One of the faster brain rhythms is called gamma activity. Gamma rhythms involve specific groups of brain cells firing synchronously very rapidly, around 30 to 80 times per second (Hz), and play an important role in coordinating activity between brain regions during thinking and learning. In Alzheimer’s disease, this fast rhythmic activity tends to be weaker and less well coordinated, reflecting a breakdown in how brain networks work together.
Importantly, these oscillations are flexible and can be nudged into syncing with external rhythms, a process known as neural entrainment. This is similar to how your body naturally starts moving in time with music. Rhythmic sounds or lights can encourage the brain to align its activity to the same pattern.
Over the past decade, animal studies have shown that repeatedly stimulating the brain at gamma-range frequencies, particularly around 40 Hz (cycles per second), can lead to striking neurobiological changes, including reductions in Alzheimer’s-related brain pathology and improvements in memory. These findings have fuelled interest in whether simple, non-invasive sensory stimulation, such as sound, might one day support brain function in people with Alzheimer’s disease.
Translating this work to humans, however, has so far been more complicated. Clinical studies of sensory gamma stimulation show mixed results, with modest benefits in some cases and little effect in others. One likely explanation to explain the differences between human and animal studies is that people do not respond to neuromodulation uniformly. Simply put, it is more challenging to control or individual differences in human studies: age, sex, baseline brain activity and disease severity all influence how easily the brain can synchronise to external rhythms, yet these factors are rarely examined directly.
Most studies focus on average group effects, masking potentially important individual differences. As a result, we still lack clarity on who responds to gamma stimulation, and under what conditions.
Our recently published systematic review addresses this gap by examining how individual and group characteristics shape responses to auditory gamma stimulation, in both healthy individuals and populations with cognitive decline or differences. Understanding this variability is essential if sensory stimulation is to advance to a realistic, evidence-based intervention for Alzheimer’s disease.
We screened 1,310 records and assessed 336 full texts for eligibility. In total, 76 studies met inclusion criteria, of which 62 formed the main evidence base, encompassing data from 2,179 participants across a wide age range (three months to 75 years) and a mix of observational, experimental, longitudinal and clinical trial designs. Fourteen additional studies were identified as ongoing or available only as abstracts, highlighting how rapidly the field is still evolving.
To date, no clinical trial has yet demonstrated that sound-based gamma stimulation clears the build-up of amyloid plaques related to Alzheimer’s disease in humans. This so far contrasts with findings from animal models. That said, the absence of amyloid clearance does not mean the approach lacks promise.
Across the 62 studies included in the main synthesis, auditory gamma stimulation consistently influenced brain activity. While amyloid levels remained unchanged, several trials reported modest improvements or stabilisation in outcomes that matter to people living with cognitive decline, including aspects of memory, daily functioning, sleep quality, brain connectivity and rates of brain atrophy. These effects were not universal but they were observed often enough, across sufficiently diverse samples, to justify continued investigation.
So why are the results so mixed? A major issue is that the field has no shared definition of what it means to successfully ‘entrain’ the brain. Across the studies we reviewed, researchers used 32 different neurophysiological measures to quantify gamma entrainment. Some focused on power, others on amplitude, phase synchronisation or coherence, often interchangeably. When different studies measure different things and treat them as equivalent measures of entrainment, meaningful comparison becomes challenging.
This methodological variability also obscures an important and consistent pattern across the literature: people do not respond to rhythmic sound in the same way. Across the more than two thousand participants studied, age, sex, baseline brain activity, brain structure, attention and disease stage all influenced how strongly the brain synchronised to external rhythms. However, a critical point is that almost no study found that entrainment could not be achieved at all, rather, it varied between individuals and groups.
Another key finding from the review is that 40 Hz stimulation may not be the best option for everyone. Although it is widely used, studies that tested a range of frequencies often found stronger brain responses at slightly higher or lower gamma frequencies, and the most effective frequency can differ between individuals (37–48 Hz). This likely reflects the greater complexity of the human brain and helps explain why results from animal studies do not always neatly translate to humans.
Taken together, the findings of this review suggest that auditory gamma stimulation is a plausible and promising approach, but one that requires greater precision in how it is studied and applied. Variability in clinical outcomes could reflect differences in measurement, stimulation parameters and individual neurobiology, rather than a lack of neural responsiveness to rhythmic sound. Across studies, neural entrainment is consistently observed, although its strength and optimal frequency vary between individuals.
These results indicate that the next phase of research should move beyond one-size-fits-all protocols and focus instead on clarifying what changes in brain activity are being induced, how these relate to cognitive and clinical outcomes, and for whom stimulation is most effective. Addressing these questions will be critical for translating sound-based gamma stimulation into clinically meaningful, personalised and patient-centred interventions for Alzheimer’s disease and other neurodegenerative conditions.