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Background: Currently, brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer's disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis., Objective: To apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus., Methods: Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®) = 0, amyloid β (Aβ)-negative, n = 34]; Preclinical AD (CDR = 0, Aβ-positive, n = 19); and mild AD (CDR = 0.5 or 1, Aβ-positive, n = 17)., Results: In hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as "Dark Matter", and the other, with relatively preserved neurons, "Viable Tissue". Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group; neuronal loss ranged between 31% and 43%, while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration., Conclusion: In vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection.

Background: Behavioral markers for Alzheimer's disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework., Objective: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD., Methods: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall., Results: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = -0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall., Conclusion: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.

Background: Changes in resting state functional connectivity (rs-fc) occur in Alzheimer's disease (AD), but few longitudinal rs-fc studies have been performed. Most studies focus on single networks and not a global measure of rs-fc. Although the amyloid tau neurodegeneration (AT(N)) framework is increasingly utilized by the AD community, few studies investigated when global rs-fc signature changes occur within this model., Objective: 1) Identify a global rs-fc signature that differentiates cognitively normal (CN) individuals from symptomatic AD. 2) Assess when longitudinal changes in rs-fc occur relative to conversion to symptomatic AD. 3) Compare rs-fc with amyloid, tau, and neurodegeneration biomarkers., Methods: A global rs-fc signature composed of intra-network connections was longitudinally evaluated in a cohort of cognitively normal participants at baseline (n = 335). Biomarkers, including cerebrospinal fluid (Aβ42 and tau), structural magnetic resonance imaging, and positron emission tomography were obtained., Results: Global rs-fc signature distinguished CN individuals from individuals who developed symptomatic AD. Changes occurred nearly four years before conversion to symptomatic AD. The global rs-fc signature most strongly correlated with markers of neurodegeneration., Conclusion: The global rs-fc signature changes near symptomatic onset and is likely a neurodegenerative biomarker. Rs-fc changes could serve as a biomarker for evaluating potential therapies for symptomatic conversion to AD.

Background: The influence of reserve variables and Alzheimer's disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on "non-cognitive" outcomes, including functional abilities and mood., Objective: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior., Methods: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants., Results: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers., Conclusions: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.

The hippocampus is often treated as a uniform structure, but possesses differential projections to surrounding cortex along its longitudinal axis. This heterogeneity could create varied susceptibility to pathological influences, potentially leading to non-uniform volumetric associations with advancing age and Alzheimer's disease (AD). Previous examinations of aging and AD effects on hippocampal subdivisions have produced highly discrepant findings. To clarify these inconsistencies, we examined the hippocampal head, body, and tail in a large sample of 292 cognitively normal, 37 very mildly demented, and 18 mildly demented individuals, divided into two independent samples. As often done in the literature, we characterized qualitative patterns across these regions, but extended these results by explicitly testing for quantitative differences. In each sample of cognitively normal individuals, the head and body demonstrated greater age effects than the tail. In each sample contrasting AD and cognitively normal individuals, all three regions showed significant volume reductions, with the greatest effect on the head. When examining increasing severity of dementia, the hippocampal head showed progressive volume loss, while the body and tail did not. The patterns of results examining both aging and AD were relatively consistent across the independent samples. These results indicate that there is an anterior-to-posterior gradient of loss within the hippocampus with both advancing age and AD.