Insomnia in Alzheimer’s Disease

Alzheimer's disease is one of the most common causes of dementia, impacting a significant percentage of those over 65 years of age. Sleep disruption has been established to be a fairly prevalent occurrence affecting those with the neurodegenerative condition, with potential negative resultant impact on health, quality of life, cognition, and caretaker dynamics. Emerging data have suggested lack of sleep as being a possible contributor to the development of Alzheimer’s disease pathology, placing insomnia as a prospective target to positively impact underlying disease progression. Diagnosis and treatment of insomnia can be a challenge in general, with even more complexities occurring in the population of Alzheimer's disease. Treatment data is overall limited. However, multiple non-pharmacological and pharmacological interventions are available for consideration for management. 

Insomnia, defined as difficulty falling or staying asleep along with resulting daytime consequences, is a common but complex sleep disorder with an often interactive influence from biological, psychological, and social factors. In the setting of Alzheimer’s Disease (AD), sleep can be even further disrupted due to disease-associated burdens originating from these potentially contributing realms. Neuronal architecture changes provoked by accumulation of neurofibrillary tangles forming from misfolded β-amyloid (Aβ) and hyperphosphorylated tau proteins can alter sleep-related biological structures and pathways. Deteriorating social cues and changes in living situations can weaken circadian entrainment, affect sleep hygiene, and worsen mood state, all negatively impacting ability to sleep. An increased occurrence of comorbid sleep disorders and medical conditions with age and AD [1] can further make the already challenging task of managing insomnia even more formidable. 

Adequate quantity and quality of sleep are integral for physical and mental health [2]. Sleep disruption has been demonstrated to worsen cognitive function, increase the risk of other adverse health outcomes, such as cardiovascular disease, and negatively impact quality of life [3], which are already areas of concern with aging in general, and reserving even more salient apprehension in the setting of AD. Additionally, there is a growing conclave of evidence suggesting that poor sleep quality can further exacerbate the underlying disease process contributing to AD itself [4-6], making treatment of sleep disruption in this population even more paramount.

Diagnosis and monitoring of treatment response in cases of insomnia and AD can be more complicated than in the general population due to the subjective nature of symptoms, with perception of sleep disruption at times being compromised in the setting of dementia [7]. This has impact on both clinical and research outcomes. Objective measures can be difficult to ascertain, with surrogate markers of sleep disruption via tools such as actigraphy often being employed. Caretaker input during history can be valuable, with evaluation of the impact of patient symptoms on caretaker relationship potentially included in the discussion. 

Initial therapy for insomnia involves non-pharmacological strategies. Sleep hygiene and lifestyle factors should be addressed, along with identifying and treating other sleep and medical comorbidities contributing to sleep disruption [8,9]. The preeminent treatment for insomnia is Cognitive Behavioral Therapy for Insomnia (CBT-I), based on evidence supported long–term efficacy and generally innocuous adverse effect profile [10]. This likely holds true as well in people with AD [11], although cognitive function may at times limit effectiveness. Other non-pharmacological interventions such as bright light therapy have shown some potential in providing a positive response to symptoms in some studies [12]. 

In treating insomnia, certain clinical scenarios may arise which warrant consideration for pharmacological measures. Due to the additional challenges inherent to sleep disruption in AD, this may be a realistic situation, although prescribing approaches also require a higher degree of precaution in regard to adverse effects in this population. Several agents have historical clinical use, including melatonin, tricyclic antidepressants, nonbenzodiazepine receptor site-specific γ-aminobutyric acid agonists, herbal and over-the-counter substances, but with limited quality evidence supporting usage for insomnia in the general population, and with even less data available regarding patients with AD [13]. Newer medications in the dual orexin receptor agonists (DORAs) class have a few clinical trials supporting some utility [14,15], with agent suvorexant being FDA approved for insomnia in mild-to-moderate AD, although further supporting data would provide enhanced confidence and guidance of use. 

Sleep disruption in AD remains a complex but pertinent issue. It presents an opportunity to improve quality of life for both patient and caretaker, conceivably improve overall health and cognitive function, and potentially even reduce progression of underlying disease pathology. In the general population, insomnia’s contributing etiologies and treatment approaches can be intricate, with AD providing further possible compounding factors to consider. Treatment of insomnia in AD should focus on non-pharmacological interventions as the mainstay, however, several pharmacological agents are at clinicians’ disposable if needed for adjunctive therapy, or if behavioral interventions are not feasible or are limited in efficacy due to dementia or other disease-related impacting factors. Therapeutic strategies should be individualized to particular patient scenarios, with close monitoring of effects of interventions. Further research and evidence bolstered by quality randomized placebo-controlled studies are needed to better direct management and assist in advancing the ability to improve sleep in AD.

1. Borges CR, Poyares D, Piovezan R, Nitrini R, Brucki S (2019) Alzheimer's disease and sleep disturbances: a review. Arq Neuropsiquiatr 77: 815-824.
2. Ramar K, Malhotra RK, Carden KA (2021) Sleep is essential to health: an American Academy of Sleep Medicine position statement. J Clin Sleep Med 17: 2115-2119.
3. Medicine IO (2006) Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. In: Colten HR, Altevogt BM (eds.). Institute of Medicine (US) Committee on Sleep Medicine and Research. The National Academies Press, Washington, USA.
4. Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA (2013) Sleep Fragmentation and the Risk of Incident Alzheimer's Disease and Cognitive Decline in Older Persons. Sleep 36: 1027-1032.
5. Sprecher KE, Koscik RL, Carlsson CM, Zetterberg H, Blennow K, et al. (2017) Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults. Neurology 89: 445-453.
6. Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, et al. (2013) Sleep quality and preclinical Alzheimer disease. JAMA Neurol 70: 587-593.
7. Oliveira FF, Bertolucci PHF, Chen ES, Smith MACS (2014) Assessment of sleep satisfaction in patients with dementia due to Alzheimer's disease. J Clin Neurosci 21: 2112-2117.
8. Shub D, Darvishi R, Kunik ME (2009) Non-pharmacologic treatment of insomnia in persons with dementia. Geriatrics 64: 22-26.
9. Derex LP, Yammine P, Bastuji H, Croisile B (2015) Sleep and Alzheimer's disease. Sleep Med Rev 19: 29-38.
10. Mitchell MD, Gehrman P, Perlis M, Umscheid CA (2012) Comparative effectiveness of cognitive behavioral therapy for insomnia: a systematic review. BMC Fam Pract 13: 40.
11. Eagle EC, Siebern A, Unti L, Glassman J, Hara RO (2018) Neuropsychological Functioning in Older Adults with Mild Cognitive Impairment and Insomnia Randomized to CBT-I or Control Group. Clin Gerontol 41: 136-144.
12. Maanen A, Meijer AM, Heijden KB, Oort FJ (2016) The effects of light therapy on sleep problems: A systematic review and meta-analysis. Sleep Med Rev 29: 52-62.
13. Roland JP, Bliwise DL (2021) Impact of Pharmacotherapy on Insomnia in Patients with Alzheimer's Disease. Drugs Aging.
14. Herring WJ, Ceesay P, Snyder E, Bliwise D, Budd K, et al. (2020) Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial. Alzheimers Dement 16: 541-551.
15. Moline M, Thein S, Bsharat M, Rabbee N, Waliczky MK, et al. (2021) Safety and Efficacy of Lemborexant in Patients With Irregular Sleep-Wake Rhythm Disorder and Alzheimer's Disease Dementia: Results From a Phase 2 Randomized Clinical Trial. J Prev Alzheimers Dis 8: 7-18.