I n early 2018, two high-profile clinical trials of drugs for Alzheimer's disease ended in disappointment. The drugs joined a long list of potential treatments that have failed to deliver significant benefits in people. Their development was guided by an idea that has dominated research on Alzheimer's disease for more than 25 years: the amyloid hypothesis, which is the assumption that accumulation of the peptide amyloid-β is the main cause of the condition. Researchers proposed that when amyloid-β clumps together to form deposits in the brain, it triggers neurodegenerative processes that lead to the loss of memory and cognitive ability that is observed in Alzheimer's disease. Amyloid-β is therefore an obvious therapeutic target-if you can deal with the peptide, then you can treat the condition. The amyloid hypothesis has never been universally accepted, and the failed drug trials have only emboldened its critics. "It's led to a mixture of some careful thinking and recriminations about whether the right things have been done, " says John Hardy, a neurogeneticist at University College London, and a pioneer of the hypothesis. He and many other researchers remain undeterred, however. "We're all disappointed, but there are concrete reasons why each failure occurred, " says Dennis Selkoe, a neurologist at Harvard Medical School in Boston, Massachusetts. These might be as simple as the drugs being administered too late With the continued failure of potential drugs for Alzheimer's disease, is it time to look beyond amyloid-β as the root cause of the condition?

This study asks whether perceptual mechanisms that compensate for the spectral-envelope distortion of transmission channels also contribute to compensation for speaker differences. Subjects identified test words that were played after a carrier sentence. In some conditions the carriers were synthesized with F1 in low- and high-frequency ranges and in others they were distorted by filters whose frequency response is the spectral envelope of one vowel minus the spectral envelope of another. The filter /I/ minus /epsilon/ and its inverse were used. Test words were drawn from an /Itch/ to /epsilon tch/ continuum. Carriers filtered by /I/ minus /epsilon/ and its inverse give a phoneme boundary difference, indicating compensation for spectral envelope distortion. A phoneme boundary difference also occurs between carriers with F1 in low and high ranges, indicating compensation for speaker differences. Neither of these effects is reduced by playing the carrier backwards, even though a measurement of the perceived naturalness of carriers is sharply reduced by this manipulation. Analysis of carriers synthesized with low and high F1 showed that they have different long-term spectra, and subsequent experiments used time-stationary filters to alter this characteristic. The results showed that the long-term spectra of the carriers govern their influence on the identity of subsequent test sounds. However, measurements of perceptual confusions among the carriers and of perceived talker-differences between carriers revealed that other, time-varying factors are more important for voice identification.

When speech is in competition with interfering sources in rooms, monaural indicators of intelligibility fail to take account of the listener's abilities to separate target speech from interfering sounds using the binaural system. In order to incorporate these segregation abilities and their susceptibility to reverberation, Lavandier and Culling [J. Acoust. Soc. Am. 127, 387-399 (2010)] proposed a model which combines effects of better-ear listening and binaural unmasking. A computationally efficient version of this model is evaluated here under more realistic conditions that include head shadow, multiple stationary noise sources, and real-room acoustics. Three experiments are presented in which speech reception thresholds were measured in the presence of one to three interferers using real-room listening over headphones, simulated by convolving anechoic stimuli with binaural room impulse-responses measured with dummy-head transducers in five rooms. Without fitting any parameter of the model, there was close correspondence between measured and predicted differences in threshold across all tested conditions. The model's components of better-ear listening and binaural unmasking were validated both in isolation and in combination. The computational efficiency of this prediction method allows the generation of complex "intelligibility maps" from room designs.

Features in a sound's spectral envelope are important for perceptual identification but they are likely to be accompanied by spurious features due to distortion by the transmission channel between source and listener. Previous experiments have demonstrated that there is perceptual compensation for this distortion, and the present experiments ask whether the compensation involves a separation of spurious and salient features. Listeners identified words containing a vowel test sound in an /aept/ to /ppt/ continuum, with a carrier phrase before each word. Effects of transmission channels were simulated by filtering the carrier and the /pt/ following the test sound. Filters were pairs with frequency responses that were the difference of the spectral envelopes from the end-point vowels. Contrasts were altered by multiplying decibel values of the carrier filter's frequency response or the test sound's spectral envelope by a positive number. This keeps features such as peaks at the same frequencies but changes the difference in level between peaks and valleys. When the contrasts of the carrier filters and test sound were the same, the continuum's phoneme boundary was shifted in a manner consistent with a perceptual compensation for the filters that affects the neighboring test sound. However, this shift decreased when the carrier-filter's contrast was less than that of the test sound, and increased slightly when the test-sound's contrast was less than the carrier-filter's contrast. Therefore, the amount of compensation increases with the amount of distortion, even when spectral features such as peaks are kept at the same frequencies. So compensation seems to occur before any perceptual extraction of these features.

Three experiments measured constancy in speech perception, using natural-speech messages or noise-band vocoder versions of them. The eight vocoder-bands had equally log-spaced center-frequencies and the shapes of corresponding "auditory" filters. Consequently, the bands had the temporal envelopes that arise in these auditory filters when the speech is played. The "sir" or "stir" test-words were distinguished by degrees of amplitude modulation, and played in the context; "next you'll get _ to click on." Listeners identified test-words appropriately, even in the vocoder conditions where the speech had a "noise-like" quality. Constancy was assessed by comparing the identification of test-words with low or high levels of room reflections across conditions where the context had either a low or a high level of reflections. Constancy was obtained with both the natural and the vocoded speech, indicating that the effect arises through temporal-envelope processing. Two further experiments assessed perceptual weighting of the different bands, both in the test word and in the context. The resulting weighting functions both increase monotonically with frequency, following the spectral characteristics of the test-word's [s]. It is suggested that these two weighting functions are similar because they both come about through the perceptual grouping of the test-word's bands.