A Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Single and Multiple Doses of AL002 in Healthy Participants and in Participants with Mild to Moderate Alzheimer*s Disease.

1. Total body weight between 50 and 120 kg, inclusive.
2. Clinical laboratory evaluations (including chemistry panel fasted [fasted at
least 8 hours], complete blood count, and urine analysis) within the reference
range for the test laboratory, unless deemed not clinically significant by the
Investigator. A count of the segmented neutrophils and bands should be
performed when results from the white blood cells (WBCs) are not within the
reference range.
3. Negative test for selected drugs of abuse at screening (does not include
alcohol) and at admission (testing at admission does include alcohol breath
test). A positive result may be verified by re-testing (up to 1 false positive
result permitted) and may be followed up at the discretion of the Investigator.
4. Females must be non-pregnant and non-lactating, and either surgically
sterile (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral
oophorectomy), or use highly effective contraceptive method (oral
contraceptives pills [OCPs], long acting implantable hormones, injectable
hormones, a vaginal ring or an intrauterine device [IUD]) from screening until
study completion, including the follow-up period for at least 16 weeks after
the last dose of AL002, or be post-menopausal for *12 months. For healthy
volunteers, post-menopausal status will be confirmed through testing of FSH
levels (* 40 IU/mL) at screening; for participants with AD, post-menopausal
status will be assessed through medical history with assessment of potential
alternative causes of amenorrhea as clinically indicated). Females who are
abstinent from heterosexual intercourse will also be eligible.
5. Women of child-bearing potential (WOCBP) must have a negative pregnancy test
at screening and admission and be willing to have additional pregnancy tests as
required throughout the study.
6. Males must be surgically sterile (>30 days since vasectomy with no viable
sperm), abstinent, or if engaged in sexual relations with a WOCBP, the
participant and his partner must be surgically sterile (e.g. tubal occlusion,
hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or using an
acceptable, highly effective contraceptive method from screening until study
completion, including the follow-up period, for at least 16 weeks after the
last dose of AL002. Acceptable methods of contraception include the use of
condoms and the use of an effective contraceptive for the female partner
(WOCBP) that includes: OCPs, long acting implantable hormones, injectable
hormones, a vaginal ring or an IUD. Male participants whose female partner is
post-menopausal, and participants who are abstinent from heterosexual
intercourse will also be eligible. Male participants must agree to refrain from
donating sperm from screening until study completion, including the follow-up
period, for at least 16 weeks after the last dose of AL002.

In addition, for the MD cohorts (i.e. participants with AD):
9. Ages 50-85 years, inclusive.
10. The participant should be capable of completing assessments either alone or
with the help of the study partner (where appropriate), per local guidelines.
11. Availability of a person (*study partner*) who, in the Investigator's
judgment, has frequent and sufficient contact with the participant and is able
to provide accurate information regarding the participant*s cognitive and
functional abilities, agrees to provide information at clinic visits, which
require partner input for scale completion, and signs the necessary consent
form, per local guidelines.
12. Clinical diagnosis of probable AD dementia based on National Institute on
Aging Alzheimer*s Association criteria.
13. Screening MMSE score of 16-28 points, inclusive.
14. Screening Clinical Dementia Rating-Global Score (CDR-GS) of 0.5, 1.0, or
2.0.
15. Positive amyloid-PET scan by qualitative read, as defined in the PET
Imaging Charter.
16. If already taking cholinesterase inhibitor and/or memantine therapy for AD,
on a stable dose for at least 4 weeks prior to screening. There should be no
intent to initiate, discontinue, or alter the dose of any therapy for AD for
the duration of the study.
In addition, for MD Cohort M (i.e. participants with AD with a TREM2 mutation):
17. The participant must carry at least 1 of the TREM 2 mutations: R47H or
R62H.

1. Pregnant, lactating, or intending to become pregnant within 16 weeks after
last dose of study drug.
2. Participation in a clinical trial within 30 days before randomization; use
of any experimental oral therapy within 30 days or 5 half-lives prior to Day 1,
whichever is greater; or use of any biologic therapy within 12 weeks or 5
half-lives prior to Day 1, whichever is greater. Participants who have received
an experimental therapy that has no half-life, like a vaccine, should have
completed that therapy at least 12 weeks prior to Day 1. Participants who have
received an experimental vaccine against a central nervous system target, such
as beta-amyloid or tau, are not eligible for this study.
3. Any non-experimental vaccine within 2 weeks of randomization, until 2 weeks
after the last dose. It is advised that prospective participants receive their
annual influenza vaccine as early as possible in advance of the flu season, and
then wait 2 weeks prior to randomization. It is permitted to receive the annual
influenza vaccine during the screening period.
4. Surgery or hospitalization during the 4 weeks prior to screening.
5. Planned procedure or surgery during the study.
6. Blood transfusion within 8 weeks prior to screening.
7. Donation or loss of blood (excluding the volume of blood that will be drawn
during screening procedures) as follows: 50-499 mL of blood within 30 days or >
499 mL of blood within 56 days prior to study drug administration.
8. Poor peripheral venous access.
9. History of major depression (within the past 5 years) unless effectively
treated at enrollment and for the duration of the study, at the discretion of
the Investigator. History of schizophrenia, schizoaffective disorder, or
bipolar disorder.
10. Alcohol and/or substance abuse or dependence (according to the Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition) within the past 2
years.
11. Within the last 2 years, unstable or clinically significant cardiovascular
disease (e.g. myocardial infarction, angina pectoris, New York Heart
Association Class II or more cardiac failure).
12. Uncontrolled abnormal blood pressure
a. For healthy volunteers, as indicated by sustained supine systolic blood
pressure (BP) > 140 or < 90 mm Hg or supine diastolic blood pressure > 90 or
<50 mm Hg at screening or admission. Duplicate assessments will be performed
and the average of the 2 assessments of BP will be used to exclude a
participant.
b. For MD participants with AD, sustained diastolic blood pressure >95 mm Hg
performed either sitting or supine. No repeated measurements for eligibility
are required for multidose participants.
13. Resting heart rate at screening of >100 or < 40 beats per minute.
14. Chronic kidney disease as indicated by a screening creatinine clearance <
30 mL/min as calculated by the central laboratory using the Cockcroft Gault
formula, which remains < 30 mL/min if retested.
15. Impaired hepatic function as indicated by screening aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) * 2 or total bilirubin
* 1.5 x the upper limit of normal, which remains above these limits if retested
due to a slightly elevated initial result or abnormalities in synthetic
function tests that are judged by the Investigator to be clinically significant.
16. History of, or known to currently have, Human Immunodeficiency Virus (HIV)
infection, hepatitis B or hepatitis C infection that has not been adequately
treated in the opinion of the Investigator.
17. History or presence of infections of the central nervous system (e.g.
syphilis, Lyme, or borreliosis, viral or bacterial meningitis/encephalitis, HIV
encephalopathy).
18. History or presence of central nervous system or systemic autoimmune
disorders including but not limited to rheumatoid arthritis, multiple
sclerosis, lupus erythematosus, anti-phospholipid antibody syndrome, Behçet
disease.
19. Present or past history of uveitis requiring medical intervention, chronic
inflammatory or degenerative condition of the eye, current eye infection, any
ongoing eye disorder requiring injectable medical therapy (e.g. ranibizumab or
aflibercept for macular degeneration) or planned invasive eye procedure during
the study period.
20. Systemically, clinically significantly immunocompromised patients, owing to
continuing effects of immune suppressing medication.
21. Positive for Hepatitis C virus (HCV) antibody, Hepatitis B surface antigen
(HBsAg), or HIV antibody.
22. History of cancer except:
a. if considered likely to be cured,
b. is not being actively treated with anti-cancer therapy or radiotherapy and,
in the opinion of the Investigator, is not likely to require treatment in the
ensuing 3 years,
c. considered to have low probability of recurrence (with supporting
documentation from the treating oncologist if possible),
d. for prostate cancer or basal cell carcinoma, no significant progression over
the last 2 years,
e. Adequately resected squamous cell skin cancer.
23. Known history of severe allergic, anaphylactic, or other hypersensitivity
reactions to chimeric, human, or humanized antibodies or fusion proteins.
24. Past history of seizures, with the exception of childhood febrile seizures.
25. At risk of suicide in the opinion of the Investigator.
26. Any serious medical condition or abnormality in clinical laboratory tests
that, in the Investigator*s judgment, precludes the participant*s safe
participation in and completion of the study.
27. History or presence of an abnormal ECG that is clinically significant in
the Investigator*s opinion, including complete left bundle branch block,
second- or third-degree heart block, evidence of prior myocardial infarction
(except if due to a myocardial infarction that occurred more than 2 years
before screening).
28. History of ventricular dysrhythmias or risk factors for ventricular
dysrhythmias such as structural heart disease (e.g. severe left ventricular
systolic dysfunction, left ventricular hypertrophy), coronary heart disease
(symptomatic or with ischemia demonstrated by diagnostic testing), clinically
significant electrolyte abnormalities (e.g. hypokalemia, hypomagnesemia,
hypocalcemia), or family history of sudden unexplained death or long QT
syndrome.
29. Current treatment with medications that are well known to prolong the QT
interval, at the Investigator*s discretion.
30. Immunosuppression caused by disease (such as HIV) or medications,
immunosuppressive therapy (such as long-term systemic corticosteroid therapy)
within 12 months before screening through the entire study period.
31. Smoking more than 5 cigarettes, 1 cigar, or 1 pipe daily.
32. Contraindication to lumbar dural puncture, including coagulopathy,
concomitant anticoagulation (except for platelet inhibitor such as aspirin or
clopidogrel), thrombocytopenia, or other factor that precludes safe lumbar
puncture in the opinion of the Investigator.
In addition, for SAD cohorts (i.e. healthy adults):
33. QT interval corrected using Fridericia*s formula (QTcF) > 450 msec
demonstrated by at least 2 ECGs > 30 minutes apart.
34. The use of all prescribed medication is not allowed (unless discussed and
agreed upon by both the Sponsor and the PI) at least 30 days prior to admission
to the clinical research center until follow-up. The use of all over the
counter medication, vitamin preparations and other food supplements or herbal
medications (e.g. St. John*s Wort) is not allowed (unless discussed and agreed
upon by both the Sponsor and the PI) for at least 14 days prior to admission to
the clinical research center until follow-up. The use of
paracetamol/acetaminophen (up to 2000 mg/day) is allowed for the treatment of
headache or any other pain. Other medication to treat AEs may only be
prescribed if deemed necessary by the Investigator.
In addition, for the MD cohorts (i.e. participants with AD):
35. A lack of ability to consent, in accordance with the local regulations,
guidelines, and independent ethics committee (IEC) or institutional review
board (IRB).
36. Dementia due to a condition other than AD, including, but not limited to,
Frontotemporal Dementia, Parkinson*s disease, dementia with Lewy bodies,
Huntington disease, or vascular dementia.
37. History or presence of clinically evident vascular disease potentially
affecting the brain (e.g. clinically significant carotid, vertebral stenosis or
plaque; aortic aneurysm; intracranial aneurysm; cerebral hemorrhage;
arteriovenous malformation) that in the opinion of the Investigator has the
potential to affect cognitive function.
38. History or presence of stroke within the past 2 years or documented history
of transient ischemic attack within the last 12 months.
39. History of severe, clinically significant (persistent neurologic deficit or
structural brain damage) central nervous system trauma (e.g., cerebral
contusion).
40. Inability to tolerate MRI procedures or contraindication to MRI, including,
but not limited to, presence of pacemakers (with the exception of MRI-safe
pacemakers), aneurysm clips, artificial heart valves, ear implants, or foreign
metal objects in the eyes, skin, or body that would contraindicate an MRI scan;
or any other clinical history or examination finding that, in the judgment of
the Investigator, would pose a potential hazard in combination with MRI.
41. MRI evidence of:
a. more than 2 lacunar infarcts,
b. any territorial infarct > 1 cm3, or
c. significant FLAIR hyperintense lesions in the cerebral white matter that
may, in the Investigator*s opinion, contribute to cognitive dysfunction.
42. Any other severe or unstable medical condition that, in the opinion of the
Investigator or Sponsor, could be expected to progress, recur, or change to
such an extent that it could put the participant at special risk, bias the
assessment of the
clinical or mental status of the participant to a significant degree, interfere
with the participant*s ability to complete the study assessments, or would
require the equivalent of institutional or hospital care.
43. Residence in a skilled nursing facility such as a convalescent home or
long-term care facility. Participants who subsequently require residence in
these facilities during the study may continue in the study and be followed for
efficacy and safety, provided that they have a study partner who meets the
minimum requirement.
44. The following medications are prohibited as daily treatment from 1 month
prior to screening until the end of the study. They are, however, permitted on
an intermittent, as needed basis at any point during the study, provided that
no dose is taken within 2 days before any neurocognitive assessment:
a. typical anti-psychotic or neuroleptic medication,
b. narcotic analgesics,
c. sedative, hypnotic, or benzodiazepine medication,
d. tricyclic antidepressant medications,
e. any sedating antihistamine medication (diphenhydramine or other similar over
the counter antihistamine therapy).
45. QT interval corrected using Fridericia*s formula (QTcF) > 470 msec
demonstrated by at least 2 ECGs > 30 minutes apart for male participants and QT
interval corrected using Fridericia*s formula (QTcF) > 480 msec demonstrated by
at least 2 ECGs > 30 minutes apart for female participants.