White matter alterations in Alzheimer's disease without concomitant pathologies

Area of Science:

• Neuroscience
• Neuropathology
• Molecular Biology

Background:

• Alzheimer's disease (AD) neuropathology often co-exists with other conditions, impacting white matter (WM) integrity.
• Understanding WM changes in AD, particularly in the absence of co-morbidities, is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To analyze oligodendrocyte and myelin markers in the frontal WM of Alzheimer's disease (AD) cases lacking clinical or pathological co-morbidities.
• To investigate the impact of co-morbidities on WM integrity in AD.

Main Methods:

• Analysis of 206 AD autopsy cases, with 33 selected for lacking co-morbidities.
• Evaluation of WM alterations in coronal sections of the frontal lobe.
• Quantitative real-time PCR (RT-qPCR) and immunohistochemistry to assess oligodendrocyte and myelin marker expression in frontal WM.

Main Results:

• White matter (WM) demyelination was more pronounced in AD cases with co-morbidities compared to those without.
• In AD cases without co-morbidities, mRNA expression of myelin proteins (MBP, PLP1, CNP, MAG, MAL, MOG, MOBP) was preserved early (stages I-II/0-A) but decreased significantly later (stages III-IV/0-C).
• Reduced expression of NG2 and PDGFRA mRNA, fewer NG2-, Olig2-, and HDAC2-immunoreactive cells, and decreased glucose transporter immunoreactivity were observed, with partial recovery of some markers at advanced stages (V-VI/B-C).

Conclusions:

• Co-morbidities significantly impact white matter (WM) integrity in elderly individuals and those with Alzheimer's disease (AD).
• Early alterations in oligodendrocytes and myelin-related gene transcription occur in the WM of AD cases even without co-morbidities.
• These findings suggest that oligodendrocytopathy is an integral component of Alzheimer's disease pathogenesis.