Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Aging Research

Background:

• Aging is the primary risk factor for Alzheimer's disease (AD).
• The apolipoprotein E4 (APOE4) allele is a significant genetic risk factor for AD and is linked to reduced longevity.
• Pathways affected by aging and APOE4 are implicated in AD, suggesting longevity interventions may be repurposed for AD treatment.

Purpose of the Study:

• To investigate the efficacy of two longevity interventions, fasting mimicking diet (FMD) and 17α-estradiol (17αE2), in an Alzheimer's disease mouse model.
• To determine the independent and combined effects of FMD and 17αE2 on AD neuropathology.
• To assess the influence of the apolipoprotein E (APOE) genotype (APOE3 vs. APOE4) on treatment efficacy.

Main Methods:

• Utilized EFAD mice (human APOE3 or APOE4 crossed with 5xFAD AD model).
• Administered 17α-estradiol (17αE2) and/or a cyclic fasting mimicking diet (FMD) to 16-month-old male mice for nine weeks.
• Compared outcomes across four groups: vehicle + ad libitum diet, vehicle + FMD, 17αE2 + ad libitum diet, and 17αE2 + FMD.

Main Results:

• Both 17αE2 and FMD independently reduced Alzheimer's disease neuropathology in a manner dependent on the APOE genotype.
• The protective effects of FMD and 17αE2 were most pronounced in mice carrying the APOE4 genotype.
• Combining 17αE2 and FMD did not yield additive therapeutic benefits.

Conclusions:

• Interventions that enhance longevity show significant potential as therapeutics for Alzheimer's disease.
• These treatments may be effective even when initiated late in the disease process.
• Further research and refinement of these translatable interventions are warranted for AD treatment.