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Disease/definitions Aging Clinical Animal models Miscellaneous

Organ Indication Sub-indication(s) Preclinical (animal) assays Human diagnostic measurements Etiological hypothesis and acceptance References used for columns D-F Incidence at age 25 (M/F) Incidence at age 50 (M/F) Incidence at age 75 (M/F) References used for columns H-J Aging biology strongly implicated Aging biology weakly implicated References used for columns L+M Patient population (US, 2022 unless noted) References for column S Prognosis Current Standard of Care Treatments Clinical endpoints References for columns Q-S Total trial duration (months)* Trial enrollment (# people): Q1, Q2, Q3

Phase 1 Phase 2 Phase 3 Phase 1 Phase 2 Phase 3

Q1 Q2 Q3 Q1 Q2 Q3 Q1 Q2 Q3 Q1 Q2 Q3 Q1 Q2 Q3 Q1 Q2 Q3 Current Clinical Pipeline (link) How well do mice model? Species that spontaneously get disease Species with human-like anatomy + physiology Notes on model access/logistics References for columns AN-AQ Existing political lobbying strength for this disease Existing umbrella organization political lobbying strength Disease costs/market (US) References for AU

Brain Alzheimer's Familial AD (early onset), late onset AD, mixed dementia Neuropsychological testing; imaging (PET, CT, MRI, multiphoton); biomarkers in CSF and blood; histology Plaque formation; cognitive function; behavioral function Dominant hypothesis (amyloid beta) strongly supported by human genetics but recently under attack due to failure of treatments - i) accumulation of amyloid β (Aβ) plaques (ii) accumulation of hypophosphorylated tau protein in the form of intracellular neurofibrillary tangles (NFT) (iii) sustained inflammation and (iv) cerebrovascular damage and dysfunction https://www.nature.com/articles/s41572-021-00269-y ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785514/ Minimal <<1000 ~4000 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943081/ See also: https://www.nature.com/articles/ncomms11398; https://doi.org/10.1111/jgs.16027 Impaired autophagy, inflammation, protein aggregation, vascular aging AGE accumulation, cellular senescence, epigenetic changes, ER stress, immunosenescence (reduced clearance of pathogens), metabolic dysfunction, mitochondrial dysfunction https://doi.org/10.1016/S1474-4422(15)70016-5 ; https://www.jci.org/articles/view/158453 ; https://pubmed.ncbi.nlm.nih.gov/30530798 ; https://doi.org/10.1111/febs.14332 ; https://pubmed.ncbi.nlm.nih.gov/30936558/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355252/ ; https://www.nature.com/articles/s41419-022-05153-5 5.8 million (2020, out of 329.5 million Americans) CDC 7.6 years (but dependent on age at diagnosis) No interventions to treat underlying disease. Cholinergic agents used to improve impaired cognitive function but don't halt progress of disease. Cognitive and functional measures, MRI imaging https://doi.org/10.1016/S2666-7568(21)00140-9 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061129/; https://alzres.biomedcentral.com/articles/10.1186/s13195-014-0087-9; 6 14 33 20 32 45 22 35 50 16 36 53 39 72 168 205 421 933 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066743/ 2 Grey mouse lemurs recapitulate some features Nonhuman primates (esp. macaques), dogs https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253109/pdf/nihms839392.pdf; https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12114 3 1 (brain) $305 billion https://aaic.alz.org/downloads2020/2020_Facts_and_Figures_Fact_Sheet.pdf

Brain Vascular dementia Small vessel dementia, hypoperfusion dementia, multi-infarct dementia, hereditary vascular dementia, mixed dementia Cerebral blood flow assays (e.g. laser speckle flowmetry); neuropsychological testing; imaging (PET, CT, MRI, multiphoton); histology Cognitive function; blood-based biomarkers; imaging Strokes (recurrent or acute), hemorrhages, loss of BBB permeability, general breakdown of the cerebrovascular system - etiology is unclear https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2685259 ; https://doi.org/10.1016/S0140-6736(15)00463-8 ; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3058404/ Minimal No data No data https://www.alz.org/alzheimers-dementia/facts-figures Inflammation, vascular aging (arterial stiffness, microvascular rarefaction, narrowing of blood vessels) Cellular senescence, ER stress, impaired autophagy, mitochondrial dysfunction, oxidative stress https://doi.org/10.1016/j.arr.2016.09.007 ; https://doi.org/10.1002/jcp.27332 ; https://www.hindawi.com/journals/omcl/2015/504678/ 1.9 million https://www.hindawi.com/journals/bmri/2014/908915/ 6.5 years (but dependent on age at diagnosis) None Cognitive and functional measures https://doi.org/10.1016/S2666-7568(21)00140-9 ; https://www.ahajournals.org/doi/10.1161/jaha.117.005568 12 20 46 22 37 46 25 40 52 18 40 80 51 95 215 210 349 543 https://www.ahajournals.org/doi/full/10.1161/JAHA.117.005568 1.5 Dogs recapitulate some features Dogs, nonhuman primates https://doi.org/10.1186/s12916-017-0793-9 (see Table 1 for breakdown of specific animal models) Although less prevalent than AD, VaD costs more per patient https://doi.org/10.1016/S0022-510X(02)00257-5; https://www.ahajournals.org/doi/10.1161/01.STR.0000017878.85274.44

Brain Parkinson's Idiopathic, early-onset, familial Behavioral and motor tests (e.g. locomotor activibity, gait analysis, grip strength), imaging (e.g. dopamine transporter levels) Medical history; neurological examination; CSF and blood biomarkers (e.g. alpha-synuclein species); imaging (e.g. dopamine transporter levels); responsiveness to levo-DOPA Degeneration of dopaminergic neurons in the midbrain that are part of the basal ganglia—>not enough dopamine; degeneration of noradrenergic neurons; presence of Lewy bodies. Molecular mechanisms of pathogenesis largely unknown. Certain genetic mutations/variants and environmental risk factors are associated with susceptibility to PD, however this is a multifactorial disease so studies altering only one factor typically do not replicate the etiology of PD. https://link.springer.com/article/10.1007/s10654-011-9581-6 ; https://www.ncbi.nlm.nih.gov/books/NBK536725/ Minimal 6.2 (M), 5.1 (F) 140.7 (M), 78.4 (F) https://www.researchgate.net/publication/10734381_Incidence_of_Parkinson's_Disease_Variation_by_Age_Gender_and_RaceEthnicity (note: 2003, small sample size. For age 50, averaged stats for 40-49 and 50-59) ER stress, impaired autophagy, inflammation, mitochondrial dysfunction, protein aggregation AGE accumulation, cellular senescence, oxidative stress, telomere attrition https://doi.org/10.1016/j.freeradbiomed.2017.10.379 ; https://movementdisorders.onlinelibrary.wiley.com/doi/pdf/10.1002/mds.27037 ; https://www.sciencedirect.com/science/article/pii/S0753332221001128 ; https://doi.org/10.1016/j.tins.2014.02.010 ; https://doi.org/10.1111/ene.12252 ; https://doi.org/10.1002/mds.21867 ; https://www.sciencedirect.com/science/article/pii/S0753332221001128 ; https://www.frontiersin.org/articles/10.3389/fnins.2019.00560/full ; https://doi.org/10.1155/2013/239854 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698446/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355252/ 0.9 million (2020) Parkinson's Foundation PD is a progressive neurodegenerative disorder in which patients can do well for a number of years with dopamine-related drugs to boost or replace dopamine. Dopamine drugs do little to alleviate non-motor symptoms, which may appear before motor symptoms, and include constipation, disrupted sleep, and depression. No interventions to alter underlying degenerative process; treatment centered on reducing effect of distressing symptoms e.g. levodopa to increase dopamine levels, deep brain stimulation, along with non-drug therapies like exercise Functional scores (UPDRS, Hoehn and Yahr); self-administered questionnaire; wearables e.g. Parkinson’s Kinetigraph; balance tests https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142835/ 4 10 18 14 24 39 20 27 37 15 24 50 22 42 77 103 249 419 https://content.iospress.com/download/journal-of-parkinsons-disease/jpd219006?id=journal-of-parkinsons-disease%2Fjpd219006; https://www.nature.com/articles/nrd.2018.136 1.5 None known (possibly because of shorter lifespan of most other species) Nonhuman primates e.g. macaques https://www.hindawi.com/journals/pd/2011/658083/; https://febs.onlinelibrary.wiley.com/doi/full/10.1111/j.1742-4658.2012.08491.x; https://onlinelibrary.wiley.com/doi/pdf/10.1002/bies.10067?casa_token=0-wZWMg0m48AAAAA:5oWeHL_2u9jMxQokdpO0bPMZMyMAsYtbnJZU24gRXT9ZbLcTmN_Jo-prHs3FVINYRCkKlrGy7n_XWkNR 2 $25.4 billion https://www.nature.com/articles/s41531-020-0117-1

Brain Frontotemporal dementia Neuropsychological testing; imaging (PET, CT, MRI, multiphoton); biomarkers in CSF and blood; histology Differential diagnosis via behavioral change progression; family history and genetic testing; neuropsychological testing; bloodwork; imaging (MRI, FDG-PET, CT) Sporadic or genetic. Possibly: TAR DNA-binding protein; mutations in progranulin gene, C9orf72, and other less common genes https://www.sciencedirect.com/science/article/pii/S0140673615004614?casa_token=yjteX4uRpPQAAAAA:oUiNj5jtFVAogdB4LzUIgFXFgc5GOrcLCU-gdfDbqO8vETNBmvZI0UK424BP2pU5hrn7zwF0glXK; https://www.sciencedirect.com/science/article/pii/S1474442210702994?casa_token=3IUZ8NP1wucAAAAA:WjjKlDhOWFITefhwknUMqj0zqSmla2633_wTurTZ6LOtkf4XhwOm6BeSJQqUHMtYfymFxAqSX9fS; https://www.science.org/doi/full/10.1126/science.1134108?casa_token=b0QBXUwWSS0AAAAA%3AUnb6NCgFvrOzTw_szrqSQUHUgeRo8zs6VN6BJ6lXZTglmnKunxO7HtzMiN8zPwGguRfO4IhrYvG07TQT; https://www.nature.com/artic