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Objective: To investigate the particular pathology of the Arctic APP (APParc) early-onset familial Alzheimer disease (eoFAD) mutation for the first time in vivo with PET in comparison with other eoFAD mutations and sporadic Alzheimer disease (sAD).

Methods: We examined 2 APParc mutation carriers together with 5 noncarrier siblings cross-sectionally with 11C-labeled Pittsburgh compound B (PiB) and 18F-fluorodeoxyglucose (FDG) PET, as well as MRI, CSF biomarkers, and neuropsychological tests. Likewise, we examined 7 patients with sAD, 1 carrier of a presenilin 1 (PSEN1) mutation, 1 carrier of the Swedish APP (APPswe) mutation, and 7 healthy controls (HCs).

Results: Cortical PiB retention was very low in the APParc mutation carriers while cerebral glucose metabolism and CSF levels of A[beta]1-42, total and phosphorylated tau were clearly pathologic. This was in contrast to the PSEN1 and APPswe mutation carriers revealing high PiB retention in the cortex and the striatum in combination with abnormal glucose metabolism and CSF biomarkers, and the patients with sAD who showed typically high cortical PiB retention and pathologic CSF levels as well as decreased glucose metabolism when compared with HCs.

Conclusions: The lack of fibrillar [beta]-amyloid (A[beta]) as visualized by PiB PET in APParc mutation carriers suggests, given the reduced glucose metabolism and levels of A[beta]1-42 in CSF, that other forms of A[beta] such as oligomers and protofibrils are important for the pathologic processes leading to clinical Alzheimer disease.

GLOSSARY: A[beta]: [beta]-amyloid

AD: Alzheimer disease

APParc: Arctic APP

APPswe: Swedish APP mutation carrier

CAA: cerebral amyloid angiopathy

eoFAD: early-onset familial Alzheimer disease

FDG: 18F-fluorodeoxyglucose

MCI: mild cognitive impairment

MMSE: Mini-Mental State Examination

p-tau: phosphorylated tau

PiB: Pittsburgh compound B

sAD: sporadic Alzheimer disease

t-tau: total tau

varAD: variant AD

(C)2012 American Academy of Neurology