The Role of APOE ∊4 in Modulating Effects of Other Risk Factors for Cognitive Decline in Elderly Persons

ContextCognitive decline in elderly persons is often an early predictor of dementia. Subclinical cardiovascular disease (CVD) and diabetes mellitus may contribute to substantial decline in cognitive function in the elderly. These risks may be modified by gene-environment interactions between apolipoprotein E (APOE) genotype and CVD risk factors or subclinical CVD.ObjectivesTo examine the association between subclinical CVD and decline in cognitive functioning in the elderly and to examine effect modification by the APOE genotype of the association between subclinical disease and cognitive decline.DesignThe Cardiovascular Health Study, a population-based, prospective cohort study.Setting and PopulationA total of 5888 randomly selected Medicare-eligible participants from Sacramento County, California; Forsyth County, North Carolina; Washington County, Maryland; and Pittsburgh, Pa, aged 65 years or older, who were recruited in 1989-1990 (n = 5201) and in 1992-1993 (n = 687) and who were followed up for 7 and 5 years, respectively.Main Outcome MeasuresChange over time in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test as a function of APOE genotype, subclinical CVD, and diabetes mellitus.ResultsSeventy percent of participants had no significant decline on the Modified Mini-Mental State Examination. Systolic blood pressure, the ankle-arm brachial index, atherosclerosis of the internal carotid artery, diabetes mellitus, and several diagnoses of prevalent CVD were significantly associated with declines in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test. The rate of cognitive decline associated with peripheral vascular disease, atherosclerosis of the common and internal carotid arteries, or diabetes mellitus was increased by the presence of any APOE ∊4 allele.ConclusionsMost healthy elderly people did not experience cognitive decline. Measures of subclinical CVD were modest predictors of cognitive decline. Those with any APOE ∊4 allele in combination with atherosclerosis, peripheral vascular disease, or diabetes mellitus were at substantially higher risk of cognitive decline than those without the APOE ∊4 allele or subclinical CVD. High levels of atherosclerosis increased cognitive decline independently of APOE genotype.

[1]  T. Harris,et al.  Longitudinal association of vascular and Alzheimer’s dementias, diabetes, and glucose tolerance , 1999, Neurology.

[2]  L. Beckett,et al.  Current and remote blood pressure and cognitive decline. , 1999, JAMA.

[3]  J. Yesavage,et al.  The APOE ∍4 allele Is Associated with Decline on Delayed Recall Performance in Community‐Dwelling Older Adults , 1998 .

[4]  V. Chandra,et al.  Gene-Environment Interaction in Alzheimer’s Disease:A Potential Role for Cholesterol , 1998, Neuroepidemiology.

[5]  A. Hofman,et al.  Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. , 1998, Archives of neurology.

[6]  L. Bäckman,et al.  Three-year changes in cognitive performance as a function of apolipoprotein E genotype: evidence from very old adults without dementia. , 1998, Psychology and aging.

[7]  L. Fried,et al.  Relationship between ApoE, MRI findings, and cognitive function in the Cardiovascular Health Study. , 1998, Stroke.

[8]  K. Blennow,et al.  A population study of apoE genotype at the age of 85: relation to dementia, cerebrovascular disease, and mortality , 1998, Journal of neurology, neurosurgery, and psychiatry.

[9]  J. Crawford.  Alzheimer's disease risk factors as related to cerebral blood flow: additional evidence. , 1998, Medical hypotheses.

[10]  B. Psaty,et al.  The Association Of Antihypertensive Agents with MRI White Matter Findings and with Modified Mini‐Mental State Examination in Older Adults , 1997, Journal of the American Geriatrics Society.

[11]  A. Roses,et al.  Apolipoprotein E Genotyping as a Diagnostic Adjunct for Alzheimer's Disease , 1997, International Psychogeriatrics.

[12]  Johanna Kuusisto,et al.  Association between features of the insulin resistance syndrome and alzheimer's disease independently of apolipoprotein e4 phenotype: cross sectional population based study , 1997, BMJ.

[13]  J. Haines,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. , 1997, JAMA.

[14]  J. Haines,et al.  Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis , 1997 .

[15]  A. Hofman,et al.  Insulin and Cognitive Function in an Elderly Population: The Rotterdam Study , 1997, Diabetes Care.

[16]  N. Phillips,et al.  Cognitive deficits in peripheral vascular disease. A comparison of mild stroke patients and normal control subjects. , 1997, Stroke.

[17]  B. Winblad,et al.  Low blood pressure and five-year mortality in a Stockholm cohort of the very old: possible confounding by cognitive impairment and other factors. , 1997, American journal of public health.

[18]  A. Hofman,et al.  Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation. , 1997, JAMA.

[19]  C. Finch,et al.  Aging, Metabolism, and Alzheimer Disease: Review and Hypotheses , 1997, Experimental Neurology.

[20]  N. Desai,et al.  Cognitive Function in Younger Type II Diabetes , 1997, Diabetes Care.

[21]  H. Steingrüber,et al.  Cognitive function in elderly non-insulin-dependent diabetic patients before and after inpatient treatment for metabolic control. , 1997, Journal of diabetes and its complications.

[22]  F. Baralle,et al.  Polymorphism of the apolipoprotein E gene and early carotid atherosclerosis defined by ultrasonography in asymptomatic adults. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[23]  A. Hofman,et al.  Non-insulin-dependent Diabetes Mellitus (niddm) Association of Diabetes Mellitus and Dementia: the Rotterdam Study , 2022 .

[24]  G. Worrall,et al.  Cognitive function and glycosylated hemoglobin in older patients with type II diabetes. , 1996, Journal of diabetes and its complications.

[25]  P. Amouyel,et al.  Early effect of ApoE-ϵ4 allele on cognitive results in a group of highly performing subjects: the EVA study , 1996, Neuroscience Letters.

[26]  B. Hyman,et al.  Apolipoprotein E and cognitive change in an elderly population , 1996, Annals of neurology.

[27]  M. Aloia,et al.  The effects of glucose on nonmemory cognitive functioning in the elderly , 1996, Neuropsychologia.

[28]  A. Kurita,et al.  Neurophysiological Evidence for Altered Higher Brain Functions in NIDDM , 1996, Diabetes Care.

[29]  Janice E. Knoefel,et al.  Apolipoprotein E element 4 association with dementia in a population-based study , 1996, Neurology.

[30]  M. Laakso,et al.  Memory functions in human subjects with different apolipoprotein E phenotypes during a 3-year population-based follow-up study , 1996, Neuroscience Letters.

[31]  M. Gagnon,et al.  Glucose regulation and cognitive functions: relation to Alzheimer's disease and diabetes , 1996, Behavioural Brain Research.

[32]  R H Myers,et al.  Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study. , 1996, Neurology.

[33]  P. Amouyel,et al.  Early effect of ApoE-epsilon 4 allele on cognitive results in a group of highly performing subjects: the EVA study. Etude sur le Vieillissement Artériel. , 1996, Neuroscience letters.

[34]  R. Havlik,et al.  The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. , 1995, JAMA.

[35]  A. Kurita,et al.  Changes in auditory P300 event‐related potentials and brainstem evoked potentials in diabetes mellitus , 1995, Acta neurologica Scandinavica.

[36]  L. Kuller,et al.  Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study. , 1995, Annals of epidemiology.

[37]  L H Kuller,et al.  Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study. , 1995, Annals of epidemiology.

[38]  S. Ibayashi,et al.  Cerebral blood flow and brain function in hypertension. , 1995, Hypertension research : official journal of the Japanese Society of Hypertension.

[39]  W. Applegate,et al.  Impact of the treatment of isolated systolic hypertension on behavioral variables. Results from the systolic hypertension in the elderly program. , 1994, Archives of internal medicine.

[40]  A. Hofman,et al.  Cerebral white matter lesions, vascular risk factors, and cognitive function in a population‐based study , 1994, Neurology.

[41]  J. J. Claus,et al.  Cardiovascular disease and distribution of cognitive function in elderly people: the Rotterdam study , 1994, BMJ.

[42]  K. Mortel,et al.  Prospective Studies of Cerebral Perfusion and Cognitive Testing Among Elderly Normal Volunteers and Patients with Ischemic Vascular Dementia and Alzheimer's Disease , 1994, Angiology.

[43]  M. Laakso,et al.  Essential hypertension and cognitive function. The role of hyperinsulinemia. , 1993, Hypertension.

[44]  C. Ryan,et al.  Effects of insulin-dependent diabetes on learning and memory efficiency in adults. , 1993, Journal of clinical and experimental neuropsychology.

[45]  J. Gardin,et al.  Assessment of cerebrovascular disease in the Cardiovascular Health Study. , 1993, Annals of epidemiology.

[46]  L. Fried,et al.  Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study. , 1993, Annals of epidemiology.

[47]  G. Worrall,et al.  Effect of type II diabetes mellitus on cognitive function. , 1993, The Journal of family practice.

[48]  L. Whalley,et al.  Blood pressure and cognitive function in healthy old people. , 1993, Journal of the American Geriatrics Society.

[49]  Richard A. Kronmal,et al.  Distribution and Correlates of Sonographically Detected Carotid Artery Disease in the Cardiovascular Health Study , 1992, Stroke.

[50]  B. Psaty,et al.  Major electrocardiographic abnormalities in persons aged 65 years and older (the Cardiovascular Health Study). Cardiovascular Health Study Collaborative Research Group. , 1992, The American journal of cardiology.

[51]  P. Tun,et al.  Cognitive and affective disorders in elderly diabetics. , 1990, Clinics in geriatric medicine.

[52]  M. Lezak,et al.  The Mental Efficiency of the Elderly Person with Type II Diabetes Mellitus , 1990, Journal of the American Geriatrics Society.

[53]  G. Reaven,et al.  Relationship Between Hyperglycemia and Cognitive Function in Older NIDDM Patients , 1990, Diabetes Care.

[54]  K. Perryman,et al.  Cortical function in elderly non-insulin dependent diabetic patients. Behavioral and electrophysiologic studies. , 1988, Archives of internal medicine.

[55]  D. Nathan,et al.  Triglyceride levels affect cognitive function in noninsulin-dependent diabetics. , 1988, The Journal of diabetic complications.

[56]  H. Chui,et al.  The Modified Mini-Mental State (3MS) examination. , 1987, The Journal of clinical psychiatry.

[57]  S. Zeger,et al.  Longitudinal data analysis using generalized linear models , 1986 .

[58]  A. Baron,et al.  Improved digit symbol substitution by older women as a result of extended practice. , 1981, Journal of gerontology.