Benejam et al. Alzheimer’s Research & Therapy (2022) 14:123 https://doi.org/10.1186/s13195-022-01064-x RESEARCH Open Access Neural correlates of episodic memory in adults with Down syndrome and Alzheimer’s disease Bessy Benejam1†, Mateus Rozalem Aranha2†, Laura Videla1,2,3, Concepción Padilla2, Silvia Valldeneu2, Susana Fernández1, Miren Altuna2,3, Maria Carmona‑Iragui1,2,3, Isabel Barroeta2,3, Maria Florencia Iulita2,3, Víctor Montal2,3, Jordi Pegueroles2,3, Alexandre Bejanin2,3, Sandra Giménez4, Sofía González‑Ortiz5, Sebastián Videla6,7, David Bartrés‑Faz8, Daniel Alcolea2,3, Rafael Blesa2,3, Alberto Lleó2,3 and Juan Fortea1,2,3*    Abstract Background: Adults with Down syndrome are at an ultra-high risk of developing early-onset Alzheimer’s disease. Episodic memory deficits are one of the earliest signs of the disease, but their association with regional brain atrophy in the population with Down syndrome has not been explored. We aimed to investigate the neuroanatomical cor‑ relates of episodic memory in adults with Down syndrome and symptomatic Alzheimer’s disease. Methods: Single-center, cross-sectional study. A total of 139 adults with Down syndrome (85 asymptomatic and 54 with symptomatic Alzheimer’s disease) were included in the study (mean age 43.6 ± 10.9 years, 46% female). Epi‑ sodic memory was assessed using the modified Cued Recall Test. Immediate (trial 1 free immediate recall, trial 3 free immediate recall, total free immediate recall score, and total immediate score) and delayed scores (free delayed recall score and total delayed score) were examined. Cortical thickness from magnetic resonance imaging was determined with surface-based morphometry using the FreeSurfer 6.0 software package. The clusters of reduced cortical thick‑ ness were compared between symptomatic and asymptomatic participants to create a cortical atrophy map. Then, the correlation between cortical thickness and the modified Cued Recall Test subscores were separately assessed in symptomatic and asymptomatic subjects, controlling for age, sex, and severity of intellectual disability. Results: Compared with asymptomatic participants, those with symptomatic Alzheimer’s disease showed a pattern of cortical atrophy in posterior parieto-temporo-occipital cortices. In symptomatic subjects, trial 1 immediate free recall significantly correlated with cortical atrophy in lateral prefrontal regions. Trial 3 free immediate recall and total free immediate recall were associated with the most widespread cortical atrophy. Total immediate score was related to posterior cortical atrophy, including lateral parietal and temporal cortex, posterior cingulate cortex, precuneus, and medial temporal lobe areas. Delayed memory scores were associated with cortical atrophy in temporoparietal and † Bessy Benejam and Mateus Rozalem Aranha have equally contributed to this manuscript. *Correspondence: jfortea@santpau.cat 2 Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau-Universitat Autònoma de Barcelona, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Conclusions: Different episodic memory measures were associated with cortical atrophy in specific brain regions in adults with Down syndrome and Alzheimer’s disease. These results overlap with those described in sporadic Alzhei‑ mer’s disease and further support the similarities between Down syndrome-associated Alzheimer’s disease and that in the general population. Keywords: Down syndrome, Alzheimer’s disease, Dementia, Episodic memory, MRI, Cortical thickness Background atrophy in patients with mild AD. Specifically, encoding Down syndrome (DS) is the most frequent genetic has been associated with atrophy in parietal and tem- form of intellectual disability [1] and is associated to an poral regions, storage with atrophy in entorhinal and increased risk of developing early Alzheimer’s disease parahippocampal regions, and retrieval with atrophy (AD) dementia due to the presence of an extra copy of in a widespread network encompassing frontal regions the amyloid β precursor protein gene, which is coded [13]. Similarly, Wolk et al. investigated the relationship on chromosome 21, and is thus overexpressed in people between performance on different stages of the Rey Audi- with DS [2]. tory Verbal Learning Test (RAVLT), a verbal episodic Episodic memory refers to the ability to learn, store, and memory test, and structural brain measures in patients retrieve information about unique personal experiences with mild AD from the general population, including that occur in daily life [3]. Episodic memory impairment immediate and delayed memory recall [14]. This study is the hallmark symptom of typical Alzheimer’s disease also found dissociable relationships between regional (AD) in the general population and has been associated brain atrophy and different aspects of memory function, with early atrophy of medial temporal lobe structures indicating that different cognitive processes support dif- [4]. As the disease progresses, AD pathology spreads to ferent stages of episodic memory performance. other cortical regions, including ventral and lateral tem- In DS, episodic memory has been evaluated using poral cortex, followed by parietal and frontal cortices [4, adapted tests such as the modified Cued Recall Test 5], affecting other cognitive domains. In DS, neurode- (mCRT), which has demonstrated to be useful to detect generative changes due to AD follow a similar pattern as memory decline due to early-stage AD [15] and, more those described in sporadic AD, although it occurs at a recently, for the diagnosis of prodromal AD [16]. The younger age [6–8]. Early longitudinal studies suggested mCRT has emerged as a promising cognitive indicator of executive dysfunction and behavioral and psychological transition to the preclinical and prodromal stage of AD symptoms of dementia as commonly observed symp- in subjects with DS [11]. Furthermore, poor performance toms during the early stages of AD in DS [9], although on this episodic memory test has recently been related to the identification of imaging and fluid biomarkers in the white matter degeneration prior to the onset of dementia past 5 years has provided new opportunities to character- in adults with DS [17]. The association between regional ize the sequence of cognitive decline during the preclini- cortical atrophy and different stages of episodic memory cal and prodromal stages of the disease in this population performance in patients with DS and symptomatic AD [10]. Recent research now indicates that individuals with has not yet been studied. DS have a similar clinical presentation to that of people The aim of this study was to investigate the neural cor- with sporadic or autosomal dominant AD, more specifi- relates of different episodic memory processes measured cally, declines in episodic memory and attention meas- with the mCRT in a large cohort of adults with DS, with ures early in the course of the disease [11, 12]. and without symptomatic AD. Understanding the ana- Although medial temporal lobe regions play a central tomic basis of the processes underlying episodic memory role in episodic memory, other cortical regions are also has potential practical implications, as it may facilitate necessary to accurately remember new information. the integration of clinical and radiological information, More specifically, three different processes or stages have helping increase the diagnostic accuracy of AD in this been described in episodic memory that are sustained by population. different brain networks: encoding, retrieval, and storage [13]. In the general population, these memory processes Methods have been assessed with the Free and Cued Selective Study design and participants Reminding Test (FCSRT) through different subscores In this single-center cross-sectional study, adults and have been associated with different patterns of brain with DS aged 18 years or older were recruited from a Benejam et al. Alzheimer’s Research & Therapy (2022) 14:123 Page 3 of 10 population-based health plan designed to screen for AD or profound intellectual disability, based on caregiver’s dementia. This health plan includes an annual neuro- reports of the individuals’ best-ever level of functioning. logical and neuropsychological assessment, undertaken at the Alzheimer-Down Unit from the Catalan Down Assessment of episodic memory Syndrome Foundation and Hospital of Sant Pau, in Bar- The mCRT is an adapted test to assess episodic mem- celona, Spain. Individuals who are also interested in par- ory in people with intellectual disability [15]. This test ticipating in research studies are included in the Down was selected because it is based on semantic cueing, Alzheimer Barcelona Neuroimaging Initiative (DABNI) which allows controlled encoding processes and facili- cohort. The aim of the DABNI project is to improve our tates retrieval from stored information. The mCRT was understanding of the natural history and mechanisms administered according to the procedure described by that drive AD in DS. It includes multimodal biomarker Devenny et al. [15]. Briefly, participants are asked to assessments, comprising magnetic resonance imaging memorize 12 stimuli (black-and-white line drawings of (MRI), positron emission tomography, lumbar puncture, objects representing a distinct semantic category) pre- sleep studies, and blood and genetic analyses. sented on three, 4-item cards. The test consists of three We included adults with DS (mild or moderate intel- trials of free and cued recall performed immediately after lectual disability) with available MRI and a complete the learning phase to compute a total free immediate neuropsychological assessment. Patients showing any recall score (FIRS) and a total immediate score (FIRS + psychiatric or medical disorder that could affect cog- cued recall; TIS). The maximum score for both measures nition and/or functionality were excluded. We also is 36. The same recall procedure (free and cued) is done excluded those patients not able to complete the mCRT after a 20-min delay to compute a free delayed recall due to severe cognitive decline or due to severe or pro- score (FDRS) and a total delayed score (FDRS + cued found intellectual disability [16]. recall; TDS). The maximum score for both delayed scores The study was approved by the Sant Pau Ethics Com- is 12. In the general population, some authors found that mittee following the standards for medical research in early immediate learning trials rely on different brain humans recommended by the Declaration of Helsinki regions than later immediate learning trials [14]; there- and reported to the Ministry of Justice, according to fore, we also analyzed the data for trial 1 free immediate the Spanish law for research in people with intellectual recall (T1) and trial 3 free immediate recall (T3), repre- disabilities. All participants or their legally authorized senting early and late immediate learning, respectively. representative gave written informed consent before enrollment. Diagnostic categories As in previous studies [6, 20], participants with DS were classified by the neurologists and neuropsychologists Neuropsychological assessment who assessed them in a consensus meeting into the fol- Caregivers completed a semi-structured adapted health lowing groups: asymptomatic, in those with no clinical questionnaire, the Cambridge Examination for Mental or neuropsychological suspicion of AD; prodromal AD, Disorders of Older People with Down syndrome and oth- in those who had cognitive decline, but symptoms did ers with intellectual disabilities (CAMDEX-DS), aimed to not fulfill criteria for dementia; or AD dementia, in those evaluate cognitive decline in people with intellectual dis- who had cognitive decline that significantly interfered in ability [18]. subject’s activities of daily living. In this study, partici- The neuropsychological test battery included the Cam- pants were divided into symptomatic (including prodro- bridge Cognitive Examination for Older Adults with mal AD and AD dementia) and asymptomatic groups. Down’s syndrome (CAMCOG-DS), a neuropsycho- logical test battery included in the CAMDEX-DS, com- prising subscales for the assessment of the following Structural MRI cognitive domains: orientation, language, memory, atten- All participants underwent MRI in a 3-T Philips Achieva tion, praxis, abstract thinking, and perception. For the (Philips Healthcare) or a 3-T Siemens Prisma (Siemens assessment of episodic memory, the mCRT was used (see Healthcare) MR scanner (protocols detailed in the sup- below). plements). Cortical thickness was assessed with surface- based analysis in FreeSurfer 6.0 (https://​surfer.​nmr.​mgh.​ harva​rd.​edu/) using an automated standard pipeline Level of intellectual disability detailed elsewhere [21–23]. Briefly, this pipeline normal- The level of intellectual disability was categorized accord- izes T1-weighted images to a standard space (MNI305), ing to the Diagnostic and Statistical Manual of Mental removes non-brain tissue, classifies each brain voxel Disorders, Fifth Edition [19] as mild, moderate, severe, as gray of white matter, and defines interfaces between Benejam et al. Alzheimer’s Research & Therapy (2022) 14:123 Page 4 of 10 gray and white matter (GM and WM, respectively) and asymptomatic and symptomatic participants with QDEC. between GM and cerebrospinal fluid (CSF), generat- To this purpose, a general linear model was applied, con- ing WM and pial surfaces, respectively. To correct for trolling for sex, age, and degree of intellectual disability. eventual defects on these surfaces, manual edits were The results were corrected for multiple comparisons performed when needed. The cortical thickness is given using Monte Carlo null-Z simulation (cluster analysis) as by the distance between WM and pial surfaces at each implemented in QDEC (p corrected = 0.05) [24]. point. Finally, each surface was smoothed with a Gauss- ian filter of 15mm before statistical analysis. Results Demographic characteristics Statistical analysis Between May 1, 2013, and Jun 7, 2021, 148 participants Demographic data met the inclusion criteria and were included in this study Differences between asymptomatic and symptomatic (see study flowchart in Supplementary Fig. 1). From this subjects in demographic characteristics and between the group, 9 participants with scan artifacts impairing auto- episodic memory scores were assessed using Student’s mated image processing had to be excluded. From the t-test. The chi-squared test was used for testing relation- remaining sample (139 participants), 85 were asymp- ships on categorical variables (sex and level of intellectual tomatic and 54 met criteria for prodromal AD or AD disability). A p-value of ≤ 0.05 was considered signifi- dementia (28 and 26 subjects, respectively. These sub- cant. The statistical analyses were performed using IBM jects constituted the symptomatic AD group). SPSS Statistics Software (version 22). Demographic characteristics and episodic mem- ory scores for these groups are shown in Table 1. As Neuroimaging data expected, symptomatic participants were significantly Initially, cortical thickness was compared between older and had lower performance on all mCRT scores asymptomatic and symptomatic individuals with DS than the asymptomatic participants (p < 0.001). There using FreeSurfer’s QDEC (Query, Design, Estimate, Con- were no differences in sex (p = 0.46) or severity of intel- trast) interface in order to identify regions where cortical lectual disability (p = 0.29) between the asymptomatic thickness is significantly reduced in symptomatic subjects and symptomatic groups. and create a cortical atrophy map. Sex, age, and degree of intellectual disability were included as covariates. We Pattern of cortical atrophy in participants with DS then performed correlation analyses between the differ- and symptomatic AD ent memory performance scores and cortical thickness Compared with asymptomatic adults with DS, indi- using a whole-brain vertex-wise analysis separately in viduals with DS and symptomatic AD showed cortical Table 1 Demographic characteristics and episodic memory scores All participants Asymptomatic Symptomatic p-values (N = 139) (N = 85) (N = 54) Age (mean, sd) 43.6 (10.9) 38.5 (10.1) 52.2 (4.6) <0.001 Female sex, n (%) 64 (46) 37 (43.5) 27 (50) 0.456 Severity of ID, n (%) 0.288 Mild 46 (33.1) 31 (36.5) 15 (27.8) Moderate 93 (66.9) 54 (63.5) 39 (72.2) Time between MRI and mCRT, days (mean, sd) 108.2 (81.4) 116.2 (79.0) 95.5 (84.2) 0.088 mCRT scores (mean, sd) Trial 1 free recall (0–12) 4.3 (2.3) 5.4 (1.9) 2.5 (1.7) <0.001 Trial 3 free recall (0–12) 5.8 (2.9) 7.7 (1.7) 2.7 (2.6) <0.001 Free immediate recall score (0–36) 15.3 (7.4) 19.8 (4.7) 7.7 (5.3) <0.001 Total immediate score (0–36) 29.5 (9.3) 35 (1.6) 20.7 (9.9) <0.001 Free delayed recall score (0–12) 5 (3.5) 6.8 (2.7) 1.7 (2.4) <0.001 Total delayed score (0–12) 9.7 (3.3) 11.5 (1.0) 6.3 (3.6) <0.001 p values are given for comparison between asymptomatic and symptomatic subjects. Age refers to the age recorded on the day of the mCRT administration. Brackets next to each episodic memory measure reflect the total possible range of scores ID Intellectual disability, mCRT​ Modified Cued Recall Test Benejam et al. Alzheimer’s Research & Therapy (2022) 14:123 Page 5 of 10 atrophy in the temporoparietal, precuneus-posterior cin- In asymptomatic participants, no clusters of significant gulate, and occipital areas (Fig. 1). association between immediate memory scores and cor- tical thickness were observed (Supplementary Fig. 2). Cortical thickness and memory performance Immediate recall Delayed recall Figure 2 shows the correlation analyses between corti- Figure 3 shows the correlation between cortical thickness cal thickness and the immediate memory scores (T1, T3, and delayed memory scores (FDRS and TDS) in symp- FIRS, and TIS) in symptomatic participants. T1 scores tomatic participants. FDRS was associated with cortical showed a significantly positive relationship with cortical thickness in areas mainly localized in anterior lateral and thickness in the lateral prefrontal regions of both hemi- medial temporal regions, including both temporal poles, spheres. Performance on T3 correlated positively with left entorhinal cortex, and right lateral superior and mid- cortical thickness in a more widespread network encom- dle temporal gyri. We also found significant associations passing lateral regions in frontal, temporal, parietal, and with cortical thickness in both inferior frontal gyri and in occipital lobes, bilaterally, with the most significant clus- left postcentral and supramarginal gyri (p ≤ 0.05). ters located in the left middle frontal, inferior frontal, TDS was significantly associated with cortical thick- supramarginal, and lingual gyri, and in the right temporal ness in medial and lateral temporal lobe structures of pole and superior frontal gyrus. T3 in addition also cor- both hemispheres. Clusters of significant correlation related with a small cluster located in the right parahip- were also found in both supramarginal gyri, in the medial pocampal cortex. face of both superior frontal gyri, and in the left posterior The distribution of the clusters with significant asso- cingulate gyrus (p≤0.05). ciation between cortical thickness and FIRS resembled We did not find clusters of significant correlations that observed for T3, but with more widespread cortical between cortical thickness and delayed memory meas- atrophy also involving the right inferior frontal gyrus and ures in asymptomatic participants (Supplementary superior parietal lobule, as well as the left posterior cin- Fig. 2). gulate gyrus and precuneus. TIS was mostly associated with cortical thickness in Discussion bilateral parieto-temporal regions, involving both pre- To our knowledge, this is the first study that investi- cuneus and posterior cingulate gyri, and the right medial gates the neuroanatomical correlates of different pro- temporal lobe structures, namely the entorhinal and par- cesses involved in episodic memory in a cohort of adults ahippocampal cortex (with p ≤ 0.05) (Fig. 2). with DS. Using structural MRI and an adapted episodic Fig. 1 Pattern of cortical atrophy in symptomatic DS compared to asymptomatic DS participants. The clusters in blue-cyan scale represent the brain regions of statistically significant cortical atrophy in subjects with symptomatic Alzheimer’s disease (AD) compared to asymptomatic participants, after correction for multiple comparisons (threshold for significance p corrected = 0.05) Benejam et al. Alzheimer’s Research & Therapy (2022) 14:123 Page 6 of 10 Fig. 2 Correlation analyses between cortical thickness and immediate memory scores in symptomatic participants. The clusters in red-yellow scale represent the brain regions where each score was significantly related to cortical thickness after correction for multiple comparisons (threshold for significance p corrected = 0.05). Scatter plots on the right show the correlation between each score and the cortical thickness at the most significant vertex. CTh, cortical thickness (in millimeters) Fig. 3 Correlation analyses between cortical thickness and delayed memory scores in symptomatic participants. The clusters in red-yellow scale represent the brain regions where each score was significantly related to cortical thickness after correction for multiple comparisons (threshold for significance p corrected = 0.05). Scatter plots on the right show the correlation between each score and the cortical thickness at the most significant vertex. CTh, cortical thickness (in millimeters) Benejam et al. Alzheimer’s Research & Therapy (2022) 14:123 Page 7 of 10 memory test, the mCRT, we found different correlations networks, are necessary for successful episodic memory between the subtests assessing the different episodic [13, 14, 35, 36]. We found that performance on T1 of the memory processes and cortical thickness in sympto- mCRT was associated with cortical thickness in frontal matic AD, suggesting that different anatomical regions lobe regions, but not in medial temporal lobe structures play unique roles at different stages of episodic memory in subjects with symptomatic AD, thus indicating that processing. initial encoding was more dependent on regions support- Adults with DS and symptomatic AD showed a pattern ing cognitive functions such as attention, working mem- of cortical atrophy in lateral parieto-temporo-occipital ory, or executive functions. Ventrolateral and dorsolateral cortices and in the posterior cingulate and precuneus. prefrontal cortex have been described to implement con- This pattern of widespread posterior cortical thinning trol processes that support memory encoding (e.g., selec- has been previously described in amyloid-positive indi- tion processes that direct attention toward goal-relevant viduals with DS [25] and is very similar to that observed information or organizational processes necessary for in sporadic AD [26]. optimal memory encoding, respectively) [37, 38]. Our Relationships in symptomatic individuals are detailed results are in line with those reported by Wolk et al. in hereafter. The correlations between episodic memory sporadic AD, who also found a lack of influence of medial measures and cortical thickness extended well beyond temporal structures during early list learning trials in the medial temporal lobe structures. The different mCRT patients with mild AD from the general population [14]. subscores were associated with cortical atrophy in dif- The temporal pole consistently appeared to be related ferent regions. T1 immediate free recall, a score that to immediate and delayed memory measures (with the reflects initial encoding processes [13], mainly involved exception of T1 immediate recall) in our study. In this frontal lobe areas. FIRS, a score used to assess immediate sense, functional neuroimaging studies have related the retrieval [13], was associated with a widespread cortical anterior temporal lobes to semantic processing (mental network encompassing lateral frontal, parietal, temporal, representations of the meaning of words, objects, peo- and occipital regions, bilaterally, while TIS, which reflects ple, and factual information about the world) [39, 40]. immediate storage [13], was associated with more pos- The semantic organization of the information that has terior cortical atrophy, including regions in the lateral to be encoded allows for a deeper processing and thus parietal, temporal and occipital cortices, precuneus, pos- facilitates posterior retrieval processes. Our results are terior cingulate cortex, and medial temporal lobe corti- again consistent with previous studies relating the atro- ces. In contrast to the immediate memory trials, delayed phy of the temporal pole with poor immediate recall per- memory performance was related to a less distributed formance in patients with early-stage AD in the general pattern of cortical atrophy, predominantly involving lat- population [14, 35]. eral and medial temporal lobe regions. Importantly, these In addition, episodic memory performance (particu- associations were only seen in symptomatic participants larly T3, FIRS and TIS immediate recall scores, and TDS) and not in asymptomatic, possibly reflecting the smaller was related to cortical thickness in the lateral posterior dynamic range of the mCRT scores and the milder atro- parietal cortex (PPC). These areas have been implicated phy in asymptomatic individuals [16]. To our knowledge, in episodic memory retrieval because of their role in no other studies have related cortical thickness to differ- attentional processes (attention to internal representa- ent episodic memory measures in asymptomatic indi- tions). The dorsal PPC is implicated in the voluntary ori- viduals with DS. In the general population, some authors enting of attention to relevant stimuli based on retrieval have attempted to correlate FCSRT performance with goals (top-down attentional processes), while the ven- volumetric measures of the hippocampal formation or tral PPC responds to the detection of new behaviorally entorhinal cortex in healthy aging subjects, without find- relevant stimuli which are outside the focus of atten- ing significant associations [27, 28]. tion defined by the dorsal PPC (bottom-up attentional Episodic memory impairment is a hallmark symptom processes) [41, 42]. Moreover, inferior parietal regions of sporadic AD and DS-related AD during the early and (together with regions within the inferior frontal gyrus) middle stages of the disease [29–31] and has been tra- have been associated with the storage function of the ditionally associated with medial temporal lobe dam- phonological loop and the visuospatial sketchpad sup- age [32–34]. In the last decades, a growing number of porting speech-based and visuospatial working memory, neuroimaging studies have demonstrated that episodic respectively [43]. Working memory, which temporarily memory does not depend solely on medial temporal maintains and stores information, is crucial for the trans- structures. Several cognitive processes, like language, fer of information into a long-term store. Other regions working memory, semantic processing, attention, and also reported to be supportive of working memory are executive functions, which rely upon distinct brain the posterior superior temporal gyrus, the premotor Benejam et al. Alzheimer’s Research & Therapy (2022) 14:123 Page 8 of 10 cortex, and the dorsolateral prefrontal cortex [44], to be related to episodic memory in our study are in line regions found to be strongly associated with immediate with those previously described in sporadic AD. Our memory measures in our study. results thus reinforce the similarities between AD in DS Atrophy in medial temporal lobe (MTL) structures, in and sporadic AD. Third, our results also support the use particular the entorhinal and parahippocampal cortices, of the mCRT as a potential neuropsychological marker was found to be related to TIS and TDS. Low scores on for the diagnosis of AD in people with DS, and particu- both measures reflect storage deficits (immediate and larly the TIS and the TDS (measures reflecting stor- delayed storage, respectively). Many studies support the age deficits), as these scores correlated well with medial role of MTL regions in the acquisition and maintenance temporal lobe regions, areas considered to be the earliest of episodic memory [3, 13, 36]. The association between affected by AD neuropathology. TIS and atrophy of extrahippocampal MTL regions in the Our study has several strengths, including the large right hemisphere in our study is not in line with previ- sample size of subjects included in our study with symp- ous research using the FCSRT or the RAVLT in patients tomatic AD, as well as the fact that our participants come with sporadic AD [35, 36]. One possible explanation from a large population-based cohort of adults with DS. for these discrepancies could be the visual nature of the stimuli used in the present study, unlike the FCSRT used Limitations in the general population, which is based on the learn- We also acknowledge some limitations. First, this is a ing of verbal stimuli. Similarly, we found that immediate single-center study and did not include an age-matched and delayed recall measures were also associated with control group of euploid individuals to test the neurode- atrophy in occipital regions. Ventral occipito-temporal velopmental abnormalities. Thus, our results need to be regions have been related to visual object processing [45]. replicated in other cohorts to confirm the generalizabil- Poor performance on some mCRT measures, which is ity of our results. Second, as patients with prodromal AD based on the recall of familiar line drawings, could partly and AD dementia were analyzed together, it has not been be explained by damage to this visual processing pathway. possible to characterize AD in its earliest stages. Future Performance on the TIS, and to a lesser extent the studies should include a more homogeneous sample of TDS, was also associated with posteromedial regions, subjects with prodromal AD to better characterize the namely the precuneus and the posterior cingulate cor- early stages of AD in this population. tex. Recent functional imaging studies have suggested that memory function is subserved by a set of distrib- Conclusions uted networks which include the medial temporal lobe Our results provide new evidence about the neuroana- system and a set of cortical regions collectively referred tomical correlates of the episodic memory deficits in to as the default mode network (DMN). The regions of adults with DS and symptomatic AD that largely corre- the DMN include the anteromedial prefrontal cortex, the sponds with the findings described in sporadic AD. This posterior cingulate cortex, the precuneus, the angular study further supports the similarities of the AD patho- gyrus, and the medial temporal lobe [46]. Some authors physiological process in sporadic AD and in DS. have demonstrated that early amyloid deposition in spo- radic AD occurs in areas mainly located within the DMN [47] and that this network plays a key role orienting the Abbreviations AD: Alzheimer’s disease; CAMCOG-DS: Cambridge Cognitive Examination for focus of attention to stored representational knowledge Older Adults with Down’s syndrome; CAMDEX-DS: Cambridge Examination [48]. In DS subjects, recent research found that reduc- for Mental Disorders of Older People with Down syndrome and others with tions in DMN connectivity to posterior brain regions intellectual disabilities; CSF: Cerebrospinal fluid; DABNI: Down Alzheimer Barcelona Neuroimaging Initiative; DMN: Default mode network; DS: Down’s were linked to the presence of AD neuropathology in a syndrome; FCSRT: Free and Cued Selective Reminding Test; FDRS: Free delayed pattern substantially similar to that seen in sporadic AD recall score; FIRS: Free immediate recall score; GM: Gray matter; ID: Intellectual [49, 50], even in asymptomatic individuals. Nevertheless, disability; mCRT​: Modified Cued Recall Test; MRI: Magnetic resonance imag‑ ing; MTL: Medial temporal lobe; PPC: Posterior parietal cortex; QDEC: Query, the association between the effects of AD neuropathol- Design, Estimate, Contrast; RAVLT: Rey Auditory Verbal Learning Test; T1: Trial 1 ogy on the DMN and performance on episodic memory free immediate recall; T3: Trial 3 free immediate recall; TDS: Total delayed score; measures in the DS population has not been described. TIS: Total immediate score; WM: White matter. Our results have several implications. First, the pattern of cortical atrophy observed in individuals with DS and Supplementary Information AD in our study is remarkably similar to that described in The online version contains supplementary material available at https://​doi.​ org/​10.​1186/​s13195-​022-​01064-x. the general population with AD [26], indicating that AD in individuals with DS targets the same cortical regions Additional file 1: Supplementary Figure 1. Study flow chart. Descrip‑ affected in sporadic AD. Second, the cortical areas found tion of data: flow chart of included and excluded subjects. Footnote: ID, Benejam et al. Alzheimer’s Research & Therapy (2022) 14:123 Page 9 of 10 Competing interests intellectual disability; mCRT, modified Cued Recall Test; MRI, magnetic The authors declare that they have no competing interests. resonance imaging; OCD, obsessive compulsive disorder. Additional file 2. MRI acquisition protocols. Author details 1 Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Bar‑ Additional file 3: Supplementary Figure 2. Correlation analyses celona, Spain. 2 Memory Unit, Department of Neurology, Hospital de la Santa between cortical thickness and immediate and delayed memory scores Creu i Sant Pau - Biomedical Research Institute Sant Pau-Universitat Autònoma in asymptomatic participants. Legend: Brain regions where each score de Barcelona, Barcelona, Spain. 3 Center of Biomedical Investigation Network was significantly related to cortical thickness (threshold for significance p for Neurodegenerative Diseases, Madrid, Spain. 4 Multidisciplinary Sleep Unit, corrected = 0.05, after correction for multiple comparisons). No clusters Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. of significant correlation between cortical thickness and immediate or 5 Parc de Salut, Hospital del Mar, Barcelona, Spain. 6 Clinical Research Support delayed memory scores were observed in asymptomatic participants. Unit (HUB‑IDIBELL), Clinical Pharmacology Department, Bellvitge University Hospital, l’Hospitalet de Llobregat, Barcelona, Spain. 7 Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine Acknowledgements and Health Sciences, IDIBELL, University of Barcelona, l’Hospitalet de Llobregat, The authors would like to thank all the participants with Down’s syndrome, Barcelona, Spain. 8 Department of Medicine, Faculty of Medicine and Health their families, and their carers for their support of and dedication to this Sciences, Institute of neurosciences, University of Barcelona, and Institut research. We also acknowledge the Fundació Catalana Síndrome de Down for d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. global support, Tania Martínez and Cecilia Mota for administrative support, and Concepción Escolá and Diana Garzón for nursing handling. Received: 19 October 2021 Accepted: 19 August 2022 Authors’ contributions JF and BB designed the study. Acquisition of the data was performed by BB, MRA, LV, CP, SV, SF, MA, MCI, IB, VM, JP, SGO, and JF. BB, MRA, and JF performed the data analysis. BB, MRA, and JF interpreted the data and wrote the manu‑ script. All authors reviewed the full paper providing important intellectual References content and approved the final manuscript. 1. Ballard C, Mobley W, Hardy J, Williams G, Corbett A. Dementia in Down’s syndrome. Lancet Neurol. 2016;15:622–36. Funding 2. Wiseman FK, Al-Janabi T, Hardy J, Karmiloff-Smith A, Nizetic D, Tybulewicz This study was supported by the Fondo de Investigaciones Sanitario (FIS), VLJ, et al. A genetic cause of Alzheimer disease: mechanistic insights from Instituto de Salud Carlos III (PI14/01126, PI17/01019, and PI20/01473 to Juan Down syndrome. Nat Rev Neurosci. 2015;16:564–74. Fortea; PI13/01532 and PI16/01825 to Rafael Blesa; PI18/00335 to Maria Car‑ 3. Dickerson BC, Eichenbaum H. The episodic memory system: neurocir‑ mona-Iragui; INT19/00016 and PI18/00435 to Daniel Alcolea; and PI14/1561 cuitry and disorders. Neuropsychopharmacology. 2010;35:86–104. and PI17/01896 to Alberto Lleó) and the CIBERNED program (Program 1, 4. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topo‑ Alzheimer Disease to Alberto Lleó and SIGNAL study, www.​signa​lstudy.​ graphical and neuroanatomical distribution of neurofibrillary tangles es), partly jointly funded by Fondo Europeo de Desarrollo Regional, Unión and neuritic plaques in the cerebral cortex of patients with Alzheimer’s Europea, Una manera de hacer Europa. This work was also supported by the disease. Cerebral cortex (New York, NY : 1991). 1991;1:103–16. National Institutes of Health (NIA grants 1R01AG056850–01A1; R21AG056974 5. Braak H, Braak E. Neuropathological stageing of Alzheimer-related and R01AG061566 to Juan Fortea), Fundació La Marató de TV3 (20141210 changes. Acta Neuropathol. 1991;82:239–59. to Juan Fortea and 044412 to Rafael Blesa), Fundació Catalana Síndrome de 6. Fortea J, Vilaplana E, Carmona-Iragui M, Benejam B, Videla L, Barroeta I, Down, and Fundació Víctor Grífols i Lucas partially supported this work. This et al. Clinical and biomarker changes of Alzheimer’s disease in adults work was also supported by Generalitat de Catalunya (SLT006/17/00119 with Down syndrome: a cross-sectional study. Lancet (London, England). to Juan Fortea, SLT002/16/00408 to Alberto Lleó, and SLT006/17/00125 to 2020;395:1988–97. Daniel Alcolea) and a grant from the Fundació Bancaria La Caixa to Rafael 7. Annus T, Wilson LR, Hong YT, Acosta-Cabronero J, Fryer TD, Cardenas- Blesa. Horizon 21 Consortium is partly funded by Jérôme Lejeune Foundation Blanco A, et al. The pattern of amyloid accumulation in the brains of (clinical and trial outcome measures for dementia in individuals with Down adults with Down syndrome. Alzheimers Dement. 2016;12:538–45. syndrome). Maria Florencia Iulita acknowledges financial support from the 8. Neale N, Padilla C, Fonseca LM, Holland T, Zaman S. Neuroimaging and Jerome Lejeune Foundation. Dr Bejanin was supported by a Miguel Servet I other modalities to assess Alzheimer’s disease in Down syndrome. Neuro‑ grant (CP20/00038) from the Carlos III Health Institute. Image Clin. 2018;17:263–71. The article describes independent research, and the views expressed are 9. Lautarescu BA, Holland AJ, Zaman SH. The early presentation of dementia those of the authors and not necessarily those of the funders. The sponsors of in people with Down syndrome: a systematic review of longitudinal stud‑ the study did not take part in the design and conduct of the study; collection, ies. Neuropsychol Rev. 2017;27:31–45. management, analysis, and interpretation of the data; writing and review of 10. Fortea J, Zaman SH, Hartley S, Rafii MS, Head E, Carmona-Iragui M. the report; or the decision to submit the article for publication. Alzheimer’s disease associated with Down syndrome: a genetic form of dementia. Lancet Neurol. 2021;20:930-42. Availability of data and materials 11. 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A longitudinal study of brain anatomy changes pre‑ • support for research data, including large and complex data types ceding dementia in Down syndrome. NeuroImage Clin. 2018;18:160–6. 35. Putcha D, Brickhouse M, Wolk DA, Dickerson BC. Fractionating the • gold Open Access which fosters wider collaboration and increased citations Rey Auditory Verbal Learning Test: distinct roles of large-scale corti‑ • maximum visibility for your research: over 100M website views per year cal networks in prodromal Alzheimer’s disease. Neuropsychologia. 2019;129:83–92. At BMC, research is always in progress. 36. Sarazin M, Chauviré V, Gerardin E, Colliot O, Kinkingnéhun S, de Souza LC, et al. The amnestic syndrome of hippocampal type in Alzheimer’s disease: Learn more biomedcentral.com/submissions an MRI study. J Alzheimer’s Dis. 2010;22:285–94.