INTRODUCTION: The Western diet (WD), originating in the USA, is characterized by ultra-processed foods rich in simple sugars and saturated fats. It is a major risk factor for metabolic disorders, insulin resistance, and inflammation accelerating aging. Long-term WD consumption is believed to impair brain function, trigger neuroinflammation, and increase the risk of Alzheimer’s Disease (AD). AD, the leading cause of dementia, is defined by Aβ plaque accumulation and neurofibrillary tangles composed of hyperphosphorylated tau. There are two AD forms: late-onset sporadic AD (SAD) and early-onset familial AD (FAD). Recent studies highlight the role of unhealthy diet in SAD represented of 95% cases.

AIM(S): This study aimed to determine whether the WD, as a modifiable lifestyle factor, promotes AD by inducing neuroinflammation and brain insulin resistance, and to compare its impact on SAD and FAD models to identify early targets for prevention.

METHOD(S): Male C57BL/6J wild-type mice (SAD model) and APPswe mice (Tg2576, FAD model) were fed WD or a standard diet (CTR) from 3 months of age and analyzed at 4, 8, 12, and 16 months. Neuroinflammation (P2RY12, CD68, GFAP), brain insulin resistance (p-IRS-1 Ser616), and AD hallmarks (p-Tau Thr231, APP, Aβ) were studied in the entorhinal cortex.

RESULTS: Results indicate the entorhinal cortex of wild-type mice is sensitive to metabolic changes, showing brain insulin resistance, impaired macrophage phagocytosis, early microglial activation, disrupted p-Tau localization, and reduced APP. In APPswe mice, WD mainly enhanced astroglial activity. Tau-related lesions were present in both models, while wild-type mice showed intensified Aβ labeling. Senile plaques appeared in APPswe mice.

CONCLUSIONS: Our findings highlight the Western diet as a key modifiable risk factor for neuroinflammation, brain insulin resistance, and Alzheimer’s pathology, revealing distinct mechanisms in SAD vs. FAD and opening new avenues for targeted prevention strategies.

FINANCIAL SUPPORT: Polish National Science Centre grants: SONATA 2014/15/D/NZ4/04361, OPUS 2022/47/B/NZ7/03005