Roles of vascular and metabolic components in cognitive dysfunction of Alzheimer disease: short- and long-term modification by non-genetic risk factors

Abstract

It is well known that a specific set of genetic and non-genetic risk factors contributes to the onset of Alzheimer disease (AD). Non-genetic risk factors include diabetes, hypertension in mid-life, and probably dyslipidemia in mid-life. This review focuses on the vascular and metabolic components of non-genetic risk factors. The mechanisms whereby non-genetic risk factors modify cognitive dysfunction are divided into four components, short- and long-term effects of vascular and metabolic factors. These consist of (1) compromised vascular reactivity, (2) vascular lesions, (3) hypo/hyperglycemia, and (4) exacerbated AD histopathological features, respectively. Vascular factors compromise cerebrovascular reactivity in response to neuronal activity and also cause irreversible vascular lesions. On the other hand, representative short-term effects of metabolic factors on cognitive dysfunction occur due to hypoglycemia or hyperglycemia. Non-genetic risk factors also modify the pathological manifestations of AD in the long-term. Therefore, vascular and metabolic factors contribute to aggravation of cognitive dysfunction in AD through short-term and long-term effects. β-amyloid could be involved in both vascular and metabolic components. It might be beneficial to support treatment in AD patients by appropriate therapeutic management of non-genetic risk factors, considering the contributions of these four elements to the manifestation of cognitive dysfunction in individual patients, though all components are not always present. It should be clarified how these four components interact with each other. To answer this question, a clinical prospective study that follows up clinical features with respect to these four components: (1) functional MRI or SPECT for cerebrovascular reactivity, (2) MRI for ischemic lesions and atrophy, (3) clinical episodes of hypoglycemia and hyperglycemia, (4) amyloid-PET and tau-PET for pathological features of AD, would be required.

Plasma Cholinesterase Activity in Alzheimer's Disease

“…This is based on observations that LMD and DM are associated with pChE [3,4] and that AD is positively related to pChE [5] because pChE metabolizes ACh and causes inflammatory hyperactivation [17]. The preliminary results of our current study also suggest that the effectiveness of Riv was related to pChE downregulation.…”

“…Dyslipidemia or lipid metabolic disorder (LMD) and diabetes mellitus (DM) are also positively related to pChE activity [3,4]. AD is also thought to be related to LMD and DM [5]. Therefore, it is reasonable to assume that AD is positively related to pChE.…”

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

“…Chronic cerebral hypoperfusion (CCH) is relatively common in the elderly and it is a major contributor to cerebrovascular dementia (Cankurtaran et al, 2008, Valerio Romanini et al, 2013 and also an important risk factor for Alzheimer's disease (AD) (Sato and Morishita, 2013). However, the molecular background how CCH causes cognitive impairment and how it contributes to Alzheimer's pathogenesis is poorly understood, even though a deeper understanding of the molecular process would be essential for developing new therapeutic strategies to prevent the progression of CCH towards AD.…”

Effects of Type 2 Diabetes on Brain Structure and Cognitive Function: African American–Diabetes Heart Study MIND

“…3–6 Furthermore, evidence is growing that the central nervous system effects of T2D may accelerate the rate of cognitive decline among the elderly and increase the risk of developing dementia and Alzheimer disease. 7–9 …”