1. Introduction
Dementia is a progressive neurodegenerative disorder affecting individuals’ brain function, memory, and activities of daily living [
1]. The prevalence of dementia is expected to triple in the next 40 years, leading to an estimated 14 million people with dementia by 2060 [
2]. The Alzheimer’s Association estimates the total direct medical expenditures related to Alzheimer’s disease-related dementias (ADRD) will increase from
$236 billion in 2016 to over
$1 trillion in 2050 [
3].
Mild cognitive impairment (MCI) is defined as self- or informant-reported functional impairment or impaired test performance on neuropsychological measures that does not reach the severity of dementia [
4]. MCI can be a precursor of dementia [
5,
6], with over 30 percent of individuals diagnosed with MCI progressing to dementia within five years [
1]. MCI is estimated to affect 15–20 percent of older adults in the US [
1,
7,
8,
9]. While there are several subtypes of MCI with diverse etiology, there is still much debate regarding the pathogenesis of MCI and dementia [
5]. Previous research has identified several modifiable and immutable factors contributing to an individual’s risk for dementia and MCI including socio-demographics, comorbidities, family history, and lifestyle factors [
1,
5,
8,
10,
11,
12].
Growing evidence has linked sleep disturbances and insomnia to greater risk of MCI and dementia [
13,
14,
15,
16,
17,
18,
19,
20,
21,
22,
23,
24]. In particular, the association between insomnia, which includes difficulty falling asleep, awakening during the night, early-awakening without being able to fall asleep again, and non-restorative sleep [
25], and cognitive decline has received significant research attention. Results from several studies indicate that individuals with insomnia are more likely to have clinically significant alterations in attention and episodic memory and more likely to develop dementia [
26,
27,
28]. However, very little is known regarding the frequency or level of insomnia that would result in MCI and dementia. Published studies examining the associations between insomnia and MCI or dementia have predominantly assumed insomnia symptoms to be stagnant over time or have not considered the severity or type of insomnia symptoms [
14,
17,
29,
30,
31,
32]. These assumptions may be especially tenuous among older adult populations, as previous research shows that insomnia symptoms vary significantly over time and frequently increase as individuals get older [
28]. Further, research suggests that measuring insomnia at only one timepoint may lead to biased estimates of the associations with MCI and dementia, which may have important implications for public health and clinical approaches to addressing cognitive health [
31]. Thus, to understand the role of insomnia in the development of MCI and dementia, it is necessary to distinguish chronic insomnia disorder from presence of insomnia symptoms at a single point in time.
Given the limitations of previous analyses, this study examined the dynamic effect of changes in insomnia on cognitive decline and dementia over time. Our primary aim was to estimate the association between time-varying insomnia and MCI or dementia using a nationally representative cohort of US adults age 51 and older from 2002 to 2014. We hypothesized that time-varying insomnia symptoms would be associated with greater risk of incident MCI and dementia.
4. Discussion
Using a nationally representative sample of adults age 51 and older, this study found that time-varying insomnia severity was associated with a greater likelihood of developing MCI and dementia over time. In support of our hypothesis, over 12 years of follow-up, results suggested that for each additional insomnia symptom, there was a 5 percent greater hazard of incident MCI (HR = 1.05; 95% CI: 1.04–1.06) and dementia (HR = 1.05; 95% CI: 1.03–1.06), after adjusting for baseline gender, race, education, BMI, smoking status, drinking status, and chronic disease index.
Previous research regarding the associations between insomnia and MCI/dementia are mixed and sometimes contradictory. For instance, Hung et al. (2018) found that insomnia was associated with a 2.14 times greater dementia risk [
28]. Conversely, Lysen et al. (2018) found that sleep quality was not associated with incident dementia (HR: 0.91; 95% CI: 0.82–1.02) [
39]; however, these studies used different sleep measures and different study designs and did not account for time-varying insomnia symptoms, which may explain inconsistent results. Our findings are consistent with a positive association between insomnia and greater risk of incident cognitive decline and dementia. The degree of risk is similar to that found in a meta-analysis by Xu et al. (2020) [
23].
Differences between our study and previously conducted studies with different or null findings could be related to several methodologic and sample differences. Our study used a longitudinal study design with time-varying insomnia, while other studies have used cross-sectional [
23] or case-control [
28] study design or assessed insomnia only at baseline [
39]. Additionally, we considered insomnia symptoms on a continuous scale while other studies used clinical diagnosis [
28] or categorical insomnia definitions [
23]. Consistent with previous research, our results demonstrate that insomnia symptoms vary significantly over time [
40,
41]. The use of time-invariant insomnia symptoms in analysis may thus fail to distinguish the effects of chronic insomnia from more transient insomnia episodes, for instance due to illness or use of medications. Previous research shows that a significant proportion of people with transient insomnia might not develop chronic insomnia and the consequences of transient insomnia may be subtle [
42]. In contrast, chronic insomnia has been associated with a wide range of deleterious health consequences including an increased risk of hypertension, diabetes, obesity, depression, heart attack, and stroke, [
28,
43], which are also related to risk of cognitive decline and dementia. Information about the duration and changing severity of insomnia may thus provide more information about the cumulative effects of insomnia, both directly and indirectly, on cognition.
Several potential mechanisms have been proposed to explain how insomnia may increase risk of MCI and dementia. First, poor sleep—as defined by insomnia, sleep duration, sleep quality, intake of hypnotics, and sleep-disorder related to breathing—has been shown to be associated with neuronal degradation, structural changes of the brain and lower brain volumes [
44,
45]. A recent review by Joo (2015) found that insomnia may be associated with abnormal brain structures in the frontal cortex, hippocampus, and anterior cingulate cortex, areas important for memory, executive functions and other cognitive domains. These changes were due to a decrease in gray matter volumes in key regions associated with cognitive function [
44]. More specifically, the researchers found evidence of greater atrophy among those with insomnia compared to controls in the CA2-4-DG region of the hippocampus, which was associated with impairment in verbal information processing, verbal memory, verbal processing, and visual memory [
45]. Additional studies have found that insomnia symptoms in aging populations are independently associated with neuronal loss in the hippocampus [
46]. During healthy sleep, the human brain clears amyloid-beta (Aβ) peptide accumulated during wake phases via the glymphatic pathway [
47,
48]. Sleep disturbances may thus interrupt or hamper this process resulting in an accumulation of Aβ in the brain, a hallmark of AD pathogenesis [
49]. Alternatively, some research suggests that there may be a bidirectional association between sleep disturbances, MCI and dementia [
49,
50,
51]. This bidirectional association may suggest that preclinical MCI or dementia may be influencing the development of insomnia followed by the development of detectable cognitive problems. Further, several modifiable and immutable factors, such as socio-demographics, comorbidities, family history, and lifestyle factors, are associated with insomnia, and over time, can lead to cognitive problems, including dementia and MCI [
1,
5,
8,
10,
11,
12].
The current study has many strengths, including a large sample size, 12-year follow-up, and use of a representative sample of adults age 51 and over in the United States; however, there are some limitations to note. First, insomnia symptoms were self-reported from the BIQ questionnaire and were compiled into an unweighted linear symptom index assuming equal weighting of all symptoms. Additionally, we were unable to confirm a clinical diagnosis of insomnia. Second, both outcome variables relied on cognitive and neuropsychological tests. Using imaging methods and/or clinical diagnosis of MCI and dementia could have led to different estimates of the association with insomnia. Last, this study did not differentiate between types of dementias which and cannot be interpreted in the light of specific forms of dementia, just an overall assessment. Future research should focus on understanding how time-varying insomnia is differentially associated with MCI and dementia compared to baseline or time-invariant insomnia. Additionally, it should be understood whether time-variant insomnia is associated with structural brain changes similar to those found in previous research.