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The two-hit hypothesis of AD. The first hit (HIT 1) is due to variables such as lifestyle, genetic predispositions and risk factors, environmental factors, and vascular damage described in this paper. The variables initiate a cascade of neurodegenerative changes. With BBB damage, the accumulation of Aβ starts, which strongly contributes to HIT 2. From HIT 2, through inflammation and Aβ and p-Tau accumulation, neurodegenerative changes lead to NDs (based on [51]).
