Table 1.

FDG-PET studies in clinically and cognitively normal subjects

Reference	Study design	Subjects	Method	Regions with CMRglc reductions		Interpretation
Small et al. [63]	Cross-sectional study	31 SCI and FH–subjects aged 44–67 years old: 12 E4+, 19E4−	ROI	Parietal (only ROI investigated)		N/A
Reiman et al. [56]	Cross-sectional study	33 normal subjects FH+ aged 50–62 years old: 11 E4+ homozygotes, 22 E4−	ROI	Frontal		Acceleration of certain aging processes that herald the onset of Alzheimer’s dementia
				Temporal
				Parietal
				Posterior cingulate cortex (effect is maximal)
Small et al. [57]	Longitudinal study over 2 years	At baseline, 54 normal subjects aged 57–75 years old: 27 E4+, 27E4−	SPM + ROI	Parietala		N/A
				Temporala
				Posterior cingulate cortexa
		At follow-up, 20 normal subjects: 10 E4+, 10 E4−
Reiman et al. [58]	Longitudinal study over 2 years	25 normal FH+ aged 50–63 years old: 15 E4+ heterozygotes, 10 E4−	ROI	Frontal		Interaction between E4 allele and aging rather than a static trait Acceleration of aging processes, necessary but not sufficient for AD
				Temporal
				Posterior cingulate cortex
				Parahippocampal gyrus,
				Hippocampal formation
				Fusiform gyrus
				OccipitoTemporal Cortex
				Lingual gyrus
				Basal forebrain
				Thalamus
				Midbrain
				Cerebellum
				Lentiform nucleus
Reiman et al. [59]	Cross-sectional study	27 normal subjects aged 25–36 years old: 12 E4+ heterozygotes, 15E4−	ROI	Frontal		AD pathology Functional alterations provide a foothold (vulnerability) for subsequent onset of neuropathology Prenatal or early postnatal abnormal neurological development
				Temporal
				Parietal
				Posterior cingulate cortex
Reiman et al. [60]	Cross-sectional study	160 normal subjects aged 47–68 years old: 82 E4+ (36 homozygotes, 46 heterozygotes), 78 E4−	SPM + ROI	Frontal		N/A
				Parietal, Precuneus
				Temporal
				Posterior cingulate cortex
Rimajova et al. [61]	Cross-sectional study	30 E4+ normal or SCI subjects aged 55–78 (26 heterozygotes, 4 homozygotes, 23 healthy and 7 SCI), 30 healthy controls age-matched individuals from a database	VOI	Temporal		AD pathology
				Posterior cingulate cortex
				Anterior cingulate cortex
				All effects are higher in heterozygotes
		(Japanese database of non demented elderly people aged 60–90 whose E4 status are unspecified)
Mosconi et al. [62]	Cross-sectional study	28 normal or SCI subjects aged 45–70 years old: 13 E4+, 15 E4-	SPM	Frontal		N/A
				Parietal
				Temporal
				Fusiform gyrus
				Middle occipital gyrus
				Thalamus
Mosconi et al. [64]	Cross-sectional study	49 FH+ normal or SCI subjects aged 46–80 years old: 16 FHm, 8 FHp, 25 FH-	SPM	FHm vs. FH−:	FHm vs. FHp:	Hypometabolism in FHm may be due to mitochondrial deficits, genetic imprinting, chromosome X-related mechanisms, or other causes
				Frontal	–
				Parietal	Parietal
				Temporal	Temporal
				Posterior cingulate cortex	Posterior cingulate cortex
				Parahippocampal gyrus	Parahippocampal gyrus
				Hippocampus	Hippocampus
Mosconi et al. [65]	Longitudinal 2-year study	66 normal or SCI subjects aged 50–82 years old: 20 FHm, 9 FHp, 37 FH–	SPM	FHm vs. FH−:	FHm vs. FHp:	CMRglc decline may be due to a pathologic process that precedes cognitive deficit in healthy elderly
				Frontal	Frontal
				Parietala	Parietal
				Temporala	Temporal
				Posterior cingulate cortexa	Posterior cingulate cortex
				Parahippocampal gyrus	Parahippocampal gyrus
				–	Hippocampus

^aSignificantly higher rate of decline over 2 years

E4+ ApoE E4 carriers, E4− ApoE E4 non-carriers, FH+ family history of AD in at least one first-degree relative, FHm maternal FH, FHp paternal FH, CMRglc Cerebral metabolic rate of glucose, SCI subjective cognitive impairment, FH+ family history of AD in at least one first-degree relative, ROI region of interest, VOI volume of interest, SPM statistical parametric mapping, N/A not available