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Published in final edited form as:

J Alzheimers Dis. 2023 ; 92(4): 1427–1438. doi:10.3233/JAD-221244.

Sleep Disturbances Predict Cognitive Decline in Cognitively

Healthy Adults
Ifrah Zawara,1,*, Meghan K. Mattosb,c,1, Carol Manningd, James Patriee, Mark Quigga,f
aDepartment of Neurology, Comprehensive Epilepsy Program, University of Virginia,
Charlottesville, VA, USA
bSchool of Nursing, University of Virginia, Charlottesville, VA, USA
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cSchool of Medicine, Division of Geriatrics, University of Virginia, Charlottesville, VA, USA

dDepartment of Neurology, Memory Disorders Program, University of Virginia, Charlottesville, VA,
USA
eDepartment of Public Health, Division of Biostatistics, University of Virginia, Charlottesville, VA,
USA
fSleep Center, University of Virginia, Charlottesville, VA, USA

Abstract
Background: The effect of nighttime behaviors on cognition has not been studied independently
from other neuropsychiatric symptoms.
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Objective: We evaluate the following hypotheses that sleep disturbances bring increased risk
of earlier cognitive impairment, and more importantly that the effect of sleep disturbances is
independent from other neuropsychiatric symptoms that may herald dementia.

Methods: We used the National Alzheimer’s Coordinating Center database to evaluate the
relationship between Neuropsychiatric Inventory Questionnaire (NPI-Q) determined nighttime
behaviors which served as surrogate for sleep disturbances and cognitive impairment. Montreal
Cognitive Assessment scores defined two groups: conversion from 1) normal to mild cognitive
impairment (MCI) and 2) MCI to dementia. The effect of nighttime behaviors at initial visit
and covariates of age, sex, education, race, and other neuropsychiatric symptoms (NPI-Q), on
conversion risk were analyzed using Cox regression.
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Results: Nighttime behaviors predicted earlier conversion time from normal cognition to MCI
(hazard ratio (HR): 1.09; 95% CI: [1.00, 1.48], p = 0.048) but were not associated with MCI to
dementia conversion (HR: 1.01; [0.92, 1.10], p = 0.856). In both groups, older age, female sex,
lower education, and neuropsychiatric burden increased conversion risk.

*
Correspondence to: Ifrah Zawar, MD, Assistant Professor, POB 800994, HSC, Department of Neurology, University of Virginia,
School of Medicine, Charlottesville, VA 22908, USA. Tel.: +1 434 327 9703; Fax: +1 434 982 1726; ifrah.zawar@gmail.com.
1These authors contributed equally to this work.
CONFLICT OF INTEREST
The authors have no conflicts of interest to report.
SUPPLEMENTARY MATERIAL
The supplementary material is available in the electronic version of this article: https://dx.doi.org/10.3233/JAD-221244.
 Zawar et al. Page 2

Conclusion: Our findings suggest that sleep disturbances predict earlier cognitive decline
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independently from other neuropsychiatric symptoms that may herald dementia.

Keywords
Dementia; mild cognitive impairment; neuropsychiatric symptoms; nighttime behaviors; sleep
disturbances

INTRODUCTION
Sleep disturbances, including insomnia, poor sleep quality, and sleep fragmentation, are
implicated in the development and progression of Alzheimer’s disease (AD) and related
dementias in older adults [1–7]. Proposed mechanisms include an association between sleep
disturbances and reduced clearance of amyloid-β from the brain [8–11] as well as circadian
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rhythm disturbances to accelerated neurodegeneration [12].

Sleep disturbances in those at risk for dementia often do not appear in isolation.
Neuropsychiatric symptoms have a strong association with cognitive impairment [13–
17] and are known predictors of progression of cognitive decline among patients with
pre-existing dementia [18]. A systematic review found mixed results in the interactions
between sleep regulation and cognition [19], suggesting that comorbid neuropsychiatric
symptoms often preclude clear results [19]. These findings highlight the need to identify
reliable parameters to measure the relationship between sleep disturbances and cognition.
Additionally, they identify a knowledge gap about how this relationship is influenced by the
presence of neuropsychiatric symptoms such as depression and anxiety.

The Neuropsychiatric Inventory Questionnaire (NPI-Q) is a validated screening tool for

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assessing neuropsychiatric symptoms among cognitively impaired individuals [20, 21]

and includes a sleep disturbance item [18, 22, 23]. The sleep disturbances item in the
NPI-Q, referred to as “nighttime behaviors,” is defined as “interruptions of sleep and
daytime sleepiness.” We used the prospective National Alzheimer’s Coordinating Center
(NACC) Uniform Data Set (UDS), a large longitudinal database, to evaluate the following
hypotheses: 1) nighttime behaviors bring increased risk of earlier cognitive impairment, and
2) the effect of nighttime behaviors is independent from other neuropsychiatric symptoms
that may herald dementia. These risks are important to clarify since interventions for sleep
problems may attenuate or slow cognitive decline in susceptible individuals.

MATERIALS AND METHODS

Database
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The NACC UDS contains prospective de-identified data collected under the National
Institute on Aging’s Alzheimer’s Disease Center (ADC) program to facilitate collaborative
research in Alzheimer’s disease and related dementias [24–27]. Thirty-nine ADC sites have
their own participant eligibility criteria, and all are required to contribute to the NACC UDS.
Informed consent was obtained at the respective centers. Data from visits conducted between
September 2005 and December 2021 were included in the analysis. All participants with a
diagnosis of dementia at initial visit were excluded from analysis.

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Primary measures
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Nighttime behaviors measured the presence or absence of sleep disturbance. This clinician-
evaluated variable contains the response to the question, “Does the patient awaken you
during the night, rise too early in the morning, or take excessive naps during the day?”
This variable is based on the co-participants interview (i.e., spouse, children, or other
caregivers). This measure of sleep disturbances was validated as significantly associated
with the severity of cognitive impairment and biomarkers associated with Alzheimer’s
Disease in the cross sectional analysis [28].

The Montreal Cognitive Assessment (MoCA) score was used to assess the severity of the
cognitive deficit [29]. During the course of the NACC data collection, the MoCA replaced
the Mini-Mental Status Examination. To provide a homogeneous score of cognition, the
database variable NACCMMSE was converted using a validated conversion nomograph
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[30]. To create cognitive categories, MoCA cut-off scores of dementia < 20, 20≤MCI≤25,
and normal > 25 were used [31].

To measure the effects of nighttime behaviors on the conversion to and progression of

cognitive impairment, we defined two groups based on the MoCA cut-off scores described
above.

Conversion from normal to MCI included those who scored within the normal MoCA
range at the initial visit and converted to MCI (versus those who remained normal) during
follow-up.

Conversion from MCI to dementia included those who scored as MCI at the initial visit and
converted to dementia (versus maintenance of MCI) during follow-up.
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Predictors of conversion
To account for the cumulative prognostic effect of other neuropsychiatric symptoms,
we created a covariate, the NPI weight (“NPIweight”). We defined NPIweight as the
sum of the positive answers on the NPI-Q survey, excluding the “nighttime behaviors”
variable, divided by the number of valid answers in the NPI-Q. The symptoms of
the NPI-Q (excluding nighttime behaviors) included agitation, anxiety, apathy, appetite
problems, delusions, depression/dysphoria, disinhibition, elation, hallucinations, irritability,
and/or motor disturbances. The inclusion of NPIweight allowed us to evaluate the
effect of nighttime behaviors (and its underlying sleep disturbances) separate from other
neuropsychiatric symptoms while preserving degrees of freedom in the statistical model.
Like nighttime behaviors, the rest of NPI-Q variables were also based on co-participants or
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the caregiver’s interview.

Age (years, determined at the initial visit), sex (male versus female), race (dichotomized to
white and non-white), and education (total years) were utilized as other covariates because
older age, female sex, lower education level and non-white race are well-established risk
factors for dementia [32–34].

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Statistical analysis
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Data summarization—Baseline categorical scaled clinical characteristics were

summarized by frequencies (n) and relative frequencies (%), while continuous scaled and
integer scaled baseline characteristic were summarized by the median, interquartile range
(IQR), and range of the empirical distribution.

Univariate analyses—Univariate relationships between nighttime behaviors and the

remaining baseline characteristics (i.e., age at initial visit, sex, race, education, and NPI-
weight), were examined by using the Fisher-exact test for the nighttime behavior versus sex,
and the nighttime behaviors versus race comparisons and using the two sample Wilcoxon
Rank Sum test for the nighttime behaviors versus age at initial visit, the nighttime behaviors
versus education, and the nighttime behaviors versus NPIweight comparisons.
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Cox multivariate regression analyses—Using the patients’ baseline information for

nighttime behaviors, age at initial visit, education, NPIweight, sex and race, two independent
Cox multivariate regression analyses were conducted. One regression analysis was focused
on examining if there are unique associations between the time to conversion from
normal cognitive function to MCI and nighttime behaviors, age at initial visit, education,
NPIweight, sex, and race, while the other regression analysis focused on examining if there
are unique associations between the time to conversion from MCI to dementia and nighttime
behaviors, age at initial visit, education, NPIweight, sex, and race.

The predictor variable “nighttime behaviors” was specified as a categorical variable with
levels: “yes” and “no”. “Age at initial visit” was specified as a categorical variable with
levels:<40 years, [40–50 years], [50–60 years], [60–70 years], [70–80 years], [80–90
years], and > 90 years. “Education” was specified as an integer scaled continuous variable.
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“NPIweight” was specified as continuous scaled variable. “Sex” and “race” were specified
as categorical variables with levels “male”/“female” and “white”/“non-white”, respectively.

With regard to time-to-event censoring, in the Cox regression analyses for time to
conversion, normal cognition to MCI conversion times and MCI to dementia conversion
times for those patients who failed to convert were treated as right censored observations.

In terms of hypothesis testing, the type-III Wald Chi-square statistic served as the hypothesis
testing pivotal quantity. Per Wald Chi-square test, the null hypothesis was stated in the
conventional Cox multivariate regression null hypothesis testing framework, i.e., where
under the null hypothesis it is assumed that there is no unique association between the
instantaneous risk for the event (e.g., time to conversion from normal cognitive function
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to MCI) and the level/value of the predictor variable (e.g., nighttime behaviors). Rejection
of the null hypothesis implies that there is a unique association between the instantaneous
risk of the event and the level/value of the predictor variable. The null hypothesis rejection
criterion was set a priori at the 0.05 significance level for all of the type-III Wald Chi-square
tests.

The proportional hazards assumption was tested via the Therneau and Grambsh proportional
hazards tests [35].

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Missing data—Due to the censoring aspect of the outcome data, we did not attempt
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to impute missing time to event data. For the “conversion time from normal cognitive
function to MCI” Cox multivariate regression analysis, 4,232 (26.7%) patients were
missing conversion time information, and of the 11,656 patients who had conversion
time information (5,621 right censored times, 6,035 non-censored times), 11,074 (95.0%)
patients (5,357 right censored times, 5,717 non-censored times) had complete predictor
variable information. For the “conversion time from MCI to dementia” Cox multivariate
regression analysis, 4,215 (33.6%) patients were missing conversion time information, and
of the 8,332 patients who had conversion time information (4,794 right censored times,
3,538 non-censored times), 7,927 (95.1%) patients (4,548 right censored times, 3,379 non-
censored times) had complete predictor variable information. Due to the small percentage of
patients who had missing predictor variable information among those with conversion time
information, we did not impute missing predictor variable information.
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RESULTS
Baseline characteristics
Baseline clinical characteristics of the two groups are summarized in Table 1A and 1B.
Table 1A shows the associations between nighttime behaviors and baseline characteristics
of the normal to MCI group, while Table 1B shows the associations between nighttime
behaviors and baseline characteristics of the MCI to dementia group. Of the 15,568 patients
in the normal to MCI group, 2,229 (14.3%) endorsed nighttime behaviors at the initial visit
(Table 1A). The median age of patients with nighttime behaviors at initial visit was 69.0
years (IQR: [63.0, 75.5 years]). 56.4% of the patients were female (n = 1,258), and 87.6%
were white (n = 1,953).
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Of the 12,281 patients in the MCI to dementia group, 2,636 (21.5%) endorsed nighttime
behaviors at the initial visit (Table 1B). The median age of patients with nighttime behaviors
at initial visit was 72.0 years (IQR: [65.0, 78.0 years]). 45.1% (n = 1,188) were female, and
83% (n = 2,177) were white. In general, patients who presented with nighttime behaviors on
the initial visit were significantly younger, disproportionately male and disproportionately
white. Those with nighttime behaviors also significantly presented with a significantly
greater neuropsychological burden (higher NPIweight). Those with nighttime behaviors, in
the normal to MCI group, at the initial visit had an average of two other positive NPI-Q
symptoms; those without nighttime behaviors usually had no other symptoms in the NPI-Q
survey. Comorbid neuropsychiatric symptoms were even more frequent in the MCI to
dementia group. Those with nighttime behaviors had about three other NPI-Q symptoms and
those without nighttime behaviors had about one other neuropsychiatric symptom. These
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findings indicate that those with nighttime behaviors also presented with a larger burden of
other neuropsychiatric symptoms, or in other words, with more advanced clinical features of
disease.

Nighttime behaviors and conversion from normal cognition to MCI

After adjusting for other predictors, the instantaneous risk for conversion from normal
cognitive function to MCI was uniquely associated with nighttime behaviors (Table 2A, Fig.

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1). The instantaneous risk for conversion from normal cognitive function to MCI was 1.09
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time greater (95% CI: [1.00, 1.18], p = 0.048) for those patients who at their initial visit
reported experiencing nighttime behaviors than for those patients who at their initial visit
did not report experiencing nighttime behaviors. Those with nighttime behaviors who were
cognitively normal at the initial visit converted to MCI about 12.1 months earlier than those
without nighttime behaviors at the sample median (Corresponding median times to MCI
conversion are provided in Supplementary Table 1).

After adjustment for all remaining predictor variables, increasing age, lower education,
greater NPIweight, non-white race, and female sex categories were uniquely associated with
greater risks of MCI conversion (Table 2B).

Diagnostic analysis revealed that the Cox model proportional hazards assumption held for
all Cox regression terms other than sex (p = 0.034).
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Nighttime behaviors and conversion from MCI to dementia

After adjusting for other predictors, the instantaneous risk for conversion from MCI to
dementia was not associated with nighttime behaviors (Table 2 C). The instantaneous
risk for conversion from MCI to dementia was 1.01 times greater (95% CI: [0.92, 1.10],
p = 0.856) for those patients who at their first visit reported experiencing nighttime
behaviors than for those patients who at their first visit did not report experiencing nighttime
behaviors.

After adjustment for all remaining predictor variables, increasing age, lower education,
greater NPIweight, non-white race, and female sex categories were uniquely associated with
greater risks of MCI conversion (Table 2D).
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Diagnostic analysis revealed that the Cox model proportional hazards assumption held for
all Cox regression terms.

DISCUSSION
Our findings demonstrate that the presence of sleep disturbances, defined in the NACC
database as nighttime behaviors encompassing frequent awakening during the night, early
awakening, and daytime sleepiness, predicted higher risk of conversion from normal
cognition to MCI. More importantly, because our statistical model accounted for other
neuropsychiatric symptoms, our results indicate that nighttime behaviors predicted earlier
cognitive decline independent of other neuropsychiatric symptoms.
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The present study supports our earlier findings that the cross-sectional prevalence of
sleep disturbances increases with worsening cognition [28]. Insomnia, sleep fragmentation,
shorter sleep time, poor sleep quality and excessive daytime sleepiness all have been
associated with poor cognitive outcomes and increased dementia risk [1–5, 36–38]. The
present study extends these associations by statistically modeling the longitudinal risk of
cognitive conversion over a consistently maintained large sample of patients seen in long-
term follow-up.

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Our selection of variables is an important consideration in the evaluation of dementia risk

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factors. We used the nighttime behaviors variable in the NACC database as our primary
marker for sleep disturbances. Our previous work established that nighttime behaviors
identified on the initial visit were associated with worse cognition, smaller hippocampal
volumes, and higher levels of CSF biomarkers [28] and that “nighttime behaviors” are a
more informant marker of sleep disturbances compared to some of the other more subjective
tools of insomnia assessment in this patient population [28]. The “nighttime behaviors”
variable assesses sleep-wake cycle, daytime sleepiness, and wakefulness at night. Nighttime
behaviors, as assessed by the NPI-Q, may be useful in the clinical setting as it is an efficient
and easy yet reliable way of assessing sleep disturbances.

The NACC database contains complementary variables for the clinical determination of
MCI or dementia. We used MoCA scores as our cognitive measurement because it provided
consistent, uniform and objective, cognitive measurements important in the construction of
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survival curve models. Various ADCs participate in NACC. Variability in assessment by

different clinicians and the center’s practice may lead to a more subjective assessment of
cognitive status. Despite its limitations, a score-based assessment of cognitive status such
as MoCA or MMSE is likely to be longitudinally stable and reliable overtime because
it utilizes the same objective questionnaire and is less dependent on clinician judgment.
Moreover, MoCA scores in NACC database are adjusted for patient’s education. The use of
MoCA scores also allowed us to synchronize our findings with our earlier study from the
same database that determined that MoCA scores, in terms of sleep variables available in the
database, returned meaningful relationships with dementia biomarkers [28].

Potential mechanisms by which sleep disturbances may play a role in cognitive impairment
include circadian rhythm disturbances, and alteration in homeostatic and motivational
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processes [12, 39–41]. Sleep dysregulation may result from a variety of factors; some
aspects of the variable “nighttime behaviors” can be interpreted as representing disruption
or dysregulation of sleep-wake cycles. Irregular sleep-wake rhythm disorder, prevalent in
dementia, is a loss of a circadian pattern in sleep-wake cycles and presents as nighttime
sleep fragmentation and daytime sleep [42]. Both human and animal studies have shown that
circadian rhythm disturbances occur in dementia, maybe associated with increased risk of
incident dementia and may even appear years before onset of cognitive decline [40]. Animal
models have identified a possible role of circadian dysfunction in dementia and worsening
neurodegeneration [12]. Thus, it is possible that circadian rhythms beyond sleep-wake states
may play a role in pathology in dementia patients [40]. Interactions between sleep regulation
and neurodegeneration are likely bi-directional. Although patients with normal cognition
who presented with nighttime behaviors converted earlier to MCI—which may imply cause-
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and-effect—earlier subclinical neurodegenerative processes could have been present. We

propose that the nighttime behaviors were not predictive in those who presented with MCI
because sleep and cognition were already mutually intertwined, and the clinical sign of
nighttime behaviors was not sensitive enough to predict earlier conversion to dementia.

Neuropsychiatric symptoms are prevalent in patients with cognitive impairment and as many
as 75% of dementia patients may have one or more neuropsychiatric symptoms [15, 43].
In the present study, we controlled for the effect of combined neuropsychiatric symptoms

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by the use of the variable NPIweight, since the number of positive responses on the NPI-Q
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was a strong predictor of cognitive worsening. Our study supports earlier work that showed
that patients with an initial NPI-Q score greater than zero (endorsement of any symptom[s]),
experienced a 1.37 times greater risk of conversion to dementia [44] than those with no
symptoms of the NPI-Q. While higher NPI-Q scores have been shown to predict cognitive
decline [23] and mortality among the cognitively impaired [45], nighttime behaviors variable
has only been studied in a handful of studies [46, 47]. And the role of nighttime behaviors,
independent of other neuropsychiatric symptoms, in predicting cognitive decline has not
been studied previously. We extend earlier work by demonstrating that nighttime behaviors
at the initial visit have a significant effect on conversion risk beyond those of a symptom
complex assessed by the NPI-Q score. The importance of the effect of sleep disturbances
lies in that sleep disturbances represent symptoms that may be easily modified, and thereby
possibly attenuate the severity or delay the onset of dementia.
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We found older age, female sex, lower education, and non-white race to be risk factors for
conversion to dementia and MCI. These findings are consistent with previous literature [17,
32–34, 48]. Similar to some of the previous studies [3, 5], in our cohort, men were more
likely to endorse nighttime behaviors at the initial visit [3, 5]. Thus, even though men were
more likely to present with nighttime behaviors, females were more likely to convert to
worsening cognition.

Limitations of our study lie in the measurement and operationalization of sleep disturbances
as available in the NACC UDS. The assessments of sleep available in the NACC database
are not physiological measurements of sleep disturbances, and they bear the limitations
of any survey of clinical history. Our preliminary study determined, however, that the
“nighttime behaviors” variable was the most informant proxy of sleep disturbances in the
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NACC UDS because it fit well with the expected relationship between sleep and cognition
within this patient population and was associated with biomarkers of dementia such as
hippocampal volume loss and CSF biomarkers [28]. However, further studies are needed
to validate nighttime behaviors against direct measures of sleep and to evaluate what
physiological changes in sleep accompany the label of “nighttime behaviors” as gathered
in the NACC database. NPI-Q is a brief questionnaire that does not provide a comprehensive
assessment or severity of insomnia or sleep disturbances. Future studies may find that a
specific tool like the Insomnia Severity Index [49] may provide a better assessment of sleep
disturbances. The full score of the NPI-Q battery (range 0–12) was not always available, and
the missing data for individual questions may have affected our results. Although a large
database such as the NACC UDS provides a rich data source, it could mean that statistically
significant findings may carry unclear clinical significance. Moreover, our analyses did not
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include the range of all possible comorbid medical conditions that could affect cognitive
decline, such as diabetes mellitus or hypertension, because the incomplete documentation
of these combined conditions severely decreased the number of subjects with complete data
available for analyses. Medications which could affect sleep or were prescribed to treat sleep
disturbances, such as psychotropic or sedative hypnotics, were not documented reliably
in the NACC database. Another notable limitation of our study is that the response to
nighttime behaviors variable and the other NPI-Q questions was provided by the caregiver.
Therefore, these reflect subjective assessments based on caregiver perception. However, as

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cognitive impairment progresses, the patient with dementia may not be able to accurately
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report neuropsychiatric symptoms. Finally, another limitation of our work is that NACC
UDS participants do not comprise a nationally representative sample, which may affect
generalizability of our results.

In summary, we provide additional evidence for an association between sleep disturbances

and risk of cognitive impairment. While neuropsychiatric symptoms have a strong
association with cognitive impairment, our findings identify nighttime behaviors as an
independent predictor of cognitive decline.

Early identification of sleep disturbances via routine screening in cognitively healthy

and cognitively at-risk adults may have significant implications. Measures to treat sleep
disturbances may counter the deleterious effects of sleep disturbances on maintenance
of cognition and delay the onset of cognitive decline. Early intervention and aggressive
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management of sleep disturbances, therefore, may present a path to mitigation of cognitive

decline.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

ACKNOWLEDGMENTS
The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded
ADCs: P50 AG005131 (PI James Brewer, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005134 (PI
Bradley Hyman, MD, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG005138 (PI Mary Sano, PhD),
P50 AG005142 (PI Helena Chui, MD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005681 (PI John Morris,
MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG008051 (PI Thomas Wisniewski, MD), P50 AG008702 (PI
Scott Small, MD), P30 AG010124 (PI John Trojanowski, MD, PhD), P30 AG010129 (PI Charles DeCarli, MD),
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P30 AG010133 (PI Andrew Saykin, PsyD), P30 AG010161 (PI David Bennett, MD), P30 AG012300 (PI Roger
Rosenberg, MD), P30 AG013846 (PI Neil Kowall, MD), P30 AG013854 (PI Robert Vassar, PhD), P50 AG016573
(PI Frank LaFerla, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P30 AG019610 (PI Eric Reiman, MD),
P50 AG023501 (PI Bruce Miller, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG028383 (PI Linda Van
Eldik, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P30 AG035982 (PI Russell Swerdlow, MD), P50
AG047266 (PI Todd Golde, MD, PhD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD), P50 AG047366 (PI
Victor Henderson, MD, MS), P30 AG049638 (PI Suzanne Craft, PhD), P30 AG053760 (PI Henry Paulson, MD,
PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053
(PI Marwan Sabbagh, MD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD),
P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD).

FUNDING
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit
sectors.

The following internal and external funding of investigators offers no potential conflicts of interest. Drs. Quigg and
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Zawar acknowledge funding from NIH-NINDS (NeuroNEXT U24NS107182). Dr Quigg acknowledges funding
from the University of Virginia Brain Institute. Dr. Zawar acknowledges funding from Alzheimer’s Association. Dr.
Manning acknowledges funding from the DoD (W81XWH2010448), NIH (SB1AG037357-04A1, R01AG068128)
and HRSA (4 U1QHP287440400). Dr. Mattos acknowledges funding from National Institute on Aging of the
National Institutes of Health under Award Number K76AG074942. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National Institutes of Health.

DATA AVAILABILITY
De-identified data for this article is available via National Alzheimer’s Coordinating Center.

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REFERENCES
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[1]. Lim ASP, 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.
[PubMed: 23814339]
[2]. Sindi S, Kaareholt I, Johansson L, Skoog J, Sjöberg L, Wang HX, Johansson B, Fratiglioni L,
Soininen H, Solomon A, Skoog I, Kivipelto M (2018) Sleep disturbances and dementia risk: A
multicenter study. Alzheimers Dement 14, 1235–1242. [PubMed: 30030112]
[3]. Cricco M, Simonsick EM, Foley DJ (2001) The impact of insomnia on cognitive functioning in
older adults. J Am Geriatr Soc 49, 1185–1189. [PubMed: 11559377]
[4]. Grau-Rivera O, Operto G, Falcón C, Sánchez-Benavides G, Cacciaglia R, Brugulat-Serrat A,
Gramunt N, Salvadó G, Suárez-Calvet M, Minguillon C, Iranzo Á, Gispert JD, Molinuevo JL,
Camí J, Crous-Bou M, Deulofeu C, Dominguez R, Gotsens X, Hernández L, Huesa G, González-
De-Echávarri JM, Huguet J, León M, Marne P, Arenaza-Urquijo EM, Menchcón T, Milà M,
Pascual M, Polo A, Pradas S, Sala-Vila A, Segundo S, Shekari M, Soteras A, Tenas L, Vilanova
M, Vilor-Tejedor N (2020) Association between insomnia and cognitive performance, gray
Author Manuscript

matter volume, and white matter microstructure in cognitively unimpaired adults. Alzheimers
Res Ther 12, 4. [PubMed: 31907066]
[5]. Potvin O, Lorrain D, Forget H, Dubé M, Grenier S, Préville M, Hudon C (2012) Sleep quality and
1-year incident cognitive impairment in community-dwelling older adults. Sleep 35, 491–499.
[PubMed: 22467987]
[6]. Yuen K, Rashidi-Ranjbar N, Verhoeff NPLG, Kumar S, Gallagher D, Flint AJ, Herrmann N,
Pollock BG, Mulsant BH, Rajji TK, Voineskos AN, Fischer CE, Mah L (2019) Association
between sleep disturbances and medial temporal lobe volume in older adults with mild cognitive
impairment free of lifetime history of depression. J Alzheimers Dis 69, 413–421. [PubMed:
31104028]
[7]. Chen JC, Espeland MA, Brunner RL, Lovato LC, Wallace RB, Leng X, Phillips LS, Robinson
JG, Kotchen JM, Johnson KC, Manson JE, Stefanick ML, Sarto GE, Mysiw WJ (2016) Sleep
duration, cognitive decline, and dementia risk in older women. Alzheimers Dement 12, 21–33.
[PubMed: 26086180]
[8]. Mander BA, Winer JR, Jagust WJ, Walker MP (2016) Sleep: A novel mechanistic pathway,
Author Manuscript

biomarker, and treatment target in the pathology of Alzheimer’s disease? Trends Neurosci 39,
5552–566.
[9]. Sadeghmousavi S, Eskian M, Rahmani F, Rezaei N (2020) The effect of insomnia on development
of Alzheimer’s disease. J Neuroinflammation 17, 289. [PubMed: 33023629]
[10]. Ju YES, Ooms SJ, Sutphen C, Macauley SL, Zangrilli MA, Jerome G, Fagan AM, Mignot
E, Zempel JM, Claassen JAHR, Holtzman DM (2017) Slow wave sleep disruption increases
cerebrospinal fluid amyloid-β levels. Brain 140, 2104–2111. [PubMed: 28899014]
[11]. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ,
Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M (2013) Sleep drives metabolite clearance
from the adult brain. Science 342, 373–377. [PubMed: 24136970]
[12]. Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, Roh JH, Ortiz-Gonzalez X, Dearborn
JT, Culver JP, Herzog ED, Hogenesch JB, Wozniak DF, Dikranian K, Giasson BI, Weaver
DR, Holtzman DM, FitzGerald GA (2013) Circadian clock proteins regulate neuronal redox
homeostasis and neurodegeneration. J Clin Invest 123, 5389–5400. [PubMed: 24270424]
Author Manuscript

[13]. Dillon C, Serrano CM, Castro D, Leguizamón PP, Heisecke SL, Taragano FE (2013) Behavioral
symptoms related to cognitive impairment. Neuropsychiatr Dis Treat 9, 1443–1455. [PubMed:
24092982]
[14]. Mah L, Binns MA, Steffens DC (2015) Anxiety symptoms in amnestic mild cognitive
impairment are associated with medial temporal atrophy and predict conversion to Alzheimer
disease. Am J Geriatr Psychiatry 23, 466–476. [PubMed: 25500120]
[15]. Monastero R, Mangialasche F, Camarda C, Ercolani S, Camarda R (2009) A systematic review of
neuropsychiatric symptoms in mild cognitive impairment. J Alzheimers Dis 18, 11–30. [PubMed:
19542627]

J Alzheimers Dis. Author manuscript; available in PMC 2023 August 29.

 Zawar et al. Page 11

[16]. A. Köhler C, F. Magalhaes T, M.M.P. Oliveira J, S. Alves G, Knochel C, Oertel-Knöchel

V, Pantel J, F. Carvalho A(2016) Neuropsychiatric disturbances in mild cognitive impairment
Author Manuscript

(MCI): A systematic review of population-based studies. Curr Alzheimer Res 13, 1066–1082.
[PubMed: 27137220]
[17]. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D (2006) Depression and risk for
Alzheimer disease: Systematic review, meta-analysis, and metaregression analysis. Arch Gen
Psychiatry 63, 530–538. [PubMed: 16651510]
[18]. Edwin TH, Strand BH, Persson K, Engedal K, Selbæk G, Knapskog AB (2021) Trajectories
and risk factors of dementia progression: A memory clinic cohort followed up to 3 years from
diagnosis. Int Psychogeriatr 33, 779–789. [PubMed: 33213607]
[19]. Brewster GS, Varrasse M, Rowe M (2015) Sleep and cognition in community-dwelling older
adults: A review of literature. Healthcare (Basel) 3, 1243–1270. [PubMed: 27066397]
[20]. Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, Lopez OL, DeKosky
ST (2000) Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J
Neuropsychiatry Clin Neurosci 12, 233–239. [PubMed: 11001602]
[21]. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J (1994)
Author Manuscript

The neuropsychiatric inventory: Comprehensive assessment of psychopathology in dementia.

Neurology 44, 2308–2314. [PubMed: 7991117]
[22]. Edwin TH, Strand BH, Persson K, Engedal K, Selbæk G, Knapskog AB (2021) Neuropsychiatric
symptoms and comorbidity: Associations with dementia progression rate in a memory clinic
cohort. Int J Geriatr Psychiatry 36, 960–969. [PubMed: 33462872]
[23]. Teng E, Lu PH, Cummings JL (2007) Neuropsychiatric symptoms are associated with
progression from mild cognitive impairment to Alzheimer’s disease. Dement Geriatr Cogn
Disord 24, 253–259. [PubMed: 17700021]
[24]. Beekly DL, Ramos EM, Lee WW, Deitrich WD, Jacka ME, Wu J, Hubbard JL, Koepsell TD,
Morris JC, Kukull WA, Reiman EM, Kowall N, Landreth G, Shelanski M, Welsh-Bohmer K,
Levey AI, Potter H, Ghetti B, Price D, Hyman B, Petersen RC, Sano M, Ferris SH, Mesulam
MM, Kaye J, Bennett DA, Yesavage J, Marson D, Beck C, DeCarli C, Cotman C, Cummings JL,
Thal LJ, Markesbery W, Gilman S, Trojanowski JQ, DeKosky ST, Chui H, Rosenberg R, Raskind
M (2007) The National Alzheimer’s Coordinating Center (NACC) database: The uniform data
set. Alzheimer Dis Assoc Disord 21, 249–258. [PubMed: 17804958]
Author Manuscript

[25]. Beekly DL, Ramos EM, Van Belle G, Deitrich W, Clark AD, Jacka ME, Kukull WA (2004) The
National Alzheimer’s Coordinating Center (NACC) database: An Alzheimer disease database.
Alzheimer Dis Assoc Disord 18, 270–277. [PubMed: 15592144]
[26]. Morris JC, Weintraub S, Chui HC, Cummings J, DeCarli C, Ferris S, Foster NL, Galasko D,
Graff-Radford N, Peskind ER, Beekly D, Ramos EM, Kukull WA (2006) The Uniform Data
Set (UDS): Clinical and cognitive variables and descriptive data from Alzheimer disease centers.
Alzheimer Dis Assoc Disord 20, 210–216. [PubMed: 17132964]
[27]. Weintraub S, Salmon D, Mercaldo N, Ferris S, Graff-Radford NR, Chui H, Cummings J, DeCarli
C, Foster NL, Galasko D, Peskind E, Dietrich W, Beekly DL, Kukull WA, Morris JC (2009)
The Alzheimer’s Disease Centers’ Uniform Data Set (UDS): The neuropsychologic test battery.
Alzheimer Dis Assoc Disord 23, 91–101. [PubMed: 19474567]
[28]. Ifrah Zawar, Mattos MK, Manning CA Q M (2022) Sleep disturbances, cognitive status, and
biomarkers of dementia. J Alzheimers Dis 89, 1367–1374. [PubMed: 36031904]
[29]. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL,
Author Manuscript

Chertkow H (2005) The Montreal Cognitive Assessment, MoCA: Abrief screening tool for mild
cognitive impairment. J Am Geriatr Soc 53, 695–699. [PubMed: 15817019]
[30]. Bergeron D, Flynn K, Verret L, Poulin S, Bouchard RW, Bocti C, Fülüp T, Lacombe G, Gauthier
S, Nasreddine Z, Laforce RJ (2017) Multicenter validation of an MMSE-MoCA conversion table.
J Am Geriatr Soc 65, 1067–1072. [PubMed: 28205215]
[31]. Milani SA, Marsiske M, Cottler LB, Chen X, Striley CW (2018) Optimal cutoffs for the Montreal
Cognitive Assessment vary by race and ethnicity. Alzheimers Dement (Amst) 10, 773–781.
[PubMed: 30505927]

J Alzheimers Dis. Author manuscript; available in PMC 2023 August 29.

 Zawar et al. Page 12

[32]. Van Der Flier WM, Scheltens P (2005) Epidemiology and risk factors of dementia. Neurol Pract
76(Suppl 5), v2–7.
Author Manuscript

[33]. Sharp ES, Gatz M (2011) Relationship between education and dementia: An updated systematic
review. Alzheimer Dis Assoc Disord 25, 289–304. [PubMed: 21750453]
[34]. Kornblith E, Bahorik A, Boscardin WJ, Xia F, Barnes DE, Yaffe K (2022) Association of race
and ethnicity with incidence of dementia among older adults. JAMA 327, 1488–1495. [PubMed:
35438728]
[35]. Grambsch PM, Therneau TM (1994) Proportional hazards tests and diagnostics based on
weighted residuals. Biometrika 81, 515–526.
[36]. Nebes RD, Buysse DJ, Halligan EM, Houck PR, Monk TH (2009) Self-reported sleep quality
predicts poor cognitive performance in healthy older adults. J Gerontol B Psychol Sci Soc Sci 64,
180–187. [PubMed: 19204069]
[37]. Sabia S, Fayosse A, Dumurgier J, van Hees VT, Paquet C, Sommerlad A, Kivimäki M, Dugravot
A, Singh-Manoux A (2021) Association of sleep duration in middle and old age with incidence
of dementia. Nat Commun 12, 2289. [PubMed: 33879784]
[38]. Jaussent I, Bouyer J, Ancelin ML, Berr C, Foubert-Samier A, Ritchie K, Ohayon MM, Besset A,
Author Manuscript

Dauvilliers Y (2012) Excessive sleepiness is predictive of cognitive decline in the elderly. Sleep
35, 1201–1207. [PubMed: 22942498]
[39]. Tranah GJ, Blackwell T, Stone KL, Ancoli-Israel S, Paudel ML, Ensrud KE, Cauley JA, Redline
S, Hillier TA, Cummings SR, Yaffe K (2011) Circadian activity rhythms and risk of incident
dementia and mild cognitive impairment in older women. Ann Neurol 70, 722–732. [PubMed:
22162057]
[40]. Musiek ES, Xiong DD, Holtzman DM (2015) Sleep, circadian rhythms, and the pathogenesis of
Alzheimer disease. Exp Mol Med 47, e148. [PubMed: 25766617]
[41]. Eban-Rothschild A, Appelbaum L, De Lecea L (2018) Neuronal mechanisms for sleep/wake
regulation and modulatory drive. Neuropsychopharmacology 43, 937–952. [PubMed: 29206811]
[42]. Sack RL, Auckley D, Auger RR, Carskadon MA, Wright KP, Vitiello MV, Zhdanova IV (2007)
Circadian rhythm sleep disorders: Part II, advanced sleep phase disorder, delayed sleep phase
disorder, free-running disorder, and irregular sleep-wake rhythm: An American Academy of
Sleep Medicine review. Sleep 30, 1484–1501. [PubMed: 18041481]
Author Manuscript

[43]. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S (2002) Prevalence of
neuropsychiatric symptoms in dementia and mild cognitive impairment. JAMA 288, 1475–1483.
[PubMed: 12243634]
[44]. Rosenberg PB, Mielke MM, Appleby BS, Oh ES, Geda YE, Lyketsos CG (2013) The association
of neuropsychiatric symptoms in MCI with incident dementia and alzheimer disease. Am J
Geriatr Psychiatry 21, 685–695. [PubMed: 23567400]
[45]. Huang MF, Lee WJ, Yeh YC, Lin YS, Lin HF, Wang SJ, Yang YH, Chen CS, Fuh JL
(2021) Neuropsychiatric symptoms and mortality among patients with mild cognitive impairment
and dementia due to Alzheimer’s disease. J Formos Med Assoc 121, 1705–1713. [PubMed:
34933801]
[46]. Atayde AL, Fischer CE, Schweizer TA, Munoz DG (2022) Neuropsychiatric Inventory-
questionnaire assessed nighttime behaviors in cognitively asymptomatic patients with
pathologically confirmed Alzheimer’s disease predict more rapid cognitive deterioration. J
Alzheimers Dis 86, 1137–1147. [PubMed: 35180114]
[47]. Atayde AL, Fischer CE, Schweizer TA, Munoz DG (2020) Neuropsychiatric Inventory-assessed
Author Manuscript

nighttime behavior accompanies, but does not precede, progressive cognitive decline independent
of Alzheimer’s disease histopathology. J Alzheimers Dis 74, 839–850. [PubMed: 32116249]
[48]. Levine DA, Gross AL, Briceño EM, Tilton N, Giordani BJ, Sussman JB, Hayward RA, Burke
JF, Hingtgen S, Elkind MSV, Manly JJ, Gottesman RF, Gaskin DJ, Sidney S, Sacco RL, Tom SE,
Wright CB, Yaffe K, Galecki AT (2021) Sex differences in cognitive decline among US adults.
JAMA Netw Open 4, e210169. [PubMed: 33630089]
[49]. Bastien CH, Vallières A, Morin CM (2001) Validation of the insomnia severity index as an
outcome measure for insomnia research. Sleep Med 2, 297–307. [PubMed: 11438246]

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Fig. 1.
Kaplan Meire curves for the cumulative probability for no conversion to MCI by Nighttime
Behavior (A), age at visit 1(B), years of education (C), NPIweight (D), race (E) and sex (F).
Corresponding median times to conversion to MCI are provided in Supplementary Table 1.
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 Zawar et al. Page 14
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Fig. 2.
Kaplan Meier curves for the cumulative probability for no conversion from MCI to dementia
by Nighttime Behavior (A), age at visit 1 (B), years of education (C), NPIweight (D),
race (E), and sex (F). Corresponding median times to conversion to MCI are provided in
Supplementary Table 2.
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Table 1A

Univariate comparisons of baseline characteristics: age, education, NPIweight (an adjusted sum of the neuropsychiatric inventory questionnaire (NPI-Q)
score), race, and sex by presence or absence of nighttime behaviors on the initial visit of patients assessed in the NACC database for (A) the sample of
those who tested in the normal range of cognition according to Montreal Cognitive assessment at initial visit and (B) those who tested with minimal
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cognitive impairment (MCI) at initial visit. Empirical distributions for age at first visit, education, and NPIweight are summarized by the median and
interquartile range (IQR), and range of the empirical distribution and between nighttime behavior comparisons were conducted by way of the Wilcoxon
Rank Sum test. Empirical frequency distributions for race and sex are summarized as frequencies (n) and relative frequencies (%) and between nighttime
behavior comparisons of race and sex were conducted by way of the Fisher’s exact test. A. Normal to MCI

Nighttime behaviors N Median [IQR] Range [Min, Max] p

Age at first visit (y) Present 2,229 69.0 [63.0, 75.5]] [21.0, 97.0] <0.001
Absent 13,339 70.0 [64.0, 76.0] [18.0, 104.0]
Education (y) Present 2,222 16.0 [14.0, 18.0] [10.0, 28.0] 0.001
Absent 13,298 16.0 [14.0, 18.0] [0, 29.0]
NPI weight Present 2,179 0.18 [0.00, 0.27] [0.00, 1.00] <0.001
Absent 12,887 0.00 [0.00. 0.09] [0.00, 0.91]
n Nonwhite (n, %) White (n, %) p

Race Present 2,229 276 (12.4%) 1,953 (87.6%) 0.001

Absent 13,339 2002 (15.0%) 11,337 (85.0%)
Male (n, %) Female (n, %)

Sex Present 2,229 971 (43.6%) 1,258 (56.4%) <0.001

Absent 13,339 4728 (35.4%) 8,611 (64.6%)

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Table 1B

B. MCI to dementia

Nighttime behaviors N Median [Interquartile Range] Range [Min, Max] p

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Age at first visit (y) Present 2,636 72.0 [65.0, 78.0] [21.0, 99.0] <0.001
Absent 9,645 73.0 [67.0, 79.0] [18.0, 102.0]
Education (y) Present 2,627 16.0 [12.0, 18.0] [0, 26.0] 0.483
Absent 9,618 16.0 [13.0, 18.0] [0, 30.0]
NPI weight Present 2,578 0.27 [0.09, 0.46] [0, 1.00] <0.001
Absent 9,350 0.00 [0.00, 0.18] [0, 0.91]
n Nonwhite (n, %) White (n, %) p

Race Present 2,636 459 (17.4%) 2,177 (82.6%) <0.001

Absent 9,645 2,349 (24.4%) 7,296 (75.6%)
Male (n, %) Female (n, %)

Sex Present 2,636 1,448 (54.9%) 1,188 (45.1%) <0.001

Absent 9,645 4,330 (44.9%) 5,315 (55.1%)

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Table 2A

Cox-multivariate regression model type-III Wald Chi-square ANOVA summary and hazard ratio estimates for comparing the instantaneous risk of
conversion to MCI for the sample of patients who tested in the normal range of cognition according to the Montreal Cognitive Assessment at the initial
visit (A, B), and for comparing the instantaneous risk of conversion from MCI to dementia for those who tested with minimal cognitive impairment
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(MCI) according to the Montreal Cognitive Assessment at the initial visit (C, D). Table 2A lists the Cox multivariate regression model type-III Wald Chi-
square ANOVA results for testing the null hypothesis that there is no unique association between the predictor variable and time to conversion to MCI.
Table 2B lists the Cox multivariate regression model hazard ratios for comparing the instantaneous risk of conversion to MCI. Table 2C lists the Cox
multivariate regression model type-III Wald Chi-square ANOVA results for testing the null hypothesis that there is no unique association between the
predictor variable and time to conversion from MCI to dementia. Table 2D lists the Cox multivariate regression model hazard ratios for comparing the
instantaneous risk of conversion from MCI to dementia. A-B: Conversion from Normal to MCI

Predictor Variable Degrees of Freedom Wald Type III Chi-Square Statistic p

Nighttime Behavior 1 3.91 0.048
Age at Visit #1 6 791.09 <0.001
Educations 1 153.20 <0.001
NPIweight 1 204.35 <0.001
Race 1 241.65 <0.001
Sex 1 206.67 <0.001
Model 11 1601.60 <0.001

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Table 2B

Predictor Variable Ratio Hazard Ratio [95% CI] Type III Wald Chi-Square Statistic p
Nighttime Behavior Yes: No 1.09 [1.00, 1.18] 3.91 0.048
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Age at Visit #1 40–50:<40 1.90 [1.11, 3.26] 5.42 0.020

50–60:<40 2.31 [1.40, 3.80] 10.86 0.001
60–70:<40 3.36 [2.06, 5.50] 23.47 <0.001
70–80:<40 5.16 [3.16, 8.43] 43.07 <0.001
80–90:<40 7.73 [4.72, 12.65] 66.20 <0.001
>90:<40 12.06 [6.98, 20.86] 79.47 <0.001

Education† X years: X + 1 years 1.06 [1.05, 1.07] 153.20 <0.001

NPI Weight‡ X + 0.1: X 1.16 [1.14, 1.18] 204.35 <0.001

Race Non-white: White 1.75 [1.63, 1.88] 241.65 <0.001

Sex Female: Male 1.49 [1.41, 1.58] 206.68 <0.001

†
X denotes the X years of education and X + 1 denotes X + 1 years of education.
‡
denotes a NPIweight of X, and X + 0.1 denotes a NPIweight of X + 0.1.

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Table 2C

C-D: Conversion from MCI to Dementia

Predictor Variable Degrees of Freedom Wald Type III Chi-Square Statistic p

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Nighttime Behavior 1 0.03 0.855

Age at Visit #1 6 152.22 <0.001
Educations 1 43.93 <0.001
NPIweight 1 364.25 <0.001
Race 1 0.41 0.521
Sex 1 4.35 0.037
Model 11 608.98 <0.001

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Table 2D

Predictor Variable Ratio Hazard Ratio [95% CI] Type III Wald Chi-Square Statistic p
Nighttime Behavior Yes: No 1.01 [0.92, 1.10] 0.03 0.856
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Age at Visit #1 40–50:<40 1.61 [0.67, 3.89] 1.13 0.289

50–60:<40 2.10 [0.94, 4.73] 3.23 0.072
60–70:<40 2.11 [0.95, 4.72] 3.33 0.068
70–80:<40 2.83 [1.27, 6.31] 6.47 0.011
80–90:<40 3.53 [1.58, 7.89] 9.47 0.002
>90:<40 4.60 [2.01, 10.53] 12.99 <0.001

Education† X years: X + 1 years 1.04 [1.03, 1.05] 43.93 <0.001

NPI Weight‡ X + 0.1: X 1.21 [1.19, 1.23] 364.25 <0.001

Race Non-white: White 0.97 [0.89, 1.06] 0.41 0.521

Sex Female: Male 1.08 [1.00, 1.16] 4.35 0.037

†
X denotes the X years of education and X + 1 denotes X + 1 years of education.
‡
denotes a NPIweight of X, and X + 0.1 denotes a NPIweight of X + 0.1.

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