Amyloid load in nondemented brains correlates with APOE e4

179 Cognitively healthy adults enrolled in the Sun Health Brain Donation program between 7/91 and 12/07 were at least 60 years old and nondemented at the time of death (21 had developed mild cognitive impairment [MCI]). Amyloid plaque density, congophilic amyloid angiopathy (CAA), and neurofibrillary tangle (NFT) density scores were based on CERAD criteria and compared in apolipoprotein E (APOE) e4 carriers (n=42) and noncarriers (NC) (n=137). Mean age (83.4+/-.6), gender (45% women), interval between death and brain harvest (3.1+/-2.4h), and brain weight (1200+/-119 g) did not differ between e4 carriers (n=42) and NC. Total plaque density was higher in e4 carriers than NC (6.8+/-4.9 vs. 4.3+/-4.4, p=.002), and this was true in each of 5 subregions examined. Total CAA (p=.002) and all subregion CAA burden was also higher in e4 carriers. Total neuritic plaque density (1.2+/-1.0 vs. 1.0+/-1.0, p=.18) and total NFT density (3.9+/-2.4 vs. 3.6+/-2.3, p=.50) did not differ between e4 carriers and NC, nor in any subregion. Eliminating the 21 with MCI did not alter these results. Nondemented APOE e4 carriers over age 60 have a higher burden of total parenchymal and vascular amyloid neuropathology than NC, but no difference in neuritic plaque and NFT pathology.

[1]  Peter Davies,et al.  Identification of normal and pathological aging in prospectively studied nondemented elderly humans , 1992, Neurobiology of Aging.

[2]  G. Alexander,et al.  Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. , 2009, The New England journal of medicine.

[3]  G. Alexander,et al.  Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease , 2009, Proceedings of the National Academy of Sciences.

[4]  B. Hyman,et al.  The Neuropathological Diagnosis of Alzheimer’s Disease: Clinical-Pathological Studies , 1997, Neurobiology of Aging.

[5]  D. T. Vernier,et al.  Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. , 1990, Journal of lipid research.

[6]  David A. Bennett,et al.  Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles , 2009, Neurology.

[7]  Majaz Moonis,et al.  Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees , 2007, The Journal of Neuroscience.

[8]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[9]  L A Hansen,et al.  The importance of neuritic plaques and tangles to the development and evolution of AD , 2004, Neurology.

[10]  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.

[11]  G. Alexander,et al.  Correlations between apolipoprotein E ε4 gene dose and brain-imaging measurements of regional hypometabolism , 2005 .

[12]  A. D. Roses,et al.  Association of apolipoprotein E allele €4 with late-onset familial and sporadic Alzheimer’s disease , 2006 .

[13]  J. Ashford,et al.  “Preclinical” AD revisited , 2000, Neurology.

[14]  L. Thal,et al.  Clinical Dementia Rating training and reliability in multicenter studies , 1997, Neurology.

[15]  J. Morris,et al.  Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease , 1999, Annals of neurology.

[16]  G. Alexander,et al.  Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  N R Relkin,et al.  Increased apolipoprotein E ϵ4 in epilepsy with senile plaques , 1997, Annals of neurology.

[18]  A. Smith,et al.  Relative roles of plaques and tangles in the dementia of Alzheimer's disease: correlations using three sets of neuropathological criteria. , 1995, Dementia.

[19]  H. Braak,et al.  Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories , 1997, Neurobiology of Aging.

[20]  H. Braak,et al.  Staging of alzheimer's disease-related neurofibrillary changes , 1995, Neurobiology of Aging.

[21]  E. Mandelkow,et al.  Tau in Alzheimer's disease. , 1998, Trends in cell biology.

[22]  K. Davis,et al.  Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. , 2000, JAMA.

[23]  J C Mazziotta,et al.  Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. , 1995, JAMA.

[24]  M Schwaiger,et al.  Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease , 2009, Neurology.

[25]  S. M. Sumi,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1991, Neurology.

[26]  Richard J. Caselli,et al.  Correlations Between Apolipoprotein E ε4 Gene Dose and Whole Brain Atrophy Rates , 2007 .

[27]  Bradley T. Hyman,et al.  Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease , 1992, Neurology.

[28]  Sirkka Goebeler,et al.  Apolipoprotein E–dependent accumulation of Alzheimer disease–related lesions begins in middle age , 2009, Annals of neurology.

[29]  A. Fagan,et al.  Alzheimer’s disease risk variants show association with cerebrospinal fluid amyloid beta , 2009, neurogenetics.

[30]  J. Morrison,et al.  Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital. , 1994, Cerebral cortex.

[31]  D. Connor,et al.  The Sun Health Research Institute Brain Donation Program: Description and Eexperience, 1987–2007 , 2007, Cell and Tissue Banking.