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The Journal of Prevention of Alzheimer's Disease logoLink to The Journal of Prevention of Alzheimer's Disease
. 2017 Jul 18;5(1):42–48. doi: 10.14283/jpad.2017.29

Cognitive Frailty and Incidence of Dementia in Older Persons

Hiroyuki Shimada 1,a, H Makizako 1, K Tsutsumimoto 1, T Doi 1, S Lee 1, T Suzuki 2
PMCID: PMC12280713  PMID: 29405232

Abstract

Background

Cognitive frailty may be a preventive or therapeutic target for preventing dementia and functional decline with age.

Objectives

To examine the relationship between physical and cognitive frailty and the incidence of dementia in community-living older persons.

Design

A prospective cohort study. Setting: General community in Japan. Participants: A total of 4072 persons aged ≥ 65 years.

Setting

A community in Japan.

Participants

A total of 4072 community-dwelling older persons aged ≥ 65 years participated in the study.

Measurements

We characterized physical frailty as ≥ 3 of the following criteria: slow walking speed, muscle weakness, exhaustion, low physical activity, and weight loss. We used the National Center for Geriatrics and Gerontology-Functional Assessment Tool, which includes tests of word list memory, attention, and executive function, and processing speed to screen for cognitive frailty. The presence of ≥ 2 cognitive impairments, indicated by an age-adjusted score of at least 1.5 standard deviations below the reference threshold, was defined as cognitive frailty. The incidence of dementia was determined using data collected by the Japanese Health Insurance System over 24 months.

Results

The overall prevalence rates of physical frailty, cognitive impairment, and cognitive frailty (i.e., coexistence of frailty and cognitive impairment) were 5.1%, 5.5%, and 1.1%, respectively. During the follow-up period, 81 participants (2.0%) developed dementia. We found significant relationships between the incidence of dementia and cognitive impairment (hazard ratio (HR): 3.85, 95% confidence interval (95% CI): 2.09–7.10) and cognitive frailty (HR: 6.19, 95% CI: 2.7–13.99). However, the association between dementia and physical frailty did not reach significance (HR: 1.95, 95% CI: 0.97–3.91).

Conclusions

Individuals with cognitive frailty had the highest risk of dementia. Future research should implement dementia prevention strategies among older persons with cognitive frailty.

Key words: Cognition, frailty, aged, elderly, dementia incidence

Introduction

The 2015 World Alzheimer Report estimated that 46.8 million people worldwide were living with dementia in 2015. This number will almost double every 20 years and is estimated to reach 74.7 million in 2030 and 131.5 million in 2050 (1). The global societal economic cost of dementia was estimated at USD818 billion in 2015, with huge effects on quality of life in individuals living with dementia and their families, and on the carers of those living with dementia (1).

Cognitive decline is associated with physical frailty in older persons (2), and cognitive impairment and physical frailty often coexist in older persons (3, 4). This coexistence may result from multiple types of risk factors. The possible physiological factors include activation of inflammation, decreased immune function, anemia, endocrine system alterations, musculoskeletal alterations and medical illness including stroke, diabetes, hypertension, cancer, and chronic obstructive pulmonary disease (5, 6, 7, 8, 9). Sociodemographic and psychological factors that may contribute to cognitive decline include age, sex, socioeconomic status, inactive lifestyle, and depressive symptoms (10).

Numerous studies have reported on the conceptualization, epidemiology, physiology, pathophysiology, biological mechanisms, and rationale and strategies for the treatment of frailty (11). By contrast, there is insufficient research on the operational definition, rationale, and validity of cognitive frailty (12). An International Consensus Group on Cognitive Frailty was organized by the International Academy on Nutrition and Aging (IANA) and the International Association of Gerontology and Geriatrics (IAGG) in 2013. This International Consensus Group has provided the first definition of cognitive frailty as a condition affecting older persons (13), and proposed the identification of cognitive frailty as a heterogeneous clinical manifestation characterized by the simultaneous presence of physical frailty and cognitive impairment. Four categories were established: (1) robust older individuals; (2) physically frail older persons with normal cognitive function; (3) non-physically frail older persons with cognitive impairment; and (4) physically frail older persons with cognitive impairment (13). An IAGG consensus conference has defined cognitive frailty as reduced cognitive function due to either physical or brain disease, or accelerated brain aging in the absence of evident brain disease (14). Cognitive training (15) and exercise training (16) and combinations of these types of training (17) can enhance cognitive function and functional status in older adults. These previous studies suggest that cognitive frailty may be a preventive or therapeutic target for preventing dementia and functional decline with age.

We have previously reported on the combined prevalence of physical frailty and cognitive impairment (i.e., cognitive frailty), and the relationship between cognitive frailty and activities of daily living (ADL) in older Japanese persons (18). We found that the overall prevalence rates of physical frailty, cognitive impairment, and cognitive frailty were 7.2%, 5.2%, and 1.2%, respectively. Using cross-sectional data, we found higher odds ratios (ORs) of ADL limitations among older persons with cognitive frailty than among those with physical frailty or cognitive impairment. The present study aimed to examine the association between cognitive frailty (as defined by IANA and IAGG) and dementia incidence using data from the National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes (NCGG-SGS), a Japanese national cohort study (19). We hypothesized that individuals with cognitive frailty would show greater effects of incident dementia than would individuals with physical frailty or cognitive impairment or robust older individuals.

Methods

Participants

Of the people recruited from Nagoya or Obu, Japan, for the NCGG-SGS, 4072 community-dwelling older persons aged ≥ 65 years participated (19). The inclusion criteria were residence in either Obu or Nagoya and age ≥ 65 years at the time of the examination (August 2011-February 2012, June 2013). The exclusion criteria were: the Japanese certified public long-term care insurance system, which requires support or care; the inability to perform basic daily living tasks, such as eating, dressing, bathing and showering, functional mobility, climbing up and down stairs, personal hygiene and grooming, and toilet hygiene (ADL); and the inability to undergo performance-based assessments (4). Participants with a history of Parkinson’s disease, stroke, depression, or dementia were also excluded. Because participants who scored < 21 on the Mini-Mental State Examination (MMSE) (20) possibly had moderate dementia, these were also excluded (21). In addition, we excluded participants whose responses contained missing data for the cognitive frailty assessment and other measurements. Of the initial 5104 participants, 1032 were excluded, and data from 4072 older persons were analyzed (1985 men and 2087 women). Their mean age was 71.6 ± 5.2 years (range: 65-96 years). All participants gave their informed consent before they were included in the study. The study protocol was approved by the Ethics Committee of the National Center for Geriatrics and Gerontology.

Operationalization of cognitive frailty

Following Fried’s original studies, we considered physical frailty as satisfying 3 of the following criteria (10): slow walking speed, weakness, exhaustion, low physical activity, and weight loss. Participants showing none of these components were considered to be non-frail, and those showing 1 or 2 components were considered to be pre-frail. Using a stopwatch, walking speed was measured in seconds. The participants walked on a flat and straight surface at a comfortable walking speed and markers were used to indicate both the start and the end of a 2.4 m walking path. A 2 m section was marked at the start and end of the walking path. This was traversed by patients before passing the start marker so that they were walking at a comfortable pace by the time they reached the timed path. To ensure a consistent walking pace while on the timed path, participants were asked to continue walking for an additional 2 m past the end of the timed path. A cutoff of < 1.0 m/s was established as slowness (4, 22). Weakness, measured in kilograms, was defined according to maximum grip strength using a Smedley-type handheld dynamometer (GRIP-D; Takei Ltd., Niigata, Japan). Sex-specific cutoffs (< 26 kg for men and < 18 kg for women) were used to establish weakness (23). If the participant responded “yes” to the question “In the last two weeks, have you felt tired without a reason?”, exhaustion was considered present. This question was from the Kihon Checklist, a self-report comprehensive health checklist developed by the Japanese Ministry of Health, Labour and Welfare (24): We evaluated physical activity using the following questions about time spent engaged in sports and exercise: (1) “Do you engage in moderate levels of physical exercise or sports aimed at health?” and (4) “Do you engage in low levels of physical exercise aimed at health?” If participants answered “no” to both of these questions, we considered them to engage in low levels of activity (19). Weight loss was assessed by a response of “yes” to the question: “Have you lost 2 kg or more in the past 6 months?” (24)

The National Center for Geriatrics and Gerontology-Functional Assessment Tool (NCGG-FAT) (25) was used to conduct cognitive screening. The NCGG-FAT consists of the following domains: (1) memory (word list memory-I (immediate recognition) and word list memory-II (delayed recall)); (2) attention (an electronic tablet version of the Trail Making Test, TMT-part A); (3) executive function (an electronic tablet version of the TMT-part B); and (4) processing speed (an electronic tablet version of the Digit Symbol Substitution Test). Participants were given about 20 min to complete the battery. The NCGG-FAT has been shown to have high test-retest reliability and moderate to high validity among community-dwelling older persons (26). The assessments of cognitive functioning in community were conducted by well-trained study assistants using community facilities, such as community halls. All staff received training from the authors in the correct protocols for administering the assessment measures before the study began. Established standardized thresholds were used for all tests conducted in this study to define impairment in the corresponding domain for a population-based cohort comprising community-dwelling older persons (scores > 1.5 standard deviations (SDs) below the age- and education-specific means). Major cognitive impairment was characterized by deficits on ≥ 2 of the NCGG-FAT’s domains. Participants without deficits were considered to be cognitively intact; those with 1 deficit were considered to have minor cognitive impairment. The NCGG-SGS cognitive frailty criteria did not consider minor cognitive impairment as cognitive impairment.

Participants were categorized into the following groups: (1) robust older individuals with no physical frailty or cognitive impairment (robust group); (2) physically frail older persons without cognitive impairment (physical frailty group); (3) non-physically frail older persons with major cognitive impairment (cognitive impairment group); and (4) physically frail older persons with cognitive impairment (cognitive frailty group) (19).

Measurement of the incidence of dementia

Participants who did not have dementia at the baseline and who were diagnosed with dementia at the follow-up were considered to have incident dementia; the data were collected from the Japanese Health Insurance System. In Japan, all adults aged ≥ 65 years have public health insurance comprising 1 of the following: health insurance for employed individuals (Employees’ Health Insurance), national health insurance for unemployed and self-employed individuals aged 65-74 years (Japanese National Health Insurance), or health care for individuals aged ≥ 75 years (Later-Stage Medical Care) (27). In the present research, participants were tracked monthly for newly incident dementia (Alzheimer’s disease (AD) or other dementia subtypes) as recorded by the Japanese National Health Insurance and Later-Stage Medical Care systems. Participants were considered to have dementia based on a diagnosis by medical doctors according to the International Classification of Diseases-10.

Potential confounding factors

Dementia results from numerous factors that occur together over a long period. Demographic variables, chronic medical conditions, lifestyle, physical performance, cognitive function, and psychosocial factors are associated with dementia incidence in older persons (14, 28). All multivariate models reported include the following covariates unless otherwise specified: age at enrollment, sex, educational level, depressive symptoms, current smoking, and the presence or absence of chronic medical illnesses. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS) (29). The presence of the following self-reported chronic medical illnesses was entered into the models: heart disease, pulmonary disease, hypertension, hyperlipidemia, and diabetes mellitus.

Statistical analysis

Analysis of variance, Student’s t test, and Pearson’s chi-squared test were used to test differences in the baseline characteristics according to frailty status and between participants with and without dementia. The chi-square test with adjusted standardized residuals was used to determine whether cognitive frailty significantly affected the dementia incidence. Residuals followed the t distribution: t > 1.96 was accepted as indicating P < .05 and t > 2.56 as P < .01. Participants who moved away or died were excluded from the univariate analyses of dementia incidence.

We calculated the cumulative dementia incidence during the follow-up according to the baseline frailty status grouping. Intergroup differences were estimated using the log-rank test. Cox proportional-hazards regression models were used to analyze associations between cognitive frailty and dementia incidence. After adjusting for age and sex for Model 1, we then used a multiple adjustment model that was adjusted for demographic variables, primary diseases, lifestyle, and psychological variables as possible confounding factors. Adjusted hazard ratios (HRs) for dementia incidence and their 95% confidence intervals (CIs) were estimated. All analyses were performed using IBM SPSS v.20.0 (IBM Japan, Tokyo). Statistical significance was set at P < .05.

Results

The robust, physical frailty, cognitive impairment, and cognitive frailty groups accounted for 88.4%, 5.1%, 5.5%, and 1.1% of participants, respectively. Eighty-one participants (2.0%) were diagnosed with dementia; 16 participants (0.4%) moved away from Obu, and 43 (1.1%) participants died during the follow-up period. The prevalence rates of dementia incidence in the robust, physical frailty, cognitive impairment, and cognitive frailty groups were 1.3%, 5.8%, 6.3%, and 18.6%, respectively. In the residual analyses, the cognitive frailty group included significantly more participants with incident dementia (P < .01).

Table 1 presents the possible confounding factors for dementia incidence for participants grouped according to frailty status and the presence or absence of dementia. Significant differences were found for age, sex, educational level, GDS score, pulmonary disease, hypertension, and diabetes between the cognitive frailty subgroups. Age, sex, educational level, and GDS differed significantly between participants with and without dementia.

Table 1.

Comparisons of baseline characteristics according to frailty status and between participants with and without dementia

Frailty status Robust (n = 3601) Physical frailty (n = 206) Cognitive impairment (n = 222) Cognitive frailty (n = 43) P value Dementia status With dementia (n = 81) Without dementia (n = 3932) P value
Age (years)* 71.1 (4.9) 76.9 (6.5) 72.9 (5.2) 77.2 (6.0) < .001 76.1 (5.7) 71.5 (5.2) < .001
Sex (male)** 1775 (49.3) 90 (43.7) 107 (48.2) 13 (30.2) .005 30 (37.0) 1913 (48.7) .038
Education (years)* 11.6 (2.5) 10.6 (2.6) 10.8 (2.5) 9.6 (2.5) < .001 11.5 (2.5) 10.4 (2.6) < .001
GDS-15 score* 2.5 (2.4) 4.8 (3.0) 3.1 (2.6) 5.1 (3.2) < .001 3.3 (2.8) 2.6 (2.5) < .001
Smoking (yes)** 630 (8.2) 48 (7.6) 52 (11.3) 9 (8.3) .116 9(11.1) 384 (9.8) .687
Heart disease (yes)** 553 (15.4) 44 (21.4) 36 (16.2) 10 (23.3) .067 18 (22.2) 609 (15.5) .098
Pulmonary disease (yes)** 389 (10.8) 34 (16.5) 19 (8.6) 3 (7.0) .035 11 (13.6) 421 (10.7) .409
Hypertension (yes)** 1549 (43.0) 110 (53.4) 109 (49.1) 20 (46.5) .010 36 (44.4) 1727 (43.9) .925
Hyperlipidemia (yes)** 1500 (41.7) 86 (41.7) 75 (33.8) 15 (34.9) .108 31 (38.3) 1632 (41.5) .559
Diabetes (yes)** 445 (12.4) 47 (22.8) 33 (14.9) 9 (20.9) < .001 11 (13.6) 510 (13.0) .872
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* Mean (SD), ** Number (%)

Figure 1 presents the dementia survival rates for the frailty status subgroups. Survival analyses using the Kaplan–Meier analysis and log-rank tests showed that the probability of dementia was significantly higher in the physical frailty, cognitive impairment, and cognitive frailty groups compared with the robust group (P < .001). Additionally, significant differences were found in dementia incidence between the cognitive frailty and physical frailty groups (P = .004) and between the cognitive frailty and cognitive impairment groups (P = .006). No significant difference was found between the physical frailty and cognitive impairment groups (P = .850).

Figure 1.

Figure 1

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Kaplan-Meier estimates of the rates of dementia incidence according to frailty status

a: robust group, b: physical frailty group, c: cognitive impairment group, d: cognitive frailty group.

Cox proportional-hazards regression models were used to analyze the associations between frailty and dementia incidence (Table 2). In the first model (Model 1), which was adjusted for age, sex, and educational level, compared with the robust group, a significantly higher dementia incidence was found for the physical frailty group (HR: 2.33, 95% CI: 1.17–4.61), cognitive impairment group (HR: 4.16, 95% CI: 2.28–7.61), and cognitive frailty group (HR: 7.60, 95% CI: 3.42–16.88). Age was significantly associated with increased dementia incidence. In the fully adjusted model (Model 2), compared with robust participants, the following HR were obtained: 1.95 (95% CI 0.97–3.91) for the physical frailty group; 3.85 (95% CI: 2.09–7.10) for the cognitive impairment group; and 6.19 (95% CI: 2.73–13.99) for the cognitive frailty group. No significant association was found between physical frailty and dementia incidence. In Model 2, age, sex, and GDS score correlated positively with the incidence of dementia.

Table 2.

Hazard ratios for dementia according to frailty status and confounding factors

 Model 1
 Model 2
Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value
Age, years* 1.10 (1.06-1.15) < .001 1.11 (1.06-1.15) < .001
Sex, male 0.67 (0.42-1.06) .089 0.59 (0.36-0.97) .039
Education, years* 0.97 (0.88-1.07) .561 0.99 (0.90-1.09) .817
GDS-15, score* − 1.09 (1.01-1.18) .020
Smoking (yes) − 1.78 (0.85-3.71) .126
Heart disease (yes) − 1.28 (0.75-2.19) .365
Pulmonary disease (yes) − 1.16 (0.61-2.21) .659
Hypertension (yes) − 0.85 (0.55-1.33) .482
Hyperlipidemia (yes) − 0.95 (0.60-1.51) .830
Diabetes (yes) − 0.96 (0.50-1.82) .891
Frailty status (robust) 1 1
Physical frailty 2.33 (1.17-4.61) .016 1.95 (0.97-3.91) .062
Cognitive impairment 4.16 (2.28-7.61) < .001 3.85 (2.09-7.10) < .001
Cognitive frailty 7.60 (3.42-16.88) < .001 6.19 (2.73-13.99) < .001
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* Mean (standard deviation)

Discussion

In this prospective study, dementia risk was significantly positively associated with physical frailty, cognitive impairment, and cognitive frailty. Several cross-sectional studies have reported an association between physical frailty and cognitive function. (10, 30, 31, 32) In addition, longitudinal studies indicate that physical frailty is associated with an increased risk of incident AD (33, 34) and mild cognitive impairment (MCI). (35, 36) There are sufficient data to recommend the evaluation and clinical monitoring of persons with MCI because of their increased dementia risk. (37) Screening instruments (e.g., the Mini-Mental State Examination) have proven to be clinically useful in measuring cognitive impairment, as have neuropsychological batteries, brief focused cognitive instruments, and certain structured informative interviews (37). In prospective studies of people with amnestic MCI, measures of episodic memory (38, 39), semantic memory (39, 40) and executive function (41, 42) have consistently predicted conversion to dementia. Multi-domain cognitive tests (e.g., examining general cognitive function, memory, and executive function) are useful for assessing the risk of dementia in older individuals. The NCGG-FAT, an iPad application, comprises the domains of memory, attention, executive function, and processing speed. All of its tests possess established standardized thresholds for the definition of cognitive impairment in the corresponding domain (scores > 1.5 SDs below age- and education-specific means) for population-based cohorts comprising community-dwelling older persons. We consider that early detection of the risk of physical and cognitive decline using validated test batteries, such as the frailty criteria or NCGG-FAT, would help to identify and possibly delay the appearance of dementia in community and clinical settings.

The associations between dementia risk and cognitive impairment and cognitive frailty remained significant after adjusting for age, sex, educational level, depressive mood, and the presence or absence of chronic medical illnesses. Compared with the robust group, the risk of dementia incidence was 3.9 times and 6.2 times higher in the groups with cognitive impairment and cognitive frailty, respectively. Our data are consistent with those of other prospective studies and indicate that older people with motoric cognitive risk syndrome (defined and operationalized similarly to cognitive frailty) are at higher risk of incident dementia and especially of incident vascular dementia (43). Risk factors affecting cardiovascular disease and common vascular diseases correlate with frailty (44) and AD (45). Increased levels of inflammatory markers (e.g., C-reactive protein, proinflammatory interleukins) are common and have been implicated in frailty (46), cognitive impairment (47), and AD (48, 49). Neuropathological changes occurring with AD may also underlie the link between frailty and AD. AD neuropathology is known to diffuse into the brain fields involved in motor control such as the substantia nigra, primary and supplementary motor cortices, and striatum. In particular, striatal diffuse plaques occur relatively early in the progression of AD pathology and coincide with neocortical pathology and cognitive changes (50). Further, AD pathology such as plaque and tangled brain cells may contribute to the progression of physical frailty (51).

Older persons who show signs of physical frailty and cognitive impairment may be more likely to develop functional decline than are those with either physical frailty or cognitive impairment. We found that individuals with cognitive frailty were at the highest risk of limitations to instrumental ADL (18) and that older individuals with cognitive frailty were at higher risk of dementia than were those with only physical frailty or cognitive impairment. Health care providers should therefore implement physical assessment as well as cognitive assessment to evaluate dementia risk. Furthermore, multimodal, multifactor, and multilevel interventions addressing the physical and cognitive domains may be useful in identifying and possibly delaying the future appearance of dementia among older persons and especially among those with cognitive frailty (52, 53).

This study has the following limitations. First, participants were not randomly recruited, and this may have caused underrepresentation of physical frailty and cognitive impairment because the participants were sufficiently healthy to receive the health checkups in their homes. Second, data were not collected about the dementia subtype (e.g., AD, vascular dementia, dementia with Lewy bodies, frontotemporal dementia). The data thus do not permit inferences regarding the correlations between frailty and dementia pathology. Third, we were unable to contact an informant (e.g., a family member) to verify medical records, lifestyle information, and asymptomatic aberrant behavior for some participants. Finally, information was collected about the participants’ medical conditions and comorbidities via self-report, and because we did not have access to medical records, we were unable to confirm these reports. However, in earlier research, self-reported medical conditions and actual medical diagnoses have agreed well (54).

This study has the following strengths and implications. A strength is that our findings are consistent with comprehensive geriatric assessments designed to identify frailty and cognitive impairment. In addition, to our knowledge, this is the first study to use a large population-based sample to examine correlations between cognitive frailty and dementia incidence. Our study showed that individuals with coexisting physical frailty and cognitive impairment faced an elevated risk of incident dementia compared with both robust older persons and older persons with either physical frailty or cognitive impairment.

To summarize, the present results indicate that physical frailty, cognitive impairment, and cognitive frailty affect the incidence of dementia in older persons. This is especially evident in older persons with comorbid physical frailty and cognitive impairment, who appear to face a higher risk of dementia compared with both robust older persons and older persons with either physical frailty or cognitive impairment.

Acknowledgements: We wish to thank the health care staff involved in this study for their assistance with the assessments: Dr. Sung Chul Lee, Dr. Kazuhiro Harada, Dr. Ryo Hotta, Ms. SeongRyu Bae, Mr. Sho Nakakubo, Mr. Kenji Harada, Dr. Daisuke Yoshida, and Mr. Yuya Anan.

Statement of author’s contributions to manuscript: Shimada planned the study and wrote the first draft of the manuscript, and coordinated the review and editing process leading to the final manuscript. Makizako, Sangyoon Lee, and Doi participated in the design of the study and wrote the paper. SungChul Lee, Tsutsumimoto, Kazuhiro Harada, Hotta, Bae, Nakakubo, and Kenji Harada corrected data and contributed to the editorial process and review of the manuscript. Suzuki supervised the study and suggested many of the ideas that have been pursued in this research, and participated in the planning, editorial, and review processes that led to the final manuscript.

Ethical standards: Ethical standards for epidemiological study were adhered to according to guidelines from the Ministry of Health, Labour and Welfare, Japan.

Sources of Financial Support: This work was supported by the Health and Labor Sciences Research Grants (Comprehensive Research on Aging and Health), the Research Institute of Science and Technology for Society (RISTEX) from the Japan Science and Technology Agency (JST) for redesigning communities for aged society in 2012, a Grant-in-Aid for Scientific Research (B) (grant number 23300205), Research Funding for Longevity Sciences (22–16) from the National Center for Geriatrics and Gerontology, Japan, and MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2015-2019 from the Ministry of Education, Culture, Sports, Science and Technology (S1511017).

Conflicts of interest disclosure: There are no conflicts of interest.

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