Reversing Alzheimer's disease dementia with clemastine, fingolimod, or rolipram, plus anti‐amyloid therapy

Abstract A few anti‐amyloid trials offer a slight possibility of preventing progression of cognitive loss, but none has reversed the process. A possible reason is that amyloid may be necessary but insufficient in the pathogenesis of AD, and other causal factors may need addressing in addition to amyloid. It is argued here that drugs addressing myelination and synaptogenesis are the optimum partners for anti‐amyloid drugs, since there is much evidence that early in the process that leads to AD, both neural circuits and synaptic activity are dysfunctional. Evidence to support this argument is presented. Evidence is also presented that clemastine, fingolimod, and rolipram, benefit both myelination and synaptogenesis. It is suggested that a regimen that includes one of them plus an anti‐amyloid drug, could reverse AD.

to form the sheaths of myelin. A small fraction of OPCs is maintained in an immature and slowly proliferative or quiescent state in the adult central nervous system (CNS) where they are called "adult OPCs," which are present in all brain structures and account for up to 9% of the total cellular population of the CNS. Typical OPC markers are platelet-derived growth factor receptor-alpha (PDGF-Rα), neuroregulin 2 (NG2), and Olig1; when OPCs start to differentiate to pre-oligodendrocytes, they express different antigens such as Oligodendrocytes are particularly vulnerable to dysfunction for three reasons. First, the mechanism of myelination requires that oligodendrocytes have an extremely high metabolic rate. Second, myelination involves many enzymes that require iron as a co-factor, causing OPCs and oligodendrocytes to have the largest intracellular stores of iron in the brain, which may lead to formation of reactive nificantly elevated by 2.2-fold at age 6 months but was already substantially increased by 1.3-fold (N.S.) at 2 months. At age 6 months, myelin deposition was also abnormal. Using an intrabody, which is an antibody functioning within a cell (see Paganetti et al. 3 ), showed that blocking parenchymal Aβ 1-42 accumulation abrogated the abnormalities in both oligodendrocytes and myelin.

Role of adenosine in oligodendrocyte precursor maturation
Adenosine is relevant because it has a key role in oligodendro-

Diffusion tensor imaging and mean diffusivity
Microstructural changes in white matter are shown by diffusion tensor imaging (DTI), which measures the fractional anisotropy of proton diffusion and decreases with decreased myelination. By contrast, higher values of mean diffusivity tend to reflect a downturn in the health or integrity of the tissue in which it is measured. As will be seen below, fractional anisotropy and mean diffusivity often identify abnormal myelination but in different brain areas.

1.4.2
Myelination in cognitively normal persons at risk for AD, and also in aged monkeys Ringman et al. studied persons who either had, or were at risk for having, known pathogenic PS1 or APP mutations. 6 Compared to the 8 non-carriers of mutations, the 12 carriers had reductions of fractional anisotrophy in the fornix of 24% (P = .02) and in frontal white matter of 12.5% (P = .02). It is worth mentioning that similar findings, vis-àvis age, were reported by Makris et al., who compared DTI results from seven young and seven elderly rhesus monkeys. 7 1.4.3 Myelination in patients with mild cognitive impairment Liu et al. performed DTI scans on 83 patients with amnestic mild cognitive impairment (aMCI) and 85 healthy controls. 8 The patients with aMCI showed decreased mean fractional anisotropy in the fornix, and higher mean diffusivity in the fornix and bilateral uncinate fasciculus, that is, had decreased myelination in those areas. These results were confirmed in two subtypes of aMCI: 32 with single-domain aMCI, and 23 with multiple-domain aMCI, compared to 23 healthy controls. 9 Neuropsychological measures and DTI data showed that both aMCI groups had significantly reduced fractional anisotropy in the right superior longitudinal fasciculus. showed that MBP+ areas, that is, myelinated ones, were significantly decreased in AD patients in both the cortex and hippocampus, indicating widespread myelin loss in regions that are critical for memory and other cognitive functions. 13

Synaptogenesis is associated with myelination
Some studies have suggested that the effects of neuronal activity on myelination may be mediated by the release of neurotransmit-ters from synaptic vesicles, and it is known that stimulation of neuronal firing can promote myelination along manipulated axons. Almeida

Summary to this point
The presented data show widespread abnormalities in white matter in patients with preclinical AD, MCI, and AD, confirming the abnormality of myelin in AD and its precursor states. The data also show that there is a close association between the occurrence of myelination and synaptogenesis, although the mechanism is unknown. Addressing myelination and synaptogenesis offers a possibility of reversing the white matter abnormalities and thereby of reversing AD.

1.7
Drugs to benefit oligodendrocytes and myelination 1.7.1 General background justifying drugs to benefit oligodendrocytes and myelination Major myelin proteins are MBP, MOG, MAG, and proteolipoprotein (PLP), which are mainly expressed at the peripheral processes of the oligodendrocytes that cover the myelin sheath. 18 Demyelination by specific antibodies against MOG caused disintegration of myelin sheaths. 19  rats with Aβ 1-42 , which induced memory deficits that were reversed by rolipram in a dose-dependent manner. 27 In another study that used mini-syringes to deliver rolipram to the hippocampus, Monti et al. were able to show that this enhanced both CREB phosphorylation and the expression of the cAMP-dependent, memory-related Arc gene, causing a significant slowing down of the memory extinction rate. 28 In the brains of six AD patients with Braak stages V-V1, Liang et al.
found a selective reduction in the levels of regulatory and catalytic subunits of cAMP-dependent PKA as well as of its enzymatic activity. 29 They also observed that in mouse brain, PKA subunits were proteolyzed by calpain, and that the levels of those subunits correlated negatively with calpain activation in the AD brain-inferring that decreased levels of PKA components that they saw in AD brain were most likely caused by calpain overactivation. Further, PKA levels produced by extracts of brain were reduced in AD compared to age-matched controls. Their findings led them to propose that in the brain of AD, overactivation of calpain because of calcium dysregulation causes increased degradation and thus decreased activity of PKA, which contributes, in turn, to downregulation of CREB and impaired cognition and memory. In brief, the approved drug rolipram benefits both the myelination and function of the brain.
Rolipram has not been used in AD but has been used for depression in several trials but in doses of 1.5 to 3.0 mg daily. In those doses, headache and nausea have affected 10% to 20% of subjects. It seems unlikely that .25 mg twice daily would cause major side effects. that S1P receptors are prevalent throughout the cerebral cortex and amygdala in rats, and that their activation inhibited, beneficially, glutamatergic neurotransmission. 43

Clinical trial
The benefit of the proposed drugs should be validated by clinical trials.
Each drug should be used with adacanumab, an antiamyloid preparation approved by the FDA. The drug, its dosage, and use in which particular stage of AD is based upon the severity of its side effect profile: clemastine 5.36 mg twice daily for non-amnestic MCI; rolipram 0.5 mg daily for amnestic MCI; fingolimod 0.25 mg daily for established AD.
Note that the dosages for rolipram and fingolimod are half the usual ones, to minimize the risks of side effects.

DISCUSSION
There have been very limited clinical benefits from hundreds of clinical trials of anti-amyloid therapies despite the encouraging pre-clinical evaluations showing that those therapies reduce the cerebral burden of amyloid. One possible reason for this is that pyroglutamate Aβ is more toxic than unmodified Aβ; 46 yet even donanemab, which antagonizes pyroglutamate Aβ, gave only slight benefit. 47 Perhaps the many failures are not surprising, in light of the multiple pathways that participate in the pathogenesis of AD, 48 and it seems likely that those failures show the need to address more than one major pathogenetic influence.
Clearly important as determinants of AD are the effects of myelination and synaptogenesis; and they are benefitted by available drugs clemastine, fingolimod, and rolipram. It is argued here that using one of those three in combination with anti-amyloid therapy offers a good chance of reversing AD. This article provides the evidence that supports that argument, which could be validated by clinical trials.

CONCLUSIONS AND SUMMARY
• Because anti-amyloid drugs have been largely unsuccessful in either halting progression of AD or reversing it, addition to such treatment might be effective.
• Abnormal myelination and synaptic dysfunction occur in MCI and AD, and correlate with cognitive loss in them as well as in healthy individuals. • Clemastine, fingolimod, and rolipram benefit myelination and, therefore, synaptogenesis.
• Using one of those three drugs in combination with anti-amyloid therapy might reverse the dementia of AD.

ACKNOWLEDGMENTS
No funds for this article were received from the public or private sectors. There are no conflicts of interest. Adrian Mars, MA, provided helpful technical advice.