As the population ages, late-onset Alzheimer's disease (AD) is becoming an increasingly important public health issue. Clinical trials targeted at reducing AD progression have demonstrated that patients continue to decline despite therapeutic intervention. Thus, there is a pressing need for new treatments aimed at novel therapeutic targets. A shift in focus from risk to resilience has tremendous potential to have a major public health impact by highlighting mechanisms that naturally counteract the damaging effects of AD neuropathology. Interestingly, at autopsy, approximately 30% of cognitively normal individuals have the pathological features of AD. Research from our group has begun to uncover genetic factors that explain some of the observed disconnect between neuropathology and clinical dementia. More specifically, through integration of in vivo biomaker and autopsy data into a unified model of resilience, we are able to perform large, comprehensive analyses of genetic resilience.
Quantifying resilience is challenging. Past research was often limited to individuals with “asymptomatic” Alzheimer’s disease (AD), a phenomenon in which individuals show no memory loss or other symptoms of AD during life, but after death their brains show all the signs of this disease (e.g., β-amyloid plaques and aggregation of tau). However, this definition of resilience drastically compromises statistical power by focusing on only a small subset of the population. Adding to the challenge, resilience definitions often combine the construct of reserve (e.g., predisposition towards protection) with resilience (e.g., better than expected performance despite neuropathology).
Our work addresses these challenges by leveraging a continuous resilience measure. Response to pathology appears to be best represented on a continuum given that the vast majority of cognitively normal individuals have at least some neuropathology at autopsy, and there is substantial heterogeneity across people who meet pathological criteria for AD. Building on the cognitive and brain reserve literature, we integrated co-calibrated cognitive data along with AD biomarkers to construct composite resilience measures (Figure 1). Our composite resilience measures can be harmonized across datasets, strongly predict protection from cognitive impairment (Figure 2), are easy to interpret, and enable large, well-powered resilience analyses.
Figure 1. Partial least squares (PLS) path model results. PLS path model results are presented; the goodness of fit was 0.76. Each first-order latent variable is presented as an oval. The variables included in each latent trait because we used reflective measurement. For the resilience metrics, each rectangle represents the residuals from a single linear regression model relating the given biomarker to the given outcome. The second-order latent variable (global resilience) is presented in a dotted oval. The loadings for each first-order latent variable are presented numerically above the bold arrows pointing to global resilience. (Hohman et al., Neurology, 2016)
Figure 2: 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., Neurology, 2016.)
Characterizing Drivers of Resilience
Identifying the molecular factors that underlie the resilience observed in asymptomatic AD may provide novel therapeutic targets for clinical intervention and provide additional insight into the genetic architecture of AD.
Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such understanding of drivers of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals.
Figure 3: (Dumitrescu et al. In Press, Brain.)
Validating Drivers of Resilience
Robust Vascular endothelial growth factor (VEGF) is associated with the clinical manifestation of Alzheimer's disease (AD). However, the role of the VEGF gene family in neuroprotection is complex due to the number of biological pathways they regulate. Our studies in the associations between brain expression of VEGF genes with cognitive performance and AD pathology have found that VEGF ligand and receptor genes, specifically genes relevant to FLT4 and FLT1 receptor signaling, are associated with cognition, longitudinal cognitive decline, and AD neuropathology. Future work should confirm these observations at the protein level to better understand how changes in VEGF transcription and translation relate to neurodegenerative disease.
Figure 4: FLT1 expression associates with (A) longitudinal cognition, (B) clinical diagnosis, and (C) amyloid pathology. (Hohman et. al 2019, Molecular Psychiatry)
Figure 5: (A) NRP1 expression associations with global cognitive performance at the final neuropsychological assessment, stratified by APOE-ε4 allele status. Overall interaction:NRP1 × APOE-ε4, β=−0.28, p.fdr=0.007; APOE-ε4 carriers, β=−0.17, p=0.038; APOE-ε4 non-carriers, β=0.11, p=0.004. (B) VEGFA expression associations with global cognitive performance at the final neuropsychological assessment, stratified by APOE-ε4 allele status. Overall interaction: VEGFA × APOE-ε4, β=−0.03, p.fdr=0.026; APOE-ε4 carriers, β=−0.03, p=0.019; APOE-ε4 non-carriers, β=0.004, p=0.4. (Hohman et al. 2020, Neurobiology of Aging)
- Logan Dumitrescu, MS, PhD / Research Assistant Professor at Vanderbilt University Medical Center
- Angela Jefferson, PhD / Professor of Neurology at Vanderbilt University Medical Center
- Katherine Gifford, PsyD / Assistant Professor of Neurology at Vanderbilt University Medical Center
- Reña A. S. Robinson, PhD / Associate Professor of Chemistry at Vanderbilt University Medical Center
- Catherine Kaczorowski, PhD / Assistant Professor of Medicine at Tufts University, Evnin Family Chair in Alzheimer’s Research, Jackson Laboratories
- Vladislav Petyuk, PhD / Data Scientist at Pacific Northwest National Laboratory
- William S. Bush, PhD / Associate Professor at Case Western Reserve University
- The Alzheimer’s Disease Genetics Consortium
- The Alzheimer’s Disease Sequencing Project
- Religious Orders Study and the Memory and Aging Project (ROS/MAP)
- Accelerating Medicines Partnership – Alzheimer’s Disease (AMP-AD)
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