ALPP and familial Alzheimer disease: Therefore, we theorize that the P436S mutation may have a less severe impact on PSEN1 function compared to P436Q (which shows defective PSEN1 autoproteolysis, a very early age at onset, and is also associated with spastic paraparesis and posterior cerebral clinical features 33, 43) yet still cause fAD with a relatively early age at onset due to the importance of the PALP motif.