Higher Amyloid Pathology and Small Vessel Disease Are Associated with Lower Cognitive Functioning in Non-Demented Older Adults with T2D

Orit Lesman-Segev ^1,2 Sapir Golan ^2,3 Ramit Ravona Springer ^2,3,5 Abigail Livny ^1,2,3 Hung-Mo Lin ⁴ Yuxia Ouyang ⁴ Maya Zadok ² Chen Hoffmann ^1,3 Liran Domachevsky ³ Michal Schnaider Beeri ^2,6

¹Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Israel
²The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel
³Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Israel
⁴Department of Population Health Science and Policy, The Icahn School of Medicine at Mount Sinai, New York, NY, USA, USA
⁵Memory Clinic, Sheba Medical Center, Tel Hashomer, Israel
⁶Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, USA

Purpose: We assessed the association between imaging metrics of brain pathology with cognitive functioning in older adults with type 2 diabetes (T2D).

Methods: Community-dwelling, non demented, older adults with T2D from the Israel Diabetes and Cognitive Decline Study with brain MRI and F18-Flutemetamol amyloid-PET were included. Gray matter (GM) and white matter hyperintensities (WMH) volume were extracted using Statistical Parametric Mapping. Amyloid PET was quantified using standardized uptake value ratio (SUVR) with the cerebellar gray and white matter as reference region. Global cognitive functioning was assessed by neuropsychological testing and summarized into four domains (executive functions, attention, memory, and language) and an average of the four domains comprised global cognition. Linear regression models were used in a stepwise manner controlling for demographics, HbA1c, and duration of T2D.

Results: 47 participants with MRI and amyloid-PET were included, mean age 78 [SD=3.7], 64% females, 9 (19%) amyloid positive. On average, participants had good glycemic control (mean HbA1C=6.7). Higher amyloid burden and greater WMH volume were both associated with lower global cognition (Estimate=-1.3,p=0.01 and -0.02,p=0.03 respectively). Additional adjustment for glycemic control and GM volume did not alter the results. Higher amyloid burden was associated with lower executive (-1.24,p=0.01) and language functioning (-1.1,p=0.04), while greater WMH was associated with lower attention (-0.03,p=0.03) and approached significance with lower executive functions and language. Amyloid in all lobes contributed significantly to the associations.

Conclusions: In our cohort of non demented older adults with T2D, both amyloid pathology and small vessel disease were associated with cognitive functioning. These associations were not mediated by diabetic control or GM volume suggesting that amyloidosis and small vessel disease are distinct pathological mechanisms that independently contribute to cognitive functioning, supporting a multimodal approach for the diagnosis, prevention, and treatment of cognitive decline in this population.