Molecular Neuropathology and Very Early Treatment of Alzheimer's Disease

Takeshi Iwatsubo, MD

Department of Neuropathology, Graduate School of Medicine

The University of Tokyo, Principal Investigator of J-ADNI

Deposition of amyloid bpeptides (Ab) as senile plaques and tau as neurofibrillary changes constitutes the hallmark neuropathological lesions of Alzheimer's disease (AD); these fibrous protein deposits are implicated in its pathogenesis and regarded as the prime target for the disease-modifying therapies (DMT). Abis produced by sequential proteolytic cleavages by b- and g-secretases. g-Secretase, harboring presenilins (PS) as the catalytic center, forms the C terminus of Abthat determines its propensity to aggregate: missense mutations in PS genes cause familial AD by altering the preferred g-secretase cleavage sites to increase production of pathogenic Ab42 species. Protease inhibitors to suppress Abproduction or anti-Abantibodies to promote its clearance were tested in recent clinical trials for DMTs, which altogether failed to meet the clinical endpoints, underscoring the needs for early intervention and biomarkers. To establish imaging and fluid biomarkers that surrogate the AD pathology, longitudinal observational clinical studies including the AD Neuroimaging Initiative (ADNI) and Japanese ADNI were conducted, and have contributed greatly toward the goal of very early treatment, hopefully at the MCI and preclinical AD stages. Based on the J-ADNI data that have been made in public from the National Bioscience Database Center in Japan, we found that the progression profiles of mild cognitive impairment (MCI) due to AD, i.e., prodromal stage of AD, in J-ADNI were remarkably similar to those in US-ADNI, supporting the feasibility of global clinical trials including Caucasian and Asian populations [1]. Based on these international research activities, anti-Abintervention trials in preclinical AD (e.g., the A4 and AHEAD studies) as well as those in early AD (e.g., aducanumab, donanemab) are underway. The bottleneck for the DMT trials consists in the difficulty in recruiting eligible trial candidates, especially those in the asymptomatic preclinical AD stage. Trial-ready cohorts for the prevention of AD are being established in the US (TRC-PAD) and Japan (J-TRC) [2], paving the way toward the prevention of AD.

References

[1]Iwatsubo T, Iwata A, Suzuki K, Ihara R, Arai H, Ishii K, Senda M, Ito K, Ikeuchi T, Kuwano R, Matsuda H, Sun CK, Beckett LA, Petersen RC, Weiner MW, Aisen PS, Donohue MC: Japanese and North American Alzheimer’s Disease Neuroimaging Initiative studies: harmonization for international trials. Alzheimers Dementia14:1077-1087, 2018

[2]Sato K, Ihara R, Suzuki K, Niimi Y, Toda T, Jimenez-Maggiora G, Langford O, Donohue MC, Raman R, Aisen PS, Sperling RA, Iwata A, Iwatsubo T: Predicting amyloid risk by machine learning algorithms based on the A4 screen data: Application to the Japanese Trial-Ready Cohort study. Alzheimers Dement (NY) 7:e12135, 2021