Vigil Neuroscience Small Molecule KOL Event

Today's Agenda 7:30 - 7:35 AM (5 min) 8:30 - 8:45 AM

(15 min) Opening Remarks & Corporate Overview Alzheimer's Disease Treatment & Unmet Need Ivana Magov evi -Liebisch, PhD, JD Samuel E. Gandy, PhD, MD Chief Executive Officer, Vigil Neuroscience, Inc. Mount Sinai Professor of

Alzheimer's Disease Research, Professor of Neurology & Psychiatry Associate Director of Mount Sinai Alzheimer's Disease Research Center, NYC 7:35 - 7:50 AM (15 min) Past Chairman, National Medical & Scientific Advisory

Council of the TREM2 Concept in Alzheimer's Disease Alzheimer's Association Marco Colonna, MD Robert Rock Belliveau Professor of Pathology & Immunology 8:45 - 8:50 AM (5 min) Washington University School of Medicine, St. Louis, MO

Clinical Development of VG-3297, Vigil's Small Molecule TREM2 Vigil Neuroscience, Inc. Scientific Advisory Chairman Agonist 7:50 - 8:30 AM (40 min) David Gray, PhD Chief Science Officer, Vigil Neuroscience, Inc. Overview of Vigil's

Small Molecule TREM2 Agonist Program David Gray, PhD Chief Science Officer, Vigil Neuroscience, Inc. 8:50 - 9:00 AM (10 min) Closing Remarks and Q&A Session Christian Mirescu, PhD Vice President, Head of Neuroimmunology, Vigil

Reminders Webcast scheduled to end at 9:00am U.S. ET

Presentation is available in investors section under Events & Presentations at www.vigilneuro.com Moderated Q&A session following prepared remarks To submit a written question, fill out form on webcast home page Webcast

Forward-Looking Statements This presentation contains

"forward-looking statements," which are made pursuant to the safe harbor provisions of the federal securities laws, including the Private Securities Litigation Reform Act of 1995. Any statements that are not statements of historical fact

may be deemed to be forward-looking statements. Such statements may contain words such as "may," "might," "will," "could," "should," "would," "expect,"

"intend," "plan," "prepare," "look," "seek," "anticipate," "believe," "estimate," "predict," "potential," "possible,"

"continue," "ongoing" or the negative of these terms, or other comparable words. These forward-looking statements include, among others, statements relating to: the Company's strategy, business plans, focus and value of

future milestones; the progress and timing of the preclinical development, clinical development and regulatory development of Vigil's programs, including VGL-101 and VG-3927 and the availability of data from our clinical trials involving our

product candidates and expected timing of first dosing for VG-3927; our ability to discover and build a platform of precision medicine based therapies targeting the microglia; and the patient burden of Alzheimer's disease and potential

therapeutic benefit of our product candidates. These forward-looking statements, which are only predictions, involve risks and uncertainties, many of which are beyond our control and are based on our current beliefs, expectations and assumptions

regarding our business. As such, you should not place undue reliance on any forward-looking statements because such risks and uncertainties could cause actual results, performance or achievement to differ materially and adversely from those

anticipated or implied in the forward-looking statements. Factors that could cause actual results to differ from those predicted in our forward-looking statements include, among others, risks and uncertainties related to conducting and reporting

data analyses; product development, including delays or challenges that may arise in the development and regulatory approval of our current and future product candidates or programs; uncertainties as to the availability, analyses and timing of

results and data from preclinical and clinical studies and whether results from preclinical studies and early interim data will be predictive of the results of later preclinical studies and data readouts, and other clinical trials; the timing of our

ability to submit and obtain regulatory clearance for investigational new drug applications and initiate additional clinical trials; our ability to work with the FDA to successfully remove the partial clinical hold on VG-3927; our ability to

initiate and complete our current and expected clinical trials; whether our cash resources will be sufficient to fund our foreseeable and unforeseeable operating expenses and capital expenditure requirements; our ability to raise additional funding

on favorable terms, or at all; the rate and degree of market acceptance and clinical utility of our product candidates; the accuracy of our data analyses or estimates for the potential and market for our products; our ability, and the ability of our

collaborators, to protect our intellectual property and to conduct activities for the development and commercialization of our candidates in view of third party intellectual property positions; our financial performance; our ability to retain and

recruit key personnel, as well as the potential contribution of our employees and board to our growth and success as a Company; developments and projections relating to our competitors or our industry; changes in general economic conditions and

global instability, in particular economic conditions in the markets on which we or our suppliers operate; changes in laws and regulations; and those risks and uncertainties identified in our filings with the Securities and Exchange Commission

(SEC), including under the heading "Risk Factors" in Quarterly Report on Form 10-Q for the quarter ended June 30, 2023, and such other risks and uncertainties that may be described in other filings we make with the SEC. You should not

rely upon forward-looking statements as predictions of future events or performance, or as a representation or warranty (express or implied) by us or any other person that we will achieve our objectives and plans in any specified time frame, on such

specified terms, or at all. Although our management believes that the expectations reflected in our statements are reasonable, we cannot guarantee that the future results, performance or events and circumstances described in the forward-looking

statements will be achieved or occur. These forward-looking statements speak only as of the date such statements are made. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties.

Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. 4 Vigil

Corporate Overview Ivana Magov evi -Liebisch, PhD, JD Chief

Vigil Neuroscience Vigil Neuroscience is a clinical-stage microglia-

focused therapeutics company Founded ~3 years ago in July 2020 Our purpose: to treat rare and common neurodegenerative diseases by restoring the vigilance of microglia, the brain's sentinel immune cells Precision-based

strategy for developing microglia therapeutics Only company known to have 2 modalities for TREM2 agonism - monoclonal an body and small molecule Highly experienced, execution-focused management team and Board of Directors

Vigil's Precision Medicine Strategy to Target Broad Range of

Neurodegenerative Diseases Pipeline Candidates for Genetically Defined Subpopulations in First Indication Common Indications Rare (AD) Microgliopathy Further Expansion (ALSP) into Broader Populations in Data Driven Common Indications Expansion in

Other Rare Microgliopathies Apply learnings from genetically defined subpopulations to larger indications 7 ALSP: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; AD: Alzheimer's Disease Vigil Neuroscience, Inc.

Vigil TREM2 Agonists: Differentiated Strategy & Multiple Modalities

Vigil Neuroscience Small Molecule TREM2 mAb in TREM2 Agonist in Development for Development for ALSP: VGL101 AD: VG-3927 st The 1 & ONLY TREM2 small The ONLY targeted drug candidate molecule agonist entering clinical in development for ALSP

VG-3927: Small Molecule TREM2 Agonist Well-Positioned for AD

First & only small molecule TREM2 agonist entering clinical development Excellent profile as potential treatment for Alzheimer's Disease (AD): - Oral dosing - Superior brain penetration & differentiated

pharmacokinetics & MoA vs antibody-based therapeutics > Novel MoA potentiates TREM2 response to natural damage ligands may enable Improved potency & specificity in active disease state Potentially more favorable safety

profile - Absence of Fc effector domain may limit observations of ARIA Investigational New Drug (IND) is now open - Phase 1 clinical trial in healthy volunteers allowed to proceed with partial clinical hold related to maximum

Featured Key Opinion Leaders (KOLs) Marco Colonna, MD Robert Rock

Belliveau Professor of Pathology & Immunology Washington University School of Medicine, St. Louis, MO Vigil Neuroscience, Inc. Scientific Advisory Board Chairman Samuel E. Gandy, MD, PhD Mount Sinai Professor of Alzheimer's Disease

Research, Professor of Neurology & Psychiatry Associate Director of Mount Sinai Alzheimer's Disease Research Center, NYC Past Chairman, National Medical & Scientific Advisory Council of the Alzheimer's Association 10 Vigil

TREM2 Concept in Alzheimer's Disease (AD) Marco Colonna, MD

Robert Rock Belliveau Professor of Pathology & Immunology Washington University School of Medicine, St. Louis, MO Vigil Neuroscience, Inc. Scientific Advisory Board Chairman

Unique Developmental Origin of the Brain Resident Immune System

Microglial-specific Markers: CD11b low CD45 high Cx3cr1 Tmem119 FCRLS P2RY12 Sall1 https://www.mdpi.com/1422-0067/22/18/9706 12

Microglia in Healthy & Disease States Microglia are Brain-resident

First Microglia are Key to Maintaining Normal Brain Responders to Acute Brain Injury Homeostasis and Neuronal Function Microglia surveillance of healthy brain to maintain Microglia processes quickly and precisely orient to Microglia surveillance of

healthy brain to Microglia processes quickly and precisely orient maintain tissue homeostasis to damage niche following focal photo-injury tissue homeostasis damage niche following focal photo-injury Nimmerjahn, A et al. (2005) Science 13

Microglia Migration into AD's Neuropathological Amyloid Plaque

Microenvironment Healthy Control Brain Alzheimer's Disease Brain Amyloid plaque Microglia Microglia Insoluble ApoE Microglia marker Amyloid plaque Aggregated ApoE Colonna Lab, unpublished data 14

Genetics of AD Inspire the Next Generation of Microglia-Targeted

Therapeutics Expansion of AD Sequenced Genomes Identifies AD Genetics-identified Genes Rare And Novel Causal Genetic Risk Factors Enriched in Microglia Astrocytes Oligos ABCA7 PTK2B RIN3 SORL1 SPI1 ZCWPW1 CR1 NME8 BIN1 CD33 MS4A6A IL1RAP INPP5D

PLCG2 PICALM HLA-DRB1 TREM2 ABI3 CASS4 CD2AP EPHA1 MEF2C FERMT2 CLU APOE z-score -2 0 2 Cuyvers, E and Sleegers, K (2016) Lancet Neurology; Hansen, DV et al. (2018) J Biol Chem 15 Endo cells Microglia Neurons

Targeting Neuroimmunology Specifically for Alzheimer's Disease

Distinct Genetic Links vs Inflammation Disease States Human Genetic Underpinnings of Alzheimer's Disease Biological Substrates of Multiple Point Directly to TREM2 with Further Validation by Sclerosis Points to a Distinct Multiple Pathway

Interactors Signature Adapted from Kunkle, BW et al (2019) Nature Genetics; International Multiple Sclerosis Genetics Consortium (2013) Nature Genetics 16

Why All the Focus on TREM2? Overwhelming Human Data Point to AD-risk

Associated Gene, Protein & Cellular Dysfunction Association of TREM2 Variants TREM2 Mutations in AD Gene Expression in Sporadic AD with AD Risk is Robust and Suggest Loss of Ligand Binding Further Validates Involvement of Highly Replicated and

Loss of Microglia Function the TREM2 Pathway Cd33 MS4a6a MS4a4a DAP12 Central Hub for Microglial GWAS Condello, C et al. (2018) Biol Psychiatry; Kober, D et al. (2016) eLife; Zhang, B et al. (2013) Cell 17

Microglial Loss-of-Signaling Hypothesis for TREM2 TREM2-DAP12 Pathway

& Its Importance Beyond AD TREM2-DAP12 Signaling Transduction and TREM2 and DAP12 Mutations Cause Rare Early-onset Familial Cellular Function in Microglia Microgliopathy Called Nasu-Hakola Disease (NHD) Low avidity ligand state High avidity

ligand state MRI manifestations of NHD Neuropathology in NHD patient TREM2 Ligand Organized TREM2 Clustering DAP12 pSYK Phosphorylated Signaling Complex SYK Microglia Function intracellular intracellular Satoh et al. (2010) Neuropathology; Kilic et

al. (2012) Clinical Imaging 18

TREM2's Role in Microglial Activation Disease State Molecular Evidence

AD Mouse Models Human AD Validation TREM2 promotes non-inflammatory, TREM2 is required for neuroprotection within Plaque-associated microglia protect neuroprotective microglia state the amyloid plaque niche neighboring neurons Key activated

processes Microglia chemotaxis Immune metabolism Amyloid plaque Microglia Amyloid plaque Neuronal damage Phagocytosis Microglia Keren-Shaul, H et al. (2017) Cell ; Wang, Y et al. (2015) Cell; Yuan, P et al. (2016) Neuron 19

Preclinical Proof-of-Principle via TREM2 Agonist Antibodies Target

Validation via Pharmacological Modulation TREM2 Agonist Antibody Reduces Neuronal Damage Enhanced Brain Penetration Leads to Increased Locally Around A Plaques Amyloid Reduction Control tvAb TREM2 tvAb TREM2/TfR bsAb Control TREM2 AL002c Ctrl

antibody Antibody* Amyloid plaque TREM2 tvAb: TREM2 tetravalent antibody *AL002 TREM2/TfR bsAb: TREM2 tetravalent antibody engineered for enhanced brain penetration TfR: transferrin receptor epitope Amyloid plaque Neuronal damage Wang, S et al.

Leveraging Microglia to Restore Tissue Homeostasis in AD Evidence from

Recent Anti-A Therapeutics Antibody full effector function drives microglial A Anti-A dual binding to AD substrate and microglia clearance Microglia Recruitment Microglia and A Clearance AD Pathological Forms of A

Effector inactivated mAbs fail to engage microglia and lack efficacy Chauraslya, A et al. (2023) Nanomedicine-Based Approaches for the Treatment of Dementia 21

Breakthroughs in Neuroimmunology Seed a Promising New Outlook for AD

Therapeutics Summary of Key Concepts Genetics of AD point to microglia as the next generation therapeutics TREM2 is both directly implicated as a causal gene as well as indirectly as a genetic hub Extensive research points to

their protective role in the amyloid plaque microenvironment Preclinical genetic and pharmacological studies validate the TREM2 agonism for AD concept Recently approved anti-A therapeutics provide clinical precedent that

leveraging microglia can restore tissue homeostasis in AD 22

Acknowledgements Washington Univ. Weizmann Institute University of

Brescia Vigil Neuroscience Alector Marina Cella Ido Amit Luigi Poliani David Gray Tina Schwabe Susan Gilfillan Hadas Keren-Shaul William Vermi Christian Mirescu Meer Moustafa Mattia Bugatti Borislav Dejanovic Ilaria Tassi Jonathan Kipnis Brain

research Institute Andrea S Omodei Kelley Larson Herve` Rhinn Niigata, Japan Igor Smirnov Adiljan Ibrahim Akiyoshi Kakita Arnon Rosenthal David M. Holtzman Mari Tada Jason Ulrich Masaki Takao Mayo Clinic Rochester Aivi Nguyen CST, Boston Amgen

Rachel Larsen Tyler Levy Daniel C. Ellwanger Eleni Costantopoulos Sean Beausoleil Samuel A. Hasson Richard Cho Menno van Lookeren Campagne 23

VG-3927: First & Only Small Molecule TREM2 Agonist Entering

VG-3927: First & Only Clinical Oral Small Molecule TREM2 Agonist We

Are Microglia Experts O Ou ut ts st ta an nd di in ng g & & P Po ot te en nt t T TR RE EM M2 2 a ag go on ni is sm m B Br ro oa ad d a an nd d f fa av vo or ra ab bl le e d di if ff fe er re en nt ti ia at te ed d c cl li in ni ic ca al l s

sy yn ne er rg gi iz ze es s w wi it th h n na at tu ur ra al l m mo od du ul la at ti io on n o of f c ca an nd di id da at te e f fr ro om m d da am ma ag ge e l li ig ga an nd ds s n ne eu ur ro op pa at th ho ol lo og gy y w wo or rl ld d- -c cl

VG-3927 Selected from High Quality Chemical Matter Deep Understanding

of MoA with Multiple Excellent Back-up Compounds Highly Efficient and Structurally Diverse Target Coverage in CNS via Oral Dosing Strong Development Path Consistent PK across preclinical species CNS drug properties fully optimized

Scalable and versatile synthetic route pEC50 = log [pSYK EC50] measured in HEK293T-hTREM2 cells , LogD(7.4) = Measured water/octanol partition coefficient at pH 7.4, Rat%F = percentage oral bioavailability in Wistar-Han Rats , Rat Cl =

VG-3927: Entering Phase 1 with Excellent Product Profile TREM2

EC : < 0.003 M 50 TREM1 selectivity: > 50,000-fold Clean profile (evaluated in ~350 PK consistent with QD dosing Highly Potent & off-target assays) CSF exposure free plasma Selective for TREM2

No CYP inhibition liability No TDI risk Compelling VG-3927 PK profile SIF solubility: 83 M -6 Good MDCK Papp: >10 cm /s Permeability and MDCK PGP ER: ~0.5 Solubility Well tolerated with sufficient

safety margins to support Ph1 hERG margin: > 3,500-fold Favorable Safety Profile EC : half maximal effective concentration; PK: pharmacokinetics; QD: once-daily; CSF: cerebrospinal fluid; CYP: cytochrome P450 enzymes; TDI: time-dependent

inhibition; hERG: human ether-a-go-go-related 27 50 gene; SIF: stimulated intestinal fluids; MDCK Papp: Madin-Darby canine kidney apparent permeability; PGP ER: P-glycoprotein efflux ration Vigil Neuroscience, Inc. 2023. All rights

Establishing VG-3927 for Development in AD Pharmacological &

Clinical Translation VG-3927 Pharmacological Profile VG-3927 Functional & Model System Profile TREM2 Human iPSC Human CNS Mouse Nonhuman engineered microglia tri-culture neurodegenerative primate profiling systems monocultures platform disease