Figure 1. Asymptomatic Alzheimer's disease phenomenon.
Limited empirical attention has focused on elucidating factors underlying “asymptomatic” Alzheimer’s disease (AD), a phenomenon in which individuals present with autopsy-confirmed pathological AD (β-amyloid plaques and aggregation of tau) but without the clinical manifestation of cognitive impairment. Asymptomatic AD is present in approximately 30% of cognitively normal older adults, suggesting that there may be naturally occurring factors that fight against the damaging effects of plaques and tangles (Figure 1).
This research initiative seeks to better understand asymptomatic AD by (1) building better endophenotypes of resilience using advanced biostatistical methods, and (2) leveraging the growing wealth of ‘omic data to identify novel pathways of resilience. We work in active collaboration with the Alzheimer’s Disease Genetics Consortium, while also leveraging data from our local cohort here at Vanderbilt (the Memory and Aging Project) and multiple publicly available multi-center datasets such as the Alzheimer’s Disease Neuroimaging Initiative and the National Alzheimer’s Coordinating Center dataset. We also take a multidisciplinary approach that leverages advanced techniques from the fields of neuroimaging, biomarker detection, genomics, neuropsychology, and neuropathology. Our work has built a robust phenotype of resilience leveraging advanced statistical approaches (Figure 2) resulting in a metric of resilience that is particularly sensitive to detecting preserved cognition in the presence of enhanced biomarkers of AD neuropathology (Figure 3).
Figure 2: Partial least squares path model that leverages residuals relating AD biomarkers to cognitive and neuroimaging outcomes. The model integrates our metrics of resilience within an established framework of cognitive and brain reserve. (Hohman et al., 2016, Neurology)
Figure 3: Higher levels of global resilience are related to slower rates of cognitive decline, particularly among individuals who are positive for biomarkers of AD neuropathology. (Hohman et al., 2016, Neurology)
Additional work in this initiative has evaluated complex genomic (Figure 4) and proteomic (Figure 5) interaction models to identify factors that modulate the association between known AD biomarkers and neurodegenerative disease. These research projects have resulted in the identification of novel genomic and proteomic markers of risk and resilience including the Protection of Telomeres 1 gene, Glycogen Synthase Kinase 3 beta gene, and the Vascular Endothelial Growth Factor protein. As we build out the sophistication of our endophenotype definitions and genomic/proteomic prediction models we are excited by the prospect of identifying markers of resilience that act across the spectrum of neurodegenerative diseases.
Figure 4. POT1 (rs4728029) modifies the relationship between posphorylated tau (PTau) and lateral inferior ventricular volume in ventricle dilation. The y-axis represents annual change in ventricular volume in cubic millimeter. The x-axis represents cerebrospinal fluid (CSF) PTau in pg/mL. Points and lines are color coded by rs4728029 genotype. The R2 linear for A/A carriers is 0.17, for A/G or G/A carriers it is 0.06, and for G/G carrier it is 0.02. ICV, intracranial volume. (Hohman et al., 2014, Alzheimer's & Dementia)
Figure 5: High levels of vascular endothelial growth factor (VEGF) measured in the cererbrospinal fluid are associated with a slower rate of cognitive decline. The beneficial effect of VEGF is particularly strong among individuals who are positive for biomarkers of AD neuropathology. (Hohman et al., 2015, JAMA Neurology)
- Timothy Hohman, PhD / Assistant Professor of Neurology at Vanderbilt University Medical Center
- Katherine Gifford, PsyD / Assistant Professor of Neurology at Vanderbilt University Medical Center
- Susan Bell, MBBS, MSCI / Assistant Professor of Medicine at Vanderbilt University Medical Center
- Angela Jefferson, PhD / Professor of Neurology at Vanderbilt University Medical Center
- The Alzheimer’s Disease Genetics Consortium (https://alois.med.upenn.edu/adgc/index.html)
- David Libon, PhD / Professor of Neurology at Drexel University (http://drexel.edu/medicine/Faculty/Profiles/David-Libon/)
Moore AM, Mahoney E, Dumitrescu L, De Jager PL, Koran MEI, Petyuk VA, Robinson RA, Ruderfer DM, Cox NJ, Schneider JA, Bennett DA, Jefferson AL, Hohman TJ. APOE ε4-specific associations of VEGF gene family expression with cognitive aging and Alzheimer's disease. Neurobiology of Aging. 2020 Dec;87(87). 18-25. PMID: 31791659 [PubMed] PMCID: PMC7064375
Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, Bush WS, Gifford KA, Chibnik LB, Mukherjee S, De Jager PL, Kukull W, Crane PK, Resnick SM, Keene CD, Montine TJ, Schellenberg GD, Deming Y, Chao MJ, Huentelman M, Martin ER, Hamilton-Nelson K, Shaw LM, Trojanowski JQ, Peskind ER, Cruchaga C, Pericak-Vance MA, Goate AM, Cox NJ, Haines JL, Zetterberg H, Blennow K, Larson EB, Johnson SC, Albert M, Bennett DA, Schneider JA, Jefferson AL, Hohman TJ. Sex differences in the genetic predictors of Alzheimer's pathology. Brain. 2019 Dec 1;142(142). 2581-2589. PMID: 31497858 [PubMed] PMCID: PMC6736148
Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, Sealock J, Karlsson IK, Hägg S, Athanasiu L, Voyle N, Proitsi P, Witoelar A, Stringer S, Aarsland D, Almdahl IS, Andersen F, Bergh S, Bettella F, Bjornsson S, Brækhus A, Bråthen G, De Leeuw C, Desikan RS, Djurovic S, Dumitrescu L, Fladby T, Hohman TJ, Jonsson PV, Kiddle SJ, Rongve A, Saltvedt I, Sando SB, Selbæk G, Shoai M, Skene NG, Snaedal J, Stordal E, Ulstein ID, Wang Y, White LR, Hardy J, Hjerling-Leffler J, Sullivan PF, Van der Flier WM, Dobson R, Davis LK, Stefansson H, Stefansson K, Pedersen NL, Ripke S, Andreassen OA, Posthuma D. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nature genetics. 2019 Dec;51(51). 404-413. PMID: 30617256 [PubMed] PMCID: PMC6836675
Mahoney ER, Dumitrescu L, Moore AM, Cambronero FE, De Jager PL, Koran MEI, Petyuk VA, Robinson RAS, Goyal S, Schneider JA, Bennett DA, Jefferson AL, Hohman TJ. Brain expression of the vascular endothelial growth factor gene family in cognitive aging and alzheimer's disease. Molecular psychiatry. 2019 Jul 22. PMID: 31332262 [PubMed] PMCID: PMC6980445
Dumitrescu L, Mayeda ER, Sharman K, Moore AM, Hohman TJ. Sex Differences in the Genetic Architecture of Alzheimer's Disease. Current genetic medicine reports. 2019 Mar;7(7). 13-21. PMID: 31360619 [PubMed] PMCID: PMC6662731
Mahoney ER, Dumitrescu L, Seto M, Nudelman KNH, Buckley RF, Gifford KA, Saykin AJ, Jefferson AJ, Hohman TJ. Telomere length associations with cognition depend on Alzheimer's disease biomarkers. Alzheimer's & dementia (New York, N. Y.). 5(5). 883-890. PMID: 31890852 [PubMed] PMCID: PMC6926345
Deming Y, Dumitrescu L, Barnes LL, Thambisetty M, Kunkle B, Gifford KA, Bush WS, Chibnik LB, Mukherjee S, De Jager PL, Kukull W, Huentelman M, Crane PK, Resnick SM, Keene CD, Montine TJ, Schellenberg GD, Haines JL, Zetterberg H, Blennow K, Larson EB, Johnson SC, Albert M, Moghekar A, Del Aguila JL, Fernandez MV, Budde J, Hassenstab J, Fagan AM, Riemenschneider M, Petersen RC, Minthon L, Chao MJ, Van Deerlin VM, Lee VM, Shaw LM, Trojanowski JQ, Peskind ER, Li G, Davis LK, Sealock JM, Cox NJ, Goate AM, Bennett DA, Schneider JA, Jefferson AL, Cruchaga C, Hohman TJ. Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta neuropathologica. 2018 Jul 2. PMID: 29967939 [PubMed]
Hohman TJ, Tommet D, Marks S, Contreras J, Jones R, Mungas D. Evaluating Alzheimer's disease biomarkers as mediators of age-related cognitive decline. Neurobiology of aging. 2017 Oct;58(58). 120-128. PMID: 28732249 [PubMed] PMCID: PMC5710827 NIHMSID: NIHMS890309.
Neuner S. Hohman T, Kazcorowski C. Systems genetics identifies modifiers of Alzheimer's disease risk and resilience BioRxiv Preprint. Preprint
Hohman TJ, McLaren DG, Mormino EC, Gifford KA, Libon DJ, Jefferson AL. Asymptomatic Alzheimer disease: Defining resilience. Neurology. 2016 Nov 4. Pubmed PMID: 27815399 [PubMed]
Hohman TJ, Dumitrescu L, Cox NJ, Jefferson AL. Genetic resilience to amyloid related cognitive decline. Brain imaging and behavior. 2016 Oct 14. PMID: 27743375 [PubMed]
Koran ME, Wagener M, Hohman TJ. Sex differences in the association between AD biomarkers and cognitive decline. Brain imaging and behavior. 2016 Feb 3. PMID: 26843008 [PubMed]
Hohman TJ, Chibnik L, Bush WS, Jefferson AL, De Jaeger PL, Thornton-Wells TA, Bennett DA, Schneider JA. GSK3β Interactions with Amyloid Genes: An Autopsy Verification and Extension. Neurotoxicity research. 2015 Oct;28(28). 232-8. PMID: 26194614 [PubMed]
Hohman TJ, Samuels LR, Liu D, Gifford KA, Mukherjee S, Benson EM, Abel T, Ruberg FL, Jefferson AL. Stroke risk interacts with Alzheimer's disease biomarkers on brain aging outcomes. Neurobiology of aging. 2015 Sep;36(36). 2501-8. PMID: 26119224 [PubMed] PMCID: PMC4523400
Hohman TJ, Bell SP, Jefferson AL. The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease. JAMA neurology. 2015 May;72(72). 520-9. PMID: 25751166 [PubMed] PMCID: PMC4428948
Hohman TJ, Koran ME, Thornton-Wells TA. Genetic modification of the relationship between phosphorylated tau and neurodegeneration. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2014 Nov;10(10). 637-645.e1. PMID: 24656848 [PubMed] PMCID: PMC4169762
Hohman TJ, Koran ME, Thornton-Wells TA. Interactions between GSK3β and amyloid genes explain variance in amyloid burden. Neurobiology of aging. 2014 Mar;35(35). 460-5. PMID: 24112793 [PubMed] PMCID: PMC3864626
Hohman TJ, Koran ME, Thornton-Wells TA. Genetic variation modifies risk for neurodegeneration based on biomarker status. Frontiers in aging neuroscience. 6(6). 183 p. PMID: 25140149 [PubMed] PMCID: PMC4121544