Neuropathology consistent with a diagnosis of AD, including amyloid plaques and tau-positive neurofibrillary tangles. No evidence of astrocytic gliosis, spongiosis, or prion disease.

Unknown. In silico algorithms predicted deleterious (CADD score > 20).

Unknown.

Unknown, but atomic structure indicates wild-type residue directly interacts with APP substrate, and the variant's PHRED-scaled CADD score (> 20) suggests a deleterious effect.

Unknown; imaging showed global cerebral atrophy.

In vitro, increased Aβ42 production, decreased Aβ40 production; increased Aβ42:Aβ40 ratio. In cells, increased Aβ42 and Aβ43, decreased total Aβ production, increased Aβ42:Aβ40 ratio. Disrupts endosomes via accumulation of APP β-CTF.

Unknown, but SPECT revealed hypoperfusion in posterior pariteal areas and a subsequent PET scan showed hypometabolism in prefrontal, parietal, and temporal cortices, in one case. MRI showed global cerebral atrophy.

Increased Aβ42 and decreased Aβ40 production, resulting in increased Aβ42/Aβ40 ratio in vitro. In cells, increased Aβ42/Aβ40 ratio, decreased total Aβ production and elevated levels of Aβ42 and Aβ43. Also, poromotes accumulation of APP β-CTFs which disrupt endosomes.

Neuropathology consistent with AD in at least one case.

Increased Aβ42, Aβ48, and Aβ39; Decreased Aβ40, Aβ43, and Aβ46.

In one case: neurofibrillary tangles and amyloid plaques throughout the neocortex; occasional plaques in the spinal cord; Lewy bodies in the substantia nigra and cortex; moderate to severe amyloid angiopathy in leptomeningeal, cerebral, and cerebellar vessels. Widespread amyloid deposition in another patient as assessed by PET.

Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.