Heterogeneity In Alzheimer's Disease Research Articles

Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease.

Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Alzheimer's disease heterogeneity revealed by neuroanatomical normative modeling.

Overlooking the heterogeneity in Alzheimer's disease (AD) may lead to diagnostic delays and failures. Neuroanatomical normative modeling captures individual brain variation and may inform our understanding of individual differences in AD-related atrophy. We applied neuroanatomical normative modeling to magnetic resonance imaging from a real-world clinical cohort with confirmed AD (n=86). Regional cortical thickness was compared to a healthy reference cohort (n=33,072) and the number of outlying regions was summed (total outlier count) and mapped at individual- and group-levels. The superior temporal sulcus contained the highest proportion of outliers (60%). Elsewhere, overlap between patient atrophy patterns was low. Mean total outlier count was higher in patients who were non-amnestic, at more advanced disease stages, and without depressive symptoms. Amyloid burden was negatively associated with outlier count. Brain atrophy in AD is highly heterogeneous and neuroanatomical normative modeling can be used to explore anatomo-clinical correlations in individual patients.

A review of neuroimaging-based data-driven approach for Alzheimer's disease heterogeneity analysis.

Alzheimer's disease (AD) is a complex form of dementia and due to its high phenotypic variability, its diagnosis and monitoring can be quite challenging. Biomarkers play a crucial role in AD diagnosis and monitoring, but interpreting these biomarkers can be problematic due totheir spatial and temporal heterogeneity. Therefore, researchers are increasingly turning to imaging-based biomarkers that employ data-driven computational approaches to examine the heterogeneity of AD. In this comprehensive review article, we aim to provide health professionals with a comprehensive view of past applications of data-driven computational approaches in studying AD heterogeneity and planning future research directions. We first define and offer basic insights into different categories of heterogeneity analysis, including spatial heterogeneity, temporal heterogeneity, and spatial-temporal heterogeneity. Then, we scrutinize 22 articles relating to spatial heterogeneity, 14 articles relating to temporal heterogeneity, and five articles relating to spatial-temporal heterogeneity, highlighting the strengths and limitations of these strategies. Furthermore, we discuss the importance of understanding spatial heterogeneity in AD subtypes and their clinical manifestations, biomarkers for abnormal orderings and AD stages, the recent advancements in spatial-temporal heterogeneity analysis for AD, and the emerging role of omics data integration in advancing personalized diagnosis and treatment for AD patients. By emphasizing the significance of understanding AD heterogeneity, we hope to stimulate further research in this field to facilitate the development of personalized interventions for AD patients.

Alzheimer's disease heterogeneity explained by polygenic risk scores derived from brain transcriptomic profiles.

Alzheimer's disease (AD) is heterogeneous, both clinically and neuropathologically. We investigated whether polygenic risk scores (PRSs) integrated with transcriptome profiles from AD brains can explain AD clinical heterogeneity. We conducted co-expression network analysis and identified gene sets (modules) that were preserved in three AD transcriptome datasets and associated with AD-related neuropathological traits including neuritic plaques (NPs) and neurofibrillary tangles (NFTs). We computed the module-based PRSs (mbPRSs) for each module and tested associations with mbPRSs for cognitive test scores, cognitively defined AD subgroups, and brain imaging data. Of the modules significantly associated with NPs and/or NFTs, the mbPRSs from two modules (M6 and M9) showed distinct associations with language and visuospatial functioning, respectively. They matched clinical subtypes and brain atrophy at specific regions. Our findings demonstrate that polygenic profiling based on co-expressed gene sets can explain heterogeneity in AD patients, enabling genetically informed patient stratification and precision medicine in AD. Co-expression gene-network analysis in Alzheimer's disease (AD) brains identified gene sets (modules) associated with AD heterogeneity. AD-associated modules were selected when genes in each module were enriched for neuritic plaques and neurofibrillary tangles. Polygenic risk scores from two selected modules were linked to the matching cognitively defined AD subgroups (language and visuospatial subgroups). Polygenic risk scores from the two modules were associated with cognitive performance in language and visuospatial domains and the associations were confirmed in regional-specific brain atrophy data.

Genetic and glial heterogeneity in Alzheimer disease

AbstractBackgroundAlzheimer disease (AD) has substantial genetic, molecular, and cellular heterogeneity associated with its etiology. However, much of the downstream cell‐type‐specific transcriptional and functional ramifications of familial mutations and high‐risk variants for AD are still poorly understood.MethodsWe generated unsorted single‐nuclei transcriptomic profiles (snRNA‐seq) of parietal lobes from 67 donors from the Knight ADRC and DIAN cohorts [1] to investigate altered molecular pathways in healthy and AD individuals, including carriers of pathogenic mutations in APP and PSEN1 and risk variants in TREM2. We validated our findings using snRNA‐seq from the DLPFC from the ROS‐MAP cohort [2]. We analyzed ∼294K high‐quality nuclei and identified six major cell populations. We performed deep subclustering analysis for the distinct cell types to reveal and characterize transcriptional states associated with AD genetic variants.ResultsCarriers of TREM2 AD risk variants p.R47H, p.R62H, and p.H157Y showed significantly increased proportions of nuclei in a reduced activation state (p = 3·29×10−2), consistent with in vitro experiments showing reduced microglial activation associated with these variants. [2, 3] (Figure). This state was replicated in the ROSMAP cohort (p = 7·4×10−107), and TREM2 p.R62H carriers showed a higher proportion of nuclei (p = 2·26×10−2). TREM2 risk variant carriers also showed an increased proportion of oligodendrocytes (Figure) exhibiting upregulation of 1,124 genes including TFEB (Knight ADRC p = 4·66×10−2; ROSMAP p = 2·48×10−2). Altered TFEB expression may be driven by the interaction of TREM2 with mTOR[4, 5]. TFEB is a central regulator of lysosomal biogenesis[6, 7] and represses myelination at different developmental stages.[8] Altered TFEB signaling has been implicated in several neurodegenerative diseases.[6, 9]ConclusionsAD pathogenic and risk variants are sufficient to alter human brains' transcriptional and cellular landscape. While TREM2 is mainly expressed in microglia, and its loss of function mutations cause Nasu‐Hakola disease, which is characterized by loss of myelination, suggesting TREM2‐linked oligodendrocyte‐microglia crosstalk.[10] Here, we found that AD patients with TREM2 variants showed upregulation of TFEB and lysosomal pathways in a subset of oligodendrocytes likely driven by altered microglia transcriptional states. The integration of genetic and single‐cell molecular data facilitates our understanding of the heterogeneity of pathways, biological processes, and cell types affected in AD.

SORTOUT‐AB: A Study of Race to Understand Alzheimer Biomarkers

AbstractBackgroundEthno‐racial factors may influence the multifactorial etiology and heterogeneity of Alzheimer Disease (AD). Given the conflicting reports on racial differences in AD, well‐powered cohort studies are needed to identify differences in AD biomarkers between racialized groups.MethodThis NIH‐funded study aims to determine cross‐sectional and longitudinal differences in AD biomarkers between self‐reported Black/African Americans (AA) and non‐Hispanic Whites. It implements a longitudinal design with centralized and standardized analyses of cerebrospinal fluid (CSF) and plasma samples, MRI and amyloid and tau PET scans, and harmonized clinical/cognitive outcomes. It leverages available retrospective biofluid samples and brain scans, and prospectively collected data from four ADRCs (Washington University (WU), University of Pennsylvania, Emory University, University of Alabama), and the study of African Americans Fighting Alzhiemer’s in Midlife (AA‐FAIM)), in addition to the derived data from the Harvard Aging Brain Study and the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) trial. It will further determine the roles of major risk factors and Social and Structural Determinants Influencing Aging and Dementia (SS‐DIAD) in racial differences.ResultsBy 12/31/2021, ∼3114 CSF samples, 4896 MRI scans, 3754 amyloid PET scans, and 998 tau PET scans retrospectively collected across studies were transferred to WU Knight ADRC Fluid Biomarker and Imaging Cores. CSF Aβ42, Aβ40, Tau, pTau181, and NfL were measured from all CSF samples. A subset of 3687 MRI scans and 2336 amyloid PET scans were re‐processed. Preliminary analyses on data from 179 AAs and 1180 Whites (all CDR 0 at baseline) indicated that baseline CSF Tau and pTau181 were lower, and Aβ42/Aβ40 was higher, in AAs compared to Whites. Longitudinally, CSF Aβ42/Aβ40 declined more slowly, and amyloid (PET) uptake and CSF Tau (pTau181) increased more slowly, in AAs than Whites. Additionally, a multi‐domain battery of SS‐DIAD was pilot tested, and revealed high test‐retest intraclass correlations (ICC&gt;=0.83) for multiple domains, facilitating a uniform collection of SS‐DIAD across sites.ConclusionIt is feasible to harmonize biomarker data and SS‐DIAD across multiple studies to understand cross‐sectional and longitudinal ethno‐racial differences in AD. Preliminary analyses suggest cross‐sectional and longitudinal differences in both amyloid and tau biomarkers between self‐reported AA and Whites.

Spotlight on the February 1 Issue

#### Notable in Neurology This Week This issue features an article that analyzes the trends in epilepsy center services in the United States; another evaluates the association between metabolomic profiles and incident stroke. A featured Review examines the burden of pulmonary arteriovenous malformations on ischemic stroke. ### Association of Neurofibrillary Tangle Distribution With Age at Onset–Related Clinical Heterogeneity in Alzheimer Disease: An Autopsy Study ![Graphic][1]</img> Sporadic Alzheimer disease (AD) with early age at onset may have atypical clinical and cognitive features leading to misattribution of etiology. Clinicopathologic analyses showed that atypical clinical presentations are mediated … [1]: /embed/inline-graphic-1.gif

Association of Neurofibrillary Tangle Distribution With Age at Onset-Related Clinical Heterogeneity in Alzheimer Disease: An Autopsy Study.

Patients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology. The relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TAR DNA binding protein 43 (TDP-43), and microvascular copathologies were staged, in patients with severe AD and age at onset of 51-60 (n = 40), 61-70 (n = 41), and >70 (n = 40) years. Regression, mediation, and mixed effects models examined relationships of pathologic findings with clinical features and longitudinal cognitive decline. Patients with later age at onset of AD were less likely to present with nonmemory complaints (odds ratio [OR] 0.46 per decade, 95% confidence interval [CI] 0.22-0.88), psychiatric symptoms (β = -0.66, 95% CI -1.15 to -0.17), and functional impairment (β = -1.25, 95% CI -2.34 to -0.16). TDP-43 (OR 2.00, 95% CI 1.23-3.35) and microvascular copathology (OR 2.02, 95% CI 1.24-3.40) were more common in later onset AD, and α-synuclein copathology was not related to age at onset. NFT density in midfrontal cortex (β = -0.51, 95% CI -0.72 to -0.31) and midfrontal/hippocampal NFT ratio (β = -0.18, 95% CI -0.26 to -0.10) were lower in those with later age at onset. Executive function (β = 0.48, 95% CI 0.09-0.90) and visuospatial cognitive deficits (β = 0.97, 95% CI 0.46-1.46) were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by midfrontal/hippocampal NFT ratio (β = 0.21, 95% CI 0.08-0.38) and not by concomitant non-AD pathologies. Midfrontal/hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities. Worse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.

Spotlight on the May 4 Issue

#### Notable in Neurology This Week This issue features an article that investigates whether glutamate and GABA are involved in the formation of epilepsy networks and triggering spontaneous seizures; another examines whether age-related clinical heterogeneity in Alzheimer disease is modified by APOE genotype. A featured Views & Reviews presents the new NINDS Consensus Diagnostic Criteria for traumatic encephalopathy syndrome. ### Dual Sensory Impairment and Cognitive Impairment in the Korean Longitudinal Elderly Cohort This study investigated the effect of visual or auditory impairment or a combination of both on cognitive decline in Korean adults aged …

Age-at-Onset and APOE-Related Heterogeneity in Pathologically Confirmed Sporadic Alzheimer Disease.

To characterize age-related clinical heterogeneity in Alzheimer disease (AD) and determine whether it is modified by APOE genotype or concomitant non-AD pathology, we analyzed data from 1,750 patients with sporadic, pathologically confirmed severe AD. In this retrospective cohort study, regression and mixed effects models assessed effects of estimated age at onset, APOE genotype, and their interaction on standardized clinical, cognitive, and pathologic outcome measures from the National Alzheimer's Coordinating Center database. A bimodal distribution of age at onset frequency in APOE ε4- cases showed best separation at age 63. Using this age cutoff, cases were grouped as ε4- early-onset AD (EOAD) (n = 169), ε4+ EOAD (n = 273), ε4- late-onset AD (LOAD) (n = 511), and ε4+ LOAD (n = 797). Patients with EOAD were more likely than patients with LOAD to present with noncognitive behavioral or motor symptoms or nonmemory cognitive complaints, and had more executive dysfunction, but less language impairment on objective cognitive testing. Age at onset and ε4- genotype were independently associated with lower baseline Mini-Mental State Examination scores and greater functional impairment and patients with EOAD had faster cognitive and functional decline than patients with LOAD regardless of APOE genotype. Patients with EOAD were more likely than patients with LOAD to receive a non-AD clinical diagnosis even though they were more likely to have pure AD without concomitant vascular or other non-AD neurodegenerative pathology. Early-onset sporadic AD is associated with a greater likelihood of an atypical, non-memory-dominant clinical presentation, especially in the absence of the APOE ε4 allele, which may lead to misattribution to non-AD underlying pathology.

Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics.

Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n = 425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n = 127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P > 0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P < 0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P = 0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P = 0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.

APOE is a correlate of phenotypic heterogeneity in Alzheimer disease in a national cohort.

To compare the proportion of APOE ε4 genotype carriers in aphasic vs amnestic variants of Alzheimer disease (AD). The proportion of APOE ε4 carriers was compared among the following 3 groups: (1) 42 patients with primary progressive aphasia (PPA) and AD pathology (PPA/AD) enrolled in the Northwestern Alzheimer Disease Center Clinical Core; (2) 1,418 patients with autopsy-confirmed AD and amnestic dementia of the Alzheimer type (DAT/AD); and (3) 2,608 cognitively normal controls (NC). The latter 2 groups were compiled from the National Alzheimer Coordinating Center database. Logistic regression models analyzed the relationship between groups and APOE ε4 carrier status, adjusting for age at onset and sex as needed. Using NC as the reference and adjusting for sex and age, the DAT/AD group was 3.97 times more likely to be APOE ε4 carriers. Adjusting for sex and age at symptom onset, the DAT/AD group was 2.46 times as likely to be carriers compared to PPA/AD. There was no significant difference in the proportion of APOE ε4 carriers for PPA/AD compared to NC. PPA subtypes included 24 logopenic, 10 agrammatic nonfluent, and 8 either mixed (n = 5) or too severe (n = 3) to subtype. The proportion of carriers and noncarriers was similar for logopenic and agrammatic subtypes, both having fewer carriers. The proportion of APOE ε4 carriers was elevated in amnestic but not aphasic manifestations of AD. These results suggest that APOE ε4 is an anatomically selective risk factor that preferentially increases the vulnerability to AD pathology of memory-related medial temporal areas rather than language-related neocortices.

Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease

Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease.

Drug Development, Clinical Trials, Cultural Heterogeneity in Alzheimer Disease

This article discusses the development of drugs and treatments in the context of issues of genetics, ethnicity, and culture. A brief overview of drug development, clinical trials methods, advertising and marketing practices, and the Alzheimer's Disease Cooperative Study (ADCS) recruitment program is followed by recommendations for enhancing diversity in the development of drugs for Alzheimer's disease.

Research agenda for understanding Alzheimer disease in diverse populations: work group on cultural diversity, Alzheimer's association.

The emerging evidence of ethnic variations in apolipoprotein polymorphism and Alzheimer disease risk shows that one cannot generalize findings based on a single cultural group too broadly ( Tang et al., 2001). Presence of one apolipoprotein E epsilon 4 allele is a stronger risk factor for Alzheimer disease in whites and Asians than in blacks ( Farrer et al., 1997). Environmental or genetic cofactors may modulate the effects of epsilon 4 on beta-amyloid metabolism differently in different subpopulations ( Shadlen, 1998). Recognizing this, the Alzheimer's Association has extended its goals to strengthen the scientific information base on the interactions of population diversity and Alzheimer disease heterogeneity ( NIA, 1998). This new focus is timely since minority elderly are the most rapidly increasing segment of the elderly population ( Lilienfeld and Perl, 1994, Brookmeyer et al., 1998). In this article, the authors highlight recent progress in research on Alzheimer disease among culturally diverse populations with a special emphasis on gaps in the knowledge base. The authors recommend four priorities for future Alzheimer disease research: (1) determine whether genetic causative factors interact differently in different populations; (2) reexamine the nature and role of cerebral ischemia and infarction and variations in symptom severity of Alzheimer disease; (3) explore the interaction of genes and environmental influences that are protective against Alzheimer disease; and (4) recruit and enroll ethnically diverse subjects in Alzheimer disease clinical trials.

Lewy body pathology and heterogeneity of Alzheimer's disease

Lewy body pathology and heterogeneity of Alzheimer's disease

Positron Emission Tomography in Familial Alzheimer Disease

There is increasing evidence for genetic heterogeneity in Alzheimer disease. A longitudinal clinical and imaging study had been established in order to determine whether specific phenotypic profiles are present in aetiologically distinct familial Alzheimer disease (FAD) pedigrees. [18F]fluorodeoxyglucose positron emission tomography has been used in conjunction with statistical parametric mapping to determine the relative distribution of hypometabolism. A parietotemporal deficit has been observed in individuals from both amyloid precursor protein mutation and chromosome 14 linked FAD families. Preliminary data from asymptomatic individuals at risk of FAD shows similar, although a less extensive pattern of deficit.