Increased Amyloid-β-related Hypometabolism in Cognitively Normal Individuals with Late-onset Alzheimer's Affected Parents

Cognitively normal (NL) individuals with a 1st degree family history (FH) of late-onset Alzheimer's disease (LOAD), especially those with an affected parent, are at increased risk for AD. This study examines whether NL with LOAD-affected parents show evidence for preclinical brain AD, as reflected in fibrillar amyloid-beta (Aβ) deposits on 11C-PIB PET, and glucose hypometabolism on 18F-FDG PET Forty-seven 40-80 year-old NL individuals with clinical, MRI, 18F-FDG and 11C-PIB PET scans were examined. These included 19 NL with a LOAD-mother (i.e., maternal FH; FHm), 12 with a LOAD-father (paternal FH; FHp), and 16 NL with no family history (FH-). Statistical parametric mapping and automated regions-of-interest were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios for differences across groups Groups were comparable for clinical and demographical measures. The FHm group showed increased PiB retention in posterior cingulate/precuneus (PCC), frontal, temporal and parietal cortices (Figure 1), and reduced metabolism in PCC and parieto-temporal cortices compared to FHp and FH- (Figure 2). The FHp group showed higher PiB retention in PCC compared to FH- (Figure 1), but did not show regional hypometabolism (Figure 2). Results remained significant controlling for age, gender, education and ApoE. The combination of PiB retention and metabolism distinguished FHm from the other subjects with 75% accuracy (relative risk = 3.0, 95% C.I. = 1.5-5.4, P < 0.01). Adult children of parents affected by LOAD, particularly those with affected mothers, have increased Aβ load compared to controls, which may account for the known increased risk for AD. However, only those with affected mothers showed metabolic impairments, indicating more advanced brain damage and associated risk. Overall, while Aβ accumulation is a susceptibility factor for AD, other factors are needed to trigger the "Alzheimer pathway”, resulting in neuronal dysfunction and hypometabolism. Present findings may motivate research on familial transmission and parent-of-origin effects in LOAD, and support future genetic investigations Statistical parametric maps (SPMs) showing higher PiB retention in NL with AD-mothers compared to controls (top two rows) and to NL with AD-fathers (middle two rows), and in NL with AD-fathers compared to controls (bottom two rows). Areas of increased PiB retention are represented on a red-to-yellow color-coded scale, reflecting P values between 0.01-0.001, as indicated on the right side of figure. SPMs are displayed onto the axial and sagittal views of a standard, spatially normalized MRI. Statistical parametric maps (SPMs) showing reduced glucose metabolism in NL with AD-mothers compared to controls (top two rows) and to NL with AD-fathers (bottom two rows). Areas of reduced metabolism are represented on a blue-to-yellow color-coded scale, reflecting P values between 0.01-0.001, as indicated on the right side of figure. SPMs are displayed onto the axial and sagittal views of a standard, spatially normalized MRI.