Reduced Posterior Cingulate Mitochondrial Activity in Expired Young Adult Carriers of the APOE ε4 Allele, the Major Late-Onset Alzheimer's Susceptibility Gene
Open accessAbstract
In vivo PET imaging studies of young-adult carriers of the apolipoprotein E ε4 allele (APOEε4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEε4. At-risk ε4 carriers had lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old ε4 homozygote, the ε4 carriers did not have increased soluble amyloid-β, histologic amyloid-β, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mitochondrial dysfunction is involved in early AD pathology.
“APOE4 carriers show mitochondrial dysfunction in brain areas associated with AD even before the onset of amyloid or tau pathology or cognitive changes, indicating that mitochondrial dysfunction is involved in early AD pathology [31].”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [31]
The Abstract reports reduced mitochondrial cytochrome oxidase activity in young APOE ε4 carriers’ posterior cingulate cortex, generally without detectable amyloid or tau pathology. But it identifies one carrier who did have both, and says mitochondrial mechanisms *may contribute* to AD predisposition; it does not establish that dysfunction is involved in early AD pathology. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPOE4 carriers show mitochondrial dysfunction in brain areas associated with AD even before the onset of amyloid or tau pathology or cognitive changes.
“APOE4 carriers show mitochondrial dysfunction in brain areas associated with AD even before the onset of amyloid or tau pathology or cognitive changes, indicating that mitochondrial dysfunction is involved in early AD pathology [31].”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [31]
The Abstract and Introduction report reduced mitochondrial cytochrome oxidase activity in young-adult APOE ε4 carriers in the posterior cingulate cortex, an AD-vulnerable region. The claim is broader than the evidence: the study measured mitochondrial activity in that region only, and the Results report one carrier who already had amyloid and tau pathology. The Abstract places the finding decades before possible symptom onset but does not establish the absence of cognitive changes in each donor. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn nondemented apoE4 carriers, mitochondrial complex IV activity is decreased in cortical regions susceptible to Alzheimer's disease.
“in nondemented apoE4 carriers, the activity of mitochondrial complex IV is decreased in cortical regions susceptible to AD [32]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [32]
The Results report significantly lower cytochrome oxidase (mitochondrial complex IV) activity in young-adult APOE ε4 carriers than in noncarriers, but the measurements were from the posterior cingulate cortex. The Discussion says further studies are needed to determine whether the reduction extends beyond that region, so the claim's plural “cortical regions” is broader than this study establishes. Page numbers are unavailable in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredDecrease in mitochondrial respiratory complex IV activity was observed in autopsy brains from young ApoE4 carriers.
“a decrease in mitochondrial respiratory complex IV activity was observed in autopsy brains from young ApoE4 carriers [74]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [74]
For many subjects with suspected AD or increased risk, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes.
“Our hypothesis, therefore, can accommodate a growing realization that for many subjects with suspected AD, or who have an increased risk of developing AD, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes [206-213].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [208]
In most young adult APOE4 carriers evaluated, COX activity was low even in the absence of fibrillar Aβ.
“In most of the young adult APOE4 carriers evaluated by this study COX activity was low even in the absence of fibrillar Aβ.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [133]
Young adult APOE4 carriers have an increased AD risk and lower posterior cingulate COX activities than young adult non-APOE4 carriers.
“Young adult APOE4 carriers, who also have an increased AD risk, have lower posterior cingulate COX activities than young adult non-APOE4 carriers [133].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [133]
Mitochondrial dysfunction has been suggested to occur early in the progression to AD and continues into later stages of AD.
“Mitochondrial dysfunction has been suggested to occur early in the progression to AD and continues into later stages of AD31–34.”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [32]
In a study of expired young-adult APOE4 carriers vs. non-APOE4 carriers, young-adult participants in both groups did not have amyloid or tangle deposition in the posterior cingulate cortex (PCC); yet APOE4 carriers showed reduced mitochondrial activity in PCC neurons, as measured by cytochrome oxidase levels.
“In that study, young-adult participants in both groups did not have amyloid or tangle deposition in the posterior cingulate cortex (PCC); yet, APOE4 carriers, i.e., those at greater risk for developing AD, showed reduced mitochondrial activity in PCC neurons, as measured by cytochrome oxidase levels”
From Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age (2019) · cites this paper as [32]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A default mode of brain function
Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., & Shulman, G. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.2.676 · Cited by 12,190 · see citing works
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.
Hixson, J., & Vernier, D. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)43176-1 · Cited by 2,933 · see citing works
Buckner, R. L., Snyder, A. Z., Shannon, B. J., LaRossa, G., Sachs, R., Fotenos, A. F., Sheline, Y. I., Klunk, W. E., Mathis, C. A., Morris, J. C., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2177-05.2005 · Cited by 2,140 · see citing works
Distinct patterns of brain activity in young carriers of the <i>APOE</i> -ε4 allele
Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., Smith, S. M., Matthews, P. M., Beckmann, C. F., & Mackay, C. E. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811879106 · Cited by 1,613 · see citing works
Reiman, E. M., Caselli, R. J., Yun, L. S., Chen, K., Bandy, D., Minoshima, S., Thibodeau, S. N., & Osborne, D. (1996) · New England Journal of Medicine · doi:10.1056/nejm199603213341202 · Cited by 1,366 · see citing works
Self-citationABAD Directly Links Aß to Mitochondrial Toxicity in Alzheimer's Disease
Lustbader, J. W., Cirilli, M., Lin, C., Xu, H. W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., et al. (2004) · Science · doi:10.1126/science.1091230 · Cited by 1,303 · see citing works
Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo
Cirrito, J. R., Yamada, K. A., Finn, M. B., Sloviter, R. S., Bales, K. R., May, P. C., Schoepp, D. D., Paul, S. M., Mennerick, S., & Holtzman, D. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.10.028 · Cited by 1,265 · see citing works
Cytochrome oxidase: an endogenous metabolic marker for neuronal activity
Wong-Riley, M. T. T. (1989) · Trends in Neurosciences · doi:10.1016/0166-2236(89)90165-3 · Cited by 1,238 · see citing works
Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia
Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2635903100 · Cited by 977 · see citing works
Self-citationReiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., Ayutyanont, N., Keppler, J., Reeder, S. A., Langbaum, J. B. S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900345106 · Cited by 785 · see citing works
Self-citationCytochrome oxidase deficiency in Alzheimer’s disease
Parker, W. D., Filley, C. M., & Parks, J. K. (1990) · Neurology · doi:10.1212/wnl.40.8.1302 · Cited by 598 · cited 1× · see citing works
“[9, 17,18]) as well as peripheral cells, prominently including circulating platelets [18–20], indicating a systemic mitochondrial defect.”
Liang, W. S., Reiman, E. M., Valla, J., Dunckley, T., Beach, T. G., Grover, A., Niedzielko, T. L., Schneider, L. E., Mastroeni, D., Caselli, R., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709259105 · Cited by 585 · see citing works
Self-citationAnandatheerthavarada, H. K., Biswas, G., Robin, M.-A., & Avadhani, N. G. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200207030 · Cited by 571 · see citing works
Alexander, G. E., Chen, K., Pietrini, P., Rapoport, S. I., & Reiman, E. M. (2002) · American Journal of Psychiatry · doi:10.1176/appi.ajp.159.5.738 · Cited by 532 · see citing works
Self-citationElectron transport chain defects in Alzheimer's disease brain
Parker, W. D., Parks, J. K., Filley, C. M., & Kleinschmidt-DeMasters, B. K. (1994) · Neurology · doi:10.1212/wnl.44.6.1090 · Cited by 495 · see citing works
Reiman, E. M., Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D., & Frost, J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061509598 · Cited by 467 · see citing works
Self-citationBrecht, W. J., Harris, F. M., Chang, S., Tesseur, I., Yu, G.-Q., Xu, Q., Dee Fish, J., Wyss-Coray, T., Buttini, M., Mucke, L., et al. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.4315-03.2004 · Cited by 403 · see citing works
Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500579102 · Cited by 401 · see citing works
Self-citationA TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease
Roses, A. D., Lutz, M. W., Amrine‐Madsen, H., Saunders, A. M., Crenshaw, D. G., Sundseth, S. S., Huentelman, M. J., Welsh-Bohmer, K. A., & Reiman, E. M. (2009) · The Pharmacogenomics Journal · doi:10.1038/tpj.2009.69 · Cited by 391 · see citing works
Self-citationBosetti, F. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00314-1 · Cited by 348 · see citing works
Chang, S., Ma, T. R., Miranda, R. D., Balestra, M. E., Mahley, R. W., & Huang, Y. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508254102 · Cited by 319 · see citing works
Posterior cingulate cortex in Alzheimer's disease
MINOSHIMA, S. (1994) · The Lancet · doi:10.1016/s0140-6736(94)92871-1 · Cited by 316 · see citing works
Langbaum, J. B. S., Chen, K., Lee, W., Reschke, C., Bandy, D., Fleisher, A. S., Alexander, G. E., Foster, N. L., Weiner, M. W., Koeppe, R. A., et al. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2008.12.072 · Cited by 279 · see citing works
Self-citationValla, J. E., Berndt, J. D., & Gonzalez-Lima, F. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-13-04923.2001 · Cited by 237 · see citing works
Self-citationOhm, T. G., Müller, H., Braak, H., & Böhl, J. (1995) · Neuroscience · doi:10.1016/0306-4522(95)90397-p · Cited by 222 · see citing works
The Alzheimer's disease mitochondrial cascade hypothesis: an update
Swerdlow, R. H., & Khan, S. M. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.01.011 · Cited by 206 · see citing works
Evaluation of α-synuclein immunohistochemical methods used by invited experts
Beach, T. G., White, C. L., Hamilton, R. L., Duda, J. E., Iwatsubo, T., Dickson, D. W., Leverenz, J. B., Roncaroli, F., Buttini, M., Hladik, C. L., et al. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0409-8 · Cited by 182 · see citing works
Self-citationKalback, W. M., Esh, C. L., Castaño, E. M., Rahman, A., Kokjohn, T. A., Luehrs, D. C., Sue, L. I., Cisneros, R., Gerber, F., Richardson, C., et al. (2004) · Neurological Research · doi:10.1179/016164104225017668 · Cited by 160 · see citing works
Self-citationUnderstanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure
Zhong, N., & Weisgraber, K. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.r800009200 · Cited by 159 · see citing works
Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment
Valla, J., Schneider, L., Niedzielko, T., Coon, K. D., Caselli, R., Sabbagh, M. N., Ahern, G. L., Baxter, L., Alexander, G., Walker, D. G., et al. (2006) · Mitochondrion · doi:10.1016/j.mito.2006.10.004 · Cited by 159 · see citing works
Self-citationNakamura, T., Watanabe, A., Fujino, T., Hosono, T., & Michikawa, M. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-35 · Cited by 124 · see citing works
APOE related alterations in cerebral activation even at college age
Scarmeas, N. (2005) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2004.053645 · Cited by 97 · see citing works
Zhong, N., Ramaswamy, G., & Weisgraber, K. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.014464 · Cited by 85 · see citing works
Valla, J., Schneider, L. E., Small, A. M., & Gonzalez-Lima, F. (2007) · Journal of Histotechnology · doi:10.1179/his.2007.30.4.235 · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease
Tönnies, E., & Trushina, E. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161088 · Cited by 1,750 · see citing works
Mitochondria and Mitochondrial Cascades in Alzheimer’s disease
Swerdlow, R. H. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170585 · Cited by 850 · see citing works
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786 · see citing works
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100339 · Cited by 562 · see citing works
Reiman, E. M., Quiroz, Y. T., Fleisher, A. S., Chen, K., Velez-Pardo, C., Jimenez-Del-Rio, M., Fagan, A. M., Shah, A. R., Alvarez, S., Arbelaez, A., et al. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70228-4 · Cited by 541 · see citing works
Self-citationEstrogen: A master regulator of bioenergetic systems in the brain and body
Rettberg, J. R., Yao, J., & Brinton, R. D. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.08.001 · Cited by 534 · see citing works
Trushina, E., Dutta, T., Persson, X.-M. T., Mielke, M. M., & Petersen, R. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063644 · Cited by 438 · see citing works
Perez Ortiz, J. M., & Swerdlow, R. H. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14585 · Cited by 426 · see citing works
Apolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394 · see citing works
Fleisher, A. S. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.150 · Cited by 364 · see citing works
Kashiwaya, Y., Bergman, C., Lee, J.-H., Wan, R., King, M. T., Mughal, M. R., Okun, E., Clarke, K., Mattson, M. P., & Veech, R. L. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.023 · Cited by 363 · see citing works
Alzheimer's Prevention Initiative: A Plan to Accelerate the Evaluation of Presymptomatic Treatments
Reiman, E. M., Langbaum, J. B. S., Fleisher, A., Caselli, R. J., Chen, K., Ayutyanont, N., Quiroz, Y. T., Kosik, K. S., Lopera, F. J., & Tariot, P. N. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-0059 · Cited by 340 · see citing works
Self-citationBrain aging, Alzheimer's disease, and mitochondria
Swerdlow, R. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.012 · Cited by 306 · see citing works
Association of Higher Cortical Amyloid Burden With Loneliness in Cognitively Normal Older Adults
Donovan, N. J., Okereke, O. I., Vannini, P., Amariglio, R. E., Rentz, D. M., Marshall, G. A., Johnson, K. A., & Sperling, R. A. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2016.2657 · Cited by 256 · see citing works
Low-level light therapy of the eye and brain
Gonzalez-Lima, F., & Rojas (2011) · Eye and Brain · doi:10.2147/eb.s21391 · Cited by 231 · see citing works
Lifespan brain activity, β-amyloid, and Alzheimer's disease
Jagust, W. J., & Mormino, E. C. (2011) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2011.09.004 · Cited by 221 · see citing works
Is Alzheimer’s disease a systemic disease?
Morris, J. K., Honea, R. A., Vidoni, E. D., Swerdlow, R. H., & Burns, J. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.04.012 · Cited by 219 · see citing works
Wingo, A. P., Dammer, E. B., Breen, M. S., Logsdon, B. A., Duong, D. M., Troncosco, J. C., Thambisetty, M., Beach, T. G., Serrano, G. E., Reiman, E. M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09613-z · Cited by 211 · see citing works
Self-citationFleisher, A. S., Chen, K., Liu, X., Ayutyanont, N., Roontiva, A., Thiyyagura, P., Protas, H., Joshi, A. D., Sabbagh, M., Sadowsky, C. H., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.04.017 · Cited by 202 · see citing works
Self-citationSwerdlow, R. H. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4149 · Cited by 203 · see citing works
Shared mechanisms across the major psychiatric and neurodegenerative diseases
Wingo, T. S., Liu, Y., Gerasimov, E. S., Vattathil, S. M., Wynne, M. E., Liu, J., Lori, A., Faundez, V., Bennett, D. A., Seyfried, N. T., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31873-5 · Cited by 199 · see citing works
Mitochondrial Dysfunction in Alzheimers Disease: Opportunities forDrug Development
Bhatia, S., Rawal, R., Sharma, P., Singh, T., Singh, M., & Singh, V. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210517114016 · Cited by 197 · see citing works
Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery
Mosconi, L., Berti, V., Quinn, C. G., McHugh, P. F., Petrongolo, G., Osorio, R. S., Connaughty, C., Pupi, A., Vallabhajosula, S., Isaacson, R., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185926 · Cited by 185 · see citing works
Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue
Rojas, J. C., Bruchey, A. K., & Gonzalez-Lima, F. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.10.007 · Cited by 172 · see citing works
Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging
Jagust, W. J., Landau, S. M., & Initiative, F. T. A. D. N. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.3266-12.2012 · Cited by 162 · see citing works
Protas, H. D., Chen, K., Langbaum, J. B. S., Fleisher, A. S., Alexander, G. E., Lee, W., Bandy, D., de Leon, M. J., Mosconi, L., Buckley, S., et al. (2013) · JAMA Neurology · doi:10.1001/2013.jamaneurol.286 · Cited by 161 · see citing works
Self-citationAPOE modifies the association between Aβ load and cognition in cognitively normal older adults
Kantarci, K., Lowe, V. J., Przybelski, S. A., Weigand, S. D., Senjem, M. L., Ivnik, R. J., Preboske, G. M., Roberts, R. O., Geda, Y. E., Boeve, B. F., et al. (2011) · Neurology · doi:10.1212/wnl.0b013e31824365ab · Cited by 159 · see citing works
Apolipoprotein E and Alzheimer's disease
Troutwine, B., Hamid, L., Lysaker, C. R., Strope, T. A., & Wilkins, H. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.10.002 · Cited by 164 · see citing works
Pires, M., & Rego, A. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010778 · Cited by 157 · see citing works
Ushering in the study and treatment of preclinical Alzheimer disease
Langbaum, J. B. S., Fleisher, A., Chen, K., Ayutyanont, N., Lopera, F. J., Quiroz, Y. T., Caselli, R. J., Tariot, P. N., & Reiman, E. M. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.107 · Cited by 145 · see citing works
Self-citationThe endosomal-lysosomal pathway is dysregulated by APOE4 expression in vivo
Nuriel, T., Peng, K. Y., Ashok, A., Dillman, A. A., Figueroa, H. Y., Apuzzo, J., Ambat, J., Levy, E., Cookson, M. R., Mathews, P. M., et al. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00702 · Cited by 140 · see citing works
Intranasal insulin in Alzheimer’s dementia or mild cognitive impairment: a systematic review
Avgerinos, K. I., Kalaitzidis, G., Malli, A., Kalaitzoglou, D., Myserlis, E. P., & Lioutas, V. (2018) · Journal of Neurology · doi:10.1007/s00415-018-8768-0 · Cited by 137 · see citing works
APOE genotype and stress response - a mini review
Dose, J., Huebbe, P., Nebel, A., & Rimbach, G. (2016) · Lipids in Health and Disease · doi:10.1186/s12944-016-0288-2 · Cited by 137 · see citing works
Villavicencio-Tejo, F., & Quintanilla, R. A. (2021) · Antioxidants · doi:10.3390/antiox10071069 · Cited by 135 · see citing works
Sabuncu, M. R., Buckner, R. L., Smoller, J. W., Lee, P. H., Fischl, B. R., & Sperling, R. A. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhr348 · Cited by 130 · see citing works
The effects of APOE on the functional architecture of the resting brain
Trachtenberg, A. J., Filippini, N., Ebmeier, K. P., Smith, S. M., Karpe, F., & Mackay, C. E. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.07.059 · Cited by 129 · see citing works
Lehmann, M., Madison, C. M., Ghosh, P. M., Seeley, W. W., Mormino, E., Greicius, M. D., Gorno-Tempini, M. L., Kramer, J. H., Miller, B. L., Jagust, W. J., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221536110 · Cited by 122 · see citing works
Liraz, O., Boehm-Cagan, A., & Michaelson, D. M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-16 · Cited by 118 · see citing works
SIRT3 and mitochondrial metabolism in neurodegenerative diseases
Salvatori, I., Valle, C., Ferri, A., & Carrı̀, M. T. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.04.012 · Cited by 112 · see citing works
Early Life Epidemiology of Alzheimer's Disease - A Critical Review
Seifan, A., Schelke, M. W., Obeng-Aduasare, Y., & Isaacson, R. (2015) · Neuroepidemiology · doi:10.1159/000439568 · Cited by 110 · see citing works
Díaz, F., García, S., Padgett, K. R., & Moraes, C. T. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds350 · Cited by 110 · see citing works
Caselli, R. J., & Reiman, E. M. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129026 · Cited by 109 · see citing works
Self-citationMitochondria, Cybrids, Aging, and Alzheimer's Disease
Swerdlow, R. H., Koppel, S., Weidling, I., Hayley, C., Ji, Y., & Wilkins, H. M. (2017) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2016.12.017 · Cited by 106 · see citing works
Aerobic glycolysis in the primate brain: Reconsidering the implications for growth and maintenance
Bauernfeind, A. L., Barks, S. K., Duka, T., Grossman, L. I., Hof, P. R., & Sherwood, C. C. (2014) · Brain Structure and Function · doi:10.1007/s00429-013-0662-z · Cited by 105 · see citing works
APOE-related biomarker profiles in non-pathological aging and early phases of Alzheimer's disease
Reinvang, I., Espeseth, T., & Westlye, L. T. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.05.006 · Cited by 104 · see citing works
Orr, A. L., Kim, C., Jimenez-Morales, D., Newton, B. W., Johnson, J. R., Krogan, N. J., Swaney, D. L., & Mahley, R. W. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-181184 · Cited by 103 · see citing works
Advances in Alzheimer’s disease’s pharmacological treatment
Filho, C. E. C., Loss, L. B., Pereira, C. M., Rossoni, J. V., Barcelos, R. M., Chiarelli-Neto, O., da Silva, B. S., Ambrósio, R. P., Castro, F. C. D. A. Q., Teixeira, S. F., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1101452 · Cited by 104 · see citing works
Mosconi, L., de Leon, M., Murray, J., E, L., Lu, J., Javier, E., McHugh, P., & Swerdlow, R. H. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110866 · Cited by 97 · see citing works
Cortical hypometabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease
Strom, A., Iaccarino, L., Edwards, L., Lesman-Segev, O. H., Soleimani-Meigooni, D. N., Pham, J., Baker, S. L., Landau, S. M., Jagust, W. J., Miller, B. L., et al. (2022) · Brain · doi:10.1093/brain/awab294 · Cited by 91 · see citing works
Adluru, N., Destiche, D. J., Lu, S. Y.-F., Doran, S. T., Birdsill, A. C., Melah, K. E., Okonkwo, O. C., Alexander, A. L., Dowling, N. M., Johnson, S. C., et al. (2014) · NeuroImage: Clinical · doi:10.1016/j.nicl.2014.04.008 · Cited by 85 · see citing works
Could Alzheimer’s Disease Originate in the Periphery and If So How So?
Morris, G., Berk, M., Maes, M. H. J., & Puri, B. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1092-y · Cited by 83 · see citing works
Fluorodeoxyglucose PET in Neurology and Psychiatry
Schöll, M., Damián, A., & Engler, H. (2014) · PET Clinics · doi:10.1016/j.cpet.2014.07.005 · Cited by 82 · see citing works
Caselli, R. J., Beach, T. G., Knopman, D. S., & Graff-Radford, N. R. (2017) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2017.02.011 · Cited by 81 · see citing works
Self-citationFan, J., Tao, W., Li, X., Li, H., Zhang, J., Wei, D., Chen, Y., & Zhang, Z. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20051177 · Cited by 83 · see citing works
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: A Current Overview
Swerdlow, R. H. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221286 · Cited by 83 · see citing works
Association of hypometabolism and amyloid levels in aging, normal subjects
Lowe, V. J., Weigand, S. D., Senjem, M. L., Vemuri, P., Jordan, L. G., Kantarci, K., Boeve, B. F., Jack, C. R., Knopman, D. S., & Petersen, R. C. (2014) · Neurology · doi:10.1212/wnl.0000000000000467 · Cited by 81 · see citing works
APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease
Wolf, A. B., Caselli, R. J., Reiman, E. M., & Valla, J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.10.011 · Cited by 79 · see citing works
Self-citationJournal of Parkinson’s disease & Alzheimer’s disease
Gottschalk, W. K., Lutz, M. W., He, Y. T., Saunders, A. M., Burns, D. K., Roses, A. D., & Chiba‐Falek, O. (2014) · Journal of Parkinson’s Disease and Alzheimer’s Disease · doi:10.13188/2376-922x.1000003 · Cited by 78 · see citing works
APOE and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction
Brandon, J. A., Farmer, B. C., Williams, H. C., & Johnson, L. A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00180 · Cited by 75 · see citing works
Perkins, M., Wolf, A. B., Chavira, B., Shonebarger, D., Meckel, J. P., Leung, L., Ballina, L. E., Ly, S., Saini, A., Jones, T. B., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151205 · Cited by 74 · see citing works
Self-citationLongitudinal modeling of cognitive aging and the <i>TOMM40</i> effect
Caselli, R. J., Dueck, A. C., Huentelman, M. J., Lutz, M. W., Saunders, A. M., Reiman, E. M., & Roses, A. D. (2012) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.11.006 · Cited by 69 · see citing works
“cleaving enzyme 1 (BACE1) activity and amyloidogenesis [25].”
BackgroundSelf-citationChen, Y., Zheng, H., Huang, X., Han, S., Zhang, D., Ni, J. Z., & He, X. (2015) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12473 · Cited by 69 · see citing works
Hippocampal Volume Differences Between Healthy Young Apolipoprotein E ε2 and ε4 Carriers
Alexopoulos, P., Richter‐Schmidinger, T., Horn, M., Maus, S., Reichel, M., Sidiropoulos, C., Rhein, C., Lewczuk, P., Doerfler, A., & Kornhuber, J. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110356 · Cited by 69 · see citing works
Mosconi, L., Rinne, J. O., Tsui, W. H., Murray, J., Li, Y., Glodzik, L., McHugh, P. F., Williams, S., Cummings, M., Pirraglia, E., et al. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.03.002 · Cited by 66 · see citing works
Reassessment of Pioglitazone for Alzheimer’s Disease
Saunders, A. M., Burns, D. K., & Gottschalk, W. K. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.666958 · Cited by 67 · see citing works
Mitochondrial Metabolism in Major Neurological Diseases
Zhou, Z., Austin, G. L., Young, L. E. A., Johnson, L. A., & Sun, R. C. (2018) · Cells · doi:10.3390/cells7120229 · Cited by 64 · see citing works
Wang, Y., Mishra, A., & Brinton, R. D. (2020) · F1000Research · doi:10.12688/f1000research.21599.1 · Cited by 63 · see citing works
Wilkins, H., Koppel, S. J., Bothwell, R. J., Mahnken, J. D., Burns, J. M., & Swerdlow, R. H. (2017) · Redox Biology · doi:10.1016/j.redox.2017.04.010 · Cited by 61 · see citing works
Insulin mediated novel therapies for the treatment of Alzheimer's disease
Dubey, S. K., Lakshmi, K. K., Krishna, K. V., Agrawal, M., Singhvi, G., Saha, R. N., Saraf, S., Saraf, S., Shukla, R., & Alexander, A. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117540 · Cited by 60 · see citing works
Lehmann, M., Ghosh, P., Madison, C. A., Karydas, A., Coppola, G., O’Neil, J. P., Huang, Y., Miller, B. L., Jagust, W., & Rabinovici, G. D. (2013) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2013-305858 · Cited by 60 · see citing works
A Mitochondrial Role of SV2a Protein in Aging and Alzheimer’s Disease: Studies with Levetiracetam
Stockburger, C., Miano, D., Baeumlisberger, M., Pallas, T., Arrey, T. N., Karas, M., Friedland, K., & Müller, W. E. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-150687 · Cited by 60 · see citing works
Müller, W. E., Eckert, A., Eckert, G. P., Fink, H., Friedland, K., Gauthier, S. G., Hoerr, R., Ihl, R., Kasper, S. F., & Möller, H. (2017) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2017.1308552 · Cited by 60 · see citing works
Rosenbloom, M. H., Barclay, T. R., Pyle, M., Owens, B. L., Cagan, A., Anderson, C. P., Frey, W. H., & Hanson, L. R. (2014) · CNS Drugs · doi:10.1007/s40263-014-0214-y · Cited by 58 · see citing works
Rohn, T. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140714908 · Cited by 67 · see citing works
Yang, A. C., Huang, C., Liu, M., Liou, Y.-J., Hong, C., Lo, M., Huang, N. E., Peng, C., Lin, C., & Tsai, S. (2013) · Human Brain Mapping · doi:10.1002/hbm.22398 · Cited by 57 · see citing works
Antidiabetic Drugs in Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review
Muñoz-Jiménez, M., Zaarkti, A., García-Arnés, J. A., & García‐Casares, N. (2020) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000510677 · Cited by 55 · see citing works
Apolipoprotein E as a β-amyloid-independent factor in Alzheimer’s disease
Wolf, A. B., Valla, J., Bu, G., Kim, J., LaDu, M., Reiman, E. M., & Caselli, R. J. (2013) · Alzheimer's Research & Therapy · doi:10.1186/alzrt204 · Cited by 55 · see citing works
Self-citationDong, H. K., Gim, J., Yeo, S. H., & Kim, H. (2016) · Gene · doi:10.1016/j.gene.2016.10.022 · Cited by 54 · see citing works
Li, X., Montine, K. S., Keene, C. D., & Montine, T. J. (2015) · The FASEB Journal · doi:10.1096/fj.14-262683 · Cited by 54 · see citing works
The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease
Zeitlow, K., Charlambous, L., Ng, I., Gagrani, S., Mihovilovic, M., Luo, S., Rock, D. L., Saunders, A. M., Roses, A. D., & Gottschalk, W. K. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.07.031 · Cited by 54 · see citing works
Apolipoprotein E regulates mitochondrial function through the PGC-1α-sirtuin 3 pathway
Yin, J., Nielsen, M., Carcione, T., Li, S., & Shi, J. (2019) · Aging · doi:10.18632/aging.102516 · Cited by 53 · see citing works
Entorhinal cortical defects in Tg2576 mice are present as early as 2–4 months of age
Duffy, Á., Morales‐Corraliza, J., Bermudez‐Hernandez, K., Schaner, M. J., Magagna‐Poveda, A., Mathews, P. M., & Scharfman, H. E. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.07.001 · Cited by 49 · see citing works
Triad of Risk for Late Onset Alzheimer’s: Mitochondrial Haplotype, APOE Genotype and Chromosomal Sex
Wang, Y., & Brinton, R. D. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00232 · Cited by 52 · see citing works
APOE ε4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer’s disease
Konijnenberg, E., Tijms, B. M., Gobom, J., Dobričić, V., Bos, I., Vos, S. J. B., Tsolaki, M., Verhey, F. R. J., Popp, J., Martínez‐Lage, P., et al. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00628-z · Cited by 50 · see citing works
Rosenbloom, M. H., Barclay, T. R., Kashyap, B., Hage, L. M., O'Keefe, L. R., Svitak, A. L., Pyle, M., Frey, W. H., & Hanson, L. R. (2021) · Drugs & Aging · doi:10.1007/s40266-021-00845-7 · Cited by 49 · see citing works
Use of FDG PET as an Imaging Biomarker in Clinical Trials of Alzheimer’s Disease
Herholz, K. (2012) · Biomarkers in Medicine · doi:10.2217/bmm.12.51 · Cited by 47 · see citing works
Mishra, A., Wang, Y., Yin, F., Vitali, F., Rodgers, K. E., Soto, M., Mosconi, L., Wang, T., & Brinton, R. D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101542 · Cited by 44 · see citing works
APOE Genotype Modulates Proton Magnetic Resonance Spectroscopy Metabolites in the Aging Brain
Gomar, J. J., Gordon, M. L., Dickinson, D., Kingsley, P. B., Uluğ, A. M., Keehlisen, L., Huet, S., Buthorn, J. J., Koppel, J. L., Christen, E., et al. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.05.022 · Cited by 45 · see citing works
VanItallie, T. B. (2012) · Metabolism · doi:10.1016/j.metabol.2012.08.024 · Cited by 43 · see citing works
Mahley, R. W. (2023) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2023.102684 · Cited by 43 · see citing works
Thai, C., Lim, Y. Y., Villemagne, V. L., Laws, S. M., Ames, D. J., Ellis, K. A., Rainey‐Smith, S. R., Martins, R. N., Masters, C. L., Rowe, C. C., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0139082 · Cited by 39 · see citing works
The Role of Apolipoprotein E Isoforms in Alzheimer’s Disease
Roda, A. R., Montoliu‐Gaya, L., & Villegas, S. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-180740 · Cited by 40 · see citing works
Bonvento, G., Valette, J., Flament, J., Mochel, F., & Brouillet, E. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17697989 · Cited by 36 · see citing works
Sirtuin 3 (SIRT3) Pathways in Age-Related Cardiovascular and Neurodegenerative Diseases
Silaghi, C. N., Farcas, M. F., & Craciun, A. M. (2021) · Biomedicines · doi:10.3390/biomedicines9111574 · Cited by 37 · see citing works
Shi, L., Du, X., Zhou, H., Tao, C.-L., Liu, Y.-T., Meng, F., Wu, G., Xiong, Y., Xia, C., Wang, Y., et al. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145714000601 · Cited by 38 · see citing works
Stockburger, C., Miano, D., Pallas, T., Friedland, K., & Müller, W. E. (2016) · Neural Plasticity · doi:10.1155/2016/8075903 · Cited by 36 · see citing works
Stockburger, C., Eckert, S. H., Eckert, G. P., Friedland, K., & Müller, W. E. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179915 · Cited by 36 · see citing works
Ketones improves Apolipoprotein E4-related memory deficiency via sirtuin 3
Yin, J., Nielsen, M., Li, S., & Shi, J. (2019) · Aging · doi:10.18632/aging.102070 · Cited by 35 · see citing works
Shang, Y., Mishra, A., Wang, T., Wang, Y., Desai, M. K., Chen, S., Mao, Z., Do, L., Bernstein, A. S., Trouard, T. P., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0225392 · Cited by 36 · see citing works
Genetic Variants and Oxidative Stress in Alzheimer’s Disease
Kowalska, M., Wize, K., Prendecki, M., Lianeri, M., Kozubski, W. P., & Dorszewska, J. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200224121447 · Cited by 34 · see citing works
- Authors
- Valla, J., Yaari, R., Wolf, A. B., Kusne, Y., Beach, T. G., Roher, A. E., Corneveaux, J. J., Huentelman, M. J., Caselli, R. J., & Reiman, E. M.
- Affiliations
- Barrow Neurological Institute (US)
- University of Arizona (US)
- Banner Sun Health Research Institute (US)
- Translational Genomics Research Institute (US)
- Mayo Clinic in Arizona (US)
- Corresponding author
- Valla, Jon
- ORCID
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2010-09-28
- Volume
- 22
- Issue
- 1
- Pages
- 307-313
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC3124564
- OpenAlex
- W1529577194
- Cited by
- 150
- References
- 34
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 10 · 2020: 9 · 2019: 11 · 2018: 6 · 2017: 14 · 2016: 12 · 2015: 6 · 2014: 13 · 2013: 15 · 2012: 17
- FWCI
- 9.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P30-AG-19610, R01-AG 19795, R01AG019795, R01AG031581, P30AG019610)
- National Institute of Neurological Disorders and Stroke (R01NS059873)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- APOE ε4, Alzheimer's disease
- MeSH terms
- Adolescent, Adult, Alleles, Alzheimer Disease, Electron Transport Complex IV, Female, Gyrus Cinguli, Genetic Carrier Screening, Humans, Male, Mitochondria, Genetic Predisposition to Disease, Apolipoprotein E4, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
