Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, APOE ε4, and Cognitive Impairment

Abstract

Objective: To assess the frequency of biologically defined Alzheimer disease (AD) in relation to age, sex, APOE ε4, and clinical diagnosis in a prospective cohort study evaluated with amyloid-PET and tau-PET.

Methods: We assessed cognitively unimpaired (CU) elderly (n = 166), patients with amnestic mild cognitive impairment (n = 77), and patients with probable AD dementia (n = 62) who underwent evaluation by dementia specialists and neuropsychologists in addition to amyloid-PET with [¹⁸F]AZD4694 and tau-PET with [¹⁸F]MK6240. Individuals were grouped according to their AD biomarker profile. Positive predictive value for biologically defined AD was assessed in relation to clinical diagnosis. Frequency of AD biomarker profiles was assessed using logistic regressions with odds ratios (ORs) and 95% confidence intervals (CIs).

Results: The clinical diagnosis of probable AD dementia demonstrated good agreement with biologically defined AD (positive predictive value 85.2%). A total of 7.88% of CU were positive for both amyloid-PET and tau-PET. Frequency of biologically defined AD increased with age (OR 1.14; p < 0.0001) and frequency of APOE ε4 allele carriers (single ε4: OR 3.82; p < 0.0001; double ε4: OR 17.55, p < 0.0001).

Conclusion: Whereas we observed strong, but not complete, agreement between clinically defined probable AD dementia and biomarker positivity for both β-amyloid and tau, we also observed that biologically defined AD was not rare in CU elderly. Abnormal tau-PET was almost exclusively observed in individuals with abnormal amyloid-PET. Our results highlight that even in tertiary care memory clinics, detailed evaluation by dementia specialists systematically underestimates the frequency of biologically defined AD and related entities.

Classification of evidence: This study provides Class I evidence that biologically defined AD (abnormal amyloid PET and tau PET) was observed in 85.2% of people with clinically defined AD and 7.88% of CU elderly.

Figure 1. Study Flowchart

aMCI = amnestic mild cognitive impairment; CBS = corticobasal syndrome; CU = cognitively unimpaired; DLB = dementia with Lewy bodies; FTD = frontotemporal dementia; pAD = probable Alzheimer disease; PSP = progressive supranuclear palsy.

Figure 2. Associations Between Alzheimer Disease (AD) Biomarker Status and Clinical Impairment

AD biomarker status according to Clinical Dementia Rating (CDR). Each plot represents individuals grouped according to CDR, with bar colors corresponding to AD biomarker status. Individuals with CDR 0 were the most likely to be AD biomarker–negative (72.3%). Despite lower frequency, 8.1% of cognitively unimpaired individuals were positive for both amyloid- and tau-PET biomarkers. Individuals with a CDR of 0.5 displayed heterogeneous patterns of AD biomarkers, with under 40% being biomarker-negative and under 50% being positive for both amyloid- and tau-PET. Individuals with a CDR of 1 were most likely to be positive for both amyloid- and tau-PET biomarkers (84.2%). Finally, 100% of individuals with AD dementia and a CDR of 2 were positive for both amyloid- and tau-PET biomarkers. A−T− = amyloid-negative/tau-negative (normal AD biomarkers); A+T− = amyloid-positive/tau-negative (AD pathologic change); A−T+ = amyloid-negative/tau-positive (non-AD pathologic change); A+T+ = amyloid-positive/tau positive (biological AD).

Figure 3. Frequency of Biologically Defined Alzheimer Disease (AD) Spectrum Entities Stratified by Age

Frequency of AD biomarkers rises with age. Individuals are grouped by AD biomarker status, with colored bars representing each age group. (A) Tau positivity defined in the temporal meta–region of interest. Individuals below the age of 65 were the most likely to be AD biomarker–negative (p < 0.0001). Correspondingly, the likelihood of being AD biomarker–negative decreased with each age group. In contrast, the frequency of biologically defined AD (A+T+) increased with age (p < 0.0001). There was no statistically significant association between non-AD pathologic change and age (p = 0.3). (B) When defining tau positivity using Braak I–II regions, we observed a higher frequency of the A−T+ biomarker profile until age 75. We also observed higher frequency of the A+T+ biomarker profile. Individuals with early-onset AD are excluded from this figure and presented in supplementary figure 3 (available at doi.org/10.5061/dryad.69p8cz8zr).

Figure 4. Association Between APOE4 and Biologically Defined Alzheimer Disease (AD) Spectrum Entities

Relative frequency of APOE ε4 status (ε4 noncarrier/ε4 heterozygous/ε4 homozygous) in relation to the 4 biologically defined AD spectrum entities. APOE ε4 displayed a gene–dose association with both amyloid-β and tau-PET positivity. Zero percent APOE ε4 of homozygotes were A−T+. When excluding the 4 autosomal dominant AD cases, we observed a slightly lower frequency (17% vs 19%) of A+T+ in individuals who were APOE ε4 noncarriers.

Figure 5. Biologically Defined Alzheimer Disease (AD) Spectrum Entities Stratified by Sex

Relative frequency of AD spectrum entities as stratified by sex. We did not observe statistically significant differences in the frequency of AD spectrum entities between men and women based on dichotomous cutoffs.

Figure 6. Concordance Between Biologically and Clinically Defined Alzheimer Disease (AD)

Whereas the majority of cognitively unimpaired (CU) participants had negative AD biomarkers, approximately 8% had biologically defined AD. Conversely, whereas the majority of patients with pAD dementia were positive for both amyloid-β and tau-PET, there was imperfect agreement, with 15% of patients with pAD dementia being amyloid-PET–negative but tau-PET–positive (5%), amyloid-PET–positive but tau-PET–negative (6.5%), or both amyloid-PET and tau-PET–negative (3.3%). Amyloid-PET positivity was more compatible with normal cognition than tau-PET positivity. A−T− = amyloid-negative/tau-negative (normal AD biomarkers); A+T− = amyloid-positive/tau-negative (AD pathologic change); A−T+ = amyloid-negative/tau-positive (non-AD pathologic change); A+T+ = amyloid-positive/tau positive (biological AD).