Primary Objectives:
To demonstrate that HT-4253 improves the amyloid risk profile by transitioning biomarker-positive APOE4 carriers from a positive, high risk APS2 score to a negative, low risk APS2 score.
Secondary Objectives:
* To assess the effects of HT-4253 on tau related blood biomarker progression over the study period. * To assess the effects of HT-4253 on amyloid related blood biomarker progression over the study period. * To assess the safety and tolerability of HT-4253 in the UAE population.
Participant must be 50-75 years of age, without previous AD diagnosis at the time of signing the informed consent.
Capable of giving signed informed consent.
Body mass index (BMI) between 18 and 32 kg/m2.
A positive amyloid probability score from PrecivityAD2™ test (≥ 47.5).
Any medical or neurological condition that in the opinion of the PI may be supportive of dementia.
A history of subjective memory decline with gradual onset and slow progression over the 6 months prior to Screening.
Previous or current diagnosis of AD or mild cognitive decline: MoCA < 26.
Any clinically significant CNS, cardiac, pulmonary, renal, gastrointestinal, endocrinological, respiratory, or metabolic conditions (or history), or other pathological or physiological conditions, that might interfere with the study results in the PI's opinion.
Crossover
HT-4253
DrugIt is anticipated that 112 participants will be randomized to receive HT-4253 (56 in each study arm).
Placebo
Other interventionIt is anticipated that 112 participants will be randomized to receive placebo (56 in each study arm).
Primary Objective
To evaluate that HT-4253 improves the amyloid risk profile by transitioning biomarker-positive APOE4 carriers from a positive, high risk APS2 score to a negative, lower risk APS2 score
Primary Endpoint
Proportion of participants demonstrating improvement in amyloid risk profile, as defined by movement from high risk APS2 category (≥ 47.5) at baseline to a lower APS2 category (\< 47.5) at week 48, as measured by C2N Diagnostics' PrecivityAD2™ test\*
Primary Endpoint
\*C2N PrecivityAD2™ Amyloid Probability Score 2 (APS2) Categories: •Low Risk (\< 47.5): Low likelihood of amyloid plaques in the brain, consistent with a negative amyloid Positron Emission Tomography (PET) scan
Primary Endpoint
• High Risk (≥ 47.5): A score within this range suggests that the participant is likely to have amyloid plaques, requiring further diagnostic evaluation
Secondary Objectives
Secondary Objectives: To evaluate the effects of HT-4253 on tau related blood biomarker progression over the study period
Secondary Endpoints
•Change in slope of p-tau217 over 48 weeks.
Secondary Endpoints
•Change from baseline in plasma p-tau217 at weeks 12, 24, 36, 48.
Secondary Endpoints
•Change from baseline in plasma p-tau181 at week 12, 24, 36, 48.
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