Amyloid ß and Tau Pathology Linked to Dementia With Lewy Bodies Phenotype

Daniel Ferreira, PhD

The findings of a study of a multicenter cohort of individuals with probable dementia with Lewy bodies (DLB) suggest that 2 Alzheimer disease pathologic changes—amyloid-ß and tau—are common in DLB and associated with the clinical phenotype.

Alzheimer's disease pathologic changes are common in DLB and are associated with the clinical phenotype. Amyloid-β is associated with cognitive impairment and tau pathology is associated with a lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.

Ultimately, the investigators observed that amyloid-β co-occurred with tau pathology in 15% of probable DLB patients, implying that about that percentage of probable DLB patients fulfill the biologic definition of Alzheimer, likely with mixed Lewy body disease pathology.

Conducted by Daniel Ferreira, PhD, assistant professor of neurobiology, care sciences and society, Division of Clinical Geriatrics, Karolinska Institut, and Department of Radiology, Mayo Clinic, and colleagues, the study stratified patients by amyloid-β (A+) and tau (T+) biomarker positivity, which was determined by cerebrospinal fluid (CSF) amyloid-β 1-42 and phosphorylated tau testing. The assessment included 417 patients with DLB.

Those who were A-T- made up the largest subgroup in the study population (n = 162; 39%), followed by A+T- (n = 135; 32%), A+T+ (n = 64; 15%), and A-T+ (n = 56; 13%). This distribution of amyloid-ß and tau pathology was strongly modulated by age (P <.001) with the percentage of groups with an A+ biomarker doubling with older age. In total at age 55, the A+T+ group made up 8% of the cohort and the A+T- group made up 19%. At age 85, those groups consisted of 25% and 45% of the cohort, respectively.

In contrast, the percentage of the A-T- group decreased to a third with older age, to 61% at age 55 compared to 20% at age 85. The percentage of the A-T+ group remained relatively comparable across ages.

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“The novelty of our study is that it demonstrates the frequency of amyloid-β and tau biomarkers and several influencing factors in probable DLB patients during life across a wide age range. In this context, we interpret A+T- as an Alzheimer’s pathologic change and A+T+ as AD, that is, AD likely concomitant to Lewy body disease pathology in this cohort,” Ferreira and colleagues wrote.

As well, the AT group distribution also varied according to sex (P = .017) and APOE ε4 status (P <.001). APOE ε4 positive status for each group was as follows: A-T- (28%), A-T+ (50%), A+T- (59%), A+T+ (64%). All told, 55% of the A+T+ were men compared with the A- groups (A-T- and A-T+), both of which consisted of 75% men. APOE ε4 carriers were more common ingroups who were A+ or T+ (A+T-, 59%; A-T+, 50%; A+T+, 64%) compared with the A-T- group (28%).

“When plotting sex and APOE versus age we observed that the percentage of A+T- and A+T+ seemed to increase in parallel with age in both men and women,” Ferreira et al. wrote. “In APOE ε4 carriers, we observed that the A+ groups achieved higher percentages at younger ages than in APOE ε4 non-carriers, which considerably reduced the percentage of A- groups over the age of 70 in APOE ε4 carriers.”

Of the tests the group ran for heterogeneity across centers, none were statistically significant except for Mini-Mental State Exam (MMSE) by APOE ε4 carrier status (P = .02). MMSE scores for the A-T- group was 23.6, the A-T+ group was 22.6, the A+T- group was 21.5, and for the A+T+ group was 20.3. Those with 1 or 2 positive biomarkers tended to be older (P <.001) and had lower MMSE scores (P <.05)compared with the A-T- group. Those differences in MMSE were found to be independent of age and associated with both the A+ and T+ biomarker positivity, with no significant interaction between A+ and T+ observed (P = .67).

The percentage of A-T- decreased with age and A+ and T+ increased with age both in women and men. The A+ biomarker increased more in APOE ε4 carriers with age than in non-carriers and was the main predictor of lower cognitive performance when considered together with T+. As well, T+ was associated with a lower frequency of parkinsonism and probable rapid eye movement sleep behavior disorder.

“Our data from multiple sites across Europe and the United States indicate that amyloid-β pathology is common in probable DLB, increases with age, and contributes to global cognitive impairment,” Ferreira and colleagues concluded. “Tau pathology is relatively less common and when present it seems to influence Lewy body disease clinical phenotype with a lower frequency of clinical features of probable DLB.”

“These data may help to advance our ability to distinguish the clinical phenotype associated to concomitant AD pathology in patients with probable DLB, with potential implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB,” they wrote.

REFERENCES
Ferreira D, Przybelski SA, Lesnick TG, et al. Amyloid-β and tau biomarkers and clinical phenotype in dementia with Lewy bodies. Neurology. Published online September 28, 2020. doi: 10.1212/WNL.0000000000010943