We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Out of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased Aβ levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a 10-fold increased AD risk. PLCG2 LoF carriers exhibit low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single nuclei RNAseq analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexin in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and increasing the Aβ levels and Tau phosphorylation in neurons.

Abstract Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer’s disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrate that these variants have significant association with Alzheimer’s disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE , coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation.

BACKGROUND:Cognitive frailty (CF), a condition with physical frailty and mild cognitive impairment (MCI) without dementia, is potentially reversible and linked to adverse outcomes. We aimed to investigate the impact of a multidomain lifestyle intervention on temporal dynamics of CF in older adults at risk of dementia. METHODS:In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), 1259 participants, aged 60-77, were randomized to a 2-year multidomain lifestyle intervention or standard health advice. Frailty was defined by the modified Fried phenotype, and MCI by the lowest quintile in the neuropsychological test battery z score. Having pre-frailty/frailty and MCI was classified as CF. Transition probabilities and predictiveness of CF by 4 different baseline groups (healthy, MCI, pre-frail/frail, CF) were examined using multinomial logistic regression. RESULTS:At baseline, 219 participants (18%) had CF. The risk for developing CF at 2 years was higher in the control group (risk ratio [RR], 1.88, p = .003). The intervention effect was not modified by baseline CF (p = .493). Reversal from CF to no-CF group was more likely in the intervention group, and progression to or persisting with CF was more likely in the control group. Compared with healthy participants (n = 401) at baseline, the MCI group (n = 244) had an RR of 5.10, pre-frail/frail (n = 336) of 3.06, and CF of 30.61 for having CF at 2 years, with no difference between MCI and pre-frail/frail groups (p = .116). CONCLUSIONS:The 2-year multidomain lifestyle intervention was effective in preventing and reversing CF. Participants with MCI or pre-frailty/frailty were both at increased risk for CF compared with healthy participants.

We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons.

INTRODUCTION:Brain magnetic resonance imaging (MRI) biomarkers for dementia exist, but little is known about their association with future frailty. We investigated whether baseline brain MRI findings associate with pre-frailty/frailty over 11 years. METHODS:One hundred twenty participants, aged 60 to 77 years, in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) had baseline MRI data. Frailty status (Fried phenotype) was measured at baseline, and at 2, 7, and 11 years. Risk of future pre-frailty/frailty per one standard deviation or one class greater volume/thickness/Fazekas score in baseline MRI was evaluated. RESULTS:Pre-frailty/frailty was not associated with MRI biomarkers at baseline. Smaller left hippocampal volume was associated with pre-frailty/frailty at 2 (p = 0.042) and 7 years (p = 0.017), and higher load of periventricular white matter hyperintensities (WMHs) at 2 years (p = 0.048), independently of baseline cognition. DISCUSSION:Smaller left hippocampal volume and higher periventricular WMH score in brain MRI may indicate future frailty risk. CLINICAL TRIAL REGISTRATION NUMBER:The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is registered at ClinicalTrials.gov (no. NCT01041989).

Age-related macular degeneration (AMD) is among the leading causes of vision loss. Factors increasing the risk of AMD include aging, smoking, cardiovascular diseases and heritability. Although melanin pigment is known to protect retinal homeostasis, the link between pigmentation-related genes and AMD is unclear. We investigated associations between 26 variations in six pigmentation-related genes and wet AMD risk in a Finnish population, followed by replication in the United Kingdom (UK), Hungarian and Polish cohorts, totaling 775 patients and 959 controls. Associations of genetic components with smoking and body mass index (BMI) were tested in the Finnish and UK cohorts. The functionality of candidate variants in human retinal pigment epithelial (RPE) cells was evaluated using gene promoter analysis and gene silencing.Non-coding variants, rs1407995 in the dopachrome tautomerase (DCT) intron and rs3212351 in the melanocortin-1 receptor (MC1R) promoter, were associated with wet AMD in the Finnish cohort. The variant rs3212351 disrupts a binding site for transcription factor MITF and reduces MC1R expression in RPE cells. Unlike in the Finnish cohort, the data regarding the MC1R variant suggested a protective association in the Polish cohort. The incidence of AMD increased with age in all cohorts. Smoking increased AMD risk in the cohorts studied. Sex and BMI showed no associations.These findings suggest that variations in DCT and MC1R genes known to affect skin and eye pigmentation may also play a role in development of wet AMD. The observed population differences may be related to variable pigmentation traits.

Background Frailty is a common geriatric syndrome associated with poor clinical outcomes. Effectiveness of lifestyle intervention programmes among frail older people has been examined earlier, but effects of interventions on prevention of frailty have been rarely studied. The aim of this study was to investigate to what extent the multidomain lifestyle intervention in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) affected changes in frailty status among older men and women at risk of cognitive disorders.Methods The 2-year multidomain lifestyle intervention trial including simultaneous nutritional counseling, physical exercise, cognitive training and social activity, and management of metabolic and vascular risk factors, was conducted among 1259 older people (mean age 68.9 years). A modified Fried’s frailty phenotype (weight loss, exhaustion, weakness, slowness, and low physical activity) was used to assess frailty at baseline and after the 2-year intervention. Participants with one or more components of the frailty phenotype were classified as pre-frail or frail. A multinomial regression model was applied to investigate efficacy of the intervention on frailty.Results We observed a favorable trend in reversing frailty among older men with the intervention. Pre-frail or frail men in the intervention group had higher probability of being non-frail after the intervention (44%) than pre-frail or frail men in the control group (30%) (p = 0.040). Among men, the intervention was especially beneficial in terms of increasing physical activity. Among women, multidomain lifestyle intervention did not affect the frailty status.Conclusion Modifying lifestyle-related factors may have potential to reverse first signs of frailty among older men. However, the intervention lasted only two years, therefore, research with longer follow-up is needed to see possible long-term effects of lifestyle management on the development of frailty.

BACKGROUND:The prevalence of frailty is increasing as the population ages. Lifestyle interventions have shown potential in frailty prevention. Intervention studies have been generally limited by short interventions and follow-ups or by focusing on single-domain approaches. We aimed to investigate whether a 2-year multidomain lifestyle intervention prevents phenotypic pre-frailty or frailty and whether baseline factors predict phenotypic pre-frailty or frailty. METHODS:A total of 1259 participants (aged 60-77 years) in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) were randomized to a multidomain intervention group or to a regular health advice group for 2 years. Frailty was defined by modified Fried phenotype. Pre-frail and frail participants were grouped for analyses. The prevalence of pre-frailty/frailty at baseline and at 2, 7, and 11 years, the change in prevalence from baseline, and the difference in these changes between intervention and control groups were estimated using a mixed-effects logistic regression model. RESULTS:The intervention reduced the risk of pre-frailty/frailty up to 7 years. The prevalence decreased in the intervention group from baseline (47%) to 2 years (42%), while it increased in the control group (45% to 49%), resulting in a -9.6-percentage point difference in the change (p = 0.007). After the active intervention period, the prevalence began to increase in both groups, but the difference in the change remained in favor of the intervention group at 7 years (-6.2 percentage points, p = 0.049). The beneficial effect was no longer evident at 11 years. Older age, lower protein intake, and a higher number of chronic diseases were strongly associated with pre-frailty/frailty. CONCLUSIONS:A 2-year multimodal lifestyle intervention effectively prevented phenotypic pre-frailty/frailty, with sustained benefits observed up to 7 years. Continuous support for a healthy lifestyle may be necessary to prevent late-life pre-frailty or frailty.

Heterozygous CWH43 loss-of-function (LOF) variants have been identified as iNPH risk factors, with 10–15

Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation.

The multidomain lifestyle intervention in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) showed positive effects on health-related quality of life (HRQL) during the 2-year intervention, particularly physical functioning. Our aim was to study how these benefits were maintained over an extended follow-up. A total of 1259 older adults aged 60-77 were randomized into multidomain intervention (n = 631) or control groups (n = 628). A validated HRQL scale RAND-36 with 8 subscales was collected during the original 2-year intervention (0,1,2 yrs) and during the 11-year extended follow-up (7,11 yrs). Emotional well-being subscale was also available from a mail survey during the COVID19 pandemic (approx. 9 yrs). Changes over time and intervention effect on HRQL were analyzed using mixed-effects regression. Altogether 1212 (96%) provided HRQL data at baseline, 1069 (85%) after the intervention, and 501 after 11 years (40%). During the follow-up mean RAND total score decreased from 76.4 to 69.3 All subscales were below baseline after 7 years, and physical functioning subscales started to decline already after 2 years (physical functioning, role limitations due to physical health, and bodily pain). Intervention related improvement in general health perception at the 1 st year was maintained up to 11 years (p-value for difference in change between groups 0.002), but improvement in physical functioning subscales vanished over time. Emotional well-being started to decline at the 7-year visit, without group differences. It temporarily improved during the pandemic (p-value for change from the 7-year visit 0.001) but declined back at the 11-year visit. Overall HRQL declined over time, as expected with aging. A 2-year multidomain lifestyle intervention among at-risk older adults resulted in sustained difference in general health perception, which is an important marker of general health. Lesser decline in physical functioning observed during the intervention was not sustained during the extended follow-up. In the whole group, emotional well-being declined later than physical functioning. Temporary improvement during the pandemic could be explained by the timing of the questionnaire (right after lifting restrictions), but it indicates that rapid changes due to external factors have an impact on emotional well-being of older people.

Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models. ML approaches successfully captured all genome-wide significant genetic variants identified in the training set and 22% of associations from larger meta-analyses. They highlight 6 novel loci which replicate in an external dataset, including variants which map to ARHGAP25, LY6H, COG7, SOD1 and ZNF597. They further identify novel association in AP4E1, refining the genetic landscape of the known SPPL2A locus. Our results demonstrate that machine learning methods can achieve predictive performance comparable to classical approaches in genetic epidemiology and have the potential to uncover novel loci that remain undetected by traditional GWAS. These insights provide a complementary avenue for advancing the understanding of AD genetics.

BACKGROUND:Frailty often precedes and co-occurs with dementia. A multidomain lifestyle intervention has shown favourable effects on cognition. We aimed to investigate if frailty status modifies this intervention effect. METHODS:The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) recruited 1259 participants aged 60-77 years who were at risk of dementia. They were randomised to receive a multidomain intervention (diet, exercise, cognitive training and vascular risk monitoring) or regular health advice for two years. The outcome was a change in cognition (neuropsychological test battery composite score). Frailty and prefrailty were defined according to the Fried phenotype. Mixed models were used to investigate if frailty status at baseline modified the intervention effect on cognition. RESULTS:Frailty status (prefrail/frail n = 520, robust n = 625) at baseline did not modify the effect of intervention on global cognition during the 2-year follow-up (P-value for frailty × intervention × time interaction > .05). Concerning cognitive subdomains, similar results were found. Among prefrail/frail persons, within-group analyses suggested a beneficial intervention effect on executive function and processing speed and also on global cognition when frail participants (n = 15) were excluded from the analyses. Being prefrail/frail was related to less improvement in global cognition, memory and executive function domains compared with being robust when intervention was not taken into consideration. CONCLUSIONS:A multidomain intervention is likely to be beneficial to cognition regardless of frailty status. Prefrail participants seemed particularly responsive to preventive intervention. Thus, an optimal time for a multidomain lifestyle intervention may be at the prefrailty stage.

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

Objectives:Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer's disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models. Methods:We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model. We developed a PHS model building on 720 genetic variants, including Apolipoprotein E (APOE) ε2 and ε4 alleles. We used Elastic Net-regularized Cox regression approach to develop the PHS model. Results:The new PHS model (EADB720) improved prediction accuracy compared to alternative models in European populations, with the Odds Ratio OR80/20 from the highest quintile of risk (80th risk percentile and above) to the lowest quintile of risk (20th risk percentile and below) varying between 5.10 and 13.15 within the range of age of onset from 65 - 85 years. Our model also improved risk stratification across ε3/3 individuals of European ancestry (OR80/20 ranges from 1.95 to 3.52). It was also successfully validated in independent datasets (HUSK, DemGene and ADNI) by achieving OR80/20 up to 10.00 in each independent dataset. Conclusion:Our EADB720 model significantly improves the accuracy of age-associated risk of AD across European populations (pval<0.03). Accurately predicting the age of onset of AD is of large clinical importance to implementing new AD medication and early intervention in clinical settings.

Abstract Alzheimer’s disease (AD) may be associated with early dopamine (DA) dysfunction. However, its effects on neurofunctional alterations in the neurotransmission pathways remain elusive. In this study, PET atlases and functional MRI data for 86 older adults with mild cognitive impairment (AD-MCI), 58 with mild AD dementia and 76 cognitively unimpaired (CU) were combined to investigate connectivity alterations associated with the dopaminergic and cholinergic (ACh) systems. A cross-sectional design was used to compare neurotransmitter-related functional connectivity across groups and associations between functional connectivity and cognitive performance. The findings show that the AD-dementia group showed a decline in mesocorticolimbic DA-related connectivity in the precuneus but heightened connectivity in the thalamus, whereas the AD-MCI group showed a decline in nigrostriatal connectivity in the left temporal areas. ACh-related connectivity decline was observed in both AD-MCI and AD-dementia primarily in the temporo-parietal areas. Episodic memory scores correlated positively with ACh- and DA-related connectivity in the temporo-parietal cortex and negatively with DA-related FC in the fronto-thalamic areas. This study shows that connectivity alterations in ACh and DA functional pathways parallel cognitive decline in AD and might be a clinically relevant marker in early AD.

Multidomain lifestyle trials have been shown to be effective in changing people’s behaviour during the intervention, but less is known about long-term effects of such interventions. The aim of this study was to investigate how self-reported lifestyle and self-evaluated health changed over a 10-year period in older adults participating in the FINGER randomised controlled trial. Effects of the initial lifestyle intervention and the COVID-19 pandemic on these behaviour changes were evaluated. A two-year multicentre FINGER trial recruited community-dwelling people aged 60-77 years at risk of cognitive impairment (n=1259). Participants were randomised to a multidomain lifestyle intervention or regular health advice (control). They underwent study visits annually during the original trial period (at baseline, one, and two years) and twice during the follow-up (five and seven years), and responded to a survey during the COVID-19 pandemic at approximately 10 years. Generalised estimating equations (GEE) and linear mixed-effects regression model were used to analyse physical, cognitive, and social activity, food consumption, smoking, alcohol consumption, and self-evaluated health. People in the intervention group were better able to maintain their level of physical activity up to the five-year follow-up. The intervention group also improved their diet quality: difference in fish consumption was maintained up to the seventh year, and consumption of vegetables and fruits increased during the active intervention. Cognitive and social activities increased and self-evaluated health and memory improved during the active period, but decreased thereafter, without a group difference. During the COVID-19 pandemic, physical and cognitive activities increased. Multidomain lifestyle intervention was beneficial for improving physical activity and healthy food choices in older people both in the short and long term, but had no effect on other activities, smoking, alcohol use, or self-evaluated health. Increased physical activity was the most evident pandemic-associated change in older adults’ lifestyle. ClinicalTrials.gov, NCT01041989. Registered 04/01/2010 – Retrospectively registered, https://clinicaltrials.gov/ .

Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1–4 of TYROBP and causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP. Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.

This study investigated the degree to which cognitive mechanisms support word recognition and word inflection in aging and how this changes in Alzheimer’s disease (AD). We tested competing hypotheses regarding the functional organization of language within the broader cognitive system. One set of hypotheses, derived from dual-system theories like the Declarative/Procedural (DP) model, predicts a functional architecture segregated by linguistic function. An alternative set of hypotheses posits a more integrated architecture, organized by task demands and resource availability. We analyzed participants’ performance on a lexical decision task and a word inflection task, alongside neuropsychological tests, using both behavioral and network analyses. In healthy controls (HC), the network analysis revealed a highly integrated architecture where language tasks were clustered by functional demands (e.g., speed vs. accuracy) rather than segregated along a strict lexicon/grammar divide. In the AD group, behavioral results showed a classic dissociation, with disproportionate impairment on irregular word inflection — a pattern traditionally seen as evidence for a modular memory failure. However, our network analysis revealed a different underlying mechanism. We observed a dramatic network reorganization where a core declarative memory module became functionally isolated, causing language tasks to form new, compensatory alliances with remaining frontal-executive resources. This provides clear evidence of a shift where executive functions are recruited to support language abilities when dedicated memory systems decline. These findings suggest that the cognitive substrate for language is not static but adapts dynamically in neurodegeneration, shifting its reliance from failing declarative memory systems to domain-general executive control pathways.

The increasing dementia prevalence and potential introduction of disease-modifying therapies (DMTs) highlight the need for efficient diagnostic pathways. Clear recommendations to guide the choice of diagnostic tests are lacking and may vary depending on different clinical scenarios. We used a data-driven approach to identify efficient and effective stepwise diagnostic testing for three clinical scenarios: 1) syndrome diagnosis, 2) etiological diagnosis, 3) potential eligibility for DMT. We used data from two memory clinic cohorts (ADC, PredictND), including 504 patients with dementia (302 Alzheimer’s disease, 107 frontotemporal dementia, 35 vascular dementia, 60 dementia with Lewy bodies), 191 patients with mild cognitive impairment, and 188 cognitively healthy controls (CN). Tests included digital cognitive screening (cCOG), neuropsychological and functional assessment (NP), MRI with automated quantification, and CSF biomarkers. Sequential testing followed a predetermined order (Figure 1). Subsequent tests were conducted if the diagnosis remained uncertain. Diagnostic certainty was ascertained through a data-driven clinical decision support system (CDSS) that generated a disease state index probability score (DSI, 0-1), indicating the probability of each diagnosis. Diagnosis was confirmed if the DSI exceeded a predefined threshold, set based on sensitivity/specificity cutoffs relevant for each clinical scenario and step. We assessed correct diagnoses and the need for additional testing at each step. For syndrome diagnosis, stepwise testing (cCOG, NP, MRI) accurately identified 71% of the patients, with NP needed in 42%, and MRI in 31%. For etiological diagnosis, starting with cognitive testing to rule out dementia resulted in the need for MRI in 84% of cases, including 91% of dementia patients and 25% CN. Subsequent MRI reduced CSF required to 29%, ultimately diagnosing 81% of patients with 71% accuracy. In determining DMT eligibility, stepwise testing (cCOG, NP, MRI) correctly identified 91% of potential eligible patients for confirmatory CSF testing, while only 51% of ineligible patients. Depending on the setting, alternative diagnostic pathways are accurate and efficient. As such, a data-driven tool can assist clinicians in selecting tests of added value across different clinical contexts. This becomes especially important with DMT availability, where the need for more efficient diagnostic pathways is crucial to maintain accessibility and affordability of diagnoses.