ACAA1 and Mental deterioration: We have further provided in vitro and in vivo data showing that this ACAA1 variant facilitates Aβ pathology and exacerbates cognitive decline by impairing lysosomal and synaptic function, adding this gene to the current list of AD risk and causal genes.13,14,17,22,41 ACAA1 p.N299S is a loss-of-function mutant, as it decreases enzymatic activity (Fig. 1b) and causes a catastrophic cascade with the involvement of disturbed global gene expression pattern and impaired lysosomal, autolysosomal, and synaptic functions (Fig. 2).