From 1901 to 2022, how far are we from truly understanding the pathogenesis of age-related dementia?

Abstract

From the first described AD case in 1901 to the current year 2022, understanding the pathogenesis of Alzheimer’s disease (AD) and dementia has undergone a long and tortuous journey. Many mechanisms of AD etiology have been proposed and studied. However, current medications and FDA-approved treatments cannot cure AD and AD-related dementias (AD/ADRD). Recently, brain hypoperfusion associated with neurovascular dysfunction was recognized as one of the causal factors in the development of AD dementia. Arteriosclerotic changes were observed in the first AD case. A recent study reported that the functional hyperemic response to whisker stimulation was reduced in 9–12 months old atherosclerotic mice. Interestingly, they found that evoked hemodynamic responses were not altered in age-matched AD mice or AD mice with superimposed atherosclerosis using 2D-optical imaging spectroscopy in chronic studies. However, functional hyperemia was impaired in AD mice using the same approach in an acute study. It is essential to scrutinize the available data critically since different genetic backgrounds, ages, sexes of studied animal models, and different approaches used for the same function even structural examination may provide opposite information. We certainly are closer to truly understanding the pathogenesis of dementia. We expect positive results from using aducanumab (Aduhelm®) as the first FDA-approved anti-amyloid monoclonal antibody as a treatment for AD/ADRD. We hope to identify and develop new drugs targeting other potential contributing mechanisms such as the cerebral vascular pathways.

Dementia occurs most commonly in the elderly. Age-related dementia has emerged to be one of the leading healthcare burdens worldwide, and Alzheimer’s disease (AD) accounts for an estimated 60 to 80% of all cases of dementia. The hallmarks of AD pathologies are extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tangles (NFTs), which are composed of aggregated hyperphosphorylated and misfolded tau proteins. However, over 50% of AD individuals exhibited mixed brain pathologies, such as cerebral vascular disease, and vascular dementia alone accounts for an estimated 5 to 10% of dementia [1].

Major hypotheses of AD etiology include deficiency or dysfunction of excitatory neurotransmitters, accumulation of Aβ plaques and NFTs, and cerebral vascular dysfunction. Unfortunately, current medications cannot cure AD and AD-related dementias (AD/ADRD). Among the US Food and Drug Administration (FDA)-approved treatments for AD, cholinesterase inhibitors [donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Razadyne®)], glutamate regulators [memantine (Namenda®)], or their combination [memantine (Namenda®) + donepezil (Aricept®)] that enhance the excitatory neurotransmitter function only improve impaired memory and cognition [1]. Although many other clinical trials targeting the amyloid and tau pathways have not shown to be effective [2], in 2021, the first human IgG1 anti-amyloid monoclonal antibody aducanumab (Aduhelm®) successfully reduced Aβ aggregation and was approved by the FDA [3]. It has the potential to delay the onset and progression of AD symptoms. Despite these available treatments and intensive research, 7.7 million new AD/ADRD cases are diagnosed every year. A recent population-based study, Chicago Health and Aging Project (CHAP), reported that in 2021, over 11.3% (1 in 9 people) aged 65 and older in the USA have AD/ADRD at the cost of $355 billion, which is higher than cancer and heart diseases [1, 4]. On the other hand, emerging evidence has revealed that neural damage and degeneration in AD/ADRD could result from the functional and pathogenic synergy between different types of brain cells induced by brain hypoperfusion due to cerebral vascular dysfunction [5].

In fact, “hardening of the arteries” or arteriosclerotic changes were observed in the first AD case of Auguste D., whose symptoms were identified in 1901 and reported in 1906 by German psychiatrist Alois Alzheimer [4]. The concurrent observation of vascular pathological features along with distinctive plaques and NFTs implied that cerebral vascular dysfunction might play a role in brain morphological and functional changes in AD, but the cause-effect relationships still have not been elucidated [6]. In 2022, a human brain vascular atlas study revealed that approximately 67% of AD genes in a genome-wide association study could be found in the cerebral vasculature [7]. Vascular mechanisms contributing to cerebrovascular dysfunction, brain hypoperfusion, and dementia include the impaired myogenic response and autoregulation of cerebral blood flow (CBF), neurovascular uncoupling, capillary stalling, blood–brain barrier leakage and microhemorrhages, diminished venous and neurovascular-glymphatic function [8–10]. As such, compromised functional hyperemia, as an indicator of neurovascular dysfunction, fails to fine-tune CBF. Neurovascular uncoupling has been linked with detrimental factors (oxidative stress, mitochondria dysfunction, and inflammation) that result in endothelial dysfunction, reduced pericyte and tight junction coverage on the capillaries, glial activation; and/or result from CBF dysautoregulation [11–14]. CBF reduction thus is expected in individuals exhibiting impaired functional hyperemia, which has been reported in numerous population-based human studies and experimental animal models of AD/ADRD, especially in the combination of the comorbidities of aging, hypertension, diabetes, atherosclerosis, and other risk factors [1, 15–22].

Atherosclerosis (ATH) is a progressive thickening and narrowing of arteries, including those supplying cerebral circulation. The formation of atheromatous plaques in cerebral arteries is thought to promote cerebral hypoxia and exacerbate AD pathology. Although the exact causes of atherosclerosis have not been fully understood, it shares many risk factors with AD/ADRD, and endothelial dysfunction is one of the vital contributing mechanisms [4]. In this regard, recent studies have indicated that the inward-rectifier potassium channel is activated by the increased extracellular potassium concentration due to elevations in neural activity, which hyperpolarizes capillary endothelial cells. The hyperpolarization is transmitted in a retrograde manner via endothelial cell gap junctions to dilate upstream arterioles. Moreover, flow-mediated dilation mediated by the release of nitric oxide and eicosanoids in the cerebral arterioles is thought to reinforce the functional hyperemic response further [23–25].

As expected, a recent study by Shabir et al. [26] found that the functional hyperemic response to whisker stimulation was reduced in 9–12 months old atherosclerotic PCSK9-ATH mice. However, it is somewhat surprising that they confirmed previous observations by this group that evoked hemodynamic responses were not altered in age-matched AD mice even though this model exhibits cognitive impairments at 4 months and Aβ plaques at 5–6 months. Additionally, an unexpected finding was that functional hyperemic responses were not impaired in the mixed AD/ATH model at the same age despite a threefold increase in the formation of amyloid plaques and enhanced neuroinflammation. There were also no differences in the evoked neural activity or the hemodynamic response to hypercapnia. Cortical CBF was compared using 2D-optical imaging spectroscopy (2D-OIS), and neural activity was simultaneously measured. These results conflict with the increasing evidence of diminished hemodynamic responses in most cases of AD/ADRD patients and animal models using laser Doppler flowmetry (LDF), laser speckle contrast imaging, blood oxygen level-dependent (BOLD) signal, arterial spin labeling (ASL)-magnetic resonance imaging (MRI), functional MRI (fMRI), BOLD-fMRI, positron emission tomography (PET), and many more approaches [4, 15]. It is also challenging to understand why atherosclerosis alone impaired neurovascular function but not in the mixed AD/ATH model. The authors suggested that perhaps the comorbidity of atherosclerosis accelerated capillary stalling and loss of perfusion to promote the progression of AD pathology. However, the hemodynamic alterations were partially compensated by increased angiogenesis secondary to chronic focal cerebral hypoxia in the mixed AD/ATH model [26].

There are other potential reasons to be considered for the discordant results. The AD mouse model (J20-AD) used in this study overexpresses human amyloid precursor protein (APP) with the Swedish and Indiana mutations linked to familial AD on a C57BL/6 genetic background. The mutant APP transgenes were inserted into intron 1 of the ZBTB20 gene on mouse chromosome 16 [27]. The ZBTB20 gene is a transcriptional repressor essential in hippocampal development [27]. Whether the disruption of this gene affects the evoked neural activity or the hemodynamic response awaits further study. The model of atherosclerosis (PCSK9-ATH) was induced by a single adeno-associated virus (AAV) injection of proprotein convertase subtilisin/kexin type 9 with D377Y mutation (rAAV8-mPCSK9-D377Y) combined with a high-fat Western diet for 6 months. The efficiency of transduction and the degree of ATH was dependent on genetic background, and the Western diet was less effective than the Paigen diet in inducing atherosclerosis in the aortic arch [28]. It is worth considering the significant influences of nutrition and diet habits on cerebrovascular function and the pathogenesis of age-related dementia. Unlike the Western or Paigen diets, the Mediterranean-DASH Intervention for Neurodegenerative Delay diet [29] or time-restricted feeding pattern [30] has been reported to reduce cerebral vascular dysfunction and prevent age-related vascular cognitive impairment and dementia. It was surprising that the authors did not validate whether atherosclerosis was detected in the cerebral vasculature and whether the degree of hyperlipidemia and extent of atherosclerosis in wild-type (WT) C57BL/6 and J20-AD mice were at similar levels using this approach. Finally, the experimental design and technique to measure functional hyperemia were also unique in this study. Shabir et al. used 2D-OIC to measure changes in cortical flow through a thinned cranial window over the course of 3 weeks of surgical recovery and a range of repeated whisker stimulations under hyperoxia, normoxia, and hypercapnia conditions. Whether this chronic preparation could induce inflammation and related chronic damage needs to be clarified. Although multiple trials of stimulation could accurately identify the region of interest that guides following neural electrophysiological studies, on the other hand, it may have led to differences in the desensitization of the response between the WT and AD strains. In fact, results obtained in J20-AD mice from the chronic imaging sessions were different from acute studies by this group, suggesting that baseline CBF and functional hyperemic responses are affected by experimental conditions [31].

Another interesting finding in this study is the differences in cortical spreading depression (CSD) between AD, ATH, and mixed AD-ATH mice. CSD is a wave of depolarization and silencing of neuronal activity that is associated with reduced cerebral perfusion. It does not occur in healthy brain tissue but often appears in brain injury or pathological conditions, such as stroke and migraine. In the present study, the authors found a small (10%) and transient reduction of cerebral perfusion that fully recovered within 2 min following insertion of a recording electrode in the WT control animals. However, CSD was markedly enhanced in the AD, ATH, and mixed AD/ATH models with severe (> 30%) and prolonged (> 30 min) reduction of flow. However, for some unknown reason, four nNOS-ChR2 mice, both male and female at the age of 16 to 40 weeks, were included in the WT control group. In addition to the differences in gender, age, and genetic backgrounds that all may have influenced the CSD results, the nNOS-ChR2 model is a cross of heterozygous nNOS-CreER with homozygous Ai32 mice treated with tamoxifen starting from 1 to 2 months of age. Tamoxifen has an impact on the cerebral vascular tone due to its estrogen effects [32], which may alter cerebral perfusion and neuronal activity. Nevertheless, these results suggest that increased susceptibility of cerebral vasculature to CSD following focal injury or occlusion may provide new insights into the link between stroke, cardiovascular risk factors, such as arteriosclerosis, and AD dementia.

Overall, from the first described AD case in 1901 to the current year 2022, the understanding of the pathogenesis of AD and dementia has undergone a long and tortuous journey. This journey started from the morphological and histological observation of distinctive plaques, NFTs, and “hardening of the arteries” in the 1900s, to the identification of the Aβ peptide in the 1980s, to the discovery of mutations in APP, apolipoprotein e4 gene (APOE-e4), presenilin 1 and 2 (PS1 and PS2) genes, back to the reemergence of the concept of vascular cognitive impairment and AD/ADRD (Table 1). Notably, it is essential to scrutinize the available data critically since different genetic backgrounds, ages, sexes of studied animal models, and different approaches used for the same function, and even structural examination may provide opposite information. We certainly are closer to truly understanding the pathogenesis of dementia. We look forward to seeing positive results from aducanumab (Aduhelm®) as a treatment for AD/ADRD. We hope to identify and develop new drugs targeting other potential contributing mechanisms such as the cerebral vascular pathways.

Table 1.

Timelines of the progressive improvements in understanding of age-related dementia [1, 4, 7]

Year	Milestones
1901	First observation of dementia symptoms in Aguste D
1906	Alois Alzheimer first reported the case of Aguste D
1910	Emil Kraepelin first named Alzheimer’s disease
1968	First development of cognitive measurement scales
1984	George Glenner and Cai’ne Wong identified beta-amyloid
1986	Tau protein identified
1987	First Alzheimer’s drug trial by Warner-Lambert Pharmaceutical Company (now Pfizer)
1987	First deterministic Alzheimer’s gene (amyloid precursor protein) identified
1993	First Alzheimer’s risk factor gene (apolipoprotein e4) identified
1993	First Alzheimer’s drug tacrine (Cognex) approved by FDA, which has been discontinued in the USA in 2013 due to safety concern
1995	Presenilins identified as Alzheimer’s risk factor genes
1995	First transgenic mouse model announced
2004	First report on Pittsburgh Compound B, which can be detected by positron emission tomography
2021	Aducanumab (Aduhelm™) approved by FDA
2022	The human brain vascular atlas identified 75% of top Alzheimer’s genes in GWAS expressed in brain vasculature

Funding

This study was supported by grants AG057842, P20GM104357, and HL138685 from the National Institutes of Health.

Declarations

Conflict of interest

The authors declare no competing interests.