Biology subjects

PREVENT-AD Research Group,

Publications and source records attributed to PREVENT-AD Research Group,.

8 recordsLinked to original sources

bioRxiv2025

Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease

INTRODUCTIONThe locus coeruleus (LC) is among the first sites of tau pathology in Alzheimers disease (AD) and may seed neocortical tau. METHODSWe used longitudinal neuromelanin-sensitive MRI to assess LC integrity in vivo in a cohort of cognitively unimpaired older adults with familial risk of AD in relation to tau and amyloid PET and long-term cognitive trajectories. RESULTSWe showed that both LC integrity at baseline and its rate of degeneration over time independently predicted a neocortical pattern of tau deposition. In keeping with the known function of the LC, neuropsychological tests showed that LC integrity at baseline predicted changes in attention. Finally, we found that longitudinal LC degeneration correlated with memory decline in people with elevated neocortical amyloid burden. DISCUSSIONOur findings underscore the importance of LC in AD pathogenesis. Longitudinal measurement of LC degeneration may help distinguish trajectories of age-related cognitive decline and early AD.

neuroscience↗

bioRxiv2025

Longitudinal functional connectivity during rest and task is differentially related to Alzheimer's pathology and episodic memory in older adults

Changes in functional connectivity (FC) strength involving the medial temporal lobe (MTL) and posteromedial cortex (PMC) are related to early Alzheimers pathology and alterations in episodic memory performance in cognitively unimpaired older adults, but their dynamics remain unclear. We examined how longitudinal changes in FC involving MTL and PMC during resting-state, episodic memory encoding, and retrieval relate to subsequent amyloid- and tau- PET burden, longitudinal episodic memory performance, and the APOE4 genotype in 152 cognitively unimpaired older adults from the PREVENT-AD cohort. We found APOE4- and fMRI paradigm-dependent associations of change in FC strength with pathology burden and change in episodic memory performance. Decreasing FC over time, or "hypoconnectivity", within PMC during rest in APOE4 carriers and during retrieval in APOE4 non-carriers was related to more amyloid and tau, respectively. Conversely, increasing FC over time, or "hyperconnectivity", within MTL during encoding in APOE4 carriers and between MTL and PMC during retrieval independent of APOE4 status was related to more tau. Further, increasing FC between MTL and PMC during rest, unlike during encoding, was beneficial for episodic memory. Our study highlights that pathology-related episodic memory network changes manifest differently during rest and task and have differential implications for episodic memory trajectories.

neuroscience↗

bioRxiv2024

Differential effects of aging, Alzheimer's pathology, and APOE4 on longitudinal functional connectivity and episodic memory in older adults

INTRODUCTIONBoth aging and Alzheimers disease (AD) affect episodic memory networks. How this relates to region-specific early differences in functional connectivity (FC), however, remains unclear. METHODSWe assessed resting-state FC strength in the medial temporal lobe (MTL) - posteromedial cortex (PMC) - prefrontal network and cognition over two years in cognitively normal older adults from the PREVENT-AD cohort. RESULTSFC strength within PMC and between posterior hippocampus and inferomedial precuneus decreased in "normal" aging (amyloid- and tau-negative adults). Lower FC strength within PMC was associated with poorer longitudinal episodic memory performance. Increasing FC between anterior hippocampus and superior precuneus was related to higher baseline AD pathology. Higher FC strength was differentially associated with memory trajectories depending on APOE4 genotype. DISCUSSIONFindings suggest differential effects of aging and AD pathology on longitudinal FC. MTL-PMC hypoconnectivity was related to aging and cognitive decline. Furthermore, MTL-PMC hyperconnectivity was related to early AD pathology and cognitive decline in APOE4 carriers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/627967v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@12c0cc9org.highwire.dtl.DTLVardef@fb7c6borg.highwire.dtl.DTLVardef@a56bdforg.highwire.dtl.DTLVardef@4d1773_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO A) "Normal aging" is characterized by a longitudinal decrease in functional connectivity. B) Cognitively unimpaired older adults with more Alzheimers pathology at baseline (measured via cerebrospinal fluid) exhibit a longitudinal increase in functional connectivity. C_FIG

neuroscience↗

bioRxiv2024

Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal older APOE4 carriers

The precuneus is an early site of amyloid-beta (A{beta}) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated A{beta}. However, longitudinal studies in early Alzheimers disease (AD) risk stages are lacking and the interaction with Apolipoprotein-E (APOE) genotype is unclear. In the PREVENT-AD cohort, we assessed how precuneus activity during successful memory retrieval at baseline and over time relates to future A{beta} and tau burden and to change in memory performance. We further studied the moderation by APOE4 genotype. We included 165 older adults (age: 62.8{+/-}4.4 years; 113 female; 66 APOE4 carriers) who were cognitively normal at baseline and had a family history of AD. All participants performed task-fMRI at baseline and underwent 18F-flortaucipir-PET and 18F-NAV4694-A{beta}-PET on average 5 years later. We found that higher baseline activity and greater longitudinal change in activity in precuneus were associated with higher subsequent A{beta} in APOE4 carriers but not non-carriers. There were no effects of precuneus activity on tau burden. Finally, APOE4 non-carriers with low baseline activity in the precuneus exhibited better longitudinal performance in an independent memory test compared to APOE4 non-carriers with high baseline activity and APOE4 carriers. Our findings suggest that higher task-related precuneus activity at baseline and over time are associated with subsequent A{beta} burden in cognitively normal APOE4 carriers. Our results further indicate that the absence of hyperactivation and the absence of the APOE4 allele is related with the best future cognitive outcome in cognitively normal older adults at risk for AD. Significance StatementThe precuneus is a brain region involved in episodic memory function and is an early site of amyloid-beta (A{beta}) accumulation. Alterations in task-related activity occur in the precuneus with ageing as well as with Alzheimers disease (AD) pathology even in the absence of cognitive symptoms; however, their course and implications are not well understood. We demonstrate that higher precuneus activity at baseline and its change over time during successful memory retrieval is associated with higher A{beta} burden on average 5 years after baseline in Apolipoprotein-E4 (APOE4) carriers. Lower precuneus baseline activation was related to better memory performance over time in APOE4 non-carriers. Our findings provide novel longitudinal evidence that increased activity in posterior midline regions is linked to early AD pathology in dependence of APOE4 genotype.

neuroscience↗

bioRxiv2024

Joint signatures of morphological and microstructural inter-individual variation in the Alzheimer's spectrum

Alzheimers disease (AD) is primarily characterized by the accumulation of amyloid and tau pathologies. However, alterations in the detailed organization and composition of neural tissue also contribute to the diseases early stages. Here, we sought to explore whether hippocampal and cortical microstructural changes, such as myelin alterations and inflammation-mediated increases in iron, could serve as indices of AD-related pathophysiology. In this study, we included 158 participants across the AD spectrum: from individuals without cognitive impairment, at high risk for AD, in the prodromal phase with mild cognitive impairment, and suffering from clinical dementia. We measured atrophy using structural magnetic resonance imaging (MRI) and estimated myelin and iron content using quantitative MRI (qMRI) metrics derived from T1 and T2* relaxation, times respectively. We integrated these contrasts to estimate a joint multivariate signature of tissue alterations across the cortex and hippocampus using non-negative matrix factorization. The relevance of these signatures to AD-spectrum measures of medical history, lifestyle, and cognition were further explored using partial least squares correlation. Our results reveal lower disease-related cortical thickness over large areas of the cortex while T2* provided specific variation across the brain (lower in dorsomedial and superior temporal areas, superior frontal cortex, and premotor cortex, and higher in the occipital lobe). Additionally, we observed longer T1 and T2* times in the hippocampus associated with specific lifestyle risk factors like past smoking, high blood pressure, high cholesterol levels, and higher anxiety. These patterns were significantly related to older age, associated with AD progression, being female, and being an APOE-{square}4 carrier. Taken together, our results suggest that qMRI metrics could serve as a valuable non-invasive tool for exploring the role of myelin and inflammation in AD-related pathophysiology and could be sensitive to modifiable risk factors related to lifestyle and medical history. Future studies may use these signatures to investigate their relationship in investigations related to lifestyle interventions or novel therapeutics.

neuroscience↗

bioRxiv2020

Bundle-specific associations between white matter microstructure and Aβ and tau pathology at their connecting cortical endpoints in older adults at risk of Alzheimer's disease

Beta-amyloid (A{beta}) and tau proteins, the pathological hallmarks of Alzheimers disease (AD), are believed to spread through connected regions. Combining diffusion imaging and positron emission tomography, we investigated associations between A{beta}, tau and white matter microstructure specifically in bundles connecting brain regions in which AD pathology accumulates. In 126 cognitively normal elderly at risk of AD, we focussed on free-water corrected diffusion measures in the cingulum, posterior cingulum, fornix and uncinate fasciculus. We found higher tissue fractional anisotropy and lower mean and radial diffusivity related to increased A{beta} at the cortical endpoints of the cingulum and fornix. We observed similar but stronger associations in the uncinate fasciculus, but with increased A{beta} and tau at the endpoints of this bundle. This consistent pattern of associations, with opposite directionality to the usual degeneration pattern in symptomatic individuals, suggests more restricted diffusion in bundles vulnerable to preclinical AD pathology.

neuroscience↗

bioRxiv2020

Functional brain age prediction suggests accelerated aging in preclinical familial Alzheimer's disease, irrespective of fibrillar amyloid-beta pathology

We aimed at developing a model able to predict brain aging from resting state functional connectivity (rs-fMRI) and assessing whether genetic risk/determinants of Alzheimers disease (AD) and amyloid (A{beta}) pathology contributes to accelerated brain aging. Using data collected in 1340 cognitively unimpaired participants from 18 to 94 years old selected across multi-site cohorts, we showed that chronological age can be predicted across the whole lifespan from topological properties of graphs constructed from rs-fMRI. We subsequently used the difference between the model-predicted age and the chronological age in pre-symptomatic autosomal dominant AD (ADAD) mutation carriers and asymptomatic individuals at risk of sporadic AD and assessed the influence of genetics and A{beta} pathology on brain age. Applying our predictive model in the context of preclinical AD revealed that the pre-symptomatic phase of ADAD is characterized by accelerated functional brain aging. This phenomenon is independent from, and might precede, detectable fibrillar A{beta} deposition.

neuroscience↗

bioRxiv2019

Distinct changes in morphometric networks in aging versus Alzheimer’s disease dementia

Brain gray matter (GM) morphometric changes are prevalent in both aging and Alzheimers disease (AD), though disentangling these two processes has proved challenging. Using independent component analysis, we derived morphometric networks from a large, multi-cohort dataset, and investigated how GM volume within these networks differs in young adulthood, old adulthood, and AD. Aging and AD contributed additive effects on GM loss in nearly all networks, except frontal lobe networks, where GM reductions were more specific to aging. While no networks show GM loss highly specific to AD, a higher degree of variability in the whole-brain pattern of GM volume characterized AD only. Preservation of the whole-brain GM pattern in cognitively normal older adults was related to better cognition and lower risk of developing cognitive impairment. These results suggest both aging and AD involve widespread atrophy, but that cognitive impairment is uniquely associated with disruption of morphometric organization.

neuroscience↗