GREATER RISK OF ALZHEIMER'S DISEASE IN OLDER ADULTS WITH INSOMNIA
To the Editor: Physiological changes in the continuity, architecture, and circadian timing of sleep accompany aging, the best-known risk factor for Alzheimer's disease (AD).1 In older adults, dementia is also typically associated with sleep disorders. Epidemiological evidence shows an association between sleep disorders and AD. In two longitudinal follow-up studies, subjects with insomnia were more likely than those without to have a diagnosis of AD or cognitive decline at follow-up2, 3 (Table 1). Two similar studies reported that prolonged sleep duration4 and excessive daytime sleepiness5 were also associated with risk of developing cognitive decline, although negative studies have also been published,5, 6 indicating that the relationship between sleep and risk for later development of AD is unclear. The current study assessed the relationship between insomnia and AD in 346 cognitively normal older adults evaluated during multiple visits over 7.7 years of follow-up. Participants were drawn from a larger pool of 655 normal volunteers (aged 24–96) participating in brain aging studies at New York University's Alzheimer's Disease Research Center. People selected for study had had a minimum of three examinations, with at least two during the normal stages of cognition. All participants were classified into two groups: the normal-AD group (n=25), who subsequently declined to AD, and the normal-normal group (n=321) who remained cognitively stable during all the evaluations. Insomnia was collected only during the normal cognition stage and screened using items 4, 5, and 6 from the Hamilton Depression Rating Scale (HAM-D).7 Number of follow-up visits was different between the normal-AD and the normal-normal groups, so a new average longitudinal score for insomnia was calculated as the sum of all the insomnia HAM-D scores divided by the number of follow-up visits. Subjects were considered to be depressed if they had a score of 10 or greater on the HAM-D or were diagnosed with major depression at any evaluation during the follow-up period. The inflection point of the receiver operating characteristic curve was used to define a cutoff value for the presence or absence of insomnia (with this value, 92.5% of the patients with “insomnia” had a score >1 on the HAM-D insomnia items in more than one follow-up). Odds ratios were obtained using chi-square analysis of the groups with respect to the presence or absence of insomnia. Survival analysis was used to compare risk of faster disease progression in the normal-AD group with insomnia with that in those with normal sleep. Demographic characteristic are summarized in Table 2. The two groups did not differ in age, sex, Mini-Mental State Examination (MMSE) score at baseline, and apolipoprotein E ε4 (ApoE4) status but were different in education. Presence or absence of insomnia was significantly associated with AD (odds ratio (OR)=2.39, 95% confidence interval (CI)=1.03–5.55). Depression did not confound the association, as excluding patients with depression increased the relationship (OR=3.32, 95% CI=1.33–8.28). Normal-AD patients with insomnia showed a faster progression to dementia (chi-square=3.94, P=.047). This study documents an association between insomnia assessed during a long follow-up period and incident cases of AD. Depressed mood, age, sex, MMSE score, and Apo E4 did not confound the association. This study had a number of potential limitations. First, the analysis was adjusted for a number of important confounders, but the effect of daytime sleepiness or sleep apnea cannot be excluded as they were not formally analyzed during the evaluation. Second, insomnia was captured through the insomnia HAM-D questions, with a cutoff value that was established post hoc and not validated against clinical criteria. Third, the study did not include sleep examinations or objective methods of measuring sleep such as polysomnography to document the extent of the sleep restriction or to exclude other sleep disorders. Fourth, the study was based on post hoc analysis of a large clinical sample, and the number of patients that developed AD was small. The strengths of this study include uniform assessments, long-term follow-up, strict criteria for defining the outcome groups, and unbiased evaluation of insomnia, as the variable of interest was not the original reason for the data to be collected. This is the second report about insomnia associated with incident AD. Sleep and wake changes that occur during normal aging could increase the risk of cognitive decline after a certain age by increasing Aβ production,8 and this risk could be greater in older subjects with chronic insomnia.9 Excessive daytime sleepiness has also been related to AD.4 This could portray hypersomnia as an early symptom of AD in a similar way that some depressive symptoms may be early manifestations of dementia. Alternatively, insomnia could be a risk factor for AD similar to lifetime recurrent major depression. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. This study was supported by National Institutes of Health (NIH), National Institute on Aging Grants AG13616, AG12101, AG08051, and AG022374; NIH, National Center for Research Resources Grant MO1RR0096; a grant from the Alzheimer's Disease Research Unit; CIEN Foundation—Carlos III Institute of Health; Alzheimer Center Reina Sofia Foundation, Madrid, Spain; and the Alzheimer's Association. Author Contributions: Ricardo S. Osorio: study concept and design, acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript. Elizabeth Pirraglia: acquisition of subjects and/or data, analysis and interpretation of data. Luis F. Agüera-Ortiz and Pablo Martínez-Martín: study concept and design, preparation of manuscript. Emmanuel H. During: analysis and interpretation of data, preparation of manuscript. Hayley Sacks: acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript. Indu Ayappa, Joyce Walsleben, and Anne Mooney: study concept and design. Asad Hussain and Blas Frangione: analysis and interpretation of data. Lidia Glodzik: analysis and interpretation of data, preparation of manuscript. Mony J. de Leon: study concept and design, analysis and interpretation of data, preparation of manuscript. Sponsor's Role: None.