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Background Clinical staging of Alzheimer disease (AD) may help develop novel treatment in the early stage. Aim We measured the accumulation of amyloid beta (Aβ) and tau with positron emission tomography (PET) in patients with AD to explore its utility for clinical staging. Methods Six patients with AD, two patients with mild cognitive impairment (MCI), and 12 healthy controls (HC) were studied. Aβ and tau accumulation was evaluated with [11C]PiB and [11C]PBB3, respectively. Results PBB3‐PET showed that two cases were in stage I‐II (Braak stage), one case was in stage III‐IV, and three cases were in stage V‐VI. PiB‐PET showed that all cases were in stage C. The duration of the disease correlated positively with PBB3 staging but not with PiB staging. The performance on the Mini‐Mental State Examination (MMSE) tended to decrease with advancing of PBB3 stage but not with PiB stage. PBB3 SUVR and PiB SUVR in all AD signature areas including the parahippocampal gyrus were significantly higher in AD than in HC. A decrease in MMSE is correlated with increases in PBB3 and PiB. Increase in PBB3 started with decrease in MMSE whereas increase in PiB was already observed in the point of highest MMSE, indicating amyloid is already accumulated in the earliest stage. Conclusions The expansion of tau distribution from the parahippocampal gyrus to the cerebral cortex was observed with advancing AD, whereas Aβ distribution was already advanced in the earliest stage. PBB3 may be useful in determining stages in AD based on tau distribution.

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We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer’s disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer’s disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques.

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