Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2018 Mar 1.
Published in final edited form as: JAMA Neurol. 2017 Mar 1;74(3):332–338. doi: 10.1001/jamaneurol.2016.3822

Association Between Mentally Stimulating Activities in Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOE ε4 Genotype

Janina Krell-Roesch 1, Prashanthi Vemuri 1, Anna Pink 1, Rosebud O Roberts 1, Gorazd B Stokin 1, Michelle M Mielke 1, Teresa J H Christianson 1, David S Knopman 1, Ronald C Petersen 1, Walter K Kremers 1, Yonas Geda 1
PMCID: PMC5473779  NIHMSID: NIHMS863626  PMID: 28135351

Abstract

Importance

We and others have reported cross-sectional associations between mentally stimulating activities and decreased odds of having mild cognitive impairment (MCI) or Alzheimer’s disease. However, little is known about the longitudinal outcome of incident MCI as predicted by late life (age ≥70 years) mentally stimulating activities.

Objective

To test our hypothesis on the association between mentally stimulating activities in late life and the risk of incident MCI and additionally evaluate the impact of APOE ε4 genotype.

Design

Prospective cohort study.

Setting

Population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota.

Participants

We followed 1929 participants aged ≥ 70 years who were cognitively normal at baseline to the outcome of incident MCI.

Main Outcome and Measures

At baseline, participants provided information about mentally stimulating activities within a year prior to enrolment into the study. Neurocognitive assessment was conducted at baseline and 15 month interval evaluations. Cognitive diagnosis was made by an expert consensus panel based on published criteria. We calculated hazard ratios (HR) and 95% confidence intervals (95% CI) using Cox proportional hazards models after adjusting for age, sex and education.

Results

Over a median follow-up period of 4 years, we observed that playing games (HR [95% CI], 0.78 [0.65–0.95]), and engaging in craft activities (0.72 [0.57–0.90]), computer use (0.70 [0.57–0.85]), and social activities (0.77 [0.63–0.94]) were associated with a decreased risk of incident MCI. In a stratified analysis by APOE ε4 status, the data points towards the lowest risk of incident MCI for APOE ε4 non-carriers who engage in mentally stimulating activities and towards the highest risk of incident MCI for APOE ε4 carriers who do not engage in mentally stimulating activities.

Conclusion and Relevance

Cognitively normal elderly individuals who engage in specific mentally stimulating activities, even in late life, have a decreased risk of incident MCI. The associations may vary by APOE ε4 carrier status.

Dementia has become a global epidemic causing significant burden not only for societies but also for caregivers and patient families1. Therefore, it is critical to examine potential protective, lifestyle-related factors against cognitive decline and dementia, preferably based on cohort studies involving large sample sizes.

Various terms have been used to describe activities that keep the mind active and may contribute to healthy aging. Indeed, cognitive, intellectual or mentally stimulating activities are associated with a decreased risk of cognitive decline2 and dementia3–10. To date, only few studies investigated whether cognitive activities are related to the outcome of mild cognitive impairment (MCI) which is the intermediate zone between normal cognitive aging and dementia11. Our group has reported a cross-sectional association between mentally stimulating activities and decreased odds of having mild cognitive impairment (MCI)12. A cohort study involving a convenience sample of community-dwelling elderly found an association between cognitive activities and a decreased risk of amnestic MCI13 as well as vascular cognitive impairment14.

In the current population-based cohort study, we sought to determine whether engaging in mentally stimulating activities in late life could be of potential benefit in reducing the risk of incident MCI in persons aged 70 years and above. We have made rigorous efforts to ensure that our study participants were cognitively normal at baseline and we also had a well-established research infrastructure to follow the cohort forward in time to the outcomes of incident MCI. Such an undertaking minimizes the potential for reverse causality though theoretically it may not completely eliminate it. We hypothesize that elderly persons who report engaging in mentally stimulating activities at least 1–2 times per week have a significantly decreased risk of developing new onset of MCI as compared to persons that report less mentally stimulating activities. Since Apolipoprotein E (APOE) ε4 is a well-known risk factor for MCI and dementia15–18, we also conducted a stratified analysis by APOE genotype. We hypothesize that 1) APOE ε4 carriers have a higher risk of developing incident MCI as compared to APOE ε4 non-carriers regardless of engaging in mentally stimulating activities; 2) APOE ε4 carriers who report engaging in mentally stimulating activities have a decreased risk of developing incident MCI as compared to APOE ε4 carriers who do not report engaging in mentally stimulating activities.

METHODS

Design and Setting

We conducted a prospective cohort study derived from the population-based Mayo Clinic Study of Aging (MCSA). The MCSA is an ongoing study of normal cognitive aging and MCI among elderly persons aged 70 years and older. The details of the MCSA study have been reported elsewhere19. Briefly, from the target population of 9953 elderly individuals residing in Olmsted County, Minnesota, on October 1, 2004, we recruited study participants by stratified random sampling20. The MCSA study protocols have been approved by the institutional review boards of the Mayo Clinic and Olmsted Medical Center in Rochester, Minnesota. All participants provided written informed consent.

Study Sample

We assembled a cohort of 2213 cognitively normal participants who had completed a questionnaire on engaging in mentally stimulating activities as well as a valid cognitive assessment at baseline. 284 individuals were excluded (242 withdrew prior to follow-up, 3 had no follow-up visit, and 39 died prior to follow-up). Therefore, the final cohort consisted of 1929 cognitively normal persons who were followed to the outcome of incident MCI.

Assessment of Mentally Stimulating Activities

Details of the measurement of mentally stimulating activities in the MCSA have been reported elsewhere12,21. Briefly, we modified previously validated instruments to measure these activities8,22,23. We defined the following activities as exposures of interest based on results from our cross-sectional study12: Reading books, craft activities, computer activities, playing games, and social activities (e.g., going out to movies and theaters). A research nurse or psychometrist assessed the frequency at which each participant engaged in each mentally stimulating activity by using a structured survey with ordinal responses (once a month or less, 2–3 times a month, 1–2 times per week, 3–4 times per week, 5–6 times per week, and daily). Participants were asked to provide information about engagement in these activities in the year prior to study participation (late life mentally stimulating activities).

Cognitive Evaluation

The cognitive assessment in the MCSA was described in detail elsewhere12,19 and is briefly described here. A face-to-face evaluation was completed among all study participants and included three assessment components: (1) a neurological evaluation which included a neurological history review, the administration of the Short Test of Mental Status24, and a neurological examination; (2) a risk factor assessment interview which was conducted by a nurse or study coordinator and included the Clinical Dementia Rating Scale (CDR); and (3) neuropsychological testing which was administered by a psychometrist to assess performance in 4 cognitive domains: Memory (delayed recall trials from the Auditory Verbal Learning Test25 and Wechsler Memory Scale-Revised26, Logical Memory and Visual Reproduction subtests); Language (Boston Naming Test27,28 and category fluency29); Visuospatial Skills (Wechsler Adult Intelligence Scale-Revised30, Picture Completion and Block Design subtests); and Executive Functions (Trail Making Test B31 and Wechsler Adult Intelligent Scale-Revised30, Digit Symbol Substitution subtest).

An expert consensus panel made the classifications of normal cognition and MCI after reviewing the results acquired from the clinical and neuropsychological evaluation19. Individuals were considered as cognitively normal at baseline according to published normative data developed on this community32–35. For MCI, the following revised Mayo Clinic criteria for MCI36,37 were used: (1) cognitive concern expressed by a physician, informant, participant, or nurse; (2) impairment in 1 or more cognitive domains (executive functions, memory, language, or visuospatial skills); (3) essentially normal functional activities; and (4) absence of dementia. Participants with MCI had a CDR score of 0 or 0.5; however, the final diagnosis of MCI was based on all available data.

APOE Genotyping

Blood was drawn from the study participants after receiving informed consent. DNA was amplified by means of polymerase chain reaction, and APOE genotyping was determined by standard methods38. The genotypes were determined by laboratory technicians who were kept unaware of clinical characteristics.

Statistical Analysis

To investigate the association between late life mentally stimulating activities and the outcome of incident MCI, we calculated hazard ratios (HR) and 95% confidence intervals (95% CI) by using Cox proportional hazards models with age as a time scale and after adjusting for sex, education, medical comorbidity (weighted Charlson index)39, depression (Beck Depression Inventory score <13 vs ≥13)40, and APOE genotype status.

Our hypotheses were generated from our previous cross-sectional study. Thus, the analyses were conducted separately for five different types of mentally stimulating activities in late life (within 1 year of the cognitive assessment): reading books, craft activities, computer activities, playing games, and social activities (e.g., going out to movies and theaters). In our analyses, we compared mentally stimulating activities carried out at least 1–2 times per week vs. mentally stimulating activities carried out 2–3 times a month or less (reference group) in predicting the risk of incident MCI. We measured central tendency using medians and associated interquartile ranges. Furthermore, we conducted analyses stratified by MCI subtype (amnestic vs. non-amnestic) as well as APOE ε4 status to investigate possible interactions between this genetic risk factor for AD and mentally stimulating activities in late life. Fitting all the data, we also tested for multiplicative interactions on the hazard ratio scale as well as for additive interactions. Statistical testing was performed at the conventional 2-tailed alpha level of 0.05. All analyses were performed using SAS® System, version 9.3 software (SAS Institute, Cary, North Carolina).

RESULTS

At baseline, we included 1929 cognitively normal persons aged 70 years and older (50.4% females) who had completed a valid mentally stimulating activities assessment and cognitive evaluation. We followed this cohort forward in time for a median of 4.0 years (interquartile range [IQR], 2.3–6.4 years), at which time 456 participants developed new onset MCI (Figure 1). The median age at baseline was 77 years (IQR, 74–82 years) and the median level of education was 14 years (IQR, 12–16 years). 512 participants (26.7%) were APOE ε4 carriers. APOE genotype data were missing for 9 participants. The detailed demographic characteristics are displayed in Table 1.

Figure 1.

Figure 1

Open in a new tab

Study Flow Chart

Table 1.

Demographic Characteristic of the Study Sample

Variable Total
(n = 1929)
Female, No. (%) 973 (50.4)
Age, yrsa 77 [74, 82]
 70–79 1154 (59.8)
 80–93 775 (40.2)
Education, yrsa 14 [12, 16]
 >12 1203 (62.4)
BDI-II grand totala 3 [1, 7]1
 Depression (total ≥13) 106 (5.5)
Charlson Comorbidity Index scorea 3 [2, 5]
Open in a new tab

Abbreviations: BDI-II, Beck Depression Inventory.

a

Median [interquartile range]

1

Information missing on 4 participants.

After adjusting for age, sex, and years of education, we observed that playing games (HR [95% CI], 0.78 [0.65 to 0.95]), engaging in craft activities (HR [95% CI], 0.72 [0.57 to 0.90]), computer activities (HR [95% CI], 0.70 [0.57 to 0.85]), and social activities (HR [95% CI], 0.77 [0.63 to 0.94]) were associated with a decreased risk of incident MCI. The association between reading books (HR [95% CI], 0.83 [0.68 to 1.01]) and a decreased risk of incident MCI was marginally significant. Additional adjustment for medical comorbidity, depression and APOE genotype did not significantly alter the results (Model 2). Please refer to Table 2 for a summary of results.

Table 2.

Mentally stimulating activities and risk of incident MCI

Variable No. at Risk No. with incident MCI Median Follow-up (yrs) HR (95%CI)1 p-value HR (95%CI)2 p-value
Reading books 1083 240 4.1 0.83 (0.68, 1.01) 0.06 0.86 (0.71, 1.05) 0.14
Playing games 1108 245 4.1 0.78 (0.65, 0.95) 0.012 0.83 (0.69, 1.01) 0.06
Craft activities 502 104 4.1 0.72 (0.57, 0.90) 0.004 0.78 (0.62, 0.98) 0.030
Computer activities 1077 193 4.1 0.70 (0.57, 0.85) <0.001 0.74 (0.61, 0.90) 0.002
Social activities 767 154 4.1 0.77 (0.63, 0.94) 0.009 0.79 (0.64, 0.96) 0.017
Open in a new tab

Abbreviations: HR, hazard ratio; CI, confidence interval.

1

Model adjusted for age (scale), sex, and education.

2

Model also adjusted for medical comorbidity, depression, and APOE ε4 status. No. at risk refers to the number of participants (of the total sample size of 1929) that reported engaging in a mentally stimulating activity with a frequency of at least 1–2 times per week or more. No. with incident MCI refers to the number of participants (of the total sample size of 1929) that developed incident MCI.

We also conducted stratified analyses by MCI subtype (amnestic vs. non-amnestic). We observed significant associations between craft activities (HR [95% CI], 0.76 [0.58 to 1.00]), computer activities (HR [95% CI], 0.75 [0.59 to 0.95]), social activities (HR [95% CI], 0.75 [0.58 to 0.95]) and a decreased risk of incident amnestic MCI; whereas, we only observed a significant association between computer activities (HR [95% CI], 0.42 [0.26 to 0.67]) and a decreased risk of incident non-amnestic MCI. The results of this analysis are summarized in eTable 1.

We conducted the same analyses stratified by APOE ε4 status. We observed that among APOE ε4 non-carriers, craft activities (HR [95% CI], 0.65 [0.49 to 0.85]), and computer activities (HR [95% CI], 0.73 [0.58 to 0.93]) were significantly associated with a decreased risk of incident MCI and the associations were marginally significant for reading books (HR [95% CI], 0.81 [0.64 to 1.02] and playing games (HR [95% CI], 0.81 [0.64 to 1.02]. Among APOE ε4 carriers, only computer activities (HR [95% CI], 0.65 [0.46 to 0.92]) and social activities (HR [95% CI], 0.62 [0.43 to 0.89]) were associated with a decreased risk of incident MCI (Table 3).

Table 3.

Mentally stimulating activities and risk of incident MCI stratified by APOE ε4 carrier status

Variable No. at Risk No. with incident MCI Median Follow-up (yrs) HR (95%CI)1 p-value HR (95%CI)2 p-value
APOE ε4 carriers
Reading books 283 77 3.4 0.91 (0.63, 1.29) 0.59 1.02 (0.71, 1.46) 0.94
Playing games 288 75 3.5 0.72 (0.51, 1.01) 0.06 0.78 (0.55, 1.10) 0.15
Craft activities 123 33 3.0 1.02 (0.69, 1.51) 0.92 1.08 (0.73, 1.61) 0.70
Computer activities 276 61 3.7 0.65 (0.46, 0.92) 0.014 0.71 (0.50, 1.00) 0.05
Social activities 194 45 3.9 0.62 (0.43, 0.89) 0.009 0.64 (0.45, 0.92) 0.017
APOE ε4 non-carriers
Reading books 792 162 4.2 0.81 (0.64, 1.02) 0.07 0.82 (0.64, 1.04) 0.09
Playing games 815 169 4.2 0.81 (0.64, 1.02) 0.07 0.85 (0.68, 1.08) 0.18
Craft activities 378 71 4.5 0.65 (0.49, 0.85) 0.002 0.67 (0.51, 0.88) 0.004
Computer activities 795 132 4.2 0.73 (0.58, 0.93) 0.011 0.75 (0.59, 0.95) 0.017
Social activities 571 108 4.2 0.83 (0.66, 1.06) 0.13 0.86 (0.68, 1.09) 0.22
Open in a new tab

Abbreviations: HR, hazard ratio; CI, confidence interval.

1

Model adjusted for age (scale), sex, and education.

2

Model also adjusted for medical comorbidity and depression. No. at risk refers to the number of participants (of the total sample size of 1929) that reported engaging in a mentally stimulating activity with a frequency of at least 1–2 times per week or more. No. with incident MCI refers to the number of participants (of the total sample size of 1929) that developed incident MCI.

We also examined a possible interaction between late life mentally stimulating activities and APOE genotype in predicting the risk of incident MCI. We defined the reference group as participants who did not engage in late life mentally stimulating activities and were also APOE ε4 non-carriers. We consistently observed the lowest risk of incident MCI in participants who engaged in any type of mentally stimulating activity and were APOE non-carriers as compared with the reference group. In contrast, participants who were APOE ε4 carriers and did not engage in mentally stimulating activities tended to have the highest risk for incident MCI with the exception of engaging in craft activities. None of the tests for additive interactions between late life mentally stimulating activities and APOE genotype on the risk of new-onset MCI were significant. However, the model on additive interaction was marginally significant for social activities (p = 0.088). Additional adjustment for medical comorbidity and depression did not alter the results. Please refer to eTable 2 for a summary of results and to Figure 2 for visual display of data (HR plot).

Figure 2. Hazard ratio plot on interaction between mentally stimulating activities and APOE ε4 status on the risk of incident MCI.

Figure 2

Open in a new tab

Abbreviations: HR, hazard ratio; CI, confidence interval; APOE ε4-/ APOE ε4+, APOE ε4 non-carrier/ carrier; Books+/Games+/Craft+/Computer+/Social+, reported engaging in reading books/playing games/craft activities/computer activities/social activities at least 1–2 times per week or more; Books-/Games-/Craft-/Computer-/Social-, reported not engaging in reading books/playing games/craft activities/computer activities/social activities (2–3 times a month or less).

Model adjusted for age (scale), sex, and education. Additional adjustment for medical comorbidity and depression did not significantly alter the results (data not shown).

DISCUSSION

In this population-based, prospective cohort study, we observed that engaging in mentally stimulating activities in late life was associated with a decreased risk of incident MCI. More specifically, playing games, engaging in craft, computer, and social activities significantly reduced the risk of incident MCI. In the past, we have reported decreased odds of MCI for engagement in mentally stimulating activities in late life in a population-based, case-control study12. However, we considered those findings as preliminary until confirmed by a prospective cohort study, which we are now reporting.

When comparing MCI subtypes (amnestic vs. non-amnestic MCI), we observed more associations between mentally stimulating activities and a decreased risk of amnestic MCI as compared to non-amnestic MCI. This could be explained by a limited power due to smaller sample size for the analysis on non-amnestic MCI.

As APOE ε4 is a well-known risk factor for MCI and AD15–18, we also conducted stratified analyses by APOE ε4 status in predicting the outcome of incident MCI. As expected, the data points towards a reduced risk of incident MCI for APOE ε4 non-carriers who engage in mentally stimulating activities. However, we observed fewer associations between mentally stimulating activities and a decreased risk of incident MCI for APOE ε4 carriers as compared to non-carriers. This finding may in part be explained by a lower sample size of APOE ε4 carriers which limits the statistical power of this analysis.

Our study is in line with previous research that reported a potentially protective effect of mentally stimulating activities on cognitive decline2, dementia3–10 and MCI13,21. Additionally, a recent study involving persons aged 85 years and older reported a list of risk and protective factors for advanced aging, one of which was an association between cognitive activities and a decreased risk of MCI21. To our knowledge, our study might be one of the few if not the first population-based cohort study to examine the risk of incident MCI in persons 70 years and older as predicted by engagement in mentally stimulating activities in late life.

Our study could not disentangle why some mentally stimulating activities (e.g., computer activities) had a larger effect size on the decreased risk of incident MCI than other activities (e.g., reading books). However, we can speculate the following. Perhaps, a particular mental activity, for example, the use of a computer requires specific technical and manual skills and that these could be the factors that might be associated with a decreased risk of cognitive decline. Future studies may need to examine the specific mediation factors between a particular mentally stimulating activity and the decreased risk of incident MCI.

However, we did not investigate possible mechanisms that might underlie the association between engagement in mentally stimulating activities and the risk of incident MCI. Insights on these mechanisms can be derived from animal studies. Studies involving mouse models of Alzheimer’s disease (AD) showed a protective effect of enriched environments on neuropathological changes associated with AD such as prevention of neuronal dysfunction and increased synaptic recovery41. So far, only few studies investigated the associations between mental or cognitive activities and pathological changes associated with cognitive decline and AD in humans. For example, researchers from UC Berkley reported a significant association between cognitive activities and a decreased beta amyloid deposition in the cortex42. An Australian group reported that complex mental activity across the lifespan was associated with decreased hippocampal atrophy43. A recent report indicated that higher cognitive reserve was associated with decreased age-related changes in CSF biomarkers44. Additionally, one can hypothesize that engagement in mentally stimulating activities may also be associated with other protective lifestyle factors such as engagement in physical exercise. These activities might in sum lead to a decreased risk of cognitive decline12. Also, the cognitive reserve theory states that engagement in mentally stimulating activities or a high educational level may buffer the negative effects of abnormal brain pathologies on cognitive function45. The reader is referred to our previous manuscript12 for a discussion of potential mechanisms of action.

In addition to mentally stimulating activities, several other risk and protective factors for MCI have been discussed in the literature. There is evidence that neuropsychiatric symptoms46,47 are associated with an increased risk of incident MCI. In contrast, lifestyle-related factors such as physical exercise48 and low caloric intake49 are associated with a lower risk of MCI.

The findings of our study should be interpreted within the context of its strengths and limitations. The major strength of our study pertains to its design. We conducted a population-based, prospective cohort study with a large sample size of 1929 participants at baseline that we followed over several years. In addition, MCI was assessed using face-to-face evaluations and based on a consensus panel at a center that has a well-known reputation in the field. A limitation pertains to potential recall bias that stems from the self-reported mentally stimulating activities questionnaire. Also, we did not control for mentally stimulating activities carried out in early or midlife. We can assume that individuals who engaged in mentally stimulating activities in early and/or midlife are more likely to engage in these activities in late life as compared to persons who did not engage in these activities during the lifespan. Furthermore, an observational study like ours only allows investigating associations and does not allow drawing conclusions about cause and effect. This can only be done by interventional (experimental) studies. Therefore, we cannot exclude a ‘reverse causality’ explanation, i.e. it is possible that participants who are at higher risk for MCI are less likely to engage in mentally stimulating activities. However, given that we conducted a rigorous, time intensive, large scale population-based prospective cohort study, and considering similar findings from smaller studies in the past, we can conclude that the observed associations in our study are real. In addition, it should be noted that the majority of the population in Olmsted County, Minnesota is of Caucasian descent. However, it has been indicated that the data is generalizable to the population of the United States50.

In conclusion, we observed that engaging in mentally stimulating activities, even in late life, may be protective against new onset MCI. Additionally, engaging in certain mentally stimulating activities may lower the risk of incident MCI even among APOE ε4 carriers. Future research is needed to understand the mechanisms linking mentally stimulating activities and cognition in late life.

Supplementary Material

Acknowledgments

Funding

The study was supported by NIH grants: National Institute on Aging (U01 AG006786); National Institute of Mental Health (K01 MH068351), and K01 (AG028573). Support for this research was also provided by the Robert Wood Johnson Foundation, the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program, the European Regional Development Fund: FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123), the Arizona Alzheimer’s Consortium, and the Edli Foundation, the Netherlands.

Role of Sponsor

The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Footnotes

Author Contributions

Dr. Geda had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Krell-Roesch, Roberts, Petersen, Geda.

Acquisition, analysis, or interpretation of data: Krell-Roesch, Roberts, Christianson, Knopman, Petersen, Geda.

Drafting of the manuscript: Krell-Roesch, Geda.

Critical revision of the manuscript for important intellectual content: Vemuri, Pink, Roberts, Stokin, Mielke, Knopman, Kremers, Petersen.

Statistical analysis: Christianson, Kremers.

Obtained funding: Petersen, Geda.

Administrative, technical, or material support: Roberts, Petersen, Geda.

Conflict of Interest Disclosures

Dr. Knopman serves as Deputy Editor for Neurology®; serves on a Data Safety Monitoring Board for Lundbeck Pharmaceuticals and for the Dominantly Inherited Alzheimer’s Disease Treatment Unit. He has served on a Data Safety Monitoring Board for Lilly Pharmaceuticals; served as a consultant to Tau RX, was an investigator in clinical trials sponsored by Baxter and Elan Pharmaceuticals in the past 2 years; and receives research support from the NIH.

Dr. Petersen reports being a consultant to GE Healthcare and Elan Pharmaceuticals; serving on a data safety monitoring board in clinical trials sponsored by Pfizer Incorporated and Janssen Alzheimer Immunotherapy; and gave a CME lecture at Novartis Incorporated.

All other authors report no disclosures.

References

  • 1.Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement. 2007 Jul;3(3):186–191. doi: 10.1016/j.jalz.2007.04.381. [DOI] [PubMed] [Google Scholar]
  • 2.Vemuri P, Lesnick TG, Przybelski SA, et al. Association of lifetime intellectual enrichment with cognitive decline in the older population. JAMA neurology. 2014 Aug;71(8):1017–1024. doi: 10.1001/jamaneurol.2014.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Wilson RS, Mendes De Leon CF, Barnes LL, et al. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002 Feb 13;287(6):742–748. doi: 10.1001/jama.287.6.742. [DOI] [PubMed] [Google Scholar]
  • 4.Wilson RS, Bennett DA, Bienias JL, et al. Cognitive activity and incident AD in a population-based sample of older persons. Neurology. 2002 Dec 24;59(12):1910–1914. doi: 10.1212/01.wnl.0000036905.59156.a1. [DOI] [PubMed] [Google Scholar]
  • 5.Wilson RS, Barnes LL, Aggarwal NT, et al. Cognitive activity and the cognitive morbidity of Alzheimer disease. Neurology. 2010 Sep 14;75(11):990–996. doi: 10.1212/WNL.0b013e3181f25b5e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Akbaraly TN, Portet F, Fustinoni S, et al. Leisure activities and the risk of dementia in the elderly: results from the Three-City Study. Neurology. 2009 Sep 15;73(11):854–861. doi: 10.1212/WNL.0b013e3181b7849b. [DOI] [PubMed] [Google Scholar]
  • 7.Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol. 2004 Jun;3(6):343–353. doi: 10.1016/S1474-4422(04)00767-7. [DOI] [PubMed] [Google Scholar]
  • 8.Verghese J, Lipton RB, Katz MJ, et al. Leisure activities and the risk of dementia in the elderly. N Engl J Med. 2003 Jun 19;348(25):2508–2516. doi: 10.1056/NEJMoa022252. [DOI] [PubMed] [Google Scholar]
  • 9.Then FS, Luppa M, Schroeter ML, Konig HH, Angermeyer MC, Riedel-Heller SG. Enriched environment at work and the incidence of dementia: results of the Leipzig longitudinal study of the aged (LEILA 75+) PloS one. 2013;8(7):e70906. doi: 10.1371/journal.pone.0070906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Marioni RE, Proust-Lima C, Amieva H, et al. Social activity, cognitive decline and dementia risk: a 20-year prospective cohort study. BMC Public Health. 2015;15:1089. doi: 10.1186/s12889-015-2426-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999 Mar;56(3):303–308. doi: 10.1001/archneur.56.3.303. [DOI] [PubMed] [Google Scholar]
  • 12.Geda YE, Topazian HM, Lewis RA, et al. Engaging in cognitive activities, aging, and mild cognitive impairment: a population-based study. J Neuropsychiatry Clin Neurosci. 2011 Spring;23(2):149–154. doi: 10.1176/appi.neuropsych.23.2.149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Verghese J, LeValley A, Derby C, et al. Leisure activities and the risk of amnestic mild cognitive impairment in the elderly. Neurology. 2006 Mar 28;66(6):821–827. doi: 10.1212/01.wnl.0000202520.68987.48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Verghese J, Cuiling W, Katz MJ, Sanders A, Lipton RB. Leisure activities and risk of vascular cognitive impairment in older adults. J Geriatr Psychiatry Neurol. 2009 Jun;22(2):110–118. doi: 10.1177/0891988709332938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med. 1996;47:387–400. doi: 10.1146/annurev.med.47.1.387. [DOI] [PubMed] [Google Scholar]
  • 16.Roses AD, Strittmatter WJ, Pericak-Vance MA, Corder EH, Saunders AM, Schmechel DE. Clinical application of apolipoprotein E genotyping to Alzheimer’s disease. Lancet. 1994 Jun 18;343(8912):1564–1565. doi: 10.1016/s0140-6736(94)92960-2. [DOI] [PubMed] [Google Scholar]
  • 17.Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993 Aug 13;261(5123):921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
  • 18.Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology. 1993 Aug;43(8):1467–1472. doi: 10.1212/wnl.43.8.1467. [DOI] [PubMed] [Google Scholar]
  • 19.Roberts RO, Geda YE, Knopman DS, et al. The Mayo Clinic Study of Aging: design and sampling, participation, baseline measures and sample characteristics. Neuroepidemiology. 2008;30(1):58–69. doi: 10.1159/000115751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.St Sauver JL, Grossardt BR, Yawn BP, Melton LJ, 3rd, Rocca WA. Use of a medical records-linkage system to enumerate a dynamic population over time: The Rochester Epidemiology Project. Am J Epidemiol. 2011 May 1;173(9):1059–1068. doi: 10.1093/aje/kwq482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Roberts RO, Cha RH, Mielke MM, et al. Risk and protective factors for cognitive impairment in persons aged 85 years and older. Neurology. 2015 May 5;84(18):1854–1861. doi: 10.1212/WNL.0000000000001537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Wilson RS, Bennett DA, Beckett LA, et al. Cognitive activity in older persons from a geographically defined population. J Gerontol B Psychol Sci Soc Sci. 1999 May;54(3):P155–160. doi: 10.1093/geronb/54b.3.p155. [DOI] [PubMed] [Google Scholar]
  • 23.Friedland RP, Fritsch T, Smyth KA, et al. Patients with Alzheimer’s disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3440–3445. doi: 10.1073/pnas.061002998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Kokmen E, Smith GE, Petersen RC, Tangalos E, Ivnik RC. The Short Test of Mental Status: Correlations With Standardized Psychometric Testing. Arch Neurol. 1991 Jul 1;48(7):725–728. doi: 10.1001/archneur.1991.00530190071018. 1991. [DOI] [PubMed] [Google Scholar]
  • 25.Rey A. L’examen clinique en psychologie. Paris: Presses Universitaires de France; 1964. [Google Scholar]
  • 26.Wechsler D. Wechsler Memory Scale-Revised. New York: The Psychological Corporation; 1987. [Google Scholar]
  • 27.Kaplan E, Goodglass H, Brand S. Boston Naming Test. Philadelphia: Lea & Febiger; 1983. [Google Scholar]
  • 28.Kaplan E, Goodglass H, Weintraub S. Boston Naming Test. 2nd. Philadelphia: Lippincott Williams & Wilkins; 2001. [Google Scholar]
  • 29.Lucas JA, Ivnik RJ, Smith GE, et al. Mayo’s Older Americans Normative Studies: category fluency norms. J Clin Exp Neuropsychol. 1998 Apr;20(2):194–200. doi: 10.1076/jcen.20.2.194.1173. [DOI] [PubMed] [Google Scholar]
  • 30.Wechsler D. Wechsler Adult Intelligence Scale-Revised. New York: Psychological Corporation; 1981. [Google Scholar]
  • 31.Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills. 1958;8(3):271–276. 1958/12/01. [Google Scholar]
  • 32.Ivnik RJ, Malec JF, Smith GE, et al. Mayo’s Older Americans Normative Studies: WAIS-R norms for ages 56 to 97. Clin Neuropsychol. 1992;6(sup001):1–30. 1992/06/01. [Google Scholar]
  • 33.Ivnik RJ, Malec JF, Smith GE, et al. Mayo’s Older Americans Normative Studies: WMS-R norms for ages 56 to 94. Clin Neuropsychol. 1992;6(sup001):49–82. 1992/06/01. [Google Scholar]
  • 34.Ivnik RJ, Malec JF, Smith GE, et al. Mayo’s Older Americans Normative Studies: Updated AVLT norms for ages 56 to 97. Clin Neuropsychol. 1992;6(sup001):83–104. 1992/06/01. [Google Scholar]
  • 35.Malec JF, Ivnik RJ, Smith GE, et al. Mayo’s Older Americans Normative Studies: Utility of corrections for age and education for the WAIS-R. Clin Neuropsychol. 1992;6(sup001):31–47. 1992/06/01. [Google Scholar]
  • 36.Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004 Sep;256(3):183–194. doi: 10.1111/j.1365-2796.2004.01388.x. [DOI] [PubMed] [Google Scholar]
  • 37.Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment–beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004 Sep;256(3):240–246. doi: 10.1111/j.1365-2796.2004.01380.x. [DOI] [PubMed] [Google Scholar]
  • 38.Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990 Mar;31(3):545–548. [PubMed] [Google Scholar]
  • 39.Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–383. doi: 10.1016/0021-9681(87)90171-8. [DOI] [PubMed] [Google Scholar]
  • 40.Beck AT, Steer RA, Brown GK. BDI-II, Beck Depression Inventory: Manual. 2nd. San Antonio, TX; Boston, MA: Psychological Corp.; Harcourt Brace; 1996. [Google Scholar]
  • 41.Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006 Sep;7(9):697–709. doi: 10.1038/nrn1970. [DOI] [PubMed] [Google Scholar]
  • 42.Landau SM, Marks SM, Mormino EC, et al. Association of lifetime cognitive engagement and low beta-amyloid deposition. Arch Neurol. 2012 May;69(5):623–629. doi: 10.1001/archneurol.2011.2748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Valenzuela MJ, Sachdev P, Wen W, Chen X, Brodaty H. Lifespan mental activity predicts diminished rate of hippocampal atrophy. PloS one. 2008;3(7):e2598. doi: 10.1371/journal.pone.0002598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Almeida RP, Schultz SA, Austin BP, et al. Effect of Cognitive Reserve on Age-Related Changes in Cerebrospinal Fluid Biomarkers of Alzheimer Disease. JAMA neurology. 2015 Jun;72(6):699–706. doi: 10.1001/jamaneurol.2015.0098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. The Lancet Neurology. 2012 Nov;11(11):1006–1012. doi: 10.1016/S1474-4422(12)70191-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Geda YE, Roberts RO, Mielke MM, et al. Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: a population-based study. A J Psychiatry. 2014 May 1;171(5):572–581. doi: 10.1176/appi.ajp.2014.13060821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Geda YE, Roberts RO, Knopman DS, et al. Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: population-based study. Arch Gen Psychiatry. 2008 Oct;65(10):1193–1198. doi: 10.1001/archpsyc.65.10.1193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Geda YE, Roberts RO, Knopman DS, et al. Physical exercise, aging, and mild cognitive impairment: a population-based study. Arch Neurol. 2010 Jan;67(1):80–86. doi: 10.1001/archneurol.2009.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Geda YE, Ragossnig M, Roberts LA, et al. Caloric intake, aging, and mild cognitive impairment: a population-based study. J Alzheimers Dis. 2013 Jan 1;34(2):501–507. doi: 10.3233/JAD-121270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.St Sauver JL, Grossardt BR, Leibson CL, Yawn BP, Melton LJ, 3rd, Rocca WA. Generalizability of epidemiological findings and public health decisions: an illustration from the Rochester Epidemiology Project. Mayo Clin Proc. 2012 Feb;87(2):151–160. doi: 10.1016/j.mayocp.2011.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

NIHMS863626-supplement-supplement_1.pdf (213.3KB, pdf)

RESOURCES