Memory performance in healthy elderly without Alzheimer’s disease: effects of time and apolipoprotein-E

Transgenic mice expressing human APOE-epsilon4 develop an age-dependent decline in memory without pathological features of Alzheimer's disease (AD). This implicates APOE in the maintenance of memory during normal senescence, but parallel human studies are limited because longitudinal investigations of memory usually do not exclude patients with AD or "questionable" AD (QD). The current study examined the effect of APOE on cognitive function over time in elderly without dementia. We hypothesized that, compared to other APOE alleles memory decline even in healthy elderly would be greater among those with an APOE-epsilon4. The results of neuropsychological tests, grouped into domains of memory, language and visuospatial/cognitive function by factor analysis, were examined at three intervals over a seven-year period in 563 healthy elderly without AD or QD using generalized estimating equations. Memory performance declined over time, while scores on the visuospatial/cognitive and language factors did not change. Increased age was associated with lower scores, and higher education with higher scores on all factors at each interval. No APOE allele was associated with performance on a specific cognitive factor at any interval, but the presence of an APOE-epsilon4 allele was associated with a more rapid decline in the memory factor over the follow-up period. The effect was most pronounced among individuals with less than 10 years of formal education. There was no similar time-dependent relationship between APOE-epsilon4 and the language or visuospatial/cognitive factors. Transgenic mice and elderly humans without AD or QD expressing APOE-epsilon4 show a decline in memory performance over time. These observations provide evidence for an APOE-specific effect on memory during senescence.

[1]  L. Wahlund,et al.  Inheritance of the ApoE epsilon4 allele increases the rate of brain atrophy in dementia patients. , 1999, Dementia and geriatric cognitive disorders.

[2]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[3]  J. Dodart,et al.  Behavioral deficits in APPV717F transgenic mice decient for the apolipoprotein E gene , 2000, Neuroreport.

[4]  B. Permanne,et al.  Detection of apolipoprotein E/dimeric soluble amyloid beta complexes in Alzheimer's disease brain supernatants. , 1997, Biochemical and biophysical research communications.

[5]  M. Stewart,et al.  Synaptic loss is accompanied by an increase in synaptic area in the dentate gyrus of aged human Apolipoprotein E4 transgenic mice , 2000, Neuroscience.

[6]  K. Marder,et al.  The APOE- (cid:101) 4 Allele and the Risk of Alzheimer Disease Among African Americans, Whites, and Hispanics , 2001 .

[7]  G. Cole,et al.  β‐Amyloid (Aβ)42(43), Aβ42, Aβ40 and apoE immunostaining of plaques in fatal head injury , 2000, Neuropathology and applied neurobiology.

[8]  R. Mayeux,et al.  Diagnosis of dementia in a heterogeneous population. Development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. , 1992, Archives of neurology.

[9]  Matthias Orth,et al.  Expression of Human Apolipoprotein E3 or E4 in the Brains ofApoe−/− Mice: Isoform-Specific Effects on Neurodegeneration , 1999, The Journal of Neuroscience.

[10]  Yaakov Stern,et al.  The APOE-∊4 Allele and the Risk of Alzheimer Disease Among African Americans, Whites, and Hispanics , 1998 .

[11]  N Butters,et al.  Episodic memory changes are associated with the APOE- epsilon 4 allele in nondemented older adults , 1995, Neurology.

[12]  J. Mortimer,et al.  Is APOE--epsilon4 a risk factor for cognitive impairment in normal aging? , 2000, Neurology.

[13]  Joakim Bjorkdahl.  Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease. , 2000 .

[14]  R. Mayeux,et al.  Selective decline in memory function among healthy elderly , 1999, Neurology.

[15]  Daniel Bandy,et al.  Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease , 1998, Annals of neurology.

[16]  G. Vega,et al.  Apolipoprotein E epsilon 4, other risk factors, and course of Alzheimer's disease. , 1999, Biological psychiatry.

[17]  J. Mazziotta,et al.  Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Y. Stern,et al.  Diabetes mellitus and the risk of dementia , 1999, Neurology.

[19]  A. Hofman,et al.  Apolipoprotein E genotype and progression of Alzheimer’s disease: the Rotterdam Study , 1999, Journal of Neurology.

[20]  F. Fazekas,et al.  Apolipoprotein E4allele in the normal elderly: neuropsychologic and brain MRI correlates , 1996, Clinical genetics.

[21]  R. Killiany,et al.  Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease , 2000, Annals of neurology.

[22]  B. Geiselmann,et al.  In an epidemiological sample the apolipoprotein E4 allele is associated to dementia and loss of memory function only in the very old , 1997, Neuroscience Letters.

[23]  K. Marder,et al.  Neuropsychological detection and characterization of preclinical Alzheimer's disease , 1995, Neurology.

[24]  L M Bouter,et al.  APOE-epsilon4 is associated with memory decline in cognitively impaired elderly. , 2000, Neurology.

[25]  E B Larson,et al.  Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status. , 1999, Neurology.

[26]  L. Mucke,et al.  Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Lindeboom,et al.  Low education is a genuine risk factor for accelerated memory decline and dementia. , 1997, Journal of clinical epidemiology.

[28]  H. Kraemer,et al.  The APOE epsilon4 allele is associated with decline on delayed recall performance in community-dwelling older adults. , 1998, Journal of the American Geriatrics Society.

[29]  P. Wolf,et al.  The joint effect of apolipoprotein E epsilon4 and MRI findings on lower-extremity function and decline in cognitive function. , 2000, The journals of gerontology. Series A, Biological sciences and medical sciences.

[30]  K. Horsburgh,et al.  The role of apolipoprotein E in Alzheimer’s disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models , 2000, Neurobiology of Aging.

[31]  H. Soininen,et al.  Major decrease in the volume of the entorhinal cortex in patients with Alzheimer’s disease carrying the apolipoprotein E ε4 allele , 1998, Journal of neurology, neurosurgery, and psychiatry.

[32]  E. Kaplan,et al.  The assessment of aphasia and related disorders , 1972 .

[33]  J. Lindeboom,et al.  Association between apolipoprotein E ε4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia , 1998 .

[34]  C. P. Hughes,et al.  A New Clinical Scale for the Staging of Dementia , 1982, British Journal of Psychiatry.

[35]  J. Lindeboom,et al.  Association between apolipoprotein E epsilon4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia. , 1998, Archives of neurology.

[36]  Eric M. Reiman,et al.  Preclinical memory decline in cognitively normal apolipoprotein E–ε4 homozygotes , 1999, Neurology.

[37]  L. Wahlund,et al.  Inheritance of the ApoE ε4 Allele Increases the Rate of Brain Atrophy in Dementia Patients , 1999, Dementia and Geriatric Cognitive Disorders.

[38]  S N Thibodeau,et al.  Preclinical memory decline in cognitively normal apolipoprotein E-epsilon4 homozygotes. , 1999, Neurology.

[39]  G. Vega,et al.  Apolipoprotein eϵ4, other risk factors, and course of alzheimer’s disease , 1999, Biological Psychiatry.

[40]  J. Lindeboom,et al.  The effects of intelligence and education on the development of dementia. A test of the brain reserve hypothesis , 1997, Psychological Medicine.

[41]  G. Schellenberg,et al.  Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans , 1995, Annals of neurology.

[42]  D. Kleinbaum,et al.  Applied Regression Analysis and Other Multivariate Methods , 1978 .

[43]  B. Tycko,et al.  Apolipoprotein E and alzheimer's disease: Ethnic variation in genotypic risks , 1995, Annals of neurology.

[44]  L. Thal,et al.  Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer's disease. , 1999, Psychology and aging.

[45]  D. Michaelson,et al.  Specific neurochemical derangements of brain projecting neurons in apolipoprotein E-deficient mice , 1997, Neuroscience Letters.

[46]  C. Jonker,et al.  APOE-ε4 is associated with memory decline in cognitively impaired elderly , 2000, Neurology.

[47]  G. Schellenberg,et al.  Impaired olfaction as a marker for cognitive decline: Interaction with apolipoprotein E 4 status , 1999 .

[48]  P. Albert,et al.  Models for longitudinal data: a generalized estimating equation approach. , 1988, Biometrics.

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

[50]  HERMAN BUSCHKE,et al.  Evaluating storage, retention, and retrieval in disordered memory and learning , 1974, Neurology.

[51]  Yaakov Stern,et al.  The absence of an apolipoprotein ϵ4 allele is associated with a more aggressive form of Alzheimer's disease , 1997, Annals of neurology.

[52]  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.

[53]  A D Roses,et al.  Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[54]  S. Paul,et al.  Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[55]  W. Tsai,et al.  Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City. , 1996, American journal of human genetics.

[56]  J. Mortimer,et al.  Is APOE-ε4 a risk factor for cognitive impairment in normal aging? , 2000, Neurology.

[57]  K. Hall,et al.  APOE Allele frequencies in demented and nondemented Elderly Jamaicans , 1998, Annals of neurology.

[58]  D. Michaelson,et al.  Biochemical and cognitive studies of apolipoprotein-E-deficient mice , 1996, Molecular and chemical neuropathology.

[59]  G. Ratcliff,et al.  Relation of education to brain size in normal aging , 1999, Neurology.

[60]  Bruce G. Link,et al.  Diagnosis of dementia in a heterogeneous population. A comparison of paradigm-based diagnosis and physician's diagnosis. , 1992, Archives of neurology.

[61]  M. Laakso,et al.  The association of apolipoprotein E polymorphism with memory: a population based study , 1995, Neuroscience Letters.

[62]  C. Junqué,et al.  Apo E influences declarative and procedural learning in age-associated memory impairment. , 1999, Neuroreport.

[63]  H. Soininen,et al.  Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes , 1995, Neuroscience.

[64]  J. Cauley,et al.  Apolipoprotein E phenotype and cognitive decline in a prospective study of elderly community women. , 1997, Archives of neurology.

[65]  W. Perrig,et al.  Apolipoprotein E genotypes and cognitive functions in healthy elderly persons , 1999, Acta neurologica Scandinavica.

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

[67]  O. Gureje,et al.  Apolipoprotein E—associated risk for Alzheimer's disease in the African‐American population is genotype dependent , 1997, Annals of neurology.

[68]  R J Miller,et al.  Isoform-Specific Effect of Apolipoprotein E on Cell Survival and β-Amyloid-Induced Toxicity in Rat Hippocampal Pyramidal Neuronal Cultures , 1998, The Journal of Neuroscience.

[69]  Y. Stern,et al.  Normative data for a brief neuropsychological battery administered to English- and Spanish-speaking community-dwelling elders , 1998, Journal of the International Neuropsychological Society.

[70]  Vladimir V. Frolkis,et al.  Neurobiology of Aging , 2019, Psychobiology of Behaviour.

[71]  J. Gilbert,et al.  Human Apolipoprotein E Isoform‐Specific Differences in Neuronal Sprouting in Organotypic Hippocampal Culture , 1999, Journal of neurochemistry.

[72]  E. Kaplan,et al.  The Boston naming test , 2001 .