Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's disease: a cross-sectional study

Mehul A Trivedi, Taylor W Schmitz, Michele L Ries, Britta M Torgerson, Mark A Sager, Bruce P Hermann, Sanjay Asthana, Sterling C Johnson, Mehul A Trivedi, Taylor W Schmitz, Michele L Ries, Britta M Torgerson, Mark A Sager, Bruce P Hermann, Sanjay Asthana, Sterling C Johnson

Abstract

Background: The presence of the apolipoprotein E (APOE) epsilon4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the epsilon4 allele on hippocampal activation has not been firmly established.

Methods: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD.

Results: We found that epsilon3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to epsilon3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in epsilon3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the epsilon3/3 homozygotes, but not in the epsilon3/4 heterozygotes.

Conclusion: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE epsilon4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline.

Figures

Figure 1
Figure 1
Activation Maps for fMRI task. Statistical parametric maps of the single-group analyses for ε3/3 homozygotes (panel A) and ε3/4 heterozygotes (panel B), and for regions where the ε3/3 homozygotes activated to a greater extent than the ε3/4 heterozygotes (panel C). The left side of each coronal section represents the left hemisphere. The dark-shaded area represents the MTL region to which the statistical analyses were confined. The lighter-shaded areasrepresent regions outside of the MTL mask.
Figure 2
Figure 2
Graph of signal change in the MTL. Plot of the signal change (adjusted fitted responses) for ε3/3 homozygotes and ε3/4 heterozygotes averaged over a 2 mm radius spherical ROI at the local maxima in the right hippocampus (x, y, z: 30, -14, -16), and at the same location in the left hippocampus (x, y, z: -30, -14, -16). Data are presented as mean signalchange for each group. Error bars represent the standard error of the mean. * denotes significant difference between the two groups.
Figure 3
Figure 3
RAVLT versus Signal Change. Scatter plot of the association between total words learned on the RAVLT and signal change within the left amygdala (left panel) and left anterior hippocampus (right panel) for ε3/3 homozygotes (black circles, solid lines) and ε3/4 heterozygotes (white squares, hashed lines).

References

    1. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. 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. JAMA. 1997;278:1349–1356. doi: 10.1001/jama.278.16.1349.
    1. Cupples LA, Farrer LA, Sadovnick AD, Relkin N, Whitehouse P, Green RC. Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: the REVEAL study. Genet Med. 2004;6:192–196.
    1. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921–923.
    1. Duara R, Barker WW, Lopez-Alberola R, Loewenstein DA, Grau LB, Gilchrist D, Sevush S, St George-Hyslop S. Alzheimer's disease: interaction of apolipoprotein E genotype, family history of dementia, gender, education, ethnicity, and age of onset. Neurology. 1996;46:1575–1579.
    1. Martinez M, Campion D, Brice A, Hannequin D, Dubois B, Didierjean O, Michon A, Thomas-Anterion C, Puel M, Frebourg T, Agid Y, Clerget-Darpoux F. Apolipoprotein E epsilon4 allele and familial aggregation of Alzheimer disease. Arch Neurol. 1998;55:810–816. doi: 10.1001/archneur.55.6.810.
    1. Braak H, Braak E, Bohl J. Staging of Alzheimer-related cortical destruction. Eur Neurol. 1993;33:403–408.
    1. Jack CR, Jr, Petersen RC, Xu YC, O'Brien PC, Smith GE, Ivnik RJ, Boeve BF, Waring SC, Tangalos EG, Kokmen E. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology. 1999;52:1397–1403.
    1. Hyman BT, Arriagada PV, van Hoesen GW, Damasio AR. Memory impairment in Alzheimer's Disease: An anatomical perspective. In: Parks RW, Zec RF, Wilson RS, editor. Neuropsychology of Alzheimer's disease and other dementias. 1. New York: Oxford University Press; 1993. pp. 138–150.
    1. Baxter LC, Caselli RJ, Johnson SC, Reiman E, Osborne D. Apolipoprotein E epsilon 4 affects new learning in cognitively normal individuals at risk for Alzheimer's disease. Neurobiol Aging. 2003;24:947–952. doi: 10.1016/S0197-4580(03)00006-X.
    1. Caselli RJ, Graff-Radford NR, Reiman EM, Weaver A, Osborne D, Lucas J, Uecker A, Thibodeau SN. Preclinical memory decline in cognitively normal apolipoprotein E-epsilon4 homozygotes. Neurology. 1999;53:201–207.
    1. Mayeux R, Small SA, Tang M, Tycko B, Stern Y. Memory performance in healthy elderly without Alzheimer's disease: effects of time and apolipoprotein-E. Neurobiol Aging. 2001;22:683–689. doi: 10.1016/S0197-4580(01)00223-8.
    1. Cohen RM, Small C, Lalonde F, Friz J, Sunderland T. Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women. Neurology. 2001;57:2223–2228.
    1. den Heijer T, Oudkerk M, Launer LJ, van Duijn CM, Hofman A, Breteler MM. Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes. Neurology. 2002;59:746–748.
    1. Lemaitre H, Crivello F, Dufouil C, Grassiot B, Tzourio C, Alperovitch A, Mazoyer B. No epsilon4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects. Neuroimage. 2005;24:1205–1213. doi: 10.1016/j.neuroimage.2004.10.016.
    1. Moffat SD, Szekely CA, Zonderman AB, Kabani NJ, Resnick SM. Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype. Neurology. 2000;55:134–136.
    1. Plassman BL, Welsh-Bohmer KA, Bigler ED, Johnson SC, Anderson CV, Helms MJ, Saunders AM, Breitner JC. Apolipoprotein E epsilon 4 allele and hippocampal volume in twins with normal cognition. Neurology. 1997;48:985–989.
    1. Bigler ED, Tate DF, Miller MJ, Rice SA, Hessel CD, Earl HD, Tschanz JT, Plassman B, Welsh-Bohmer KA. Dementia, asymmetry of temporal lobe structures, and apolipoprotein E genotype: relationships to cerebral atrophy and neuropsychological impairment. J Int Neuropsychol Soc. 2002;8:925–933. doi: 10.1017/S1355617702870072.
    1. Jernigan TL, Archibald SL, Fennema-Notestine C, Gamst AC, Stout JC, Bonner J, Hesselink JR. Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiol Aging. 2001;22:581–594. doi: 10.1016/S0197-4580(01)00217-2.
    1. Schmidt H, Schmidt R, Fazekas F, Semmler J, Kapeller P, Reinhart B, Kostner GM. Apolipoprotein E e4 allele in the normal elderly: neuropsychologic and brain MRI correlates. Clin Genet. 1996;50:293–299.
    1. Cabeza R, Dolcos F, Graham R, Nyberg L. Similarities and differences in the neural correlates of episodic memory retrieval and working memory. Neuroimage. 2002;16:317–330. doi: 10.1006/nimg.2002.1063.
    1. Cabeza R, Prince SE, Daselaar SM, Greenberg DL, Budde M, Dolcos F, LaBar KS, Rubin DC. Brain activity during episodic retrieval of autobiographical and laboratory events: an fMRI study using a novel photo paradigm. J Cogn Neurosci. 2004;16:1583–1594. doi: 10.1162/0898929042568578.
    1. Cabeza R, Rao SM, Wagner AD, Mayer AR, Schacter DL. Can medial temporal lobe regions distinguish true from false? An event-related functional MRI study of veridical and illusory recognition memory. Proc Natl Acad Sci U S A. 2001;98:4805–4810. doi: 10.1073/pnas.081082698.
    1. Gron G, Bittner D, Schmitz B, Wunderlich AP, Tomczak R, Riepe MW. Hippocampal activations during repetitive learning and recall of geometric patterns. Learn Mem. 2001;8:336–345. doi: 10.1101/lm.42901.
    1. Gron G, Wunderlich AP, Spitzer M, Tomczak R, Riepe MW. Brain activation during human navigation: gender-different neural networks as substrate of performance. Nat Neurosci. 2000;3:404–408. doi: 10.1038/73980.
    1. Nyberg L, McIntosh AR, Cabeza R, Habib R, Houle S, Tulving E. General and specific brain regions involved in encoding and retrieval of events: what, where, and when. Proc Natl Acad Sci U S A. 1996;93:11280–11285. doi: 10.1073/pnas.93.20.11280.
    1. Brewer JB, Zhao Z, Desmond JE, Glover GH, Gabrieli JD. Making memories: brain activity that predicts how well visual experience will be remembered. Science. 1998;281:1185–1187. doi: 10.1126/science.281.5380.1185.
    1. Grunwald T, Lehnertz K, Heinze HJ, Helmstaedter C, Elger CE. Verbal novelty detection within the human hippocampus proper. Proc Natl Acad Sci U S A. 1998;95:3193–3197. doi: 10.1073/pnas.95.6.3193.
    1. Habib R, McIntosh AR, Wheeler MA, Tulving E. Memory encoding and hippocampally-based novelty/familiarity discrimination networks. Neuropsychologia. 2003;41:271–279. doi: 10.1016/S0028-3932(02)00160-4.
    1. Knight R. Contribution of human hippocampal region to novelty detection. Nature. 1996;383:256–259. doi: 10.1038/383256a0.
    1. Stern CE, Corkin S, Gonzalez RG, Guimaraes AR, Baker JR, Jennings PJ, Carr CA, Sugiura RM, Vedantham V, Rosen BR. The hippocampal formation participates in novel picture encoding: evidence from functional magnetic resonance imaging. Proc Natl Acad Sci U S A. 1996;93:8660–8665. doi: 10.1073/pnas.93.16.8660.
    1. Tulving E, Markowitsch HJ, Craik FE, Habib R, Houle S. Novelty and familiarity activations in PET studies of memory encoding and retrieval. Cereb Cortex. 1996;6:71–79.
    1. Lepage M, Habib R, Tulving E. Hippocampal PET activations of memory encoding and retrieval: the HIPER model. Hippocampus. 1998;8:313–322. doi: 10.1002/(SICI)1098-1063(1998)8:4<313::AID-HIPO1>;2-I.
    1. Ranganath C, Rainer G. Neural mechanisms for detecting and remembering novel events. Nat Rev Neurosci. 2003;4:193–202. doi: 10.1038/nrn1052.
    1. Tulving E, Kroll N. Novelty assessment in the brain and long-term memory encoding. Psychonomic Bulletin and Review. 1995;2:387–390.
    1. Sager MA, Hermann BP, La Rue A. Middle-aged Children of Persons with Alzheimer's Disease: APOE Genotypes and Cognitive Function in the Wisconsin Registry for Alzheimer's Prevention. Journal of Geriatric Psychiatry and Neurology.
    1. Zannis VI, Kardassis D, Zanni EE. Genetic mutations affecting human lipoproteins, their receptors, and their enzymes. Adv Hum Genet. 1993;21:145–319.
    1. Wechsler D. Wechsler abbreviated scale of intelligence. 1. San Antonio, TX: Psychological Corporation; 1999.
    1. Wechsler D. Wechsler adult intelligence scale. 3. San Antonio, TX: The Psychological Corporation; 1997.
    1. Benton LA, Hamsher K, Sivan AB. Controlled Oral Word Association Test Multilingual Aphasia Examination. 3. Iowa City, IA: AJA; 1994.
    1. Spreen O, Strauss E. A Compendium of Neuropsychological Tests. New York: Oxford; 1998.
    1. Goodglass H, Kaplan E. The assessment of aphasia and related disorders. 2. Philadelphia: Lea & Febiger; 1987.
    1. Reitan RM, Wolfson D. The Halstead-Reitan Neuropsychological Test Battery: Theory and clinical interpretation. 2. Tucson: Neuropsychology Press; 1993.
    1. Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurements. 1977;1:385–401.
    1. Snodgrass J, Vanderwart M. A standardized set of 260 pictures: Norms for name agreement, image agreement, familiarity, and visual complexity. Journal of Experimental Psychology: Human Learning and Memory. 1980;6:174–215. doi: 10.1037//0278-7393.6.2.174.
    1. Moritz CH, Johnson S, Meyerand ME. Variable-length block memory encoding paradigm demonstrates individual subject hippocampal fMRI response. Proc Intl Soc Magn Res Med. 2002;10
    1. Liu TT, Frank LR, Wong EC, Buxton RB. Detection power, estimation efficiency, and predictability in event-related fMRI. Neuroimage. 2001;13:759–773. doi: 10.1006/nimg.2000.0728.
    1. Jenkinson M. Fast, automated, N-dimensional phase-unwrapping algorithm. Magn Reson Med. 2003;49:193–197. doi: 10.1002/mrm.10354.
    1. Friston KJ, Holmes AP, Worsley KJ, Poline JP, Frith CD, Frackowiak RSJ. Statistical parametric maps in functional imaging: A general linear approach. Human Brain Mapping. 1995;2:189–210. doi: 10.1002/hbm.460020402.
    1. Bullmore E, Brammer M, Williams SC, Rabe-Hesketh S, Janot N, David A, Mellers J, Howard R, Sham P. Statistical methods of estimation and inference for functional MR image analysis. Magn Reson Med. 1996;35:261–277.
    1. Johnson SC, Baxter LC, Susskind-Wilder L, Connor DJ, Sabbagh MN, Caselli RJ. Hippocampal adaptation to face repetition in healthy elderly and mild cognitive impairment. Neuropsychologia. 2004;42:980–989. doi: 10.1016/j.neuropsychologia.2003.11.015.
    1. Genovese CR, Lazar NA, Nichols T. Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage. 2002;15:870–878. doi: 10.1006/nimg.2001.1037.
    1. Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage. 2001;14:21–36. doi: 10.1006/nimg.2001.0786.
    1. Ashburner J, Friston KJ. Voxel-based morphometry--the methods. Neuroimage. 2000;11:805–821. doi: 10.1006/nimg.2000.0582.
    1. McMillan AB, Hermann BP, Johnson SC, Hansen RR, Seidenberg M, Meyerand ME. Voxel-based morphometry of unilateral temporal lobe epilepsy reveals abnormalities in cerebral white matter. Neuroimage. 2004;23:167–174. doi: 10.1016/j.neuroimage.2004.05.002.
    1. Albert MS, Moss MB, Tanzi R, Jones K. Preclinical prediction of AD using neuropsychological tests. J Int Neuropsychol Soc. 2001;7:631–639. doi: 10.1017/S1355617701755105.
    1. Reiman EM, Uecker A, Caselli RJ, Lewis S, Bandy D, de Leon MJ, De Santi S, Convit A, Osborne D, Weaver A, Thibodeau SN. Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease. Ann Neurol. 1998;44:288–291. doi: 10.1002/ana.410440226.
    1. Devanand DP, Pelton GH, Zamora D, Liu X, Tabert MH, Goodkind M, Scarmeas N, Braun I, Stern Y, Mayeux R. Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment. Arch Neurol. 2005;62:975–980. doi: 10.1001/archneur.62.6.975.
    1. Wright CI, Martis B, Schwartz CE, Shin LM, Fischer HH, McMullin K, Rauch SL. Novelty responses and differential effects of order in the amygdala, substantia innominata, and inferior temporal cortex. Neuroimage. 2003;18:660–669. doi: 10.1016/S1053-8119(02)00037-X.
    1. Cabeza R, Nyberg L. Imaging cognition II: An empirical review of 275 PET and fMRI studies. J Cogn Neurosci. 2000;12:1–47. doi: 10.1162/08989290051137585.
    1. Johnson SC, Saykin AJ, Flashman LA, McAllister TW, Sparling MB. Brain activation on fMRI and verbal memory ability: functional neuroanatomic correlates of CVLT performance. J Int Neuropsychol Soc. 2001;7:55–62. doi: 10.1017/S135561770171106X.
    1. Smith CD, Andersen AH, Kryscio RJ, Schmitt FA, Kindy MS, Blonder LX, Avison MJ. Altered brain activation in cognitively intact individuals at high risk for Alzheimer's disease. Neurology. 1999;53:1391–1396.
    1. Smith CD, Andersen AH, Kryscio RJ, Schmitt FA, Kindy MS, Blonder LX, Avison MJ. Women at risk for AD show increased parietal activation during a fluency task. Neurology. 2002;58:1197–1202.
    1. Smith CD, Kryscio RJ, Schmitt FA, Lovell MA, Blonder LX, Rayens WS, Andersen AH. Longitudinal Functional Alterations in Asymptomatic Women at Risk for Alzheimer's Disease. J Neuroimaging. 2005;15:271–277. doi: 10.1177/1051228405277340.
    1. Zec RF. Neuropsychological functioning in Alzheimer's Disease. In: Parks RW, Zec RF, Wilson RS, editor. Neuropsychology of Alzheimer's disease and other dementias. 1. New York: Oxford University Press; 1993. pp. 3–80.
    1. Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, Mazziotta JC, Small GW. Patterns of brain activation in people at risk for Alzheimer's disease. N Engl J Med. 2000;343:450–456. doi: 10.1056/NEJM200008173430701.
    1. Burggren AC, Small GW, Sabb FW, Bookheimer SY. Specificity of brain activation patterns in people at genetic risk for Alzheimer disease. Am J Geriatr Psychiatry. 2002;10:44–51. doi: 10.1176/appi.ajgp.10.1.44.
    1. Bondi MW, Houston WS, Eyler LT, Brown GG. fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology. 2005;64:501–508.
    1. Cabeza R, Daselaar SM, Dolcos F, Prince SE, Budde M, Nyberg L. Task-independent and task-specific age effects on brain activity during working memory, visual attention and episodic retrieval. Cereb Cortex. 2004;14:364–375. doi: 10.1093/cercor/bhg133.
    1. Daselaar SM, Veltman DJ, Rombouts SA, Raaijmakers JG, Jonker C. Neuroanatomical correlates of episodic encoding and retrieval in young and elderly subjects. Brain. 2003;126:43–56. doi: 10.1093/brain/awg005.
    1. Watkins MJ, Gardiner JM. An appreciation of generate-recognize theory of recall. Journal of Verbal Learning and Verbal Behavior. 1979;18:687–704. doi: 10.1016/S0022-5371(79)90397-9.
    1. Tohgi H, Takahashi S, Kato E, Homma A, Niina R, Sasaki K, Yonezawa H, Sasaki M. Reduced size of right hippocampus in 39- to 80-year-old normal subjects carrying the apolipoprotein E epsilon4 allele. Neurosci Lett. 1997;236:21–24. doi: 10.1016/S0304-3940(97)00743-X.
    1. Stark CE, Squire LR. When zero is not zero: the problem of ambiguous baseline conditions in fMRI. Proc Natl Acad Sci U S A. 2001;98:12760–12766. doi: 10.1073/pnas.221462998.
    1. Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci U S A. 2003;100:253–258. doi: 10.1073/pnas.0135058100.
    1. Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004;101:4637–4642. doi: 10.1073/pnas.0308627101.
    1. Rombouts SA, Barkhof F, Goekoop R, Stam CJ, Scheltens P. Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: An fMRI study. Hum Brain Mapp. 2005;26:231–239. doi: 10.1002/hbm.20160.
    1. Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM. Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer's Disease Treatment Studies. Am J Psychiatry. 2002;159:738–745. doi: 10.1176/appi.ajp.159.5.738.
    1. Reiman EM, Caselli RJ, Chen K, Alexander GE, Bandy D, Frost J. Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci U S A. 2001;98:3334–3339. doi: 10.1073/pnas.061509598.
    1. Reiman EM, Caselli RJ, Alexander GE, Chen K. Tracking the decline in cerebral glucose metabolism in persons and laboratory animals at genetic risk for Alzheimer's disease. Clinical Neuroscience Research. 2001;1:194–206. doi: 10.1016/S1566-2772(01)00006-8.
    1. Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, Thibodeau SN, Osborne D. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med. 1996;334:752–758. doi: 10.1056/NEJM199603213341202.
    1. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A. 2004;101:284–289. doi: 10.1073/pnas.2635903100.
    1. Small GW, Mazziotta JC, Collins MT, Baxter LR, Phelps ME, Mandelkern MA, Kaplan A, La Rue A, Adamson CF, Chang L. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA. 1995;273:942–947. doi: 10.1001/jama.273.12.942.
    1. Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, Lavretsky H, Miller K, Siddarth P, Rasgon NL, Mazziotta JC, Saxena S, Wu HM, Mega MS, Cummings JL, Saunders AM, Pericak-Vance MA, Roses AD, Barrio JR, Phelps ME. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2000;97:6037–6042. doi: 10.1073/pnas.090106797.
    1. Izumi Y, Zorumski CF. Involvement of nitric oxide in low glucose-mediated inhibition of hippocampal long-term potentiation. Synapse. 1997;25:258–262. doi: 10.1002/(SICI)1098-2396(199703)25:3<258::AID-SYN4>;2-A.
    1. Biessels GJ, Kamal A, Ramakers GM, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH. Place learning and hippocampal synaptic plasticity in streptozotocin-induced diabetic rats. Diabetes. 1996;45:1259–1266.
    1. Sokoloff L. Modeling metabolic processes in the brain in vivo. Ann Neurol. 1984;15:S1–11. doi: 10.1002/ana.410150703.
    1. Sokoloff L. Metabolic probes for localization of functional activity in the central nervous system. Int J Neurol. 1984;18:40–48.
    1. Mosconi L, De Santi S, Rusinek H, Convit A, de Leon MJ. Magnetic resonance and PET studies in the early diagnosis of Alzheimer's disease. Expert Rev Neurother. 2004;4:831–849. doi: 10.1586/14737175.4.5.831.
    1. Logothetis NK, Wandell BA. Interpreting the BOLD signal. Annu Rev Physiol. 2004;66:735–769. doi: 10.1146/annurev.physiol.66.082602.092845.
    1. Heeger DJ, Ress D. What does fMRI tell us about neuronal activity? Nat Rev Neurosci. 2002;3:142–151. doi: 10.1038/nrn730.
    1. Machulda MM, Ward HA, Borowski B, Gunter JL, Cha RH, O'Brien PC, Petersen RC, Boeve BF, Knopman D, Tang-Wai DF, Ivnik RJ, Smith GE, Tangalos EG, Jack CR., Jr Comparison of memory fMRI response among normal, MCI, and Alzheimer's patients. Neurology. 2003;61:500–506.
    1. Sperling RA, Bates JF, Chua EF, Cocchiarella AJ, Rentz DM, Rosen BR, Schacter DL, Albert MS. fMRI studies of associative encoding in young and elderly controls and mild Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2003;74:44–50. doi: 10.1136/jnnp.74.1.44.
    1. Johnson SC, Schmitz TW, Moritz CH, Meyerand ME, Rowley HA, Alexander AL, Hansen KW, Gleason CE, Carlsson CM, Ries ML, Asthana S, Chen K, Reiman EM, Alexander GE. Activation of brain regions vulnerable to Alzheimer's disease: The effect of mild cognitive impairment. Neurobiol Aging.
    1. Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E, Rentz DM, Bertram L, Mullin K, Tanzi RE, Blacker D, Albert MS, Sperling RA. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology. 2005;65:404–411.
    1. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183–194. doi: 10.1111/j.1365-2796.2004.01388.x.
    1. Gron G, Bittner D, Schmitz B, Wunderlich AP, Tomczak R, Riepe MW. Variability in memory performance in aged healthy individuals: an fMRI study. Neurobiol Aging. 2003;24:453–462. doi: 10.1016/S0197-4580(02)00128-8.
    1. Gron G, Riepe MW. Neural basis for the cognitive continuum in episodic memory from health to Alzheimer disease. Am J Geriatr Psychiatry. 2004;12:648–652. doi: 10.1176/appi.ajgp.12.6.648.
    1. Caselli RJ, Reiman EM, Osborne D, Hentz JG, Baxter LC, Hernandez JL, Alexander GG. Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology. 2004;62:1990–1995.
    1. Dik MG, Jonker C, Bouter LM, Geerlings MI, van Kamp GJ, Deeg DJ. APOE-epsilon4 is associated with memory decline in cognitively impaired elderly. Neurology. 2000;54:1492–1497.
    1. Lahiri DK, Sambamurti K, Bennett DA. Apolipoprotein gene and its interaction with the environmentally driven risk factors: molecular, genetic and epidemiological studies of Alzheimer's disease. Neurobiol Aging. 2004;25:651–660. doi: 10.1016/j.neurobiolaging.2003.12.024.
    1. Trommer BL, Shah C, Yun SH, Gamkrelidze G, Pasternak ES, Ye GL, Sotak M, Sullivan PM, Pasternak JF, Ladu MJ. ApoE isoform affects LTP in human targeted replacement mice. Neuroreport. 2004;15:2655–2658. doi: 10.1097/00001756-200412030-00020.
    1. Yun SH, Gamkrelidze G, Pasternak JF, LaDu M, Trommer BL. Oligomeric amyloid 1–42 decreases the excitability of dentate gyrus granule cells in hippocampal slices from ApoE4-TR mice. Society for Neuroscience Abstract Viewer/Itinerary Planner Online. 2004. Program No. 217.219.
    1. Raber J, Wong D, Buttini M, Orth M, Bellosta S, Pitas RE, Mahley RW, Mucke L. Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc Natl Acad Sci U S A. 1998;95:10914–10919. doi: 10.1073/pnas.95.18.10914.
    1. Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, Fish JD, Masliah E, Hopkins PC, Scearce-Levie K, Weisgraber KH, Mucke L, Mahley RW, Huang Y. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci U S A. 2003;100:10966–10971. doi: 10.1073/pnas.1434398100.

Source: PubMed

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