PNAS | 非侵入治療AD新線索：40Hz聽覺刺激的長期效應

基本信息

Title:Long-term effects of forty-hertz auditory stimulation as a treatment of Alzheimer’s disease: Insights from an aged monkey model study

發表時間：2026.1.5

Journal:PNAS

影響因子：9.1

引言

阿爾茨海默病（Alzheimer’s disease, AD）最讓人無力的地方，不是“記不住”，而是它會把學習與記憶這些最核心的能力一點點磨掉。過去幾年，靶向淀粉樣蛋白β（amyloid-beta, Aβ）的一些單克隆抗體藥物進入臨床并獲批，但整體療效多為“減速”而非“逆轉”，同時還伴隨腦水腫、出血等安全性問題，讓“更溫和、更可長期使用”的方案顯得格外迫切。

于是，一個看起來有點“反直覺”的思路逐漸走紅：不靠藥物，而用40 Hz的節律性刺激去“帶節奏”大腦。40 Hz對應腦電的γ振蕩（gamma oscillations），而γ振蕩在AD患者與模型動物中往往減弱。嚙齒動物研究提示，40 Hz的光/聲刺激可能降低Aβ負擔、改善相關病理，并可能通過類淋巴系統（glymphatic system）促進代謝廢物清除。

但問題也很現實：小鼠并不會自然發生AD，模型多依賴家族性突變；更關鍵的是，嚙齒類與人類在腦結構與腦脊液循環等方面差異明顯，導致“鼠有效、人無效”的翻譯失敗屢見不鮮。

因此，在真正走向臨床前，必須在更接近人類的非人靈長類（nonhuman primates）中做關鍵驗證。本研究抓住罕見機會，直接在26–31歲的老年恒河猴（rhesus monkeys）上開展40 Hz聽覺刺激，并以腦脊液（cerebrospinal fluid, CSF）中的Aβ與Tau作為“臨床同款”生物標志物讀數，去回答一個核心問題：40 Hz聲音刺激到底能否、以及能在多長時間尺度上調動老年靈長類大腦的Aβ/Tau代謝？

實驗設計與方法邏輯

作者將9只老年恒河猴隨機分為三組：40 Hz聽覺刺激組、隨機節律刺激組與無聲音處理對照組，通過“同樣操作、不同刺激”把聲音節律本身的特異效應從操作與環境因素中剝離；每輪刺激為連續7天、每天1小時，關鍵時間點多次腰穿采集CSF，用超敏單分子陣列（single molecule array, Simoa）檢測Aβ42、Aβ40、總Tau（t-Tau）與磷酸化Tau（p-Tau181），并在部分個體終點進行免疫組化（6E10標記Aβ斑塊、AT180標記磷酸化Tau）驗證腦內病理基礎，從而把“體液變化—時間維持—組織證據”串成閉環。

核心發現

40 Hz聽覺刺激可快速提升CSF Aβ：連續7天、每天1小時的40 Hz聲音刺激，使腦脊液Aβ42與Aβ40升至約2倍；隨機節律或無聲音對照均無此變化。

效應具有長時程“尾效應”：停止刺激后，CSF Aβ升高仍可持續5周以上（至49天）。

Tau通路未見顯著響應：CSF總Tau（t-Tau）與磷酸化Tau（p-Tau181）在各組、各時間點均無顯著改變。

組織學解釋一致：老年猴腦內Aβ斑塊普遍存在，而磷酸化Tau沉積缺失或極輕，與體液結果相吻合。

歸納總結和點評

這項工作最硬核的價值在于“把40 Hz從小鼠推到靈長類”，為“非侵入、可長期管理”的AD干預提供了難得的靈長類證據與可檢驗的機制假說，屬于向臨床可轉化邁出的關鍵一步。

核心圖表

Fig. 1. Experimental design and the effects of 40-Hz [Group (a)], random [Group (b)] or no auditory stimulation [Group (c)] on CSF Aβ42 and Aβ40 concentrations in aged monkeys.

Fig. 2. Long-term effects of 40-Hz stimulation on CSF Aβ42 and Aβ40 levels of aged monkeys.

Fig. 3. The effects of 40-Hz [Group (a)], random [Group (b)] or no [Group (c)] auditory stimulation on CSF concentrations of t-Tau and p-Tau 181 in aged monkeys.

Fig. 4. Representative images of Aβ pathology stained by 6E10 in TC of four aged monkeys.

Fig. 5. Representative images of Tau pathology stained by AT180 in TC of four aged monkeys.

Abstract

Based mainly on rodents studies, forty-hertz (40-Hz) physical stimulation has been regarded as a potential noninvasive treatment for Alzheimer’s disease (AD). Considering the brain differences between rodents and humans, the effects of 40-Hz physical stimulation need to be further validated using nonhuman primates before its clinical application. Here, we took advantage of a rare opportunity to expose nine aged rhesus monkeys (26 to 31 y old) to 40-Hz auditory stimulation. Given the strong correlation between cerebrospinal fluid (CSF) Aβ and Tau concentrations and corresponding AD pathology in brain parenchyma in clinical practice, we investigated the effects of 40-Hz stimulation on AD pathology by monitoring changes in CSF Aβ and Tau concentrations. Our results revealed that 7 consecutive days of 40-Hz auditory stimulation triggered a rapid and significant increase of Aβ levels by more than 200%, but no effect on Tau levels in the CSF. Additionally, we observed that the elevation of CSF Aβ levels persisted for more than 5 wk after cessation, which had not been reported in any previous studies. After this, a pathological examination of the temporal cortices of 4 of the experimental monkeys was carried out and the data demonstrated that all of them had prevalent extracellular Aβ senile plaque pathology, whereas Tau pathology was negative or very weak. These results provide a good explanation for the differences between the CSF Aβ and Tau protein levels. Together, these first-time results from monkeys suggest that 40-Hz auditory stimulation has strong potential of a noninvasive AD treatment method.