Home-Based Gamma tACS in Alzheimer Disease: the question, the experiment, and why it answers — a commentary on Cantoni, Casula, Tarantino et al. (JAMA Network Open, 2025)

1) The scientific question (and our positive critique)

The central question is clear and well-posed: “Is gamma–tACS over the precuneus safe, feasible, and clinically effective in a home-based setting for prodromal or mild Alzheimer disease?”

We like this question for two reasons:

1. it is clinical and operational (home-based, scalable), and

2. it forces the study to show biological engagement, not only changes on cognitive tests.

Home-Based Gamma Transcranial Alternating Current Stimulation in Patients With Alzheimer Disease

2) The experiment (how they force an answer)

To answer it, the authors designed a double-blind, randomized, sham-controlled trial, followed by an open-label extension:

• n = 50 with prodromal or mild AD, randomized to home-based gamma tACS vs sham for 8 weeks (5 sessions/week, 60 min).

• Then everyone received gamma tACS for an additional 8 weeks (open-label), followed by an 8-week follow-up.

• Outcomes included: safety/adherence, clinical efficacy (CDR-SB, ADAS-Cog-13, ADCS-ADL, FNAT), plus “biology” via EEG (gamma power), TMS-SAI as an indirect marker of cholinergic function, plasma biomarkers, and MRI connectivity (subgroup).

3) Why this experiment answers the question (causal logic)

We see strong causal coherence across three layers:

1. If the question is “does it work at home?”, the study measures real-world feasibility: high adherence, low caregiver burden, and tolerability. This directly answers the “home-based” requirement.

2. If the question is “is it clinically effective?”, they use measures that capture global severity, cognition, daily function, and associative memory. In the randomized phase, the tACS group improved on these measures compared with sham.

3. If the question is “is this placebo or true brain engagement?”, they build a biological bridge:

• increased gamma power on EEG after tACS, and

• changes in SAI (TMS) consistent with improved cholinergic-related function, not seen with sham.
  That makes the clinical effects more interpretable than an RCT based only on cognitive outcomes.

4) BrainLatam reading — APUS (extended proprioception)

We interpret “gamma” here as an attempt to restore coordination rhythms—a way for the body to regain organizational fluency to operate tasks (even when the outcomes are cognitive).
Even without direct movement measures, targeting the precuneus (a network hub) is a way to influence the “map” that supports orientation, integration, and internal coherence.

5) BrainLatam reading — Tekoha (extended interoception)

We value the use of SAI as a bridge to the cholinergic hypothesis: Alzheimer disease is not only “mental memory,” it is internal regulation of networks. When the study shows shifts in SAI alongside functional gains, we read this as a signal that the system attempted to recover regulatory capacity, not merely “train performance.”

6) Positive critique (limits that open the next step)

• The open-label phase improves access and feasibility, but it reduces contrast later; the plateau in those already treated may reflect a ceiling effect or the need for different parameters.

• The lack of change in plasma biomarkers suggests the effect may be more functional/system-level than disease-modifying within 8–16 weeks—useful for setting expectations.

• A key open problem remains: who responds best (phenotypes, genetics, stage, baseline network state), and what is the dominant mechanism (entrainment vs cholinergic modulation vs both).

7) BrainLatam translation to the organic world

BrainLatam translation to the organic world: we understand this study as evidence that neuromodulation can be feasible at home and still produce signals of brain engagement (EEG/TMS) together with measurable clinical improvement. The value is a pathway where “improvement” comes with “the body showed it changed.”

8) Open BrainLatam question

If the goal is sustainable treatment, what is the minimal marker that lets us adjust dose/duration in real time (gamma EEG? SAI? cognitive profile?)—and, most importantly, predict response before 8 weeks?

The body does not need belief to function.
It needs space, movement, and regulation.

‌Cantoni, V., Casula, E. P., Tarantino, B., Chiara Cupidi, Huber, N., Altomare, D., Enrico Premi, Zummo, E., Esposito, R., Leonardi, C., Sanna-Kaisa Herukka, Eino Solje, Ferrari, A., Cotelli, M. S., Gasparotti, R., Martorana, A., Fracassi, C., Emiliano Santarnecchi, Koch, G., & Annakaisa Haapasalo. (2025). Home-Based Gamma Transcranial Alternating Current Stimulation in Patients With Alzheimer Disease. JAMA Network Open, 8(12), e2546556–e2546556. https://doi.org/10.1001/jamanetworkopen.2025.46556