Rachel A. Whitmer

Midlife cardiovascular risk factors and risk of dementia in late life

Objective: To evaluate if midlife cardiovascular risk factors are associated with risk of late-life dementia in a large, diverse cohort. Method: The authors conducted a retrospective cohort study of 8,845 participants of a health maintenance organization who underwent health evaluations from 1964 to 1973 when they were between the ages of 40 and 44. Midlife cardiovascular risk factors included total cholesterol, diabetes, hypertension, and smoking. Diagnoses of dementia were ascertained by medical records from January 1994 to April 2003. Results: The authors identified 721 participants (8.2%) with dementia. Smoking, hypertension, high cholesterol, and diabetes at midlife were each associated with a 20 to 40% increase in risk of dementia (fully adjusted Cox proportional hazards model: HR 1.24, 95% CI 1.04 to 1.48 for hypertension, HR 1.26, 95% CI 1.08 to 1.47 for smoking, HR 1.42, 95% CI 1.22 to 1.66 for high cholesterol, and HR 1.46, 95% CI 1.19 to 1.79 for diabetes). A composite cardiovascular risk score was created using all four risk factors and was associated with dementia in a dose-dependent fashion. Compared with participants having no risk factors, the risk for dementia increased from 1.27 for having one risk factor to 2.37 for having all four risk factors (fully adjusted model: HR 2.37, 95% CI 1.10 to 5.10). Conclusion: The presence of multiple cardiovascular risk factors at midlife substantially increases risk of late-life dementia in a dose dependent manner.

Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus

CONTEXT Although acute hypoglycemia may be associated with cognitive impairment in children with type 1 diabetes, no studies to date have evaluated whether hypoglycemia is a risk factor for dementia in older patients with type 2 diabetes. OBJECTIVE To determine if hypoglycemic episodes severe enough to require hospitalization are associated with an increased risk of dementia in a population of older patients with type 2 diabetes followed up for 27 years. DESIGN, SETTING, AND PATIENTS A longitudinal cohort study from 1980-2007 of 16,667 patients with a mean age of 65 years and type 2 diabetes who are members of an integrated health care delivery system in northern California. MAIN OUTCOME MEASURE Hypoglycemic events from 1980-2002 were collected and reviewed using hospital discharge and emergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitive impairment, or general memory complaints as of January 1, 2003, were followed up for a dementia diagnosis through January 15, 2007. Dementia risk was examined using Cox proportional hazard regression models, adjusted for age, sex, race/ethnicity, education, body mass index, duration of diabetes, 7-year mean glycated hemoglobin, diabetes treatment, duration of insulin use, hyperlipidemia, hypertension, cardiovascular disease, stroke, transient cerebral ischemia, and end-stage renal disease. RESULTS At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia was diagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%). Results were not attenuated when medical utilization rates, length of health plan membership, or time since initial diabetes diagnosis were added to the model. When examining emergency department admissions for hypoglycemia for association with risk of dementia (535 episodes), results were similar (compared with patients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12-1.78) and for 2 or more episodes (HR, 2.36; 95% CI, 1.57-3.55). CONCLUSIONS Among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia. Whether minor hypoglycemic episodes increase risk of dementia is unknown.

Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study

Abstract Objective To evaluate any association between obesity in middle age, measured by body mass index and skinfold thickness, and risk of dementia later in life. Design Analysis of prospective data from a multiethnic population based cohort. Setting Kaiser Permanente Northern California Medical Group, a healthcare delivery organisation. Participants 10 276 men and women who underwent detailed health evaluations from 1964 to 1973 when they were aged 40-45 and who were still members of the health plan in 1994. Main outcome measures Diagnosis of dementia from January 1994 to April 2003. Time to diagnosis was analysed with Cox proportional hazard models adjusted for age, sex, race, education, smoking, alcohol use, marital status, diabetes, hypertension, hyperlipidaemia, stroke, and ischaemic heart disease. Results Dementia was diagnosed in 713 (6.9%) participants. Obese people (body mass index ≥ 30) had a 74% increased risk of dementia (hazard ratio 1.74, 95% confidence interval 1.34 to 2.26), while overweight people (body mass index 25.0-29.9) had a 35% greater risk of dementia (1.35, 1.14 to 1.60) compared with those of normal weight (body mass index 18.6-24.9). Compared with those in the lowest fifth, men and women in the highest fifth of the distribution of subscapular or tricep skinfold thickness had a 72% and 59% greater risk of dementia, respectively (1.72, 1.36 to 2.18, and 1.59, 1.24 to 2.04). Conclusions Obesity in middle age increases the risk of future dementia independently of comorbid conditions.

Central obesity and increased risk of dementia more than three decades later

infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611–2618. 5. Nagel MA, Forghani B, Mahalingam R, et al. The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology 2007;68:1069–1073. 6. Kleinschmidt-DeMasters, Gilden DH. Varicella-zoster virus infections of the nervous system: clinical and pathological correlates. Arch Pathol Lab Med 2001;125:770–780. 7. Case Records of the Massachusetts General Hospital (Case 5-1995). N Engl J Med 1995;332:452–459. 8. Gilden DH, Kleinschmidt-DeMasters BK, Wellish M, Hedley-Whyte ET, Rentier B, Mahalingam R. Varicella zoster virus, a cause of waxing and waning vasculitis. Neurology 1996;47:1441–1446.

Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis

Objective To investigate whether angiotensin receptor blockers protect against Alzheimer’s disease and dementia or reduce the progression of both diseases. Design Prospective cohort analysis. Setting Administrative database of the US Veteran Affairs, 2002-6. Population 819 491 predominantly male participants (98%) aged 65 or more with cardiovascular disease. Main outcome measures Time to incident Alzheimer’s disease or dementia in three cohorts (angiotensin receptor blockers, lisinopril, and other cardiovascular drugs, the “cardiovascular comparator”) over a four year period (fiscal years 2003-6) using Cox proportional hazard models with adjustments for age, diabetes, stroke, and cardiovascular disease. Disease progression was the time to admission to a nursing home or death among participants with pre-existing Alzheimer’s disease or dementia. Results Hazard rates for incident dementia in the angiotensin receptor blocker group were 0.76 (95% confidence interval 0.69 to 0.84) compared with the cardiovascular comparator and 0.81 (0.73 to 0.90) compared with the lisinopril group. Compared with the cardiovascular comparator, angiotensin receptor blockers in patients with pre-existing Alzheimer’s disease were associated with a significantly lower risk of admission to a nursing home (0.51, 0.36 to 0.72) and death (0.83, 0.71 to 0.97). Angiotensin receptor blockers exhibited a dose-response as well as additive effects in combination with angiotensin converting enzyme inhibitors. This combination compared with angiotensin converting enzyme inhibitors alone was associated with a reduced risk of incident dementia (0.54, 0.51 to 0.57) and admission to a nursing home (0.33, 0.22 to 0.49). Minor differences were shown in mean systolic and diastolic blood pressures between the groups. Similar results were observed for Alzheimer’s disease. Conclusions Angiotensin receptor blockers are associated with a significant reduction in the incidence and progression of Alzheimer’s disease and dementia compared with angiotensin converting enzyme inhibitors or other cardiovascular drugs in a predominantly male population.

Midlife Serum Cholesterol and Increased Risk of Alzheimer’s and Vascular Dementia Three Decades Later

Aims: To investigate midlife cholesterol in relation to Alzheimer’s disease (AD) and vascular dementia (VaD) in a large multiethnic cohort of women and men. Methods: The Kaiser Permanente Northern California Medical Group (healthcare delivery organization) formed the database for this study. The 9,844 participants underwent detailed health evaluations during 1964–1973 at ages 40–45 years; they were still members of the health plan in 1994. AD and VaD were ascertained by medical records between 1 January 1994 and 1 June 2007. Cox proportional hazards models – adjusted for age, education, race/ethnic group, sex, midlife diabetes, hypertension, BMI and late-life stroke – were conducted. Results: In total, 469 participants had AD and 127 had VaD. With desirable cholesterol levels (<200 mg/dl) as a reference, hazard ratios (HR) and 95% CI for AD were 1.23 (0.97–1.55) and 1.57 (1.23–2.01) for borderline (200–239 mg/dl) and high cholesterol (≥240 mg/dl), respectively. HR and 95% CI for VaD were 1.50 (1.01–2.23) for borderline and 1.26 (0.82–1.96) for high cholesterol. Further analyses for AD (cholesterol quartiles, 1st quartile reference) indicated that cholesterol levels >220 mg/dl were a significant risk factor: HR were 1.31 (1.01–1.71; 3rd quartile, 221–248 mg/dl) and 1.58 (1.22–2.06; 4th quartile, 249–500 mg/dl). Conclusion: Midlife serum total cholesterol was associated with an increased risk of AD and VaD. Even moderately elevated cholesterol increased dementia risk. Dementia risk factors need to be addressed as early as midlife, before underlying disease(s) or symptoms appear.

Body Mass Index in Midlife and Risk of Alzheimer Disease and Vascular Dementia

Prior work has suggested that obesity and overweight as measured by body mass index (BMI) increases risk of dementia. It is unknown if there is a difference in the risk of developing Alzheimer disease (AD) versus vascular dementia (VaD) associated with high body weight. The goal of this study was to examine the association between midlife BMI and risk of both AD and VaD an average of 36 years later in a large (N= 10,136) and diverse cohort of members of a health care delivery system. Participants aged 40-45 participated in health exams between 1964 and 1968. AD and VaD diagnoses were obtained from Neurology visits between January 1, 1994 and June 15, 2006. Those with diagnoses of general dementia from primary care providers were excluded from the study. BMI was analyzed in WHO categories of underweight, overweight and obese, as well as in subdivisions of WHO categories. All models were fully adjusted for age, education, race, sex, marital status, smoking, hyperlipidemia, hypertension, diabetes, ischemic heart disease and stroke. Cox proportional hazard models showed that compared to those with a normal BMI (18.5-24.9), those obese (BMI > or = 30) at midlife had a 3.10 fold increase in risk of AD (fully adjusted model, Hazard Ratio=3.10, 95% CI 2.19-4.38), and a five fold increase in risk of VaD (fully adjusted model, HR=5.01, 95% CI 2.98-8.43) while those overweight ( BMI > or = 25 and <30) had a two fold increase in risk of AD and VaD (fully adjusted model, HR=2.09, 95% CI 1.69-2.60 for AD and HR=1.95, 95% CI 1.29-2.96 for VaD). These data suggest that midlife BMI is strongly predictive of both AD and VaD, independent of stroke, cardiovascular and diabetes co morbidities. Future studies need to unveil the mechanisms between adiposity and excess risk of AD and VaD.

Midlife vs late-life depressive symptoms and risk of dementia: differential effects for Alzheimer disease and vascular dementia.

CONTEXT Depression and dementia are common in older adults and often co-occur, but it is unclear whether depression is an etiologic risk factor for dementia. OBJECTIVE To clarify the timing and nature of the association between depression and dementia. DESIGN We examined depressive symptoms assessed in midlife (1964-1973) and late life (1994-2000) and the risks of dementia, Alzheimer disease (AD), and vascular dementia (VaD) (2003-2009) in a retrospective cohort study. Depressive symptoms were categorized as none, midlife only, late life only, or both. Cox proportional hazards models (age as timescale) adjusted for demographics and medical comorbidities were used to examine depressive symptom category and risk of dementia, AD, or VaD. SETTING Kaiser Permanente Medical Care Program of Northern California. PARTICIPANTS Thirteen thousand five hundred thirty-five long-term Kaiser Permanente members. MAIN OUTCOME MEASURE Any medical record diagnosis of dementia or neurology clinic diagnosis of AD or VaD. RESULTS Subjects had a mean (SD) age of 81.1 (4.5) years in 2003, 57.9% were women, and 24.2% were nonwhite. Depressive symptoms were present in 14.1% of subjects in midlife only, 9.2% in late life only, and 4.2% in both. During 6 years of follow-up, 22.5% were diagnosed with dementia (5.5% with AD and 2.3% with VaD). The adjusted hazard of dementia was increased by approximately 20% for midlife depressive symptoms only (hazard ratio, 1.19 [95% CI, 1.07-1.32]), 70% for late-life symptoms only (1.72 [1.54-1.92]), and 80% for both (1.77 [1.52-2.06]). When we examined AD and VaD separately, subjects with late-life depressive symptoms only had a 2-fold increase in AD risk (hazard ratio, 2.06 [95% CI, 1.67-2.55]), whereas subjects with midlife and late-life symptoms had more than a 3-fold increase in VaD risk (3.51 [2.44-5.05]). CONCLUSIONS Depressive symptoms in midlife or in late life are associated with an increased risk of developing dementia. Depression that begins in late life may be part of the AD prodrome, while recurrent depression may be etiologically associated with increased risk of VaD.

Heavy Smoking in Midlife and Long-term Risk of Alzheimer Disease and Vascular Dementia

BACKGROUND Smoking is a risk factor for several life-threatening diseases, but its long-term association with dementia is controversial and somewhat understudied. Our objective was to investigate the long-term association of amount of smoking in middle age on the risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD) several decades later in a large, diverse population. METHODS We analyzed prospective data from a multiethnic population-based cohort of 21,123 members of a health care system who participated in a survey between 1978 and 1985. Diagnoses of dementia, AD, and VaD made in internal medicine, neurology, and neuropsychology were collected from January 1, 1994, to July 31, 2008. Multivariate Cox proportional hazards models were used to investigate the association between midlife smoking and risk of dementia, AD, and VaD. RESULTS A total of 5367 people (25.4%) were diagnosed as having dementia (including 1136 cases of AD and 416 cases of VaD) during a mean follow-up period of 23 years. Results were adjusted for age, sex, education, race, marital status, hypertension, hyperlipidemia, body mass index, diabetes, heart disease, stroke, and alcohol use. Compared with nonsmokers, those smoking more than 2 packs a day had an elevated risk of dementia (adjusted hazard ratio [HR], 2.14; 95% CI, 1.65-2.78), AD (adjusted HR, 2.57; 95% CI, 1.63-4.03), and VaD (adjusted HR, 2.72; 95% CI, 1.20-6.18). CONCLUSIONS In this large cohort, heavy smoking in midlife was associated with a greater than 100% increase in risk of dementia, AD, and VaD more than 2 decades later. These results suggest that the brain is not immune to long-term consequences of heavy smoking.

Metabolic Syndrome and Cognitive Decline in Elderly Latinos: Findings from the Sacramento Area Latino Study of Aging Study

OBJECTIVES: To investigate the effect of metabolic syndrome on cognitive function in an elderly Latino population and to determine whether inflammation modifies this association.