Neurobiology of Aging

The proportion of older adults in Western populations is increasing and there is, therefore, a need to define factors affecting maintenance of physical and cognitive health in old age. Variations in the Klotho (KL) gene, and specifically the KL-VS haplotype, have been identified by several authors as potentially influencing cognitive function and decline. We have attempted to verify the reported associations between KL variants, including the KL-VS haplotype, and cognitive function in up to 335,074 British Caucasian participants aged 40-79 years from the UK Biobank. We do not find evidence that KL-VS affects cognitive function or its decline with increasing age. We examined a further 244 KL variants and found that rs117650866 was associated with Prospective Memory, but could not replicate this in follow-up samples. In conclusion, there is insufficient evidence in the UK Biobank to support the concept that KL variants affect cognitive function or its rate of decline.

Medial temporal lobe (MTL) sub-structures are differentially affected in early Alzheimers disease (AD), with a specific involvement of the entorhinal cortex (ERC), the perirhinal cortex (PRC) and CA1. However, the impact of amyloid (A{beta}) pathology and APOE {varepsilon}4 on MTL subregional atrophy remains relatively unknown. Our aim was to uncover these effects to further our understanding of the mechanisms underlying MTL atrophy in a population at-risk for AD. We used baseline data from 130 unimpaired older adults (mean age: 68.9 {+/-} 3.8 years) from the Age-Well randomized controlled trial for whom high-resolution structural MRI (T2-weighted; 0.4x0.4x2.5mm3), amyloid-PET (Florbetapir) and APOE genotype were available. Participants were dichotomized into amyloid positive (A{beta}+, n=27) and negative (A{beta}-, n=103), and APOE {varepsilon}4 carrier ({varepsilon}4+, n=35) and non-carriers ({varepsilon}4-, n=95). Hippocampal subfield (CA1, CA2, CA3, dentate gyrus [DG], subiculum [SUB]) and extra-hippocampal region (ERC, Brodmann area [BA] 35 and 36, and parahippocampal cortex [PHC]) volumes were estimated using ASHS and normalized by total intracranial volume. For each subregion, group comparisons were performed (A{beta}+ vs A{beta}- and {varepsilon}4+ vs {varepsilon}4-) using ANCOVAs, including age, sex and education as covariates. Interactions with age (i.e., A{beta} status * age and APOE {varepsilon}4 status * age) were also investigated for each subregion. No significant differences were observed between A{beta}+ and A{beta}-, nor between {varepsilon}4+ and {varepsilon}4-. However, a significant A{beta} status * age interaction were observed for CA1 (p<0.05), where volumes were negatively associated with age in the A{beta}+ group only. In addition, significant APOE {varepsilon}4 status * age interactions were found for CA1, SUB, ERC, DG and the whole hippocampus (p<0.05), where volumes were negatively associated with age in the {varepsilon}4+ group only. Overall, our analyses showed that both A{beta} and APOE {varepsilon}4 status interact with age on CA1, which is known to be specifically atrophied in early AD. In addition, APOE {varepsilon}4 status mediated the effects of age on other subregions (SUB, ERC, DG), suggesting a more important contribution of APOE {varepsilon}4 than amyloid to MTL atrophy in cognitively unimpaired population. These results are particularly important to develop MRI-based biomarkers to detect early AD and further our understanding of the mechanisms underlying MTL atrophy.

The ability to choose adaptively between rewards differing in magnitude and delay (intertemporal choice) is critical for numerous life outcomes. Compared to younger adults, older adults tend to exhibit greater preference for large, delayed over small, immediate rewards (i.e., less delay discounting), which could lead to missed opportunities to obtain resources necessary for quality of life. Intertemporal choice is mediated by the prefrontal cortex, but how this is impacted by advanced age is not well understood. We used optogenetic inactivation to investigate contributions of medial prefrontal cortex (mPFC) during distinct components of an intertemporal choice task in young and aged rats. mPFC inactivation during deliberation (during decisions between small, immediate vs. large, delayed rewards) increased preference for large, delayed rewards in both age groups. In contrast, inactivation during delays prior to large reward delivery increased preference for large, delayed rewards only in aged rats. Choices were unaffected by inactivation during other task phases. Results suggest that mPFC integrates information regarding anticipated outcomes into the decision process across the whole lifespan, but that only in aging is mPFC critical for consolidating information regarding reward delays into the decision structure in order to modulate choice behavior.

Vigor reflects how motivated one is to respond to a stimulus. We previously showed that humans are more vigorous when more reward is available on average, and that this relationship is modulated by the dopamine precursor levodopa. Dopamine signalling and probabilistic reward learning degrade with age, so the relationship between vigor and reward should change with age. We test this and assess whether the relationship between vigor and reward correlates with D1 dopamine receptor availability measured using Positron Emission Tomography. We measured response times of 30 older and 30 younger subjects during an oddball discrimination task where rewards varied systematically between trial. Reward rate had a similar impact on the vigor of both groups. We observed a weak positive association across subjects between ventral striatal dopamine receptor availability and effect of average reward rate on response time, which was in the opposite direction to our prediction. Overall, the effect of reward on response vigor is similar between younger and older humans and is weakly sensitive to dopamine D1 receptor availability.

In humans, cognitive aging is highly variable, with some individuals experiencing decline while others remain stable, and different cognitive domains exhibiting uneven vulnerability to aging. The neural mechanisms driving this intra- and inter-individual variability are not fully understood, making longitudinal studies in translational models essential for elucidating the timelines and processes involved. The common marmoset (Callithrix jacchus), a short-lived nonhuman primate, offers an unprecedented opportunity to conduct longitudinal investigations of aging and age-related disease over a condensed time frame, in a highly translatable animal model. The potential of the marmoset as a model for cognitive aging is indisputable, but a comprehensive cognitive battery tailored for longitudinal aging studies has not yet been developed, applied, or validated. This represents a critical missing piece for evaluating the marmoset as a model and understanding the extent to which marmoset cognitive aging mirrors the patterns found in humans, including whether marmosets have individual variability in their vulnerability to age-related cognitive decline. To address this, we developed a comprehensive touchscreen-based neuropsychological test battery for marmosets (MarmoCog), targeting five cognitive domains: working memory, stimulus-reward association learning, cognitive flexibility, motor speed, and motivation. We tested a large cohort of marmosets, ranging from young adults to geriatrics, over several years. We found significant variability in cognitive aging, with the greatest decline occurring in domains dependent on the prefrontal cortex and hippocampus. Additionally, we observed significant inter-individual variability in vulnerability to age-related cognitive decline: some marmosets declined across multiple domains, others in just one, and some showed no decline at all. This pattern mirrors human cognitive aging, solidifies the marmoset as an advantageous model for age-related cognitive decline, and provides a strong foundation for identifying the neural mechanisms involved.

Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimers Disease. Despite their increasing application, the genetic and environmental etiology of global PBA indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 52 to 72 years. Biometrical genetic analyses twin models revealed significant and highly correlated estimates of additive genetic heritability ranging from 59% to 75%. Multivariate longitudinal modelling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences. HighlightsWe explored the genetic and environmental etiology of MRI-based predicted brain age (PBA) in a longitudinal sample of males starting in midlife. Genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and largely explained by common genetic influences.

Age-related hearing loss is a leading modifiable risk factor for dementia and is increasingly recognized as a non-motor feature of Parkinson's disease (PD). The apolipoprotein E (APOE) E4 allele is the strongest genetic risk factor for Alzheimer's disease and is associated with cognitive decline in PD, yet its relationship to hearing loss remains unclear. Therefore, we examined the independent and interactive effects of PD status and APOE E4 carrier status on age-related hearing loss using a validated web-based speech-in-noise (SIN) assessment in 239,620 23andMe Research Institute participants without PD and 4,361 PD cases. Generalized additive models for location, scale, and shape (GAMLSS) showed that both PD and APOE E4 independently exacerbated age-related hearing decline, with speech reception thresholds (SRTs) worsening non-linearly with advancing age, but without evidence of synergistic interaction. However, longitudinal analyses in a subcohort completing at least two assessments (1,434 PD cases; 36,242 controls) using GAMLSS mixed models showed a significant three-way interaction between PD status, APOE E4, and age2, such that SIN hearing loss accelerated more steeply with age in APOE E4 carriers with PD. Males and individuals with lower educational attainment also exhibited worse SIN hearing loss. These results identify APOE E4 carriers with PD as a priority population for hearing screening and intervention, and support the integration of SIN assessments into routine PD care to detect hearing decline that may compound cognitive and communicative burden in aging.

Age-related deficits in episodic memory and mnemonic discrimination are associated with an increased risk of neurodegenerative diseases, such as Alzheimers disease (AD) (Stark et al., 2013). While much research has focused on hippocampal contributions to these age-related changes (Stark et al., 2019), less is known about the role of posterior cingulate cortex (PCC) especially reduced inhibition in episodic memory deficit. PCC has connections to the medial temporal lobe and is linked to memory declines (Greicius et al., 2004). It is also one of the most vulnerable regions to amyloid deposition in AD (Yokoi et al., 2018). This study hypothesized and found that age-related declines in GABAergic function (brains major inhibitory neurotransmitter) within the PCC contributes to individual differences in memory performance in healthy older adults. Using Magnetic Resonance Spectroscopy, we measured GABA levels in the PCC in 22 healthy younger and 30 older adults. We assessed episodic memory using Rey Delayed Auditory Verbal Learning Test (RAVLT) and Mnemonic Similarity Task (MST). We found that both raw GABA levels and episodic memory performance are lower in older adults compared to young. This reduction in GABA levels is subserved by age-related changes in tissue-composition as evidenced by no age-group differences in corrected GABA levels. More importantly, lower GABA levels (independent of tissue-correction) were associated with poorer episodic performance including delayed recall and mnemonic discrimination. This research suggests that therapeutically targeting posterior cingulate GABA levels might help slow or alleviate memory decline. Significance StatementThis study provides novel insights into the role of posterior cingulate cortex (PCC) GABA+ levels in age-related memory deficits. Our findings demonstrate that lower PCC GABA+ levels in older adults are associated with poorer performance on episodic memory tasks, particularly those involving mnemonic discrimination and word-list learning. This research expands on the growing body of literature linking GABAergic dysfunction to age-related cognitive impairments and suggests that GABAergic changes in the PCC contribute to episodic memory deficits. Importantly, our results highlight the potential of targeting PCC GABA levels as a therapeutic strategy to slow or mitigate memory decline in aging. These findings also offer promising avenues for future research into early biomarkers for Alzheimers disease and other neurodegenerative conditions.

Sharp-wave/ripples are brief, high-frequency events in hippocampal subregions CA3 and CA1 that occur during rest or pauses in behavior. Ripples detected in CA1 have lower frequency in aged compared to young rats. Although CA1 ripples are theorized to manifest from CA3, ripple dynamics in CA3 have not been examined in aged animals. The current study obtained simultaneous recordings between CA1 and CA3 in young and aged rats to examine sharp-wave/ripple characteristics in both regions in relation to age. While CA1 ripple frequency was reduced with age, there were no age differences in CA3 ripples. In aged, but not young, rats there was also a significant increase in the probability of CA3 and CA1 ripples co-occurring between the pre- and post-behavior rest epochs. Moreover, in both age groups, CA1 ripples that co-occurred with a CA3 ripple had increased frequency, power, and duration. These findings suggest age differences in CA1 are not due to altered afferent input from CA3, but instead reflect distinct mechanisms of ripple generation with age. HIGHLIGHTSO_LICA1 ripple frequency is reduced with age. C_LIO_LICA3 ripple characteristics do not change with age. C_LIO_LIIn aged rats only, CA3-CA1 ripple co-occurrence increased following behavior. C_LIO_LICA1 ripples that co-occurred with CA3 had greater frequency, power, and duration. C_LI

Substantia nigra pars compacta (SNc) dopamine neurons are required for voluntary movement and reward learning, and advanced age is associated with motor and cognitive decline. In the midbrain, D2-type autoreceptors located on dendrodendritic synapses between dopamine neurons control cell firing through G protein-activated potassium (GIRK) channels. We previously showed that aging disrupts dopamine neuron pacemaker firing in mice, but only in males. Here we show that D2-receptor inhibitory postsynaptic currents (D2-IPSCs) in aged male mice are moderately smaller compared to young males as well as females, regardless of age. Local application of dopamine revealed a reduction in the amplitude of the D2-receptor currents in old males compared to young, pointing to a postsynaptic mechanism that could not be explained by impairment of the GIRK channels or degeneration of the dendritic arbor. Kinetic analysis showed no differences in D2-IPSCs in old versus young mice or between sexes. Potentiation of D2-IPSCs by corticotropin releasing factor (CRF) is also conserved in aging, indicating preservation of plasticity mechanisms. These findings have implications for understanding dopamine transmission in aging in both sexes and could explain in part the increased susceptibility of males to SNc degeneration of dopamine neurons in neurodegenerative disorders such as Parkinsons disease (PD).

Cerebrovascular dysregulation is a hallmark feature of Alzheimers disease (AD), where alterations in cerebral blood flow (CBF) are observed decades prior to symptom onset. Genome-wide association studies (GWAS) show that AD has a polygenic aetiology, providing a tool for studying AD susceptibility across the lifespan. Here, we ascertain whether AD genetic risk effects on CBF previously observed (Chandler et al., 2019) remain consistent across the lifespan. We further provide a causal mechanism to AD genetic risk scores (AD-GRS) effects by establishing spatial convergence between AD-GRS associated regional reductions in CBF and mRNA expression of the proximal AD transcripts using independent data from the Allen Brain Atlas. We analysed grey matter (GM) CBF in a young cohort (N=75; aged 18-35) and an older cohort (N=90; aged 55-85). Critically, we observed that AD-GRS was negatively associated with whole brain GM CBF in the older cohort (standardised {beta} -0.38 [-0.68 - -0.09], P = 0.012), consistent with our prior observation in younger healthy adults (Chandler et al., 2019). We then demonstrate that the regional impact of AD-GRS on GM CBF was spatially consistent across the younger and older samples (r = 0.233, P = 0.035). Finally, we show that CBF across the cortex was related to the regional expression of the genes proximal to SNPs used to estimate AD-GRS in both younger and older cohorts (ZTWO-TAILED = -1.99, P= 0.047; ZTWO-TAILED = -2.153 P = 0.032, respectively). These observations collectively demonstrate that AD risk alleles have a negative influence on brain vascular function and likely contribute to cerebrovascular changes preceding the onset of clinical symptoms, potentially driven by regional expression of proximal AD risk genes across the brain. Our observations suggest that reduced CBF is an early antecedent of AD and a key modifiable target for therapeutic intervention in individuals with a higher cumulative genetic risk for AD. This study will further enable identification of key molecular processes that underpin AD genetic risk related reductions in CBF that could be targeted decades prior to the onset of neurodegeneration.

Late-onset Alzheimer disease (LOAD), the most common form of dementia among older adults, is a neurodegenerative disease characterized by brain amyloid-{beta} (A{beta}) plaque deposition and neurofibrillary tangles. The causes of LOAD are not known but several recent lines of evidence implicate the adaptive immune system. Here, we sought to characterize somatic T-cell receptor (TCR) sequence diversity profiles and class I and II human leukocyte antigen (HLA) alleles from DNA extracted from peripheral tissues from Midwestern Amish participating in longitudinal studies of aging. We immunosequenced the TCR beta chain from genomic DNA of 72 Midwestern Amish, including participants with clinically diagnosed LOAD (n=6), mild cognitive impairment (MCI; n=16), cognitive impairment but not AD (CINAD; n=3), and 35 cognitively unaffected. TCR sequence diversity by cognitive status was examined using a variety of metrics, and tests of association were performed between cognitive status and HLA alleles. For a subset of participants, plasma biomarkers for LOAD pathogenesis were available to evaluate TCR sequence diversity by cognitive status. TCR sequence diversity measured as Simpsons clonality was lower among LOAD+MCI compared with non-LOAD, but these differences were not independent of age. Relatively few clonotypes (exact nucleotide sequences) were shared across participants; of those few shared include the Epstein Barr virus associated clonotype. HLA-A*03:01 and several HLA-DRB1 alleles were under-represented among LOAD+MCI participants compared with cognitively unaffected participants, but these associations were no longer significant in adjusted analyses. Among LOAD+MCI participants with plasma biomarkers, increased p-tau181 was associated decreased TCR sequence diversity, and the association was independent of age. In this limited Midwestern Amish sample, the observed TCR diversity associations are consistent with the involvement of the adaptive immune system in LOAD.

As individuals get older, the structural integrity of brain regions becomes progressively diminished. Neurotrophic function might aid in preventing such losses through increased synaptogenesis and neurogenesis, particularly in the hippocampus, a brain structure relevant for cognitive function. However, the carriage of certain genetic alleles for genes involved in neurotrophic function might restrain the effectiveness of neurotrophin signalling, hindering neuroprotection. Yet, research on the contribution of single nucleotide polymorphisms (SNPs) within genes coding for neurotrophins and their receptors to hippocampal volumes is scarce, with the exception of rs6265 within the brain-derived neurotrophic factor gene. Therefore, the aim of this study was to identify SNPs within genes involved neurotrophic function that are associated with hippocampal volume in a sample of 23,776 cognitively normal older adults from the UK Biobank. We found that, in individuals older than 50, homozygote carriage of the major alleles rs4839435-A within nerve growth factor gene and rs56405676-T within the neurotrophic receptor tyrosine kinase 2 gene, were associated with increase hippocampal volumes, compared to carriage of 1 or 2 copies of the minor alleles. However, only rs56405676-T was significantly associated with greater hippocampal volumes in individuals older than 60. Hence this study might serve to identify populations at higher risk of hippocampal attrition and cognitive decline.

Robust evidence points to mnemonic deficits in older adults related to dedifferentiated, i.e., less distinct, neural responses during memory encoding. However, less is known about retrieval-related dedifferentiation and its role in age-related memory decline. In this study, younger and older adults were scanned both while incidentally learning face and house stimuli and while completing a surprise recognition memory test. Using pattern similarity searchlight analyses, we looked for indicators of neural dedifferentiation during retrieval and asked whether this might explain interindividual differences in memory performance. Our findings revealed age-related reductions in neural distinctiveness during memory retrieval as well as in encoding-retrieval reinstatement in visual processing regions. We further demonstrated that the degree to which patterns elicited during encoding were reinstated during retrieval tracked variability in memory performance better than retrieval-related distinctiveness only. All in all, we contribute to meager existing evidence for age-related neural dedifferentiation during memory retrieval. We propose that the recognition task (as opposed to a cued recall task) may have revealed impairment in perceptual processing in older adults, leading to particularly widespread age differences in neural distinctiveness. We additionally provide support for the idea that well-defined reactivation of encoding patterns plays a major role in successful memory retrieval.

INTRODUCTIONBoth Alzheimers disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. METHODSWe compute heritability in five large independent cohorts (N=7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set. RESULTSSNP-based heritability of Alzheimers disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD=8%] on average when the APOE region is excluded and an additional 1% [SD=3%] when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts. CONCLUSIONThe heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes. Author SummaryEstimates of heritability in Alzheimers disease, the proportion of phenotypic variance explained by genetics, are very varied across different studies, therefore, the amount of missing heritability not yet captured by current genome-wide association studies is debated. We investigate this in five independent cohorts, provide estimates based on these cohorts and detail necessary suggestions to accurately calculate heritability in age-related disorders. We also confirm the importance of microglia relevant genetic markers in Alzheimers disease. This manuscript provides suggestions for other researchers computing heritability in late-onset disorders and the microglia gene-set used in this study will be published alongside this manuscript and made available to other researchers. The correct assessment of disease heritability will aid in better understanding the amount of missing heritability in Alzheimers disease.

Prior fMRI findings in young adults indicate that recollection-sensitive neural regions dissociate according to the time courses of their respective recollection effects. Here, we examined whether such dissociations are also evident in older adults. Young and older participants encoded a series of word-object image pairs, judging which of the denoted objects was the smaller. At test, participants first judged whether a test word was old or new. For items judged old, they were required to recall the associated image and hold it in mind across a variable delay period. A post-delay cue denoted which of three judgments should be made on the retrieved image. Older adults demonstrated significantly lower associative memory performance than young adults. Replicating prior findings, transient recollection effects were identified in the left hippocampus, medial prefrontal cortex and posterior cingulate, while sustained effects were widespread across left lateral cortex and were also evident in the bilateral striatum. With the exception of those in the left insula, all effects were age-invariant. These findings add to the evidence that recollection-related BOLD effects in different neural regions can be temporally dissociated. Additionally, the findings suggest that both transient and sustained recollection effects are largely stable across much of the healthy adult lifespan.

Amyloid-{beta} (A{beta}) and tau pathology begin accumulating decades before clinical symptoms and are influenced by APOE {varepsilon}4, a key genetic risk factor for Alzheimers disease (AD). Although the presence of A{beta}, tau, and APOE {varepsilon}4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9{+/-}5.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. A{beta} was measured using CSF A{beta}42/A{beta}40 or Florbetaben-PET imaging and tau was measured using CSF pTau181. Hippocampal univariate activity and cortical reinstatement - that is, reinstatement of patterns of neocortical activity that were present during memory encoding - were measured during successful memory retrieval. Analyses revealed that APOE {varepsilon}4 was independently associated with greater A{beta} and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by APOE {varepsilon}4. Among APOE {varepsilon}4 non-carriers, A{beta} burden was linked to a pattern of hippocampal hyperactivity. Among APOE {varepsilon}4 carriers, CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of APOE {varepsilon}4 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD. Significance StatementHippocampus-dependent cortical reinstatement is a critical mechanism supporting episodic remembering that contributes to individual differences in memory performance in older adults. However, the contribution of early Alzheimers disease (AD) pathology to variability in this mechanism is unknown. We demonstrate that associations of AD biomarkers with hippocampal activity and cortical reinstatement are moderated by APOE {varepsilon}4 in cognitively unimpaired older adults. Amyloid-{beta}-related hyperactivity was observed in the hippocampus among APOE {varepsilon}4 non-carriers, while CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among APOE {varepsilon}4 carriers. Our findings highlight synergistic effects of APOE and AD pathology on brain function and identify candidate mechanisms that may underlie increased risk of memory impairment in preclinical AD.

INTRODUCTIONComplex perceptual discrimination is supported by tau-vulnerable regions of the medial temporal lobe; notably the perirhinal cortex. This research tests whether there is a gene-dose effect of Apolipoprotein e4 on perceptual discrimination in mid-life. METHODS313 adults (45-65 years; grouped by APOE e4 gene-dose (142 APOE33, 135 APOE34, 36 APOE44)) completed a Greebles odd-one-out task. RESULTSAPOE44 carriers were significantly less accurate in their perceptual judgements than APOE33 and APOE34 individuals. There was a significant Age x APOE e4 gene-dose interaction in response speed, with the slope of age-related slowing increasing stepwise with the number of e4 alleles carried. Estimates suggest high-risk individuals are quicker than the APOE33 control group until age 54, but slower thereafter. DISCUSSIONPerceptual disadvantages specific to APOE44 individuals suggest this high-risk group show compromised MTL-function by mid-life, potentially through accelerated tau-aggregation. Task performance in APOE34 carriers is relatively preserved across the studied age range. Research in ContextO_LISystematic review: A review of the literature (e.g., PubMed; Google Scholar databases) revealed perceptual discrimination is impaired in the mild to moderate stages of Alzheimers Disease. No prior study, however, tests for an effect of APOE e4 gene-dose in healthy adulthood. C_LIO_LIInterpretation: Homozygous carriers of an APOE e4 genetic risk variant show perceptual disadvantages in mid-life. This may possibly reflect compromised MTL-function in this group, consistent with the theory perceptual discrimination will be vulnerable to early transentorhinal tau-accumulation. There is limited evidence of impairment in individuals carrying one copy of APOE e4 in mid-life. C_LIO_LIFuture directions: Whether transentorhinal and hippocampal tau mediates the relationship between APOE e4 gene-dose and perceptual discrimination remains to be established. Future research may also explore the utility of perceptual discrimination tasks in clinical trials targeting the preclinical stages of Alzheimers Disease. C_LI

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSVerbal memory tests like the Reys Auditory Learning Test (RAVLT) are widely used in Alzheimers disease assessments without consideration of females well-known advantages in verbal memory. This study explores if this form of cognitive reserve masks symptoms and delays diagnosis in females. METHODSWe employed a retrospective longitudinal cohort design (ADNI, PREVENT-AD) to model Immediate Recall subcomponents on the RAVLT over time in amyloid negative (A{beta}-) cognitively normal participants versus A{beta}+ participants that progressed to AD dementia. RESULTSOur Bayesian model successfully identified the inflection point where cognition deviates from normal onto the AD dementia trajectory. The timing of decline onset differed significantly across sexes, with A{beta}+ females maintaining normal cognition longer than A{beta}+ males. Among individuals with AD dementia, females experienced a steeper annual decline than males. DISCUSSIONDelayed onset of decline suggests that females preserve cognition despite neuropathology accumulation. This masked period represents a window for earlier detection and timely intervention before irreversible neurodegeneration. Research in ContextO_LISystematic review: The authors reviewed the literature from PubMed and Elsevier to identify verbal memory as a core feature in the Alzheimers Disease discourse. Our critical appraisal was complemented with meetings with expert neuropsychologists and neuroinformaticians. C_LIO_LIInterpretations: We find that females have superior performance on Reys Auditory Learning Test (RAVLT) Immediate Recall, females maintain performance for longer than males before being diagnosed with Alzheimers Disease, and once diagnosed, they decline faster than males. These findings underscore the importance of conducting Alzheimers Disease assessments with considerations for sex differences. C_LIO_LIFuture directions: We aim to continue the investigation of cognitive reserve in females in the context of the Amyloid, Tau and Neurodegeneration (ANT) framework. Considering the early stage of disease is of interest given that our results show the appearance of cognitive symptoms many years before official dementia diagnosis. C_LI Highlights- In cognitively healthy amyloid negative participants, females outperform males on the Reys Auditory Learning Test (RAVLT). - In the amyloid positive participants, females maintain normal verbal memory for 2.7 years longer than males. - After divergence from cognitive normality, females experience approximately a 25-50% steeper cognitive decline compared to males. - Our findings call attention to the female verbal memory advantage as an influential form of cognitive reserve that requires diagnostic consideration.

Sex differences in Alzheimers disease (AD) risk and progression are increasingly recognized, with females exhibiting higher global prevalence rates. Yet it remains unclear how genetic and biomarker indicators of Alzheimers risk, such as the apolipoprotein E-{varepsilon}4 (APOE4) allele and amyloid burden, relate to sex differences in brain and cognitive health during the preclinical stage. Using established normative models trained on ~58,000 healthy participants, we computed regional z-scores from T1-weighted MRI scans in 372 cognitively normal participants from the Insight 46 cohort. Scans were acquired at two timepoints, approximately three years apart, beginning at age 70. Regions with z-scores below -1.96 were classified as brain-structure outliers and summarized as total outlier count (tOC). We used linear mixed-effects models to examine how sex, age, and AD risk (APOE4 status and amyloid burden) relate to tOC and cognitive outcomes measured by Preclinical Alzheimer Cognitive Composite (PACC) scores. Both cross-sectional associations and longitudinal changes in tOC and PACC scores were examined, and we tested whether the effects of APOE4 status and amyloid burden on brain and cognitive measures differed by sex. Cross-sectional analyses showed that males had greater tOC than females at younger ages. At timepoint 1, spatial maps showed more regions with outliers in males, though high outlier proportions were limited to occipital areas. By timepoint 2, group differences became more spatially distinct, with males and females showing deviations in different regions. Longitudinally, older males exhibited steeper increases in tOC over time compared to females. Females showed higher PACC scores overall, while no sex differences were observed in cognitive change over time. Greater tOC and amyloid burden were both associated with poorer cognitive outcomes, with the strongest association observed in female APOE4 carriers. However, we found no evidence that AD risk influenced age-related changes in tOC or cognition over time. These findings highlight the complex interplay between sex, age, and AD risk in shaping brain structure and cognition in later life. Some of the observed patterns may reflect emerging vulnerability not yet captured by short-term longitudinal change, underscoring the importance of continued observation. In conclusion, normative modelling provides a valuable approach for detecting subtle variation in brain and cognitive aging across risk groups.