Neurodegenerative Alzheimer's Disease and Amyotrophic Lateral Sclerosis (NADALS) Basket Trial

This is an open-label, biomarker-driven basket trial of baricitinib in people with subjective cognitive disorder, mild cognitive impairment, Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), or asymptomatic carriers of an ALS-related gene, such as a hexanucleotide expansion in the C9ORF72 gene, with evidence of abnormal inflammatory signaling in cerebrospinal fluid (CSF) at baseline. Each participant will be treated with baricitinib for 24 weeks; no placebo will be given. Participants will receive baricitinib 2 mg per day by mouth for the first 8 weeks and baricitinib 4 mg per day by mouth for the remaining 16 weeks. This proof of concept trial will ascertain whether baricitinib at 2 mg per day, 4 mg per day, or both reaches therapeutic levels in the CSF and suppresses inflammatory biomarkers associated with type I interferon signaling among the study participants.

Inclusion Criteria Study participants meeting all of the following criteria will be allowed to enroll in the study: 1. Must be 55-90 years old, inclusive and have one of the following: * Subjective cognitive decline(SCD) * Minor neurocognitive disorder(mild cognitive impairment(MCI)) * Major neurocognitive disorder(possible or probable AD) OR Must be 18-80 years old, inclusive and have one of the following: * Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by the revised El Escorial criteria * Asymptomatic carrier of an ALS-causative mutation per CLIA-certified genetic testing results (MGH site only) 2. Screening CSF level of CCL2 level ≥ 250 pg/mL 3. Up-to-date immunization records per CDC guidelines * Routine vaccinations should be administered at a minimum of 14 days prior to any study visit with an LP 4. Must have received the Recombinant Zoster Vaccine (RZV, also known as Shingrix) within 4 years prior to enrollment. Note: Only one dose of RZV is needed prior to the Baseline Visit. 5. Must be fully vaccinated for COVID-19 per CDC guidelines * If a participant is planning to receive a COVID-19 booster shot, should be administered a minimum of 14 days prior to the Screening LP. 6. For participants with ALS: * Must either not be taking or be on a stable dose of any FDA approved treatment for ALS for at least 30 days or at least 1 cycle prior to screening * ALSFRS-R score ≥ 27 * Must be ambulatory, defined as able to walk at least within the home every day. Use of gait assistive devices is allowed. Some use of a wheelchair is also allowed. * Greater than 12-month life expectancy in the opinion of the investigator For participants with AD: * MoCA score ≥ 8 * The participant must have a study partner that can accompany them to every visit and co-sign any informed consent document. * Must either not be taking or be on a stable dose of any FDA approved treatment for AD for at least 30 days prior to screening. Participants cannot be taking Aducanumab(see exclusion criterion #15). 7. Ability to medically undergo LP in the opinion of the investigator (e.g., no bleeding disorder, allergy to local anesthetics, prior lumbar surgery which might make LP difficult, a skin infection at or near the LP site, evidence of high intracranial pressure, or anticipated difficulty getting into position for LP). 8. Capable of providing informed consent and following study procedures. * In the case that a participant lacks the ability to provide informed consent, informed consent will be obtained from the participant's surrogate representative and assent obtained from the participant. Exclusion Criteria Study participants meeting any of the following criteria during screening evaluations will be excluded from entry into the study: 1. Women who are pregnant, breastfeeding, or planning to become pregnant during the trial 2. Any unstable clinically significant medical condition other than ALS or AD (e.g., within six months of baseline, including but not limited to myocardial infarction, angina pectoris, congestive heart failure, or neoplasm undergoing active treatment). 3. Active cancer or history of cancer, except for the following: basal cell carcinoma, cervical carcinoma in situ, prostatic carcinoma in situ, or other malignancies curatively treated and with no evidence of disease recurrence for at least 5 years. Active cancer includes cancers with current disease manifestations or therapy that could adversely affect participant safety and longevity, create the potential for drug-drug interactions, or compromise the interpretation of study results. 4. History of diverticulitis or bowel perforation. 5. Active ulcerative colitis, Crohn's disease, and history of peptic ulcer disease within the past 5 years or after the age of 65. 6. Active, serious infection, including localized infection in the opinion of the investigator. 7. Positive for latent or active tuberculosis (TB). Note: Patients with a history of latent or active TB must have had an adequate course of treatment documented prior to study participation. 8. Evidence of active hepatitis B or C infection. 9. History of severe hepatic or renal impairment. 10. eGFR \< 60 mL/min/1.73 m2 11. Have any of the following specific abnormalities on screening laboratory tests: * ALT or AST \>2.5x upper limits of normal (ULN) * Alkaline phosphatase (ALP) ≥2x ULN * Total bilirubin ≥1.5x ULN, Note: patients with elevated bilirubin secondary to Gilbert's disease are eligible to participate in the study. * Hemoglobin \