Abstract
INTRODUCTION
Anti‐amyloid therapies (AATs) for Alzheimer's disease (AD) demonstrate modest benefit in trials, but real‐world eligibility remains uncertain. Requirements including biomarker confirmation and safety exclusions may limit access.
METHODS
Using the Brains for Dementia Research cohort, we linked longitudinal cognitive data with post mortem neuropathology to estimate trial‐like AAT eligibility. Early stage was defined using harmonized cognitive thresholds. AD pathology required Thal amyloid phase ≥3 and Braak stage ≥IV. Exclusions were applied hierarchically: (1) vascular neuropathology, (2) anticoagulant use, and (3) apolipoprotein E (APOE) ε4/ε4 homozygosity.
RESULTS
Of 1230 participants, 945 had sufficient data; 232 had early, pathology‐confirmed AD. Vascular pathology excluded 70.7%, anticoagulant use 19.1%, and APOE ε4/ε4 homozygosity 3.6% of remaining cases. Overall, 53 individuals (4.3% of those screened) were eligible. Eligibility declined with age and was driven primarily by vascular comorbidity.
DISCUSSION
Using a conservative pathology‐anchored framework, only a small proportion of this older brain‐donor cohort met trial‐like eligibility criteria.
Keywords: Alzheimer's disease, anti‑amyloid therapy, APOE, eligibility, neuropathology, vascular pathology
Highlights
Only ∼4% of the cohort met trial‐like anti‐amyloid therapy eligibility.
Vascular pathology was the main barrier to anti‐amyloid treatment eligibility.
APOE ε4/ε4 homozygosity and anticoagulants further reduced treatment suitability.
Many eligible individuals lacked a clinical AD diagnosis despite AD pathology.
Findings define key diagnostic and safety bottlenecks for therapy implementation.
1. INTRODUCTION
Alzheimer's disease (AD) represents a major and growing health burden in the United Kingdom (UK). 1 The emergence of anti‐amyloid therapies (AATs) has generated cautious optimism for the first disease‐modifying treatments in AD. In the CLARITY‐AD study, AAT was associated with modest but statistically significant cognitive benefit over 18 months, marking a pivotal shift in the therapeutic landscape. 2 , 3
Despite these advances, the translation of AATs into UK clinical practice remains challenging. Donanemab and lecanemab have received regulatory approval from the Medicines and Healthcare products Regulatory Agency (MHRA) but has not been recommended by National Institute for Health and Care Excellence on the grounds of cost‐effectiveness. 4 UK memory clinic studies estimate 14% to 24% potential eligibility, although most lacked routine biomarker confirmation and apolipoprotein E (APOE) genotyping. 5 , 6 , 7
In the absence of genetic data, limited access to biomarkers in community‐based cohorts, and uncertainty in clinical diagnoses, estimating the true size and characteristics of the eligible patient population remains highly challenging. To address this gap, this study leverages the Brains for Dementia Research (BDR) cohort, 8 which provides gold‐standard neuropathological confirmation of AD. This unique resource enables a pathology‐informed approximation of the proportion of individuals who may meet trial‐like biological and safety criteria for AATs and allows detailed characterization of exclusion reasons, including comorbid pathologies and disease stage. These findings may help inform future modeling of service planning, diagnostic infrastructure, and resource requirements surrounding the implementation of AAT within the National Health Service (NHS).
2. METHODS
2.1. Study design and cohort
This was a retrospective observational cohort study using data from the BDR cohort. The BDR is a longitudinal cohort of participants with and without dementia who undergo regular clinical phenotyping and consent to brain donation for detailed neuropathological assessment. 8 The study followed standardized protocols based on BrainNet Europe and National Institute on Aging–Alzheimer's Association (NIA‐AA) guidelines. Ethical approval for the BDR was obtained centrally, and all donors provided informed consent during life. Data access was granted from the BDR Unified Access Committee with data downloaded from the UK Brain Bank database and genetic data being provided by Dr. Brookes.
Participants were eligible for inclusion if they had (1) at least one in‐life cognitive assessment and (2) available post mortem neuropathological data. Individuals with missing key pathology variables were excluded. Table 1 presents a detailed comparison between the trial and the operational definitions used in this study.
TABLE 1.
Mapping trial/clinical criteria to the BDR proxies.
| Clinical trial | Proxy using BDR cohort |
|---|---|
| Inclusion criteria | |
| Amyloid biomarker positivity by amyloid PET or CSF Aβ1–42 | NIA‐AA ABC score: Thal≥3 (Thal 3–5) |
| Tau stage by tau PET or CSF p‐tau | NIA‐AA ABC score: Braak stage ≥ IV. |
|
Early stage (MCI/mild dementia): MMSE ≥ 20 or equivalent in RUDAS, MoCA, and ACE III score |
CDR 0.5 to 1, MMSE ≥20, or MoCA ≥18 at index visit |
| Exclusion criteria | |
| Suggestive of CAA in MRI: >4 microbleeds, prior ICH, superficial siderosis or vasogenic edema | Markers of CAA, including moderate to severe parenchymal CAA, moderate to severe arteriolar Aβ‐CAA, capillary CAA, or moderate to severe leptomeningeal CAA. |
| Severe subcortical hyperintensities (Fazekas 3) | Moderate to severe non‐amyloid small‐vessel disease |
| Severe cerebrovascular disease, >2 lacunar infarcts or infarct in major vascular territory or recent stroke | Severe arteriosclerosis or evidence of large territorial infarction (>10 mm in diameter) |
| Anticoagulant | In‐life anticoagulant use |
| APOE ε4/ε4 (not tested routinely in practice) | APOE ε4/ε4 |
Abbreviations: Aβ, amyloid beta; CAA, cerebral amyloid angiopathy; CDR, Clinical Dementia Rating; CSF, cerebrospinal fluid; ICH, intracerebral hemorrhage; MCI, mild cognitive impairment; MMSE, Mini‐Mental State Examination; MoCA, Montreal Cognitive Assessment; NIA‐AA, National Institute on Aging–Alzheimer's Association; PET, positron emission tomography; BDR, Brains for Dementia Research; APOE, apolipoprotein E.
2.2. Clinical staging and index visit
Clinical disease stage was determined using cognitive assessments. Clinical Dementia Rating (CDR), Mini‐Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA) were the key forms of evaluation. Early‑stage disease was defined as CDR 0.5 to 1, 9 MMSE ≥ 20, or MoCA ≥ 18, reflecting widely used thresholds for identifying mild cognitive impairment to early AD. For global cognitive screening, a MMSE threshold of ≥20 was used to capture early symptomatic disease while excluding more advanced impairment, consistent with the donanemab trial. 2 The MoCA threshold of ≥18 aligns with published studies showing high sensitivity and specificity for mild AD dementia. 10 , 11
RESEARCH IN CONTEXT
Systematic review: Prior UK and European memory clinic studies have estimated that 6% to 24% of patients may meet eligibility criteria for anti‐amyloid therapies, though most relied on clinical diagnosis, MRI, and limited biomarker or genetic data. Few studies incorporated neuropathological confirmation or detailed vascular comorbidity.
Interpretation: Using a longitudinal brain‐donor cohort with post mortem confirmation, we demonstrate that only ∼4% of screened individuals would meet trial‐like eligibility criteria. Vascular pathology was the dominant exclusion factor, exceeding the impact of anticoagulant use or APOE ε4/ε4 homozygosity. Fewer than half of eligible individuals had received a clinical AD diagnosis during life.
Future directions: These findings highlight the gap between trial populations and real‐world aging cohorts and underscore the need for improved vascular risk stratification, scalable biomarker pathways, and service modeling to support safe implementation of disease‐modifying therapies.
The index visit was defined as the earliest assessment at which a participant met early‐stage criteria. Time from index visit to death was calculated using recorded months‐to‐death variables.
2.3. Neuropathological definitions
Amyloid pathology was defined using Thal amyloid phase, with amyloid positivity (A+) defined as Thal phase ≥3. This stage reflected the presence of widespread neocortical amyloid deposition and is strongly associated with clinical AD and co‐occurring higher Braak stages. 12 , 13 A threshold of Thal phase ≥3 also demonstrates high concordance with in vivo amyloid biomarkers, including both amyloid positron emission tomography (PET) positivity and reduced cerebrospinal fluid Aβ42. 13 In addition, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score reflects amyloid plaque density rather than spatial distribution. CERAD ≥ 2 was used as the sensitivity threshold, as prior studies showed good concordance with in vivo biomarkers, including cerebrospinal fluid Aβ42 and amyloid PET. 13
Tau pathology burden was indexed using Braak neurofibrillary tangle stage. Braak stage ≥IV, limbic‐neocortical tau, was considered tau positivity (T+). As elevated flortaucipir PET signal corresponded most closely to Braak stage ≥ IV, this justified the biological basis of the tau threshold used in this study. 14 Consistent with current neuropathological frameworks, intermediate–high AD neuropathologic change, reflecting pathology levels typically required for biomarker confirmation in clinical practice, was defined as the presence of both amyloid and tau positivity. 15
2.4. Vascular pathology
Because in‐life MRI safety data were not available in the BDR, vascular and hemorrhagic risk was approximated using neuropathological proxies selected to reflect trial and appropriate use recommendation exclusions.
These included evidence of large territorial infarction (> 10 mm in diameter), moderate to severe non‐amyloid small‐vessel disease, severe arteriosclerosis, and markers of cerebral amyloid angiopathy (CAA), including moderate to severe parenchymal CAA, moderate to severe arteriolar Aβ‐CAA, capillary CAA, or moderate to severe leptomeningeal CAA.
These features were considered proxies for MRI‐defined exclusion criteria such as severe cerebrovascular disease, extensive white matter hyperintensities, and CAA, which were associated with increased hemorrhagic risk during AAT (Table 1 and Figure S1).
2.5. Anticoagulants and APOE
Medication history was reviewed in the BDR. Warfarin or direct oral anticoagulant use during life were identified. This reflects heightened risk of amyloid‐related imaging abnormalities (ARIAs) reported in clinical trials. APOE status was assessed in the participants. APOE ε4/ε4 homozygosity were excluded under trial‐like criteria for the AAT.
Together, these criteria defined a conservative, trial‐like eligibility framework intended to estimate the proportion of individuals who might have met biological and safety requirements for AAT.
2.6. Statistical analysis
All analyses were conducted using R (version 4.4.2). Statistical significance was set at two‐sided p < 0.05. p values were reported descriptively. Continuous variables were compared using non‐parametric tests due to unequal group sizes. Categorical variables were compared using chi‐squared or Fisher's exact tests as appropriate.
3. RESULTS
3.1. Study cohort and data availability
Among 1230 participants in the BDR cohort (recruited from 2009 to 2024), 945 (76.8%) had both neuropathological assessment and cognitive test data available and were included for screening (Figure 1). The remaining 285 individuals were excluded due to missing neuropathology and/or cognitive data.
FIGURE 1.
Hierarchical assessment of eligibility for anti‐amyloid therapy in the BDR cohort. Of 1230 individuals assessed, 945 had available neuropathology and cognitive data, of whom 788 met early clinical stage criteria. AD pathology was confirmed in 232 individuals (Thal ≥ 3 and Braak ≥ IV). Eligibility criteria were applied sequentially, excluding individuals with significant vascular pathology, anticoagulant use, and APOE ε4/ε4 homozygosity, resulting in 53 trial‐eligible individuals. AD, Alzheimer's disease; BDR, Brains for Dementia Research; APOE, apolipoprotein E.
3.2. Clinical stage and neuropathological classification
Of the 945 participants with available data, 788 (83.4%) met criteria for early clinical stage based on harmonized cognitive thresholds. Within this group, 232 individuals (29.4%) met criteria for pathology‐confirmed AD disease (A+T+), defined by Thal amyloid phase ≥3 and Braak neurofibrillary tangle stage ≥IV.
Findings were reassessed using CERAD neuritic plaque score ≥2 as an alternative amyloid criterion. The denominator differed slightly in the CERAD‐based sensitivity analysis because availability of CERAD neuritic plaque score did not fully overlap with the availability of Thal phase data. In this sensitivity analysis, 974 participants had sufficient neuropathological and clinical data, of whom 688 met early clinical stage criteria. Among these, 71 individuals met criteria for AD based on CERAD ≥2 and Braak stage ≥IV. This was substantially lower than in the primary Thal‐based analysis (71 vs 232), resulting in lower estimated eligibility rates (Figure S2). These findings suggest that plaque burden‐based definitions provide a more stringent and potentially more biomarker‐aligned estimate of treatment eligibility.
3.3. Hierarchical application of eligibility criteria
Eligibility for AAT was assessed using a stepwise hierarchical framework reflecting trial‐relevant safety considerations (Figure 1).
At the first screening step, vascular neuropathology was the predominant exclusion, affecting 164 of 232 individuals (70.7%) with early‐stage AD. This left 68 individuals eligible for further screening. At the second step, anticoagulant use led to the exclusion of 13 of the 68 remaining individuals (19.1%), leaving 55 participants. At the third step, APOE ε4/ε4 homozygosity resulted in exclusion of two of the 55 remaining individuals (3.6%).
Overall, 53 individuals met all eligibility criteria and were classified as trial‐like eligible, representing 4.3% of the total assessed BDR cohort and 22.8% of individuals with early‐stage AD. Individuals aged <65 years had the highest rate of trial eligibility (66.7%), whereas only 18.4% of those aged ≥85 years met eligibility criteria (Figure 2).
FIGURE 2.
Proportion of trial‐eligible individuals by age group. Proportion of individuals with early‐stage, pathology‐confirmed Alzheimer's disease meeting trial‐like eligibility criteria across predefined age categories. Bars represent the percentage of eligible individuals within each age group. Eligibility declined markedly with increasing age, largely reflecting the accumulation of vascular and safety‐related exclusion criteria. No upper age cut‐off was applied in the eligibility framework.
When examining overall reasons for exclusion, vascular pathology only (129 out of 232, 55.60%) was the most common cause, followed by combination of vascular pathology with anticoagulant use (24 out 232, 10.34%) (Figure 3). Thirteen cases of APOE ε4/ε4 homozygosity were identified as the reason for exclusion alone or with other reasons. Overlap analysis demonstrated substantial co‐occurrence between different CAA subtypes, with leptomeningeal and arteriolar involvement contributing to the most frequent combinations (Figure S3). Mixed pathology patterns, including co‐existing vascular lesions such as infarcts and arteriosclerosis, were also observed, supporting the heterogeneous vascular burden underlying impaired amyloid clearance (Figure S3).
FIGURE 3.
Overall reasons for exclusion from trial‐like eligibility. Distribution of exclusion reasons among individuals with early‐stage, pathology‐confirmed Alzheimer's disease who did not meet trial‐like eligibility criteria. Reasons for exclusion were shown as overall (non‐mutually exclusive) categories, reflecting the presence of one or more exclusion factors per individual. Vascular neuropathology was the most frequent reason for exclusion, either alone or in combination with anticoagulant use or APOE ε4/ε4 homozygosity. Counts were based on the full group of 232 individuals with early‐stage Alzheimer's disease.
3.4. Characteristics of eligible and non‐eligible participants
Demographic and clinical characteristics of eligible and non‐eligible participants were summarized in Table 2. Eligible and non‐eligible individuals were similar in age, sex distribution, and ethnicity. The mean age was 84.4 ± 8.3 years among eligible participants and 85.6 ± 8.4 years among non‐eligible participants. The interval from first cognitive assessment to death was slightly longer in eligible individuals (72.4 ± 40.9 months) compared to non‐eligible individuals (62.7 ± 42.7 months). It can reflect the selection of mild cases and lower vascular burden. As expected, vascular pathology, anticoagulant use, and APOE ε4/ε4 homozygosity differed between groups, as these variables formed part of the eligibility definition.
TABLE 2.
Characteristics of trial‐eligible and non‐eligible individuals. Among participants with neuropathology and cognitive data (n = 945).
| Characteristic | Non‐eligible (n = 892) | Trial eligible (n = 53) | p value |
|---|---|---|---|
| Age, years (mean ± SD) | 85.6 ± 8.4 | 84.4 ± 8.3 | 0.29 |
| Female sex, n (%) | 443 (49.7) | 28 (52.8) | 0.76 |
| White ethnicity, n (%) | 446 (99.8) | 25 (96.2) | 0.23 |
| APOE ε4/ε4 homozygous, n (%) | 42 (4.7) | 0 (0.0) | — |
| Anticoagulant use, n (%) | 123 (13.8) | 0 (0.0) | — |
| Any vascular exclusion, n (%) | 579 (64.9) | 0 (0.0) | — |
| Months from first cognitive assessment to death (mean ± SD) | 63.10 ± 42.5 | 72.4 ± 40.9 | 0.08 |
Note: p values were reported descriptively. Continuous variables were compared using non‐parametric tests due to unequal group sizes. APOE ε4/ε4 homozygosity, anticoagulant use, and vascular exclusion criteria form part of the eligibility definition; therefore, no formal statistical comparisons were reported for these variables. Categorical variables were compared using chi‐squared or Fisher's exact tests as appropriate.
Among the 53 trial‐eligible individuals, 23 (43.4%) had a recorded clinical diagnosis of AD during life, 12 (22.6%) had a non‐AD neurodegenerative diagnosis, four (7.5%) had vascular dementia, two (3.8%) had mild cognitive impairment, and 12 (22.6%) had other diagnoses or no documented dementia diagnosis (Figure 4).
FIGURE 4.
Recorded clinical diagnoses among trial‐eligible individuals. Recorded in‐life clinical diagnoses among the 53 individuals classified as trial‐like eligible for anti‐amyloid therapy. Just 43.4% had a documented clinical diagnosis of Alzheimer's disease. This highlights potential discordance between neuropathological confirmation and clinical diagnosis in real‐world settings. AD, Alzheimer's disease.
Particular attention was given to the subgroup with a time‐to‐death interval of less than 5 years, given its clinical relevance. Within this subgroup, 78 of 571 cases (13.7%) were classified as early‐stage AD. After applying exclusion criteria – including significant vascular pathology, anticoagulant use, and APOE ε4/ε4 homozygosity – 19 of the 78 cases remained eligible (Figure S4). This corresponded to eligibility rates of 3.3% in the subcohort and 24.4% among individuals in early stage within this subgroup. The primary reason for exclusion was vascular pathology, accounting for 43 of the 78 cases.
4. DISCUSSION
In this clinicopathological analysis of the BDR cohort, we applied a conservative, trial‐like hierarchical eligibility framework to explore how neuropathologically confirmed AD and co‐pathology may influence AAT eligibility in an aging brain‐donor cohort. Only a small proportion of individuals with early‐stage AD met eligibility criteria, with vascular neuropathology emerging as the dominant limiting factor. Across the primary analysis, CERAD‐based sensitivity analysis, and the <5‐year subgroup, vascular pathology consistently emerged as the principal determinant of ineligibility. These findings complement clinic‐based eligibility estimates by anchoring assessment to post mortem pathology and accounting for mixed disease mechanisms.
Several UK and European clinic‐based studies report eligibility estimates ranging from 6% to 24%, though most lacked neuropathological confirmation or routine APOE genotyping. 5 , 6 , 7 , 16 Our study provides a pathology‐anchored estimate that complements clinic‐based studies.
4.1. Vascular pathology as the principal barrier
Vascular pathology accounted for the largest proportion of exclusions. This aligns with the well‑established high prevalence of mixed cerebrovascular and neurodegenerative pathology in older adults, reinforcing concerns that clinical trial populations may not reflect real‐world disease complexity.
MRI markers such as white matter hyperintensities and microbleeds are widely used for vascular risk stratification. 17 , 18 However, translating between neuropathology and in vivo MRI markers is imperfect. Microbleeds and siderosis on MRI, for example, are indirect and sometimes insensitive proxies for CAA and may under‑ or overestimate underlying severity. Amyloid clearance is mediated by coupled peri‐arterial, glymphatic, and peri‐venous pathways, and dysfunction of these systems may further contribute to amyloid accumulation beyond what is captured by conventional MRI markers. 19 , 20 , 21
ARIAs remain a central safety concern across AATs, with higher risk among APOE ε4 carriers and in the presence of CAA‐related MRI markers. 22 Regulatory guidance continues to rely on trial‐derived safety thresholds.
4.2. Anticoagulants, APOE, and evolving safety considerations
Anticoagulant use formed the second largest exclusion. This reflects the increased risk of ARIAs in individuals receiving long‐term anticoagulation. 23 While rates of anticoagulation increase sharply with age due to atrial fibrillation and venous thromboembolism, our data suggest that even after vascular exclusions, this remains a non‐trivial source of ineligibility. In the UK expert consensus, dual antiplatelet therapy was also considered a contributor to treatment risk and recommended the multidisciplinary team discussion. 24
APOE ε4 has been identified as a risk factor of ARIAs by promoting blood–brain barrier breakdown, increasing neuroinflammation, Aβ deposition, and CAA. 25 In the phase III clinical trials for lecanemab (CLARITY‐AD) and donanemab (TRAILBLAZER‐ALZ 2), APOE ε4/ε4 homozygosity was not a prior exclusion criterion, as these individuals comprised 15.5% to 16.5% of the treated cohorts. 2 , 3 However, due to the markedly higher risk of severe ARIAs in this group, recent regulatory restrictions – such as the MHRA's decision in the UK and European Medicines Agency guidelines – have effectively shifted homozygosity into an exclusion category for routine clinical practice. 26 , 27 Similarly, APOE ε4/ε4 homozygosity was included as an exclusion criterion to mirror trial‐level safety considerations in this study. Although APOE genotyping is not yet routinely available in UK clinical practice, the introduction of AATs is likely to increase its role in diagnostic pathways, particularly for risk stratification, informed consent, and disease monitoring. Our findings therefore anticipate, rather than assume, future clinical workflows.
4.3. Age, frailty, and clinical relevance
An upper age limit was not introduced, in line with regulatory frameworks that do not specify age cut‑offs and acknowledging that brain‑bank donors are predominantly of advanced age. As a result, eligibility estimates may differ from those observed in younger clinic populations. Although pivotal AAT trials (EMERGE/ENGAGE, CALRITY‐AD, and TRAILBLAZER‐ALZ) limited enrolment to 85 to 90 years, published reports provide little scientific justification and subsequent commentaries suggest these caps reflected pragmatic concerns such as screen failure, comorbidity burden, safety monitoring, and retention rather than biological rationale. 28 , 29 There is no upper age limit specified in the current marketing authorization for AATs. In the Aducanumab trials, increasing age was associated with a small increase in the hazard of ARIA‐Haemorrhage (hazard ratio 1.06), while no association was observed between age and the risk of ARIA‐Edema. 28 In contrast, analyses from the gantenerumab program did not identify age as a predictor of overall ARIA risk; however, increasing age was associated with greater severity of ARIA‐Edema among affected individuals. 30 Although frailty was not a formal exclusion criterion in pivotal trials, a growing consensus supports incorporating geriatric assessment into real‐world treatment decisions. 6 , 31
4.4. Clinical diagnosis versus biological disease
In this study, a noteworthy finding is that fewer than half of trial‑eligible individuals had received a clinical diagnosis of AD during life. Similarly, when comparing clinical and neuropathological diagnoses in 180 cases from the BDR, only two‐thirds of cases had consistent neurodegenerative diagnoses. 32 Further, 35% of AD cases had additional vascular or dementia with Lewy bodies pathologies. 32 Analysis of the National Alzheimer's Coordinating Center dataset revealed substantial diagnostic discordance: 204 of 2311 cases were clinically diagnosed with AD but showed no AD neuropathology, while 253 individuals without a clinical AD diagnosis nonetheless met neuropathologic criteria for AD. 33
This highlights the well‑recognized discordance between clinical and neuropathological diagnoses, especially in early‑stage or mixed‑pathology presentations. With increasing dependence on biomarkers, future diagnostic pathways – particularly in the NHS – will likely need to account for the fact that clinical diagnosis alone is insufficient to identify biologically eligible individuals. This reinforces the need for scalable biomarker access, including cerebrospinal fluid and amyloid or tau PET and potentially emerging blood biomarkers as they achieve regulatory approval.
4.5. Health‐system implications
Importantly, this study addresses eligibility for AAT under trial‐like or appropriate‐use recommendation frameworks, rather than availability within a specific healthcare system. Regulatory approval does not equate to immediate access, particularly within the NHS, where diagnostic capacity, biomarker availability, and workforce constraints must be considered. 34 These findings may help inform future modeling of diagnostic pathways, resource requirements, and cost‐effectiveness.
Our hierarchical analysis highlights that attrition occurs at early biological and safety screening stages, rather than at cognitive assessment. This suggests that future service pressures may be driven less by memory clinic capacity and more by access to high‐quality neuroimaging, vascular risk stratification, and genetic counseling. 35 Some exclusions, such as advanced vascular pathology, likely reflect biological constraints, whereas others – including anticoagulant use and APOE genotyping – are influenced by service configuration, clinical guidance, and evolving risk tolerance.
4.6. Strengths and limitations
The strengths of this study include the use of neuropathological gold standards, explicit hierarchical eligibility assessment, and integration of detailed vascular pathology. A central limitation is that neuropathology was assessed at death, whereas treatment eligibility would be determined during life using in vivo biomarkers and MRI. Therefore, our analysis identifies individuals who had early‐stage clinical features and subsequently showed sufficient AD neuropathology at autopsy, rather than individuals who definitively would have met biomarker‐based treatment criteria at the index visit. The result should not be generalized directly to younger memory‐clinic or trial‐screened populations.
Other limitations include heterogeneous cognitive testing, lack of functional assessments aligned with UK clinical guidelines, and the advanced age profile of the cohort. Functional measures and clinician consensus, which are central to real‐world decision‐making, were not uniformly available and represent a critical area for future work.
Vascular assessment in this study was based on neuropathological evaluation rather than imaging‐derived density measures, allowing direct characterization of structural vascular abnormalities; however, quantitative assessment of microvascular integrity and function was not performed.
5. CONCLUSIONS
Overall, this clinicopathological study demonstrates that trial‐like eligibility for AAT may be substantially reduced in aging populations with high vascular comorbidity. These findings provide a conservative pathology‐informed benchmark for understanding how age, vascular comorbidity, anticoagulation, and APOE status may reduce treatment eligibility, while recognizing that real‐world decisions require in vivo biomarkers, MRI, and clinical judgment.
CONFLICT OF INTEREST STATEMENT
BS has served as an invited speaker for educational events sponsored by Eli Lilly and Company. MH and KB declare no conflicts of interest. The authors report no other competing interests. Author disclosures are available in the Supporting Information.
CONSENT STATEMENT
Ethical approval for the BDR was obtained centrally, and all donors provided informed consent during life.
Supporting information
Supporting Information: dad270400‐sup‐0001‐FigureS1.pdf
Supporting Information: dad270400‐sup‐0002‐FigureS2.pdf
Supporting Information: dad270400‐sup‐0003‐FigureS3.pdf
Supporting Information: dad270400‐sup‐0004‐FigureS4.pdf
Supporting Information: dad270400‐sup‐0005‐ICMJE.pdf
ACKNOWLEDGMENTS
We would like to gratefully acknowledge all donors and their families for the tissue provided for this study. Human post mortem tissue was obtained from the South West Dementia Brain Bank, London Neurodegenerative Diseases Brain Bank, Manchester Brain Bank, Newcastle Brain Tissue Resource, and Oxford Brain Bank, members of the Brains for Dementia Research Network. The provision of data used in this study was provided with support from the BDR programme, jointly funded by Alzheimer's Research UK and Alzheimer's Society. BS is funded by NIHR as an academic clinical lecturer (CL‐2023‐12‐003).
DATA AVAILABILITY STATEMENT
BDR data can be accessed through the Dementias Platform UK upon approval. Pathology data are available through the UK Brain Bank Network.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information: dad270400‐sup‐0001‐FigureS1.pdf
Supporting Information: dad270400‐sup‐0002‐FigureS2.pdf
Supporting Information: dad270400‐sup‐0003‐FigureS3.pdf
Supporting Information: dad270400‐sup‐0004‐FigureS4.pdf
Supporting Information: dad270400‐sup‐0005‐ICMJE.pdf
Data Availability Statement
BDR data can be accessed through the Dementias Platform UK upon approval. Pathology data are available through the UK Brain Bank Network.