Highlights
-
•
Lower MMSE scores—even by a single point—were independently associated with a significantly higher risk of developing ADRD.
-
•
Individuals with MMSE scores between 27 and 30 should not be viewed as a uniform group.
-
•
Further studies are needed to find ways to prevent ADRD in people who are at risk but do not yet show symptoms.
Key Words: Alzheimer’s disease and related dementias, Cardiovascular Health Study, MMSE, Older adults
Abstract
Background
The Mini-Mental State Examination (MMSE) is commonly used in clinical and research settings to assess cognitive function and scores 27–30 are considered normal. Whether individuals with lower MMSE scores within this normal range are at increased risk for Alzheimer’s disease and related dementias (ADRD) remains unclear. We sought to examine this question in the current study.
Methods
In the Cardiovascular Health Study (CHS), 4433 community-dwelling adults ≥ 65 years had MMSE 27–30: MMSE-30 (n = 1228), MMSE-29 (n = 1353), MMSE-28 (n = 1079) and MMSE-27 (n = 773). HR (95% CI) for incident ADRD during 23 years of follow-up associated with MMSE-29, MMSE-28, and MMSE-27 were estimated, adjusting for 27 baseline characteristics including activities of daily living (ADL) impairment. ADRD was defined using International Classification of Diseases (ICD) codes.
Results
Individuals with MMSE-30, MMSE-29, MMSE-28, and MMSE-27 had mean ages of 71.1, 71.9, 72.6, and 73.4 years, and mean ADL impairment scores of 0.06, 0.08, 0.12 and 0.16, respectively (both p < 0.001). Overall, 59% were women and 10% African American. ADRD occurred in 8.5%, 11.4%, 12.5% and 13.6% of those with MMSE-30, MMSE-29, MMSE-28, and MMSE-27, respectively. Compared with MMSE-30, HR (95% CI) for incident ADRD for MMSE-29, MMSE-28, and MMSE-27 were 1.48 (1.16–1.90), 1.82 (1.42–2.35) and 2.15 (1.64–2.82), respectively. These associations varied by age, sex, race, education, and self-reported general health.
Conclusions
These findings suggest that among community-dwelling older adults with normal MMSE, lower scores were associated with impaired ADL and significant, independent, and incrementally higher risk of ADRD.
Introduction
Alzheimer’s disease and related dementias (ADRD) represent a growing public health challenge,1 the societal and healthcare burden of which is projected to increase substantially in the coming decades.2,3 Early identification of individuals at risk for ADRD has therefore become a critical goal of both clinical care and population health strategies. Mini-Mental State Examination (MMSE) is widely used in clinical and research settings to assess global cognitive function.4,5, 6, 7, 8 Lower MMSE scores have been shown to be associated with higher risk of cognitive decline and ADRD.9, 10, 11, 12, 13, 14 Less is known about the prognostic value of lower MMSE in older adults with normal MMSE, particularly those living in the community. The objective of our study was to examine whether small decrements in baseline MMSE scores, even within the normal range, were independently associated with higher risk of future ADRD, after adjusting for sociodemographic and clinical covariates.
Methods
Data Source and Study Population
Funded by the United States National Heart, Lung, and Blood Institute (NHLBI), the Cardiovascular Health Study (CHS) is a cohort study to investigate risk factors for cardiovascular disease in 6888 community-dwelling older Americans.15 Starting 1987, the CHS enrolled 5201 participants ≥ 65 years, later complementing in 1992 with 687 African American participants. The study participants were enrolled from Forsyth County, North Carolina, Sacramento County, California, Washington County, Maryland, and Pittsburgh, Pennsylvania. For the current analysis, we used a public-use copy of the data obtained from NHLBI’s Biologic Specimen and Data Repository Coordinating Center, BioLINCC that included 5795 individuals who consented to be included in the public-use version of the data. After excluding 1362 individuals with MMSE < 27, the final study cohort consisted of 4433 older adults with MMSE 27 to 30 (Figure 1). Because CHS participants with MMSE 27 or higher were considered to have normal cognitive function, all CHS participants included in our study were considered to be at risk for incident ADRD.
Figure 1.
Flow chart displaying assembly of the study cohort with normal baseline Mini-Mental Status Examination (MMSE) in the Cardiovascular Health Study (CHS)
Study Exposure: MMSE
Information about baseline cognitive function was assessed using a 30-point MMSE16 in all CHS participants. Participants with MMSE ≥ 27 were considered normal. The MMSE questionnaire asks participants to provide information on their physical location and perform certain tasks. Based on their response or performance of the task the interviewer scores the activity as correct or in error. Of the 4433 CHS participants with normal cognitive function, 1228 had MMSE-30,1353 had MMSE-29,1079 had MMSE-28, and 773 had MMSE-27 (Figure 1).
Study Outcomes: Incident ADRD
Our primary outcome is time to the first occurrences of incident ADRD. Because ADRD was not a pre-specified CHS outcome and was not centrally adjudicated by CHS, it is defined using International Classification of Diseases (ICD) codes for ADRD. Information on ICD codes was obtained by CHS investigators by abstracting charts of CHS participants who had hospitalizations in CHS catchment area hospitals.
Statistical Analysis
Baseline characteristics of the four MMSE groups were compared using Pearson’s Chi-Square for categorical variables and one-way ANOVA test for continuous variables. We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs (CIs) for time to the occurrence of ADRD associated with MMSE 29, 28, and 27, using MMSE 30 as a reference. Patients were followed up for 23 years. Individuals who did not have ADRD were censored at study end or death, whichever came first. Subgroup analyses were conducted to determine the homogeneity of the association. SPSS for Windows (Version 29) was used for data analysis.
Results
Baseline Characteristics
The 4433 participants with baseline MMSE 30, 29, 28 and 27 had a mean age of 71.1 (±4.7), 71.9 (±4.9), 72.6 (±5.3), and 73.4 (±5.6) years, respectively (p < .001), 59.3%, 61.3%, 58.2%, and 55.1% (p = .40) were women, 5.8%, 8.1%, 11.9%, and 16.8% were African American (p < 0.001) (Table 1). The proportions with college or higher education were 58.1%, 49.4%, 44.2%, and 40.0% (p < .001) and with self-reported fair to poor health were 14.2%, 20.8%, 23.2%, and 27.9% (p < .001) in the MMSE 30, 29, 28 and 27 groups, respectively. The prevalences of cardiometabolic morbidities such as hypertension, diabetes mellitus, coronary artery disease, and chronic kidney disease were significantly higher in the groups with decreasing MMSE. However, such association was not observed for prevalence of non-cardiovascular morbidity such as cancer or chronic obstructive pulmonary disease.
Table 1.
Baseline Characteristics of 4433 Older Adults Without ADRD By MMSE.
| MMSE 30 | MMSE 29 | MMSE 28 | MMSE 27 | P values | |
|---|---|---|---|---|---|
| N = 1228 (27.7%) | N = 1353 (30.5%) | N = 1079 (24.3%) | N = 773 (17.4%) | ||
| Demographics | |||||
| Age (years) | 71.1 (±4.7) | 71.9 (±4.9) | 72.6 (±5.3) | 73.4 (±5.6) | <.001 |
| Female | 728 (59.3%) | 830 (61.3%) | 628 (58.2%) | 426 (55.1%) | .040 |
| African American | 71 (5.8%) | 109 (8.1%) | 128 (11.9%) | 130 (16.8%) | <.001 |
| Married | 871 (70.9%) | 937 (69.3%) | 715 (66.3%) | 514 (66.5%) | .009 |
| Education, ≥college | 714 (58.1%) | 669 (49.4%) | 477 (44.2%) | 390 (40.0%) | <.001 |
| Living alone | 135 (11.0%) | 140 (10.3%) | 124 (11.5%) | 85 (11.0%) | .768 |
| Past Medical History | |||||
| General health fair or poor | 174 (14.2%) | 282 (20.8%) | 250 (23.2%) | 216 (27.9%) | <.001 |
| Hypertension | 638 (52.0%) | 787 (58.2%) | 624 (57.8%) | 457 (59.1%) | .002 |
| Diabetes mellitus | 148 (12.1%) | 209 (15.4%) | 161 (14.9%) | 157 (20.3%) | <.001 |
| Coronary artery disease | 181 (14.7%) | 251 (18.6%) | 221 (20.5%) | 168 (21.7%) | <.001 |
| Coronary artery bypass surgery | 50 (6.5%) | 55 (5.1%) | 56 (4.1%) | 42 (3.4%) | <.001 |
| Chronic kidney disease | 211 (17.2%) | 281 (20.8%) | 236 (21.9%) | 179 (23.2%) | .001 |
| Atrial fibrillation | 20 (1.6%) | 30 (2.2%) | 33 (3.1%) | 22 (2.8%) | .026 |
| TIA | 30 (2.4%) | 25 (1.8%) | 26 (2.4%) | 27 (3.5%) | .141 |
| COPD | 155 (12.6%) | 193 (14.3%) | 125 (11.6%) | 87 (11.3%) | .165 |
| Arthritis | 574 (46.7%) | 695 (51.4%) | 529 (49.0%) | 425 (55%) | .003 |
| Cancer | 200 (16.3%) | 203 (15.0%) | 145 (13.4%) | 135 (17.5%) | .993 |
| Lifestyle | |||||
| Current smoker | 147 (12.0%) | 148 (10.9%) | 131 (12.1%) | 87 (11.3%) | .871 |
| Alcohol (drinks/week) | 3.3 (±7.5) | 2.6 (±6.4) | 2.4 (±5.7) | 2.2 (±6.1) | <.001 |
| Medications | |||||
| ACE inhibitors | 62 (5.0%) | 100 (7.4%) | 71 (6.6%) | 61 (7.9%) | .029 |
| Beta blockers | 165 (13.4%) | 183 (13.5%) | 143 (13.3%) | 96 (12.4%) | .530 |
| CCB | 129 (10.5%) | 172 (12.7%) | 146 (13.5%) | 113 (14.6%) | .004 |
| Thiazide diuretics | 136 (11.1%) | 140 (10.3%) | 117 (10.8%) | 82 (10.6%) | .830 |
| Aspirin | 27 (2.2%) | 50 (3.7%) | 28 (2.6%) | 37 (4.8%) | .015 |
| Statins | 21 (1.7%) | 22 (1.6%) | 32 (3.0%) | 20 (2.6%) | .039 |
| Functional/Geriatric Variables | |||||
| IADL impairment (ratio) | 0.27 (±0.60) | 0.3 (±0.61) | 0.31 (±0.69) | 0.36 (±0.71) | .036 |
| ADL impairment (ratio) | 0.06 (±0.30) | 0.08 (±0.36) | 0.12 (±0.48) | 0.16 (±0.60) | <.001 |
| Walking in one week (blocks) | 47.7 (±61.7) | 40.4 (±53.9) | 40.0 (±53.7) | 36.0 (±50.7) | <.001 |
| CES depression (score) | 3.9 (±3.9) | 4.4 (±4.4) | 4.7 (±4.7) | 5.0 (±4.6) | <.001 |
| Met minutes (kcal/kg/min) | 1228 (1482) | 1353 (1363) | 1079 (1366) | 773 (1248) | .009 |
| Clinical Features/Vital Signs | |||||
| Body mass index (kg/m²) | 26.2 (±4.1) | 26.6 (±3.9) | 26.7 (±4.0) | 26.8 (±4.2) | .016 |
| Pulse (beats per minute) | 67.5 (±11.0) | 67.6 (±10.7) | 67.4 (±10.8) | 68.2 (±11.6) | .389 |
| Systolic BP (mm Hg) | 133.8 (±20.5) | 135.5 (±20.9) | 135.5 (±22.0) | 138.3 (±22.7) | <.001 |
| Diastolic BP (mm Hg) | 70.8 (±10.8) | 70.9 (±10.8) | 70.3 (±11.6) | 70.7 (±11.6) | .664 |
| Ankle-arm index (ratio) | 1.09 (±0.16) | 1.08 (±0.15) | 1.07 (±0.18) | 1.05 (±0.18) | <.001 |
| Laboratory Data | |||||
| Serum glucose (mg/dL) | 108.0 (±32.4) | 110.9 (±35.6) | 109.9 (±31.6) | 113.5 (±36.8) | .005 |
| Serum creatinine (mg/dL) | 0.92 (±0.38) | 0.93 (±0.30) | 0.96 (±0.42) | 0.98 (±0.32) | <.001 |
| Serum uric acid (mg/dL) | 5.6 (±1.5) | 5.6 (±1.4) | 5.7 (±1.5) | 5.7 (±1.6) | .017 |
| Hemoglobin (g/dL) | 14.09 (±1.30) | 14.10 (±1.26) | 14.06 (±1.37) | 13.99 (±1.42) | .249 |
| Serum cholesterol (mg/dL) | 209.1 (±38.6) | 213.4 (±38.1) | 212.3 (±39.2) | 210.6 (±38.1) | .031 |
| Serum albumin (g/dL) | 3.99 (±0.29) | 4.01 (±0.29) | 4.00 (±0.28) | 4.00 (±0.30) | .334 |
| Serum C-reactive protein (mg/L) | 4.00 (±7.45) | 4.56 (±6.80) | 4.61 (±8.00) | 4.98 (±7.65) | .027 |
| Serum insulin (mg/dL) | 17.0 (±27.0) | 16.2 (±18.4) | 18.1 (±32.7) | 17.1 (±22.6) | .452 |
Baseline MMSE and Incident ADRD in Individuals with Normal MMSE
During 23 years of follow-up, incident ADRD occurred in 104 (8.5%), 154 (11.4%), 135 (12.5%), and 105 (13.6%) among individuals with MMSE 30, 29, 28 and 27, respectively. When compared with MMSE 30, unadjusted HRs (95% CIs) for ADRD associated with MMSE 29, 28 and 27 were 1.48 (1.16–1.90), 1.82 (1.42–2.35), and 2.15 (1.64–2.82), respectively (Table 2). Respective age-sex-race-adjusted HRs (95% CIs) were 1.41 (1.10–1.81), 1.70 (1.31–2.19), and 1.89 (1.44–2.49), which were unchanged when adjusted for additional baseline characteristics (Figure 2). The age-sex-race-adjusted associations of MMSE 29, 28, and 27 with incident ADRD in key subgroups of older adults without ADRD at baseline by age, sex, race, education and self-reported general health are presented in Table 3. Other significant independent predictors of incident ADRD during 22 years of follow-up included each year of age (HR, 1.11; 95% CI, 1.08–1.13), each unit of body mass index (HR, 0.97; 95% CI < 0.94–0.99), abnormal left ventricular systolic function (HR, 1.52; 95% CI, 1.05–2.20).
Table 2.
New-onset ADRD in 4433 Older Adults Without ADRD By MMSE.
| MMSE 30 | MMSE 29 | MMSE 28 | MMSE 27 | |
|---|---|---|---|---|
| N = 1228 (27.7%) | N = 1353 (30.5%) | N = 1079 (24.3%) | N = 773 (17.4%) | |
| ADRD, n (%) | 104 (8.5%) | 154 (11.4%) | 135 (12.5%) | 105 (13.6%) |
| Unadjusted HR (95% CI) | 1.00 | 1.48 (1.16–1.90) | 1.82 (1.42–2.35) | 2.15 (1.64–2.82) |
| Age, sex, and race adjusted | 1.00 | 1.41 (1.10–1.81) | 1.70 (1.31–2.19) | 1.89 (1.44–2.49) |
| Multivariable adjusted* | 1.00 | 1.43 (1.11–1.84) | 1.73 (1.33–2.25) | 1.95 (1.47–2.59) |
Abbreviations: CI, confidence interval.
In addition to age, sex, and race, the model was also adjusted for marital status, living status, education, current smoking, pack-year of smoking, duration of smoking cessation, alcohol consumption, self-reported general health, hypertension, coronary artery disease, chronic kidney disease, atrial fibrillation, stroke, chronic obstructive pulmonary disease, arthritis, anemia, cancer, ACE inhibitors, beta-blockers, alpha-blockers, calcium channel blockers, vasodilators, thiazide diuretics, loop diuretics, potassium supplements, nitrates, aspirin, statins, NSAIDs, impairments of basic and instrumental activities of daily living, daily energy expenditure as Met-minutes, physical activity as measures by number of blocks walked in past week, body mass index, pulse, systolic and diastolic blood pressure, depression scores, ankle-brachial index, left ventricular hypertrophy, left ventricular systolic function, serum values of glucose, creatinine, potassium, total and LDL cholesterol, triglyceride, albumin, uric acid, fibrinogen, interlukin-6, insulin, and C-reactive protein.
Figure 2.
Survival plots displaying the risk of Alzheimer’s disease and related dementias (ADRD) in the Cardiovascular Health Study (CHS) with normal baseline Mini-Mental Status Examination (MMSE). Using MMSE score 30 as the reference category (HR = 1.00), progressively lower but still normal scores were associated with increased ADRD risk: MMSE 29 (HR 1.41, 95% CI 1.10–1.81), MMSE 28 (HR 1.70, 95% CI 1.31–2.19), and MMSE 27 (HR 1.89, 95% CI 1.44–2.49). These results suggest that subtle differences within the normal MMSE range are associated with graded increases in future ADRD risk.
Table 3.
Age, Sex, and Race Adjusted Risk of New-Onset ADRD in Subgroups of 4433 Older Adults Without ADRD At Baseline By MMSE.
| MMSE 30 | MMSE 29 | MMSE 28 | MMSE 27 | |
|---|---|---|---|---|
| N = 1228 (27.7%) | N = 1353 (30.5%) | N = 1079 (24.3%) | N = 773 (17.4%) | |
| Age | ||||
| ≤70 years (n = 2063) | 1.00 | 1.58 (1.09–2.27) | 1.67 (1.12–2.48) | 1.91 (1.23–2.98) |
| ≥71 years (n = 2370) | 1.00 | 1.35 (0.96–1.90) | 1.76 (1.25–2.46) | 2.03 (1.42–2.89) |
| Sex | ||||
| Male (n = 1821) | 1.00 | 1.65 (0.63–1.53) | 1.81 (1.32–2.49) | 1.95 (1.38–2.77) |
| Female (n = 2612) | 1.00 | 0.98 (0.96–1.90) | 1.46 (0.94–2.27) | 1.70 (1.09–2.67) |
| Race | ||||
| Whites (n = 3995) | 1.00 | 1.46 (1.13–1.89) | 1.67 (1.27–2.18) | 2.01 (1.51–2.68) |
| African American (n = 438) | 1.00 | 0.84 (0.30–2.34) | 1.64 (0.64–4.16) | 1.01 (0.37–2.73) |
| Education | ||||
| College or higher (n = 2169) | 1.00 | 1.27 (0.91–1.80) | 1.61 (1.13–2.29) | 1.68 (1.12–2.51) |
| Less than college (n = 2264) | 1.00 | 1.56 (1.07–2.27) | 1.79 (1.22–2.63) | 2.13 (1.43–3.17) |
| Self-reported general health | ||||
| Good or excellent (n = 3511) | 1.00 | 1.63 (1.24–2.14) | 1.83 (1.38–2.43) | 2.04 (1.50–2.77) |
| Poor to fair (n = 922) | 1.00 | 0.56 (0.29–1.09) | 1.06 (0.57–1.95) | 1.66 (0.63–2.16) |
Mortality
During 23 years of follow-up, death occurred in 916 (74.6%), 1072 (79.2%), 877 (81.3%), and 635 (82.1%) among individuals with MMSE 30, 29, 28 and 27, respectively. When compared with MMSE 30, unadjusted HRs (95% CIs) for death associated with MMSE 29, 28 and 27 were 1.15 (1.06–1.26), 1.31 (1.19–1.43), and 1.40 (1.27–1.55), respectively. Respective age-sex-race-adjusted HRs (95% CIs) were 1.09 (1.00–1.19), 1.20 (1.09–1.31), and 1.11 (1.10–1.12), and multivariable-adjusted HRs (95% CIs) were 1.05 (0.96–1.14), 1.18 (1.08–1.30), and 1.04 (0.93–1.56). Other significant independent predictors of death included each year of age (HR, 1.10; 95% CI, 1.09–1.10), female sex (HR, 0.74; 95% CI, 0.66–0.82), African American race (HR, 0.75; 95% CI, 0.66–0.86), fair to poor self-reported general health (HR, 1.28; 95% CI, 1.17–1.40), left ventricular hypertrophy (HR, 1.47; 95% CI, 1.25–1.74), abnormal left ventricular systolic function (HR, 1.50; 95% CI, 1.33–1.69), and morbidities such as coronary artery disease, diabetes mellitus, chronic kidney disease, stroke, chronic obstructive pulmonary disease, anemia, and cancer.
Discussion
In this longitudinal analysis of 4433 community-dwelling older adults with normal baseline MMSE scores followed over the two decades, we found that lower MMSE scores—even by a single point—were independently associated with a significantly higher risk of developing ADRD. Compared with those scoring a perfect 30, the adjusted risk for ADRD was approximately 42% higher for those scoring 29, 71% higher for those scoring 28, and nearly doubled for those scoring 27. These findings support the concept that a small decline in baseline MMSE score, even within the accepted ``normal'' range, might reflect early subclinical neurodegenerative changes that may not be readily recognized in routine clinical assessments.
Older age, female sex, African American race, lower education, and poor general health are associated with lower MMSE scores.17, 18, 19 Thus, a normal baseline MMSE (≥27) in persons with these characteristics would be considered less likely than for a person who was younger, male, white with higher education, and overall good health. We observed that the hazard ratio for ADRD associated with MMSE 29 in individuals with older age, female sex, African American race, and poor general health was numerically lower than their counterparts with younger age, male sex, white race, and good general health. This suggests the possibility that other unmeasured variables that may have enabled these persons to achieve a baseline MMSE score of 29, could also have helped them maintain cognitive function over time. Interestingly, this pattern was less evident among individuals with lower educational attainment. The risk of ADRD associated with MMSE 29 in individuals with less than college education was numerically higher than those with college or higher education. This finding suggests that in addition to education, other social determinants of health, such as quality healthcare, income, social connections, and neighborhood characteristics may be some of the unmeasured characteristics important to the variability in risk for ADRD among persons with a normal MMSE.
Several prior studies have examined the association of lower MMSE scores and a higher risk of developing ADRD.13,20,21 In one study, 1045 individuals 65 to 88 years free of dementia underwent neuropsychological screening examination, those with lower scores for measures of new learning, recall, retention, and abstract reasoning had a higher risk developing ADRD.21 Although MMSE does not specifically measure abstract reasoning, which involves understanding complex concepts and relationships, the findings of our study are consistent with that study. However, our study is distinguished by its larger sample size, racial diversity, and normal MMSE at baseline. Future studies need to examine the risk of ADRD associated with MMSE 24-26, which are consistent with mild cognitive impairment (MCI).
The findings of our study have potential clinical and public health implications. They suggest that individuals with MMSE scores between 27 and 30 should not be viewed uniformly and clinicians should consider a drop in MMSE within normal range a potential harbinger for ADRD. Clinicians should consider conversations with patients and families about potential implications of a drop in MMSE, even in the absence of clinical evidence of cognitive decline, and recommend lifestyle modifications to support cognitive health, and proactive care planning. These discussions may include recommendations for physical activity, 22 social engagement, vascular risk factor management, and sleep hygiene. However, it is crucial to approach these conversations with sensitivity to avoid causing unnecessary anxiety or stigma. Providing clear and compassionate information about the nature of cognitive decline can empower patients and reduce the fear associated with these assessments. These findings underscore the importance of additional research into identifying preventive strategies for ADRD, especially for individuals with normal MMSE scores who may still be at increased risk. These findings also suggest that interventions targeting early cognitive decline should be personalized based on educational attainment and other sociodemographic factors. For patients with lower-normal MMSE scores, particularly those with lower education, more proactive monitoring and tailored interventions may be necessary.
Study Limitations
This study has several limitations. ADRD diagnoses were based on hospital discharge codes, which may underestimate true incidence or introduce misclassification. Also, MMSE has limited sensitivity for detecting subtle cognitive deficits and may be influenced by educational or cultural factors23,24 as suggested by our subgroup analysis by education. Although we adjusted for many baseline characteristics including functional status, residual confounding from unmeasured factors such as APOE ε4 genotype, cerebrovascular imaging findings, or biomarkers of neurodegeneration levels is possible. Emerging plasma and cerebrospinal fluid markers, such as amyloid-β42 and phosphorylated tau (e.g., p-tau217, p-tau181), are increasingly recognized as predictors of ADRD risk.25,26 Finally, the classification of “normal” MMSE scores (27–30) as a risk continuum presumes linearity which may not be tenable. We had considered cubic spline regression model to test for linearity. However, the four data points in the range of MMSE scores from 27 to 30 limits our ability to test for a nonlinear relationship. While our results suggest that lower MMSE scores within the normal range are independently associated with an elevated risk of ADRD, these findings do not exclusively indicate a linear progression. The observed associations could be influenced by unmeasured confounding factors or reflect a threshold effect rather than a continuous linear relationship. Future studies need to test for nonlinearity to better characterize the relationship between baseline normal MMSE and the risk of ADRD.
Conclusion
Among older adults with normal cognitive performance at baseline, even small decrements in MMSE score were associated with a graded and independent increase in long-term risk of ADRD. These findings suggest that the MMSE may serve a role in risk-stratifying cognitively intact older adults. Future work is needed to determine whether combining MMSE with other biomarkers or imaging tools can improve early identification and guide prevention strategies in the preclinical stages of ADRD.
CRediT authorship contribution statement
Mo-Kyung Sin: Writing – review & editing, Writing – original draft, Methodology, Investigation, Funding acquisition. Richard M. Allman: Writing – review & editing. Yuting Lin: Writing – review & editing. Fatemeh Choupani: Writing – review & editing. Ali Ahmed: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Charles Faselis: Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Funding acquisition.
Declaration of competing interest
None.
Acknowledgment
This manuscript was prepared using CHS Research Materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. The content is solely the responsibility of the authors and does not necessarily reflect the opinions or views of the CHS or the NHLBI.
CHS was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants U01HL080295, U01HL130114 and R01HL172803 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.
Footnotes
Funding: Dr. Sin was in part supported by research grants from the National Institutes of Health (1R03AG072110 and 1R03AG070579). Dr. Ahmed was in part supported by research grants from the National Institutes of Health (1RF1AG069121, 1R01HL156518, and 1R01AG073474) and the Department of Veterans Affairs (I01HX002422, 1I01HX003552, and 1I01HX003757). Dr. Faselis was in part supported by research grants from the Department of Veterans Affairs (1I01HX003757).
Authorship: This manuscript was prepared using CHS data obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) and does not necessarily reflect the opinions or views of the CHS or the NHLBI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs.
References
- 1.Alzheimer’s facts and figures report | Alzheimer’s Association. Accessed January 28, 2025. https://www.alz.org/alzheimers-dementia/facts-figures
- 2.Liu W., Deng W., Gong X., Ou J., Yu S., Chen S. Global burden of Alzheimer’s disease and other dementias in adults aged 65 years and over, and health inequality related to SDI, 1990-2021: analysis of data from GBD 2021. BMC Public Health. 2025;25(1):1256. doi: 10.1186/s12889-025-22378-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Shreya D., Fish P.N., Du D. Navigating the future of elderly healthcare: a comprehensive analysis of aging populations and mortality trends using national inpatient sample (NIS) data (2010-2024) Cureus. 2025;17(3) doi: 10.7759/cureus.80442. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Folstein M.F., Folstein S.E., McHugh P.R. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 12(3):189-198. doi:10.1016/0022-3956(75)90026-6 [DOI] [PubMed]
- 5.Jang K.I., Kim Y.I., Ju H.J., An S.J., Park P.W. Dementia classification using two-channel electroencephalography features. Sci Rep. 2025;15(1) doi: 10.1038/s41598-025-93513-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Jin Y., Kim T., Cho J. Interplay of physical activity, muscle strength, and depression in cognitive impairment among Korean older adults: a cross-sectional study. Clin Psychopharmacol Neurosci Off Sci J Korean Coll Neuropsychopharmacol. 2025;23(2):246–255. doi: 10.9758/cpn.24.1237. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Mimenza-Alvarado A.J., Herrera-Martínez D.A., Rubalcava-Ortega J., González-Putoy M.Y., Rodríguez-Callejas J de D., Aguilar-Navarro S.G. Construction and validation of the modified parietal atrophy index by magnetic resonance imaging in patients with Alzheimer’s disease in a memory clinic. Eur J Neurosci. 2025;61(7) doi: 10.1111/ejn.70095. [DOI] [PubMed] [Google Scholar]
- 8.Shang Y., Torrandell-Haro G., Vitali F., Brinton R.D. Alzheimer’s Disease Neuroimaging Initiative (ADNI). Combination therapy targeting Alzheimer’s disease risk factors is associated with a significant delay in Alzheimer’s disease-related cognitive decline. Alzheimers Dement N Y N. 2025;11(1) doi: 10.1002/trc2.70074. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Bassuk S.S., Wypij D., Berkman L.F. Cognitive impairment and mortality in the community-dwelling elderly. Am J Epidemiol. 2000;151(7):676–688. doi: 10.1093/oxfordjournals.aje.a010262. [DOI] [PubMed] [Google Scholar]
- 10.Tombaugh T.N., McIntyre N.J. The mini-mental state examination: a comprehensive review. J Am Geriatr Soc. 1992;40(9):922–935. doi: 10.1111/j.1532-5415.1992.tb01992.x. [DOI] [PubMed] [Google Scholar]
- 11.Rist P.M., Chalmers J., Arima H., et al. Baseline cognitive function, recurrent stroke, and risk of dementia in patients with stroke. Stroke. 2013;44(7):1790–1795. doi: 10.1161/STROKEAHA.111.680728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kennedy R.E., Cutter G.R., Wang G., Schneider L.S. Using baseline cognitive severity for enriching Alzheimer’s disease clinical trials: how does Mini-Mental State Examination predict rate of change? Alzheimers Dement N Y N. 2015;1(1):46–52. doi: 10.1016/j.trci.2015.03.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Hayashida D.Y., Jacinto A.F., Araújo L.M.Q., Almada Filho C de M., DI Tommaso A.B., Cendoroglo M.S. Association between baseline Mini-Mental State Examination score and dementia incidence in a cohort of oldest old. Arq Neuropsiquiatr. 2021;79(12):1090–1094. doi: 10.1590/0004-282X-ANP-2020-0543. [DOI] [PubMed] [Google Scholar]
- 14.Skoog J., Backman K., Ribbe M., et al. A longitudinal study of the mini-mental State examination in late nonagenarians and its relationship with dementia, mortality, and education. J Am Geriatr Soc. 2017;65(6):1296–1300. doi: 10.1111/jgs.14871. [DOI] [PubMed] [Google Scholar]
- 15.Fried L.P., Borhani N.O., Enright P., et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol. 1991;1(3):263–276. doi: 10.1016/1047-2797(91)90005-w. [DOI] [PubMed] [Google Scholar]
- 16.Folstein M.F., Folstein S.E., McHugh P.R. Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–198. doi: 10.1016/0022-3956(75)90026-6. [DOI] [PubMed] [Google Scholar]
- 17.Crum R.M., Anthony J.C., Bassett S.S., Folstein M.F. Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA. 1993;269(18):2386–2391. [PubMed] [Google Scholar]
- 18.Devenney E., Hodges J.R. The Mini-Mental State Examination: pitfalls and limitations. Pract Neurol. 2017;17(1):79–80. doi: 10.1136/practneurol-2016-001520. [DOI] [PubMed] [Google Scholar]
- 19.Kim H.G., Bai D.S., Koo B.H., et al. Dementia overdiagnosis in younger, higher educated individuals based on MMSE alone: analysis using deep learning technology. J Korean Med Sci. 2025;40(9):e20. doi: 10.3346/jkms.2025.40.e20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Belleville S., Fouquet C., Hudon C., Zomahoun H.T.V., Croteau J., Consortium for the Early Identification of Alzheimer’s disease-Quebec Neuropsychological measures that predict progression from mild cognitive impairment to Alzheimer’s type dementia in older adults: a systematic review and meta-analysis. Neuropsychol Rev. 2017;27(4):328–353. doi: 10.1007/s11065-017-9361-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Elias M.F., Beiser A., Wolf P.A., Au R., White R.F., D’Agostino R.B. The preclinical phase of alzheimer disease: a 22-year prospective study of the Framingham Cohort. Arch Neurol. 2000;57(6):808–813. doi: 10.1001/archneur.57.6.808. [DOI] [PubMed] [Google Scholar]
- 22.Cheng Y., Zamrini E., Faselis C., et al. Cardiorespiratory fitness and risk of Alzheimer’s disease and related dementias among American veterans. Alzheimers Dement J Alzheimers Assoc. 2023;19(10):4325–4334. doi: 10.1002/alz.12998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Matallana D., de Santacruz C., Cano C., et al. The relationship between education level and mini-mental state examination domains among older Mexican Americans. J Geriatr Psychiatry Neurol. 2011;24(1):9–18. doi: 10.1177/0891988710373597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Jones R.N., Gallo J.J. Education and sex differences in the mini-mental state examination: effects of differential item functioning. J Gerontol B Psychol Sci Soc Sci. 2002;57(6):P548–P558. doi: 10.1093/geronb/57.6.p548. [DOI] [PubMed] [Google Scholar]
- 25.Schindler S.E., Bollinger J.G., Ovod V., et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019;93(17):e1647–e1659. doi: 10.1212/WNL.0000000000008081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Thijssen E.H., La Joie R., Strom A., et al. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol. 2021;20(9):739–752. doi: 10.1016/S1474-4422(21)00214-3. [DOI] [PMC free article] [PubMed] [Google Scholar]