Table 3 Non-pharmacological sleep interventions in clinical trials for Alzheimer’s disease

Auditory and Light Stimulation/Therapy (inc. GENUS device, Neuro RX Gamma, acoustic stimulation; see Fig. 4)

Entrainment of gamma oscillations (40 Hz visual + auditory stimulation) has been linked to reducing Aβ and tau in AD models [342, 343]; reviewed in [344]. Optogenetic stimulation of parvalbumin inhibitory interneurons leads to a ~ 50% reduction of Aβ in 5xFAD mice, with increased microglial response and uptake [342]. Although a direct linkage to mechanisms of proteostasis is not described, a linkage between neuronal circuitry, in particular GABAergic inhibition, and clearance of Aβ and tau is indicated

21 (11)

Results available—NCT00946530; NCT03160027; NCT03357328^a

NCT03484143; NCT04055376^b; NCT00065689; NCT04073628^b; NCT02502045; NCT03328195; NCT03672474; NCT03777722^b; NCT03933696^b; NCT04574921; NCT02686190; NCT04277104^b; NCT05519137^b; NCT05016219^b; NCT05655195^b; NCT05260177^b; NCT05596994^b; ^bNCT05015478^b

Behavioral (inc. CBT-I, sleep education; see Fig. 4)

Therapy has no direct interaction with proteostasis; however, improvements of proteostasis via behavioral changes would strengthen the sleep-proteostasis linkage. Difficult to model pre-clinically

21 (13)

Results available—NCT04533815; NCT00013182; NCT00183378 –

No results—NCT03455569; NCT04100057^b; NCT03954210^b; NCT04779866^b; NCT03840083^a,b; NCT00393627^a; ^bNCT03256539^b; NCT01920672; NCT05309577^b; NCT05452031^b; NCT05565833^b; NCT05102565^b; NCT05138848^b; NCT05555381^a,b; NCT05015803^b; NCT05246332; NCT05050812^a,b; NCT05350410

Brain Stimulation (inc. rTMS, tDCS, DREEM headband)

Broadly, neuronal stimulation can mitigate electrophysiological dysfunction and excitatory-inhibitory imbalance that occurs in AD [345]. On top of promoting cognition and sleep, depending on the targeted brain regions/networks, balancing circuits in AD may reduce neuronal activity-mediated Aβ and tau spread

10 (5)

Results available—NCT01894620

No results—NCT04122001^b; NCT04570761; NCT03270137; NCT04855630^b; NCT03670615; NCT05544201^b; NCT05102045; NCT05200897^b; NCT05715866

CPAP (and related devices; 6); upper airway sleep surgery (1); HBOT (1)

Therapy has no direct interaction with proteostasis; improved sleep quality theoretically would improve proteostasis mechanisms in AD patients

8 (4)

Results available—^aNCT01482351; NCT01962779

No results—NCT04905238^b; NCT03929302; NCT02474251; NCT05094271^b; ^a,bNCT05433883 (surgery); NCT05349318^b (HBOT)

Music Therapy (see Fig. 4)

Therapy has no direct interaction with proteostasis; improved sleep quality theoretically would improve proteostasis mechanisms in AD patients

4 (1)

Results available—NCT04157244

No results—NCT04809545^a; NCT04327778; NCT05309369^b