”為了晦暗未明的科學爭論不休吧，你不如在這個周末給你的母親、父親、舅母或老鄰居打個電話，嘮嘮家常。誰知道呢？或許你對抗擊阿爾茨海默癥所做的貢獻，比許多制藥公司的高管還要大。（財富中文網）

譯者：嚴匡正

Alzheimer’s disease research has long been beset by a religious war of sorts: “BAPtists” ardently believe that plaques formed by beta-amyloid proteins drive the disease by gumming up and ultimately killing neurons. “TAUists” believe that the real culprits are the neurofibrillary tangles, or twisted tau proteins, that accumulate within neurons. And “ATHIEsts” believe that while both of these factors play a role, anything else may ultimately be to blame for advancing the disease.

As I mentioned in recently article (“Why the Latest Alzheimer’s Drug Has So Many People Confused”), the BAPtists have drawn the greatest number of disciples for a generation or more—on both the academic research and drug development fronts. And amyloid hypothesis backers even have a new biological model to explain how this pathological process might begin—and accelerate. The idea, as writer Laura Beil explains in a wonderfully clear feature in Science News, is called the “clean cycle”:

During normal sleep, the brain actively clears out stray beta-amyloid (also called A-beta), protein remnants that are discarded by neurons themselves. But when sleep is disrupted, the trash removal is stalled: “[T]he brain doesn’t get the chance to mop up all the A-beta that the neurons produce, according to a developing consensus,” Beil writes. “A-beta starts to collect in the small seams between cells of the brain, like litter in the gutter. If A-beta piles up too much, it can accumulate into plaques that are thought to eventually lead to other problems such as inflammation and the buildup of tau, which appears to destroy neurons and lead to Alzheimer’s disease.”

Indeed, thanks to PET scans, we can see that, even in healthy brains, the amount of this stray protein increases dramatically—by as much as 5% in certain brain regions—after only a single night of sleep deprivation. The fact that Alzheimer’s itself disrupts sleep serves only to speed up and amplify this vicious cycle. But there are gaps in the theory, too. One is a chicken-and-egg conundrum, says Beil: “If Alzheimer’s both affects sleep and is affected by it, which comes first?”

Another gap—or at least a confounder—is the fact that amyloid-clearing agents have been tested again and again in investigative clinical trials and have never been shown to halt the disease. As I wrote recently, the recent results from the Phase II trial of BAN2401, an anti-amyloid drug from Biogen and Eisai didn’t exactly break this record. Though patients who received the experimental antibody may have had some improvement in cognition, the outcomes appeared to fall short of what many had hoped for, and even expected.

On top of that comes another weighty question: Call it the seven-ton mystery—or the elephant in the room of Alzheimer’s oddities: Why don’t elephants experience the same kind of brain deterioration with aging?

The brains of Loxodonta africana, or African elephants, are nearly three times larger than their human counterparts—holding as many as 257 billion neuronscompared to our feeble 100 billion or so (though the vast majority of the elephant’s supply reside outside the cerebral cortex). But elephants seem to have extraordinary memory capacity late into life, as Michael Garstang, an emeritus distinguished research professor at the University of Virginia, details in his book Elephant Sense and Sensibility—with herd matriarchs remembering discrete faraway locations visited many decades earlier, for example, and transferring that knowledge to the next generations.

Moreover, to the extent it can be known (It’s hard to ask an elephant what they had for breakfast yesterday), there seems to be little evidence that older elephants suffer from mental decline. So far, in the handful of brains of older elephants that have been examined post-mortem, there’s also no evidence of a buildup of amyloid plaques.

As for the sleep-brain-cleaning thesis, that too runs into a snag with elephants: The creatures, on the whole, sleep very little. (Wild elephants may sleep as little as two hours a day, according to one study, though captive animals tend to sleep longer.) But in any case, if elephants are clearing any amyloid buildup during the course of their zzz’s, there isn’t much time to get it done.

One possible explanation is that elephant brains may have some other biological mechanism for keeping their neurons firing brightly through the decades.

But then, another theory isn’t mechanistic at all—rather, it goes to the heart of elephant life itself: They’re deeply social. The animals congregate for life in tight-knit extended family networks, one generation alongside another. Could that have something to with keeping aged brains humming?

As it turns out, there’s actually a fair amount of research to suggest it might. Several studies in humans have appeared to demonstrate that strong social connections reduce the risk of cognitive impairment in older adults—and that the opposite circumstance (social disengagement) makes mental deterioration worse.

Unfortunately, such evidence might offer one clue as to why Alzheimer’s deaths have been rising in this U.S., increasing 123% between the years 2000 and 2015. In the end, such a sad stat may reflect our frayed social fabric—and the lack intergenerational contact among families today—as much, perhaps, as it does some biological or chemical driver of the disease.

So while the BAPtists and TAUists and ATHIEsts debate the murky science among themselves, give your mom or dad, or aunt, or older neighbor a call this weekend and shoot the breeze. Who knows? You may end up doing more to fight Alzheimer’s than many pharma execs.